Heterocycloalkylbeta-hydroxyalkylamines for use in the treatment of hyperglycemia and disorders characterized by hyperglycemia

Abstract

In this specification, Q 1 ~Q 5 A compound of formula (I) is provided, wherein rings A, Z, n, m, and r have the meanings provided in the description. Its use in medicine is also provided herein. [Formula 1] TIFF2026514428000053.tif17165

Description

[Technical Field]

[0001] This invention relates to novel compounds and compositions in medical applications, such as the treatment of hyperglycemia and disorders characterized by hyperglycemia, including type 2 diabetes, and their uses. In particular, this invention relates to novel compounds, compositions, and methods for the treatment of conditions such as type 2 diabetes by activation of β2-adrenergic receptors. Importantly, such compounds are thought to have a beneficial side effect profile because they do not exert their effects through significant cAMP release. Such compounds are also useful for the treatment of other diseases or disorders in which the treatment is mediated by activation of β2-adrenergic receptors. [Background technology]

[0002] Any list or discussion of previously published documents in this specification should not be construed as an endorsement that such documents are part of cutting-edge technology or common general knowledge.

[0003] Hyperglycemia, or high blood sugar, is a condition in which an excess amount of glucose circulates in the plasma. If left untreated, hyperglycemia can become a serious problem and potentially develop into life-threatening conditions such as ketoacidosis. For example, chronic hyperglycemia can cause cardiac damage and is strongly associated with heart attacks and death in subjects without coronary heart disease or a history of heart failure. The causes of hyperglycemia are diverse, including diabetes and severe insulin resistance.

[0004] Severe insulin resistance (SIR) is a condition in which a patient experiences a very low level (or, in extreme cases, no significant) response to insulin. Several syndromes exist that are characterized by SIR, including Rabson-Mendenhall syndrome, Donahue syndrome (dwarfism), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy. The majority of these conditions have a genetic cause, such as mutations in the insulin receptor gene. Reported prevalences of Donahue syndrome, Rabson-Mendenhall syndrome, and insulin-resistant type A syndrome have been reported to vary from 50 to 1 per 100,000. However, because some of these conditions are severe and extremely rare, many patients are likely to go undiagnosed before death, especially in developing regions of the world. Therefore, it is difficult to estimate the exact number of patients with these syndromes.

[0005] The current standard of treatment for hyperglycemia in patients with SIR is a controlled diet supplemented with drugs that affect insulin receptor sensitivity, such as metformin, or insulin replacement therapy. However, this treatment has proven insufficient and ultimately unsuccessful, particularly for disorders caused by mutations in the insulin receptor gene.

[0006] Diabetes encompasses two distinct diseases: type 1 (or insulin-dependent diabetes) and type 2 (insulin-independent diabetes), both of which involve dysfunction of glucose homeostasis. Type 2 diabetes affects over 400 million people worldwide, and its numbers are rapidly increasing. Complications of type 2 diabetes include severe cardiovascular problems, renal failure, peripheral neuropathy, and blindness, and in the later stages of the disease, limb loss and ultimately even death. Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue, and there is currently no definitive cure. Most treatments used today focus on improving dysfunctional insulin signaling or suppressing glucose production from the liver, but many of these treatments have several drawbacks and side effects. Therefore, there is great interest in identifying novel insulin-independent methods for treating type 2 diabetes.

[0007] In type 2 diabetes, the insulin signaling pathway becomes blunted in peripheral tissues such as adipose tissue and skeletal muscle. Treatment methods for type 2 diabetes typically include lifestyle modifications, as well as insulin injections or oral medications to regulate glucose homeostasis. Individuals with late-stage type 2 diabetes develop "beta-cell dysfunction," a disorder in which the pancreas is unable to release insulin in response to high blood glucose levels. In the later stages of the disease, patients often require insulin injections in combination with oral medications to manage diabetes. Furthermore, the most common medications have side effects, including downregulation or desensitization of the insulin pathway, and / or increased lipid uptake in adipose tissue, the liver, and skeletal muscle. Therefore, there is considerable interest in identifying novel methods for treating metabolic diseases, including type 2 diabetes, that do not involve these side effects.

[0008] After a meal, the rise in blood glucose concentration stimulates the release of insulin from the pancreas. Insulin mediates the normalization of blood glucose concentration. Key effects of insulin on glucose metabolism include increased glucose uptake into skeletal muscle and adipocytes, as well as increased glycogen storage in the liver. Skeletal muscle and adipocytes are crucial sites for glucose metabolism because they are involved in insulin-mediated glucose uptake and utilization during feeding.

[0009] The downstream signaling pathways of the insulin receptor have been difficult to understand in detail. In summary, insulin regulation of glucose uptake involves the activation of the insulin receptor (IR), insulin receptor substrates (IRS), phosphoinositide 3-kinase (PI3K), and consequently the stimulation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), the mammalian target of rapamycin (also known as the rapamycin mechanism target, mTOR), Akt / PKB (Akt), and TBC1D4 (AS160), leading to the transposition of glucose transporter 4 (GLUT4) to the cell membrane. Akt activation is considered necessary for GLUT4 transposition.

[0010] It should be noted that skeletal muscle constitutes the majority of mammalian body weight and plays a crucial role in regulating systemic glucose metabolism, participating in up to 85% of systemic glucose processing. Glucose uptake in skeletal muscle is regulated by several intracellular and extracellular signals. Insulin is the most well-studied intermediary, but others exist. For example, AMP-activated kinase (AMPK) functions as an intracellular energy sensor, which can increase glucose uptake and fatty acid oxidation. Given the significant impact of skeletal muscle on glucose homeostasis, further mechanisms are thought to exist. In light of the increasing prevalence of type 2 diabetes, there is considerable interest in identifying and characterizing novel insulin-independent mechanisms for increasing glucose uptake in muscle cells.

[0011] Blood glucose levels can be regulated by both insulin and catecholamines, but they are released in the body in response to different stimuli. Insulin is released in response to an increase in blood glucose levels (e.g., after a meal), while epinephrine and norepinephrine are released in response to various internal and external stimuli such as exercise, emotions, and stress, and also to maintain tissue homeostasis. Insulin is an anabolic hormone that stimulates many processes involved in growth, including glucose uptake and glycogen and triglyceride formation, while catecholamines are primarily catabolic.

[0012] Insulin and catecholamines, while typically having opposing effects, have been shown to have similar effects on glucose uptake in skeletal muscle (Nevzorova et al., Br.J.Pharmacol, 137, 9, (2002)). In particular, catecholamines have been reported to stimulate glucose uptake via adrenergic receptors (Nevzorova et al., Br.J.Pharmacol, 147, 446, (2006), Hutchinson, Bengtsson, Endocrinology 146, 901, (2005)), supplying high-energy substrates to muscle cells. Therefore, in mammals, including humans, the adrenergic and insulin systems likely function independently and can regulate the energy demands of skeletal muscle under different circumstances. Insulin also stimulates many anabolic processes, including some that promote undesirable effects such as stimulated lipid uptake into tissues, which can lead to obesity; therefore, it would be beneficial if glucose uptake could be stimulated by other means, such as stimulation of adrenergic receptors (ARs).

[0013] All ARs are G protein-coupled receptors (GPCRs) located on the cell membrane, characterized by an extracellular N-terminus, followed by seven transmembrane α-helices (TM-1 to TM-7), three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3) linked to these, and finally an intracellular C-terminus. ARs have three distinct classes with different expression patterns and pharmacological profiles: α1-, α2-, and β-ARs. α1-ARs are α 1A , α 1B , and α 1D While it includes subtypes, α2-AR is α 2A , α 2B , and α 2C β-AR is classified into three subtypes: β1, β2, and β3, of which β2-AR is the major isoform in skeletal muscle cells. AR is a G protein-coupled receptor (GPCR) that signals via classical secondary messengers such as cyclic adenosine phosphate (cAMP) and phospholipase C (PLC).

[0014] Many of the effects occurring downstream of AR in skeletal muscle are due to classical secondary messenger signaling, such as elevated cAMP levels, PLC activity, and calcium levels. Stimulation of classical secondary messengers has many effects in different tissues. For example, the above stimuli increase heart rate, blood flow, airflow in the lungs, and glucose release from the liver, and if AR stimulation should be considered a treatment for type 2 diabetes, all of these may be harmful or considered undesirable side effects. Adverse effects of classical AR agonists include, for example, tachycardia, palpitations, tremors, sweating, agitation, and increased blood glucose levels (glucose production from the liver). Therefore, it would be beneficial if activating AR without activating these classical secondary messengers such as cAMP could increase glucose uptake in peripheral tissues without stimulating undesirable side effects.

[0015] Glucose uptake is primarily stimulated via facilitative glucose transporters (GLUTs), which mediate glucose uptake into most cells. GLUTs are transporter proteins that mediate the transport of glucose and / or fructose across the cell membrane in accordance with a concentration gradient. The GLUT family consists of 14 known members, named GLUT1-14, which are classified into three classes (Class I, Class II, and Class III) depending on their substrate specificity and tissue expression. GLUT1 and GLUT4 are the most intensively studied isoforms and, along with GLUT2 and GLUT3, belong to Class I, which primarily transports glucose (as opposed to Class II, which also transports fructose). GLUT1 is ubiquitously expressed and involved in basal glucose transport. GLUT4 is expressed only in peripheral tissues such as skeletal muscle, cardiac muscle, and adipose tissue. GLUT4 has also been reported to be expressed in the brain, kidney, and liver, for example. GLUT4 is the major isoform involved in insulin-stimulated glucose uptake. The mechanism by which insulin signaling increases glucose uptake is primarily mediated by the transposition of GLUT4 from intracellular storage to the cell membrane. GLUT4 transposition is known to be induced by stimulation of β2-adrenergic receptors.

[0016] Therefore, possible treatments for conditions involving dysregulation of glucose homeostasis or glucose uptake in mammals, such as type 2 diabetes, would likely involve activation of β2-adrenergic receptors leading to the transposition of GLUT4 to the cell membrane, and promotion of glucose uptake into skeletal muscle, leading to the normalization of systemic glucose homeostasis. In addition, if the treatment does not involve signaling via cAMP, this would be advantageous as it would result in a favorable side effect profile. [Modes for carrying out the invention]

[0017] The inventors have now surprisingly found that certain heterocyclic alkyl beta-hydroxyalkylamines which act as agonists at the β2-adrenergic receptor increase glucose uptake in skeletal muscle.

[0018] In addition, since the inventors have found that this effect is not mediated through significant cAMP release, it may reduce many of the commonly described side effects seen with conventional β2-adrenergic agonists (such as tachycardia, palpitations, tremors, sweating, agitation, etc.).

[0019] Use of such compounds in medicine represents a promising strategy for the treatment of conditions characterized by hyperglycaemic values (i.e., hyperglycaemia) such as, for example, type 2 diabetes, as described herein. [[ID=IO]]

[0020] The compounds of the invention In a first aspect of the invention, a compound of formula I

Chemical formula

[0021] To avoid any doubt, those skilled in the art will understand that any reference herein to a compound of a particular aspect of the present invention (such as the first aspect of the present invention, for example, the compound of formula I) includes references to all embodiments and their specific features, and that further embodiments may be formed by interpreting those embodiments and specific features in combination.

[0022] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains.

[0023] Examples of pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the present invention with one equivalent or more of a suitable acid or base in an optional solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., by vacuum, freeze-drying, or filtration). Salts may also be prepared, for example, by exchanging the counterion of the compound of the present invention in salt form with another counterion using a suitable ion exchange resin.

[0024] Specific acid addition salts that may be mentioned include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprinate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, hemitartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, sve Examples include phosphates, sebacinates, fumarates, malates, maleates, hydroxymaleates, hyperinates, phthalates, or terephthalates), halide salts (e.g., hydrochlorides, hydrobromitates, or hydroiodides), sulfonates (e.g., benzenesulfonates, methyl-, bromo-, or chlorobenzenesulfonates, xylenesulfonates, methanesulfonates, ethanesulfonates, propanesulfonates, hydroxyethanesulfonates, 1- or 2-naphthalenesulfonates, or 1,5-naphthalenedisulfonates), or sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, or nitrates.

[0025] Those skilled in the art will understand that the term “hemi” as used herein with respect to the hemi tartrate of the compound of formula I means that the stoichiometry between the compound of formula I and the tartrate in the salt is 1:0.5 (i.e., equal to 2:1).

[0026] Specific base addition salts that may be mentioned include salts formed by alkali metals (such as Na salts and K salts), alkaline earth metals (such as Mg salts and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, and lysine), and inorganic bases (such as ammonia and aluminum hydroxide). More specifically, base addition salts that may be mentioned include Mg salts, Ca salts, most specifically K salts, and Na salts.

[0027] Specific pharmaceutically acceptable salts that may be mentioned include hydrochloride salts and acetate salts (e.g., hydrochloride salts).

[0028] To avoid any doubt, the compounds of the first aspect of the present invention may exist as solids, and therefore the scope of the present invention includes all amorphous, crystalline, and partially crystalline forms, and may also exist as oils. If the compounds of the first aspect of the present invention exist in crystalline and partially crystalline forms, such forms may include solvates, which are also included in the scope of the present invention. The compounds of the first aspect of the present invention may also exist in solution.

[0029] Compounds according to the first aspect of the present invention may contain double bonds and therefore may exist as E (entgegen) and Z (zusammen) geometric isomers for each individual double bond. All such isomers and mixtures thereof are within the scope of the present invention.

[0030] Compounds according to the first aspect of the present invention may also exhibit tautomerism. All tautomer forms and mixtures thereof are included within the scope of the present invention.

[0031] Compounds according to the first aspect of the present invention may also contain one or more chiral carbon atoms and thus may exhibit optical isomerism and / or diastereoisomerism. Diastereoisomers can be separated using conventional techniques, e.g., chromatography or fractional crystallization. Various stereoisomers (i.e., enantiomers) can be isolated by separating racemic or other mixtures of the compound using conventional techniques, e.g., fractional crystallization or HPLC. Alternatively, the desired optical isomer can be obtained from a appropriately optically active starting material under conditions that will not cause racemization or epimerization (i.e., the "chiral pool" method), by derivatization (i.e., decomposition including dynamic decomposition, e.g., treatment with a homochiral acid followed by separation of the diastereomer derivative by conventional means such as chromatography), by reaction of a suitable starting material with a "chiral auxiliary" which can then be removed in a suitable step, or by reaction with a suitable chiral reagent or chiral catalyst, all of which can be carried out under conditions known to those skilled in the art. All stereoisomers and mixtures thereof are within the scope of the present invention.

[0032] As used herein, references to halo groups and / or halogen groups refer independently to fluoro, chloro, bromo, and iodine groups (e.g., fluoro(F) and chloro(Cl), e.g., F).

[0033] Unless otherwise specified, C as defined herein 1-z Alkyl groups (where z is the upper limit of the range) can be linear, or branched and / or cyclic if there are a sufficient number of carbon atoms (i.e., at least 3). 3-z - Forms a cycloalkyl group). If a sufficient number of carbon atoms are present (i.e., at least four), such a group may also be partially cyclic. Partially cyclic alkyl groups that can be mentioned include cyclopropylmethyl and cyclohexylethyl. If a sufficient number of carbon atoms are present, such a group may also be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic.

[0034] To avoid any ambiguity, alkyl groups can be linear (also known as straight-chained), branched (also known as branched-chain), and / or cyclic. More specifically, alkyl groups can be linear (also known as straight-chained) or branched (also known as branched-chain).

[0035] Unless otherwise specified, C as defined herein 2-z An alkenyl group (where z is the upper limit of the range) can be a linear chain, or a branched chain if there are a sufficient number of carbon atoms (i.e., at least 3).

[0036] Unless otherwise specified, C as defined herein 2-z An alkynyl group (where z is the upper limit of the range) can be a linear chain, or a branched chain if there are a sufficient number of carbon atoms (i.e., at least 4).

[0037] To avoid any doubt, those skilled in the art will understand that the term alkyl refers to a saturated hydrocarbon moiety, the term alkenyl refers to an unsaturated hydrocarbon moiety containing at least one carbon-carbon double bond, and the term alkynyl refers to an unsaturated hydrocarbon moiety containing at least one carbon-carbon triple bond.

[0038] As used herein, the term heterocyclyl may refer to non-aromatic monocyclic and bicyclic heterocyclyl groups (which may be further bridged) in which at least one (e.g., 1 to 4) of the atoms in the ring system is not carbon (i.e., heteroatom), and the total number of atoms in the ring system is 3 to 12 (e.g., 5 to 10, most preferably 3 to 8, e.g., a 5-membered or 6-membered heterocyclyl group). Furthermore, such heterocyclyl groups may be saturated and capable of forming heterocycloalkyls, or unsaturated and capable of containing one or more carbon-carbon, or, if possible, carbon-heteroatom or heteroatom-heteroatom double and / or triple bonds, e.g., C 2-z (For example, C 4-z ) Heterocycloalkenyl (where z is the upper limit of the range) or C 7-z It forms a heterocycloalkynyl group. C may be mentioned. 2-zExamples of heterocyclyl groups include 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, azilidinyl, azetidinyl, 2,3-dihydroisothiazolyl, dihydropyranyl, dihydropyridinyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazoli Examples include dinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxyranyl, piperazinyl, piperidinyl, pyranyl, pyrazolinidyl, pyrrolidinol, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, quinuclidinyl, sulforanyl, 3-sulforenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridinyl (such as 1,2,3,4-tetrahydropyridinyl and 1,2,3,6-tetrahydropyridinyl), thietanyl, thyranyl, thioranyl, tetrahydrothiopyranyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), and tropanyl. Substituents on the heterocyclyl group may, where appropriate, be located on any atom in the ring system containing the heteroatom. Furthermore, if the substituent is another cyclic compound, the cyclic compound can bond through a single atom on the heterocyclyl group, forming a so-called "spiro" compound. The bonding site of the heterocyclyl group can be via any atom in the ring system, which (where appropriate) may contain further heteroatoms (such as a nitrogen atom), or any atom on any fused carbocyclic ring that may exist as part of the ring system. The heterocyclyl group can also be in N- or S-oxidized form.

[0039] As described herein, ring A represents a five-membered or six-membered heterocycloalkyl group containing one or two heteroatoms selected from N (nitrogen) and O (oxygen).

[0040] As described in this specification, Q1 ~Q 5 A ring containing (which may be called ring Q) contains one or more Y (i.e., Y as needed). 1 or Y 2 This represents a phenyl or 5-membered or 6-membered heteroaryl that is optionally substituted with ).

[0041] Therefore, a person skilled in the art can understand Q 1 ~Q 5 A person skilled in the art will understand that the ring containing Q may contain one or more heteroatoms in addition to carbon atoms to form a suitable heteroaryl group known to those skilled in the art. Furthermore, a person skilled in the art will understand that Q 1 ~Q 5 If the ring containing Q has 5 members, 1 ~Q 5 One of them (for example, Q) 5 You will understand that ) represents a direct bond (i.e., its base does not exist).

[0042] To avoid any doubt, Q has a circle inside it. 1 ~Q 5 The depiction of a ring containing a group (for example, as in formula I) will be understood to indicate that the ring is aromatic.

[0043] To avoid any doubt, where used herein, references to heteroatoms take on their usual meaning as understood by those skilled in the art. Specific heteroatoms that may be referenced include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen, and sulfur (e.g., oxygen, nitrogen, and sulfur).

[0044] To avoid ambiguity, references to polycyclic (e.g., bicyclic or tricyclic) groups (e.g., when used in the context of cycloalkyl groups) refer to cyclic systems that require at least two cleavages to convert such rings into a straight chain, with the minimum number of such cleavages corresponding to the number of defined rings (e.g., the term bicyclic may indicate that at least two cleavages are required to convert the rings into a straight chain). To avoid ambiguity, the term bicyclic (e.g., when used in the context of alkyl groups) may refer to a group in which the second ring of a bicyclic system is formed between two adjacent atoms of the first ring, or a group in which two non-adjacent atoms are linked by an alkylene group, the latter of which may be called bridged.

[0045] The present invention also encompasses isotope-labeled compounds of the present invention in which one or more atoms are actually replaced by atoms having atomic masses or mass numbers different from those commonly found in nature (or most abundantly found in nature), but which are identical to those described herein. All isotopes of any particular atom or element identified herein are intended to be within the range of compounds of the present invention. Accordingly, the compounds of the present invention also include deuterated compounds, i.e., deuterated compounds in which one or more hydrogen atoms are replaced by hydrogen isotopes.

[0046] To avoid any doubt, if two or more substituents in the compound of the present invention may be of the same identity, the actual identity of each substituent is by no means interdependent. For example, in a situation where two or more Y groups are present, those Y groups may be the same or different. Similarly, if two or more Y groups are present, each representing a halo, the corresponding halo groups may be the same or different. Similarly, if there are multiple R groups, each independently substituted with one or more G groups, C 1-6 When representing alkyl groups, the identity of each G is by no means interdependent.

[0047] Those skilled in the art will understand that the compounds of the present invention, which are the subject of this invention, include those that are stable. That is, the compounds of the present invention include compounds that are robust enough to survive isolation, for example, isolation from a reaction mixture to a useful purity.

[0048] All embodiments and specific features of the Invention referred to herein may be interpreted alone or in combination with any other embodiments and / or specific features referred to herein without departing from the disclosure of the Invention (i.e., more specific embodiments and specific features disclosed herein are described herein).

[0049] To avoid any doubt, Q 1 ~Q 5 A ring containing (also referred to herein as ring Q) contains one or more Y 1 Phenyl or one or more Y that are optionally substituted with 2 This represents a 5-member or 6-member heteroaryl that is optionally substituted.

[0050] Therefore, a person skilled in the art can understand Q 1 ~Q 5 However, you will understand that it is one of the following: -Each represents a carbon atom, or -A carbon atom, one or more heteroatoms, and Q to form a suitable heteroaryl group known to those skilled in the art. 1 ~Q 5 If the ring containing the compound has 5 members, the direct bond is represented together.

[0051] Various heteroaryl groups such as pyridinyl, pyridonyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, and imidazolyl will be well known to those skilled in the art. Oxides of heteroaryl / heteroaromatic groups are also included within the scope of the present invention (e.g., N-oxides).

[0052] In certain embodiments, when representing a heteroaryl, Q as defined herein 1 ~Q 5 A ring containing may contain one or more (e.g., one or two, e.g., one) heteroatoms that can be selected from O, S, and N (e.g., O and N, e.g., N). For example, ring Q as defined herein may contain one heteroatom that can be selected from O, S, and N (e.g., O and N, e.g., N).

[0053] In certain embodiments representing heteroaryls, Q as defined herein 1 ~Q 5 The ring containing Q can be a 6-membered heteroaryl. Therefore, Q 1 ~Q 5 A ring containing one or more (e.g., one) Y 1 Phenyl or one or more (e.g., one) Y that are optionally substituted. 2 This can represent a 6-membered heteroaryl that is optionally substituted.

[0054] Q that may be mentioned 1 ~Q 5 More specific heteroaryl groups that represent rings containing pyridyls include pyridyls, such as pyridine-2-yl or pyridine-3-yl (referring to the standard numbering where the N atom is at position 1).

[0055] In a particular embodiment, Q 1 ~Q 5 The ring containing is One or more (for example, one) Y 1 Phenyl, which is optionally substituted, or One or more (for example, one) Y 2 This can represent pyridyl that is optionally substituted.

[0056] In a more specific embodiment, Q 1 ~Q 5 The ring containing is One or more (for example, one) Y 1Phenyl, which is optionally substituted, or One or more (for example, one) Y 2 This can represent pyridine-2-yl or pyridine-3-yl that is optionally substituted.

[0057] Therefore, in certain embodiments, the compound of formula I may be represented as the compound of formula IA, IB, or IC. [ka] In the formula, rings A, Z, Y 1 , Y 2 m, n, and r are as defined for the compound of formula I (including all its embodiments), v represents 0 to 5, and w represents 0 to 4.

[0058] To avoid any doubt, Q 1 ~Q 5 A ring containing several Y, as defined herein, depending on the context. 1 or Y 2 It can be substituted by groups. Those skilled in the art will understand that the (maximum) number and position of such substituents are determined by the size of the ring and properties of the ring such as its degree of saturation. Furthermore, those skilled in the art will understand that such substituents may be present in a preferred part of the ring Q, for example, a preferred C (carbon) part.

[0059] In a particular embodiment, Q 1 ~Q 5 The ring containing Y may have up to two (i.e., 0 to 2) Y as needed. 1 or Y 2 It is substituted with the base.

[0060] In a more specific embodiment, Q 1 ~Q 5 The ring containing may have, if necessary, up to one (i.e., 0 or 1) Y 1 or Y 2 It is substituted with the base.

[0061] In a more specific embodiment, Q1 ~Q 5 The ring containing one Y may, if necessary 1 or Y 2 It is optionally substituted in the base.

[0062] In a more specific embodiment, Q 1 ~Q 5 The ring containing one Y may, if necessary 1 or Y 2 It is substituted with a group (i.e., it requires substitution) (i.e., in the compound of formula IA, v is 1, and in the compounds of formulas IB and IC, w is 1).

[0063] In certain embodiments, with the bond site to the essential -CH(OH)- moiety designated as position 1, there is at least one (or, if only one such group is present, that) Y 1 or Y 2 The base can be located at the 2nd or 3rd position (which may also be called the ortho position and the meta position, respectively), as needed.

[0064] In a particular embodiment, Q 1 ~Q 5 The ring containing is One or more (for example, one) Y 1 Phenyl substituted with, or One or more (for example, one) Y 2 It can represent a 6-membered heteroaryl that is substituted with [the specified character].

[0065] In a more specific embodiment, Q 1 ~Q 5 The ring containing is One or more (for example, one) Y 1 Phenyl substituted with, or One or more (for example, one) Y 2 It can represent pyridyl (also called pyridinyl) which is substituted with .

[0066] For example, Q 1 ~Q 5 The ring containing is One Y1 Phenyl substituted with (e.g., at position 2 or 3 using standard numbering) or One Y 2 Pyridine-3-yl substituted with (for example, at position 5 using standard numbering, which can also be called position 3 if the bond to the essential -CH(OH)- moiety is at position 1) or One Y 2 This can represent pyridine-2-yl substituted with (for example, at position 6 using standard numbering, which may also be called position 3, if the bond to the essential -CH(OH)- moiety is at position 1).

[0067] Therefore, in certain embodiments, compounds of formulas IA, IB, and IC may be represented as compounds of formula IA', IB', or IC', respectively. [ka] In the formula, rings A, Z, Y 2 m, n, and r are as defined for compounds of formula I (such as compounds of formulas IA, IB, and IC; including all embodiments thereof), and Y 1a and Y 1b One of them is Y 1 One represents , and the other represents H.

[0068] In a particular embodiment, each Y 1 R is independent of R a1 , halo (e.g., F or Cl), -CN, -OR d1 , or -NR b1 R c1 It represents.

[0069] In a particular embodiment, R a1 C is optionally replaced by one or more halos. 1-3 Alkyl (linear or branched C) 1-3 Alkyl groups, for example, linear C 1-3 Represents alkyl.

[0070] In a more specific embodiment, R a1 R represents a C1 alkyl group (i.e., methyl) that is optionally substituted by one or more halos. For example, R a1 This can represent -CH3 or CF3.

[0071] In a more specific embodiment, each Y 1 This independently represents a halo (e.g., F or Cl) or -CN.

[0072] In a more specific embodiment, each Y 1 It represents a halo independently.

[0073] In a more specific embodiment, each Y 1 It independently represents either Cl or F.

[0074] In a more specific embodiment, each Y 1 It independently represents F.

[0075] In a more specific embodiment, R d1 This represents H.

[0076] In a more specific embodiment, R b1 represents H and / or (for example, and) R c1 is H or C 1-4 Alkyl (such as methyl), for example, represents H.

[0077] In a particular embodiment, each Y 2 R is independent of R a2 , halo (e.g., F or Cl), -CN, -OR d2 , or -NR b2 R c2 It represents.

[0078] In a particular embodiment, R a2 C is optionally replaced by one or more halos. 1-3 Alkyl (linear or branched C) 1-3 Alkyl groups, for example, linear C 1-3 Represents alkyl.

[0079] In a more specific embodiment, R a2 R represents a C1 alkyl group (i.e., methyl) that is optionally substituted by one or more halos. For example, R a2 This can represent -CH3 or CF3.

[0080] In a more specific embodiment, each Y 2 It represents a halo independently.

[0081] In a more specific embodiment, each Y 2 It independently represents either Cl or F.

[0082] In a more specific embodiment, each Y 2 It independently represents F.

[0083] In a particular embodiment, R d2 This represents H.

[0084] In a particular embodiment, R b2 represents H and / or (for example, and) R c2 is H or C 1-4 Alkyl (such as methyl), for example, represents H.

[0085] To avoid any doubt, embodiments of the present invention, as shown herein, include combinations of the embodiments described herein.

[0086] In a particular embodiment, each Y 1 R is independent of R a1 , represents a halo (e.g., F or Cl), or -CN, and each Y 2 R a2 It represents a halo (e.g., F or Cl) or -CN.

[0087] For example, in a particular embodiment that may be mentioned, Each Y 1 R is independent of R a1 , represents a halo (e.g., F or Cl), or -CN, Ra1 C is optionally replaced by one or more halos. 1-3 Alkyl (linear or branched C) 1-3 Alkyl groups, for example, linear C 1-3 Represents alkyl, Each Y 2 R is independent of R a2 , represents a halo (e.g., F or Cl), or -CN, R a2 C is optionally replaced by one or more halos. 1-3 Alkyl (linear or branched C) 1-3 Alkyl, for example, linear C 1-3 Represents alkyl groups, etc.

[0088] In certain embodiments, n represents 1 or 2.

[0089] In a more specific embodiment, n represents 1.

[0090] In certain embodiments, r represents at least 1 (i.e., it is required that at least one Z group is present), for example, r represents up to 5, for example, up to 4, up to 3, or up to 2. For example, r can represent 1 to 6, for example, 1 to 5, 1 to 4, or 1 to 3.

[0091] In a particular embodiment, r represents 1.

[0092] In certain embodiments, r represents values ​​between 0 and 2.

[0093] In more specific embodiments, r represents 0 or 1.

[0094] In a more specific embodiment, r represents 0.

[0095] To avoid any ambiguity, ring A represents a 5-membered or 6-membered heterocycloalkyl group that is optionally substituted with one or more Z atoms, and contains one or two (e.g., one) heteroatoms selected from N and O.

[0096] In some embodiments, ring A does not contain any other heteroatoms in its ring structure; that is, the only heteroatom in ring A is selected from N and O.

[0097] Various heterocycloalkyl groups such as dioxolanil (including 1,3-dioxolanil), dioxanil (including 1,3-dioxanil and 1,4-dioxanil), imidazolidinil, morpholinil, piperazinil, piperidinil, pyrazolinidyl, pyrrolidinonil, pyrrolidinil, tetrahydropyranil, and tetrahydrofuryl will be well known to those skilled in the art.

[0098] In certain embodiments, ring A may contain one heteroatom (such as only one) selected from O (oxygen) and N (nitrogen). For example, ring A may contain one O (oxygen) atom, or ring A may contain one N (nitrogen) atom.

[0099] In an alternative embodiment, ring A may contain two heteroatoms selected from O (oxygen) and N (nitrogen). For example, ring A may contain two O (oxygen) atoms or two N (nitrogen) atoms. Alternatively, ring A may contain one O (oxygen) atom and one N (nitrogen) atom.

[0100] In certain embodiments, ring A may be a five-membered or six-membered heterocycloalkyl group that is optionally substituted with one or more (e.g., one) Z groups.

[0101] In more specific embodiments, ring A may be a six-membered heterocycloalkyl group that is optionally substituted with one or more (e.g., one) Z groups.

[0102] More specific heterocycloalkyl groups that may represent ring A include piperidinyl, e.g., piperidin-3-yl or piperidin-4-yl (referring to the standard numbering where the N atom is at position 1).

[0103] Other specific heterocycloalkyl groups that may be mentioned to represent ring A include tetrahydropyranyl, e.g., tetrahydropyran-2-yl, tetrahydropyran-3-yl, or tetrahydropyran-4-yl (referring to the standard numbering where the O atom is at position 1).

[0104] In certain embodiments, ring A may represent tetrahydropyran-4-yl.

[0105] To avoid any doubt, ring A may be substituted with several Z groups as defined herein, depending on the context. Those skilled in the art will understand that the (maximum) number and position of such substituents are determined by the size of the ring and its properties, such as its degree of saturation. Furthermore, those skilled in the art will understand that such substituents may be present in a preferred portion of ring A, for example, a preferred C (carbon) or N (nitrogen) portion.

[0106] In a particular embodiment, if present on a carbon atom of ring A, each Z independently forms a halo, R a3 , CN, -N3, -N(R b3 )R c3 , -OR d3 , -S(O) p R e3 , -S(O) q N(R f3 )R g3 , -N(R h3 )S(O) t R i3 , or = represents O.

[0107] In certain embodiments, when Z is present on a carbon atom of ring A, each Z represents =O.

[0108] In a particular embodiment, when present on the nitrogen atom of ring A, each Z independently corresponds to R a3 or -S(O) p R e3 It represents.

[0109] In a particular embodiment, R a3 is Halo and G1 C is optionally substituted by one or more groups independently selected from 1-6 Alkyl (C 1-2 C such as alkyl 1-5 ) represents.

[0110] In a more specific embodiment, G 1 is -OR d4 Or, it represents O.

[0111] In a particular embodiment, R e3 C 1-2 C such as alkyl 1-6 Represents alkyl.

[0112] In certain embodiments, when present on the nitrogen atom of ring A, each Z independently is -SO2Me, -C(O)Me, -C(O) t Bu, -C(O)CF3, -C(O)OMe, -C(O)O t This represents Bu (i.e., -Boc), -C(O)NMe2, -C(O)NHMe, and -Me.

[0113] In more specific embodiments, when present on the nitrogen atom of ring A, each Z independently represents -C(O)Me or -S(O)2Me.

[0114] In certain embodiments, when present on a carbon atom of ring A, each Z independently corresponds to R a3 -CN, -N3, -N(R b3 )R c3 , -OR d3 , -S(O) p R e3 , -S(O) q N(R f3 )R g3 , -N(R h3 )S(O) t R i3 , or = represents O.

[0115] In a more specific embodiment, if present on a carbon atom of ring A, each Z independently of R a3 -CN, -N(R b3 )Rc3 , -OR d3 , -S(O) q N(R f3 )R g3 , -N(R h3 )S(O) t R i3 , or = represents O.

[0116] In a more specific embodiment, if present on a carbon atom of ring A, each Z independently of R a3 , -N(R b3 )R c3 , -OR d3 , -N(R h3 )S(O) t R i3 , or = represents O.

[0117] In more specific embodiments, when Z is present on a carbon atom of ring A, each Z represents =O.

[0118] In a more specific embodiment, when present on a carbon atom of ring A, there is one Z group, and it represents =O, and the Z group is located on a carbon adjacent to the heteroatom.

[0119] In certain embodiments, each t represents 2.

[0120] In a particular embodiment representing Z, R a3 is one or more (for example, one or two) G 1 C is optionally substituted by the element. 1-6 Alkyl (for example, C1 alkyl, etc.) 1-3 Represents alkyl.

[0121] In a specific method of operation, each R a4 This independently represents a phenyl molecule that is optionally substituted by one or more halos.

[0122] In certain embodiments, Z is -N(R b3 )R c3 When representing R, b3 represents H and / or (for example, and) R c3 C1-6 This represents alkyl groups (such as methyl groups).

[0123] To avoid any doubt, if ring A contains N (nitrogen) and no Z substituent is present on that N, then that N represents -NH-. Therefore, in certain embodiments, ring A contains at least one N atom and no Z group is present on that N atom (i.e., ring A contains an -NH- group). In more specific embodiments, ring A does not contain any Z group on any nitrogen atom of ring A.

[0124] In certain embodiments, ring A is substituted with up to two (i.e., 0 to 2) Z groups.

[0125] In more specific embodiments, ring A is substituted with up to one (i.e., zero or one) Z group.

[0126] In certain embodiments, up to one Z group (e.g., 1) is present on the carbon atom of ring A. In certain embodiments, up to one Z group (e.g., 1) is present on the nitrogen atom of ring A.

[0127] In a particular embodiment, ring A can be represented as follows: [ka] In the formula, the wavy line indicates the bonding point to the essential core of the compound, A 1 ~A 5 One or two of them are heteroatoms selected from O (oxygen) and N (nitrogen), A 1 ~A 5 The remainder represents carbon. In some embodiments, A 1 ~A 5 One of these can represent a direct bond, and therefore, ring A is a five-membered heterocycloalkyl ring.

[0128] In certain embodiments (for example, r represents 1), the Z group is located at position 3 or 4 of ring A (relative to the bonding site to the essential core of the compound).

[0129] Thus, in certain embodiments, ring A can be represented as follows:

Chemical Formula

[0130] For example, in certain embodiments that may be mentioned, Z 2 represents Z and Z 1 represents H. <00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​3 represents Z (=O, etc.). In certain such embodiments, Z 2 This represents H.

[0135] In a more specific embodiment, ring A contains oxygen. In a particular such embodiment, ring A can be represented as follows: [ka] In the formula, the wavy line indicates the binding site to the essential core of the compound.

[0136] In a particular embodiment, Z 1 ~Z 4 Each of these represents H.

[0137] In an alternative embodiment, Z 1 ~Z 4 one of them (Z 2 (etc.) represents Z, and other Z 1 ~Z 4 This represents H. In an alternative embodiment, Z 1 and Z 2 or Z 2 and Z 3 One of them represents Z, and the rest of Z 1 ~Z 4 This represents H. In certain embodiments, m represents 0 to 2 (i.e., m represents 0, 1, or 2).

[0138] In a more specific embodiment, m represents 1.

[0139] As described herein, compounds of the first embodiment of the present invention may also contain one or more chiral carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism. Furthermore, it has been found that certain such optical isomers and / or diastereoisomers may show increased usefulness in the treatment of conditions described herein, such as hyperglycemia or disorders characterized by hyperglycemia (such as type 2 diabetes).

[0140] Therefore, the compound of formula I can exist as a compound of formula ID or IE, [Chemical formula] wherein ring Q, ring A, n, m, Z, and r are as described herein (i.e., as described in the first aspect of the present invention, including all embodiments and specific features, and combinations thereof).

[0141] In certain embodiments, the compound of formula (I) is a compound of formula ID.

[0142] For the avoidance of doubt, the stereochemistry represented by the compounds of formula ID and IE can apply to all embodiments of the compound of formula I.

[0143] Those skilled in the art will understand that, in addition to the carbon atom having an essential hydroxy group, the compounds of the present invention may contain additional stereocenters. For the avoidance of doubt, unless otherwise specified, the stereochemistry at all stereocenters (including the stereochemistry present at positions other than the carbon atom having an essential hydroxy group) can be in either configuration (i.e., R or S configuration) or can be present in the compound as a mixture thereof (e.g., a racemic mixture).

[0144] Therefore, in certain embodiments, the compound of formula ID is a compound of formula IF or IG, [Chemical formula] wherein ring Q, ring A, n, m, Z, and r are as described herein (i.e., as described in the first aspect of the present invention, including all embodiments and specific features, and combinations thereof).

[0145] In certain embodiments, the compound of formula ID is a compound of formula IH or a compound of formula IJ, and the compound of formula IE is a compound of formula IK or a compound of formula IL, [Chemical formula] In the formula, ring Q, ring A, n, m, Z, and r are as described herein (i.e., as described in the first aspect of the present invention, including all embodiments and specific features, and combinations thereof).

[0146] Those skilled in the art will understand that a reference to a specific stereoisomer(s) of a compound of formula I (for example, in the case of a compound of formula I, the carbon substituted by the essential -OH group is in the R configuration) refers to a specific stereoisomer that exists in the substantial absence of other (corresponding) stereoisomers(s) (for example, in the case of a compound of formula I, the carbon substituted by the essential -OH group is in the opposite configuration, i.e., the S configuration).

[0147] As used herein, reference to the substantial absence of the corresponding opposite stereoisomer means that the desired stereoisomer (e.g., in the case of the compound of formula I, the carbon substituted with the essential -OH group is in the (R) configuration) is present with a purity of at least 80% (e.g., at least 90%, e.g., at least 95%) compared to the other (e.g., opposite) stereoisomer(s) (e.g., in the case of the compound of formula I, the carbon substituted with the essential -OH group is in the (R) configuration). Alternatively, in such cases, it may be indicated that the compound exists in the substantial absence of the compound in the other configuration(s) (i.e., the (S) configuration), which may indicate that the compound in the relevant configuration exists in an enantiomer excess (ee) of at least 80% (e.g., at least 90%, at least 95%, at least 98%, or in particular, at least 99%, e.g., at least 99.9%), or in a diastereomer excess (de) where two or more stereocenters are defined.

[0148] In some embodiments, the compound in the associated configuration is present with an enantiomer excess (ee) of at least 90% (at least 95%, at least 98%, or in particular, at least 99%, e.g., at least 99.9%), or with a diastereomer excess (de) if two or more stereocenters are defined.

[0149] To avoid any ambiguity, when multiple stereochemistrys are identified, the compound exists in the substantial absence of all other diastereoisomers.

[0150] To avoid any doubt, if the stereochemistry at a particular position is not specified, the compounds of the present invention include compounds in which that position has any of the available stereochemical configurations, or a mixture thereof (e.g., a racemic mixture). Thus, a compound said to have a particular stereochemistry at a defined position (e.g., in the case of the compound of formula I, the carbon substituted by the essential -OH group is in the R configuration) may have stereochemistry at one or more other positions and, therefore, may exist as a mixture of enantiomers or diastereoisomers in relation to the stereochemistry at those positions.

[0151] medical use As described herein, the compounds of the present invention, and therefore compositions and kits containing them, are useful as pharmaceuticals.

[0152] Accordingly, according to a second aspect of the present invention, compounds of the first aspect of the present invention as defined herein earlier (i.e., compounds defined in the first aspect of the present invention, including all embodiments and their specific features) are provided for use in medicine (i.e., for use as a pharmaceutical, which may be described as use as a drug).

[0153] The compounds described herein are β2-adrenergic receptor agonists and are therefore suitable for the treatment of diseases such as those described herein. Such activity may be observed in the compounds of the present invention by identifying compounds that stimulate glucose uptake in skeletal muscle cells, and such activity may be confirmed to be mediated by β2 receptor activation by observing that such activity is prevented or mitigated in the presence of (e.g., selective) β2-adrenergic receptor agonists (as in the biological examples provided herein).

[0154] Accordingly, a third aspect of the present invention provides a compound of the first aspect of the present invention, as defined herein, for use in the treatment of a disease or disorder in which the treatment is mediated by the activation of β2-adrenergic receptors.

[0155] An alternative third aspect of the present invention provides the use of the compounds of the first aspect of the present invention in the manufacture of a drug for use in the treatment of a disease or disorder in which the treatment is mediated by the activation of β2 adrenergic receptors.

[0156] A further alternative third aspect of the present invention provides a method for treating a disease or disorder in which the treatment is mediated by the activation of a β2-adrenergic receptor, comprising administering a therapeutically effective amount of a compound of the first aspect of the present invention to a patient in need thereof.

[0157] To avoid any ambiguity, references to the compounds defined in the first aspect of the present invention include references to the compounds of formula I (including all embodiments thereof) and their pharmaceutically acceptable salts.

[0158] As described herein, the compounds of the present invention act by inducing glucose uptake in skeletal muscle cells, thereby enabling a decrease in blood glucose concentration in vivo. Therefore, the compounds of the present invention may be particularly useful in the treatment of hyperglycemia or disorders characterized by hyperglycemia.

[0159] In a specific embodiment of a third aspect of the present invention, a compound of the first aspect of the present invention, as defined herein, is provided for use in the treatment of a disorder characterized by hyperglycemia or hyperglycemia.

[0160] An alternative embodiment of a third aspect of the present invention provides the use of a compound of the first aspect of the present invention in the manufacture of a drug for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

[0161] A further alternative embodiment of a third aspect of the present invention is provided, which is a method for treating hyperglycemia or a disorder characterized by hyperglycemia, comprising administering a therapeutically effective amount of a compound of the first aspect of the present invention to a patient in need thereof.

[0162] To avoid any doubt, the term “hyperglycemia” as used herein will be understood by those skilled in the art to refer to a condition in which an excess amount of glucose is circulating in the plasma of a subject experiencing hyperglycemia. In particular, this may refer to a subject (e.g., a human subject) having a blood glucose concentration higher than about 10.0 mmol / L (higher than about 11.1 mmol / L, e.g., higher than about 15 mmol / L), but it may also refer to a subject (e.g., a human subject) having a blood glucose concentration higher than 7 mmol / L over a prolonged period (e.g., longer than 24 hours, longer than 48 hours).

[0163] Those skilled in the art will understand that references to the treatment of a particular condition (or similarly, the act of treating that condition) take on their usual meaning in the medical field. In particular, the term may refer to achieving a reduction in the severity of one or more clinical symptoms associated with a condition. For example, in the case of type 2 diabetes, the term may refer to achieving a reduction in blood glucose concentration. In certain embodiments, when treating hyperglycemia or a condition characterized by hyperglycemia, the term may refer to achieving a reduction in blood glucose concentration (e.g., to about 10.0 mmol / L or less (e.g., to levels in the range of about 4.0 mmol / L to about 10.0 mmol / L), e.g., to about 7.5 mmol / L or less (e.g., to levels in the range of about 4.0 mmol / L to about 7.5 mmol / L), or to about 6 mmol / mL or less (e.g., to levels in the range of about 4.0 mmol / L to about 6.0 mmol / L)).

[0164] As used herein, a patient refers to a living subject being treated, including a mammalian (e.g., human) patient. Therefore, in certain embodiments of the first aspect of the present invention, the treatment is performed in a mammal (e.g., human).

[0165] As used herein, the term therapeutically effective dose refers to the amount of a compound that produces a therapeutic effect in a patient being treated. This effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of and / or feels an effect).

[0166] Compounds of the first aspect of the present invention may have such pharmacological activity, but there may be derivatives of the compounds of the present invention that are pharmaceutically acceptable (e.g., “protected”), or may not have such activity but may be administered parenterally or orally and subsequently metabolized in the body to form the compounds of the present invention. Accordingly, such compounds (which may have some pharmacological activity, provided that such compounds are considerably less active than the active compounds from which they are metabolized) may be described as “prodrugs” of the compounds of the present invention.

[0167] As used herein, a prodrug includes a compound that forms an experimentally detectable amount of the compound of the present invention within a predetermined time after enteral or parenteral administration (e.g., oral or parenteral administration). All prodrugs of the compounds of the first aspect of the present invention are included within the scope of the present invention.

[0168] To avoid any doubt, the compounds of the first aspect of the present invention are useful because they have pharmacological activity and / or are metabolized in the body after oral or parenteral administration to form compounds that have pharmacological activity. In particular, as described herein, the compounds of the first aspect of the present invention are useful in the treatment of hyperglycemia or disorders characterized by hyperglycemia (such as type 2 diabetes), and these terms will be readily understood by those skilled in the art (as described herein).

[0169] In certain embodiments, the treatment is the treatment of a disorder (which may also be called a condition or disease) characterized by hyperglycemia.

[0170] In a particular embodiment of the first aspect of the present invention, the disorder is type 2 diabetes, for example, a subtype of type 2 diabetes selected from the list consisting of young adult-onset diabetes (MODY), adult-onset ketotic diabetes, adult-onset latent autoimmune diabetes (LADA), and gestational diabetes.

[0171] In a further embodiment, the disorder is type 1 diabetes, and in particular, the treatment further includes treatment with insulin (or its derivatives and / or functional mimetic).

[0172] In certain embodiments, the compounds of the present invention (i.e., compounds of formula I, including all embodiments thereof) are intended for use in the treatment of type 2 diabetes (or are useful in the manufacture of such drugs for such treatment as described herein, or in methods for such treatment).

[0173] In a further specific embodiment, the treatment of type 2 diabetes is carried out in non-obese patients.

[0174] To avoid any doubt, a person skilled in the art will understand that a patient with a body mass index (BMI) greater than 30 is considered obese.

[0175] In certain embodiments, the treatment may be for the treatment of hyperglycemia (a condition that may be defined as prediabetes) in patients at risk of developing type 2 diabetes. Therefore, the compounds of the present invention may be useful in preventing type 2 diabetes (for example, in patients with prediabetes).

[0176] As used herein, the terms prevention (and similarly, the act of prevention) include references to prophylaxis of disease or disorder (and vice versa). Thus, references to prevention can also be references to prophylaxis, and vice versa. In particular, the term may refer to achieving a reduction in the likelihood that a patient (or a healthy subject) will develop a condition (e.g., a reduction of at least 10%, e.g., a reduction of at least 20%, 30%, or 40%, e.g., a reduction of at least 50%).

[0177] In more specific embodiments, type 2 diabetes is characterized by patients exhibiting severe insulin resistance (SIR).

[0178] In a further embodiment, the treatment may be for the treatment of hyperglycemia in patients with type 1 diabetes. Therefore, the compounds of the present invention may be useful for the treatment of hyperglycemia in type 1 diabetes.

[0179] Those skilled in the art will understand that the compounds of the present invention may be useful in treating hyperglycemia in patients with impaired insulin production, such as patients with cystic fibrosis. In a further embodiment, the disorder characterized by hyperglycemia is cystic fibrosis-associated diabetes.

[0180] It will be understood by those skilled in the art that in certain embodiments that can be mentioned, a disorder characterized by hyperglycemia is (or is characterized by) severe insulin resistance (SIR), typically referring to a disorder in which the subject has normal insulin production, or in some cases, increased insulin production, but significantly reduced insulin sensitivity. In certain cases, such patients may be non-obese (e.g., healthy weight). Therefore, in certain embodiments, such treatment is carried out in patients who are not defined as obese (e.g., patients defined as healthy weight).

[0181] For example, SIR is based on the fact that in a patient, the patient's fasting insulin level is greater than 150 pmol / L and / or peak insulin level in a glucose tolerance test is greater than 1,500 pmol / L, in particular, 30 kg / m² 2 It can be identified in individuals with a BMI of less than a certain value (these patients may have normal glucose tolerance).

[0182] More specifically, SIR may be characterized by patients who do not respond significantly to the presence of insulin, which may be due to a defect in insulin receptor function (e.g., a gene defect).

[0183] Specific disorders that may be characterized by SIR include Rabson-Mendenhall syndrome, Donahue syndrome (dwarfism), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.

[0184] More specific disorders that may be characterized by SIR include Donahue syndrome and insulin-resistant type A syndrome, and even more specifically, Rabson-Mendenhall syndrome.

[0185] Those skilled in the art will understand that treatment with a compound according to a first aspect of the present invention may further include (i.e., be combined with) further (i.e., additional / other) treatments for the same condition. In particular, treatment with a compound according to the present invention may be combined with other means for the treatment of type 2 diabetes, for example, treatment with one or more other therapeutic agents useful for the treatment of type 2 diabetes that are known to those skilled in the art, such as therapies that involve requiring the patient to follow a dietary change and / or exercise program, and / or surgical procedures designed to promote weight loss (e.g., gastric band surgery).

[0186] In particular, treatment with the compound of the present invention is (i) Compounds that can lower blood sugar levels, and / or (ii) Compounds that are insulin sensitizers, and / or (iii) It may be carried out in combination with one or more (e.g., one) additional compounds (i.e., therapeutic agents) that enhance insulin release (e.g., even in patients being treated with such agents), All of these are described below in this specification.

[0187] In alternative embodiments, the compounds of the first aspect of the present invention (i.e., the compounds of the present invention) may be useful in the treatment of non-alcoholic fatty liver disease (NAFLD).

[0188] Non-alcoholic fatty liver disease (NAFLD) is defined by excessive fat accumulation in the form of triglycerides in the liver (steatosis) (histomatically defined as an accumulation of more than 5% of hepatocytes). It is the most common liver disease in developed countries (for example, affecting about 30% of adults in the United States), and most patients are asymptomatic. If left untreated, the condition gradually worsens and can eventually lead to cirrhosis. NAFLD is particularly common in obese individuals, with an estimated 80% of people thought to have the disease.

[0189] A subgroup of NAFLD patients (e.g., 2–5% of adults in the United States) exhibit hepatocellular damage and inflammation in addition to excessive fat accumulation. This condition, designated as non-alcoholic steatohepatitis (NASH), is histologically virtually indistinguishable from alcoholic steatohepatitis. While the simple steatosis seen in NAFLD does not directly correlate with increased short-term morbidity or mortality, progression of this condition to NASH dramatically increases the risk of cirrhosis, liver failure, and hepatocellular carcinoma. In fact, NASH is now considered one of the leading causes of cirrhosis (including idiopathic cirrhosis) in developed countries.

[0190] The exact cause of NASH is still unknown and is almost certainly not the same in all patients. It is most closely associated with insulin resistance, obesity, and metabolic syndromes (including type 2 diabetes, insulin resistance, central (trunk) obesity, hyperlipidemia, low-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, and hypertension-related disorders). However, not all patients with these conditions have NASH, and not all patients with NASH suffer from one of these conditions. Nevertheless, given that NASH is a potentially fatal condition that can lead to cirrhosis, liver failure, and hepatocellular carcinoma, there is a clear need for effective treatment.

[0191] In certain embodiments, the compounds of the present invention (i.e., compounds of formula I, including all embodiments thereof) are intended for use in the treatment of non-alcoholic fatty liver disease (or are useful in the manufacture of such drugs as described herein, or in methods for such treatment).

[0192] The process by which triglyceride fats accumulate in liver cells is called steatosis (i.e., hepatic steatosis). Those skilled in the art will understand that the term “steatosis” encompasses the abnormal retention of fat (i.e., lipids) within cells. Therefore, in certain embodiments of the first aspect of the present invention, the treatment or prevention is for fatty liver disease characterized by steatosis.

[0193] During steatosis, excess lipids accumulate in vesicles, replacing the cytoplasm of cells. Over time, these vesicles can grow large enough to distort the nucleus, a condition known as macrodrip steatosis. Otherwise, the condition may be referred to as microdrip steatosis. While mild cases of steatosis are mostly harmless, a large accumulation of fat in the liver can lead to serious health problems. Risk factors associated with steatosis include diabetes, protein malnutrition, hypertension, obesity, anoxia, sleep apnea, and the presence of intracellular toxins.

[0194] As described herein, fatty liver disease is most commonly associated with alcohol or metabolic syndromes (e.g., diabetes, hypertension, obesity, or dyslipidemia). Therefore, depending on the underlying cause, fatty liver disease may be diagnosed as alcohol-related fatty liver disease or non-alcoholic fatty liver disease (NAFLD).

[0195] Specific diseases or conditions associated with non-alcohol-related fatty liver disease include metabolic conditions such as diabetes mellitus, hypertension, obesity, dyslipidemia, abetalipoproteinemia, glycogen storage disorders, Weber-Christian disease, acute fatty liver during pregnancy, and lipodystrophy. Other non-alcohol-related factors associated with fatty liver disease include malnutrition, complete parenteral nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, polycystic ovary syndrome, and diverticulosis.

[0196] The compounds of the present invention have been found to be particularly useful in the treatment or prevention of NAFLD, which may be referred to as non-alcohol-related fatty liver disease. "Non-alcohol-related" fatty liver disease can be diagnosed when the patient's alcohol consumption is not considered to be the primary causative factor. Typical thresholds for diagnosing fatty liver disease as "non-alcohol-related" are daily intakes of less than 20g for women and less than 30g for men.

[0197] If left untreated, individuals with fatty liver disease may begin to experience inflammation of the liver (hepatitis). It is hypothesized that one possible cause of this inflammation may be lipid peroxidation damage to the membranes of hepatocytes. Inflammation of fatty liver can lead to several serious conditions, and therefore, it is desirable to treat or prevent fatty liver disease before inflammation occurs. Accordingly, in certain embodiments of the first aspect of the present invention, the treatment or prevention is that of NAFLD associated with inflammation.

[0198] Non-alcoholic steatohepatitis (NASH) is the most aggressive form of NAFLD, a condition characterized by excessive fat accumulation (steatosis) accompanied by inflammation of the liver. As it progresses, NASH can lead to the development of scar tissue in the liver (fibrosis) and ultimately to cirrhosis. As described above, the compounds of the present invention have been found to be useful in the treatment or prevention of NAFLD, particularly when accompanied by liver inflammation. Therefore, the compounds of the present invention are also useful in the treatment or prevention of NASH. Accordingly, in a further embodiment of the first aspect of the present invention, the treatment or prevention is for non-alcoholic steatohepatitis (NASH).

[0199] Those skilled in the art will understand that treatment with the compounds of the first aspect of the present invention may further include (i.e., be combined with) further (i.e., additional / other) treatments for the same condition. In particular, treatment with the compounds of the present invention may be combined with other means for the treatment of fatty liver disease described herein, for example, treatment with one or more other therapeutic agents useful for the treatment of fatty liver disease that are known to those skilled in the art, such as therapies that involve requiring the patient to make changes to their diet and / or to follow an exercise program, and / or surgical procedures designed to promote weight loss (e.g., gastric band surgery).

[0200] In particular, treatment with the compounds of the present invention may be carried out in combination with one or more additional compounds (e.g., one) that can reduce the levels of fat (e.g., triglycerides) in the liver (i.e., a therapeutic agent) (e.g., even in patients being treated with such a agent).

[0201] References to the treatment of fatty liver disease may refer to achieving a therapeutically significant reduction in fat (e.g., triglyceride levels) in hepatocytes (a reduction of at least 5% by weight, e.g., at least 10%, or at least 20%, or even 25%).

[0202] As described herein, the compounds of the present invention may be useful in treating diseases or disorders in which the treatment is mediated by the activation of β2-adrenergic receptors.

[0203] In certain embodiments, the compounds of the first aspect of the present invention may be understood to positively modulate β2-adrenergic receptors, and such compounds may be referred to as β2-adrenergic receptor agonists.

[0204] Those skilled in the art will understand what “β2-adrenergic receptor” (or “β2-AR”) means. Such receptors are known in the art and are outlined, for example, in Johnson, M., J. Allergy Clin. Immunol., 117, 18-24 (2006). To avoid doubt, adrenergic receptors are a class of G protein-coupled receptors that bind to and are activated by their endogenous ligands, catecholamines, adrenaline, and noradrenaline. Adrenergic receptors are classified into five types: α1, α2, β1, β2, and β3. Because these subtypes are expressed in different patterns and are involved in different physiological processes, ligands that can selectively target one subtype have therapeutic potential for multiple diseases. The present invention relates to the β2-adrenergic receptor, but compounds may interact with one or more other adrenergic receptors (e.g., one or more other β-adrenergic receptors).

[0205] The phrase "positively modulates β2-adrenergic receptor activity" would be understood to mean that the compound can alter the signaling pathway of the receptor.

[0206] As used herein, the term “β2 agonist” is used to mean a β2 adrenergic receptor agonist. In certain embodiments, the term “β2 agonist” is understood to include compounds that are primarily β2 agonists but may also exhibit some agonism to other adrenergic receptors. In this application, the terms “β2 adrenergic receptor agonist,” “β2 AR agonist,” “β2 AR agonist,” and “β2 agonist” may be used interchangeably.

[0207] Therefore, in certain embodiments, reference to β2 agonists may include both selective and non-selective agonists.

[0208] In certain embodiments, reference to β2 agonists may include, but are not limited to, complete and partial agonists, any ligand that alters receptor signaling. Furthermore, β2 agonists that can be used according to various aspects and embodiments of this disclosure may be short-acting, long-acting, or ultra-long-acting.

[0209] As used herein, the term "mediated by activation of the β2 adrenergic receptor" is used to indicate that the activation of the receptor modulates or elicits a physiological response, which in turn provides a biological effect that corresponds to (or results in) the treatment of a disease or disorder.

[0210] As used herein, references to diseases and disorders whose treatment is “mediated by activation of β2-adrenergic receptors” may also refer, among other things, to diseases and disorders (and in particular their treatment) that are “associated with,” “mediated by,” “affected by,” “regulated by,” “modulated by,” and “linked to” β2-adrenergic receptors.

[0211] As described herein, diseases and disorders whose treatment is mediated by the activation of β2-adrenergic receptors will be known to those skilled in the art. Accordingly, those skilled in the art will understand that, with respect to certain diseases and disorders described herein, the suitability of the compounds of the present invention for the treatment of such diseases and disorders may be known to those skilled in the art, for example, based on the disclosures referenced below (the contents of which are incorporated herein by reference).

[0212] In addition to those that may be described above herein, the treatment may be for certain diseases and disorders mediated by the activation of β2 adrenergic receptors, as may be mentioned: MCI (Mild Cognitive Impairment), aMCI (Amnesic MCI), Vascular Dementia, Mixed Dementia, FTD (Frontotemporal Dementia), HD (Huntington's Disease), Rett Syndrome, PSP (Progressive Supranuclear Palsy), CBD (Corticobasal Degeneration), SCA (Spinocerebellar Ataxia), MSA (Multiple System Atrophy), SDS (Shy-Drager Syndrome), Olivopontocerebellar Atrophy, TBI (Traumatic Brain Injury), CTE (Chronic Traumatic Encephalopathy), Stroke, EKS (Wernicke-Corsa Syndrome) Neurodegenerative diseases such as Coff syndrome, normal pressure hydrocephalus, hypersomnia (narcolepsy), ASD (autism spectrum disorder), FXS (fragile X syndrome), YSC (tubular sclerosis complex), prion-related disorders, CJD (Creutzfeldt-Jakob disease), depressive disorders, DLC (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and DS (Down syndrome); Muscular dystrophy or disorders characterized by muscular dystrophy, such as muscle damage, muscle wasting, muscle atrophy, muscle degeneration, or sclerosis; Kidney diseases such as CKD (chronic kidney disease), ESRD (end-stage renal disease), and diabetic nephropathy; Inflammatory or inflammation-characterized disorders, including localized acute inflammation such as sepsis, psoriasis, dermatitis, psoriasis-like dermatitis, lacerations, or HDF (human dermal fibroblast) inflammation, and associated with endotoxemia and acute lung injury (ALI), as well as respiratory conditions associated with inflammation such as asthma and other lung disorders such as chronic obstructive pulmonary disease (COPD); Autoimmune diseases such as SLE (systemic lupus erythematosus), RA (rheumatoid arthritis), MG (myasthenia gravis), MS, and GD (Graves' disease) are examples.

[0213] The suitability of β2 adrenergic receptor agonists for treating such conditions can be demonstrated by the data provided herein and by reference to literature known to those skilled in the art, such as that described herein (the entirety of which, in particular, the experimental results presented, is understood to be incorporated herein by reference).

[0214] In particular, the suitability of β2 adrenergic receptor agonists for treating certain diseases and disorders referred to herein may be specified in the disclosures WO2020 / 198466A1 and WO2021 / 003161A1 (for the avoidance of doubt, these are incorporated herein by reference, in particular the examples provided therein), and in some cases may be confirmed therein.

[0215] In certain embodiments, compounds of the first aspect of the present invention, as defined herein, are provided for use in the treatment of neurodegenerative diseases.

[0216] In certain embodiments, neurodegenerative diseases include MCI (mild cognitive impairment), aMCI (amnesic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, EKS ( The following conditions are selected: Wernicke-Korsakoff syndrome, normal pressure hydrocephalus, hypersomnia (narcolepsy), ASD (autism spectrum disorder), FXS (fragile X syndrome), YSC (tubular sclerosis complex), prion-related disorders, CJD (Creutzfeldt-Jakob disease), depressive disorders, DLC (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and DS (Down syndrome).

[0217] Mittal. S., et al., Science., 357(6354), 891-898 (2017) describes how β2-adrenergic receptor agonists promote the health of dopamine neurons by reducing SNCA expression through H2K27 deacetylation and mitochondrial free radicals. This may be beneficial for substantia nigra dopamine neurons, which are prone to mitochondrial bioenergy dysfunction in the early stages of ruby ​​body neuropathy. β2-adrenergic receptor agonists are expressed in areas of the substantia nigra and cortex progressively affected by Parkinson's disease (PD). Therefore, β2-adrenergic receptor agonists may be used to reduce the risk and effects of PD.

[0218] Hishida, R., The Lancet, 870 (1992) describes that β2-adrenergic receptor agonists can have a beneficial effect on wearing off in patients with Parkinson's disease who are on long-term levodopa.

[0219] Uc, EY, et al., Clin. Neuropharmacol., 26(4), 207-212 (2003) describes that albuterol, a β2-adrenergic receptor agonist, was beneficial to patients with PD through two mechanisms: increased response to levodopa and increased muscle mass.

[0220] O'Neill, et al., Br.J.Pharmacol., 177, 282-297 (2019) described how β2-adrenergic receptor agonists limit microglial activation and protect against the onset and progression of dopaminergic neuronal loss and associated motor impairments caused by central or systemic inflammation. Therefore, targeting β2-adrenergic receptors with β2-adrenergic receptor agonists introduces a preventive mechanism that protects against the progression of neurodegeneration and the exacerbated motor impairment associated with systemic and central inflammation. As a result, β2-adrenergic receptor agonists may be beneficial in the treatment of inflammation-induced PD-related neurological and motor disorders.

[0221] In alternative embodiments, compounds of the first aspect of the present invention, as defined herein, are provided for use in the treatment of muscular dystrophy or disorders characterized by muscular dystrophy.

[0222] In certain such embodiments, muscular dystrophy is a condition characterized by muscle damage, muscle wasting, muscle atrophy, muscle degeneration, or sclerosis.

[0223] Jiang, G., et al., ISRN Pharma., 2011, 1-7 (2011) described that β2-AR agonists improve debilitation in animals in denervation, amyotrophic lateral sclerosis, muscular dystrophy, disuse, aging, and myocardial deloading models. Furthermore, in patients with a fixed state or muscular dystrophy, β2-AR agonists increase lean body mass and enhance skeletal muscle function. In addition, β2-AR agonists were found to promote myocardial recovery in patients with myocardial deloading atrophy resulting from the application of left ventricular assist devices.

[0224] Bartus, RT, et al., Neurobiol. Dis., 85, 11-24, 2016, has shown that β2-adrenergic receptor agonists can enhance muscle mass and strength in patients with amyotrophic lateral sclerosis (ALS) by increasing neurotrophic factors.

[0225] In alternative embodiments, compounds of the first aspect of the present invention, as defined herein, are provided for use in the treatment of kidney disease.

[0226] In certain such embodiments, the kidney disease is selected from CKD (chronic kidney disease), ESRD (end-stage renal disease), and diabetic nephropathy.

[0227] Cleveland, K., et al., FASEB Journal, 33(1), 514 (2019) has shown that β2-adrenergic receptor agonists induce mitochondrial biosynthesis (MB) and promote recovery from acute kidney injury, suggesting they may be useful as a potential treatment for diabetic nephropathy (DN).

[0228] Jesinkey, SR, et al., J.Am.Soc.Nephrol., 25, 1157-1162 (2014) describes the need for mitochondrial biosynthesis as an adaptive response to meet increased metabolic and energy demands during organ recovery following acute injury. In particular, renal mitochondrial dysfunction is associated with the pathogenesis of acute kidney injury (AKI), a disorder characterized by a rapid decline in renal excretory function and subsequent retention of harmful waste products.

[0229] In alternative embodiments, compounds of the first aspect of the present invention, as defined herein, are provided for use in the treatment of inflammation or disorders characterized by inflammation.

[0230] In certain embodiments, inflammation is (or characterized by) sepsis, psoriasis, dermatitis, psoriasis-like dermatitis, laceration, or HDF (human dermal fibroblasts).

[0231] As is known to those skilled in the art, inflammation is a tightly controlled process that ensures the proper localization of immune cells, the release of pro-inflammatory and anti-inflammatory mediators, the clearance of dead cells, and the containment of pathogens.

[0232] Those skilled in the art know that inflammation can also be the cause of respiratory conditions such as asthma and other lung disorders such as chronic obstructive pulmonary disease (COPD).

[0233] Grailer, J.Jet al., J.Innate Immun, 6, 607-618 (2014) showed that β2 adrenergic receptor blockade reduced survival and enhanced injury in mouse models of endotoxemia and LPS-induced acute lung injury, respectively. These results demonstrate the suitability of β2AR activation in the treatment of local acute inflammation, such as that associated with endotoxemia and acute lung injury.

[0234] Agac, D., et al., Brain, Behaviour and Immunity, 74, 176-185 (2018) describes a unique synergistic pathway that converts acute inflammatory signals into anti-inflammatory responses, which likely explains various phenomena known to be involved in β2-adrenergic receptor agonist-mediated immunosuppression. In particular, β2-adrenergic receptor agonist signaling directly regulates the expression of the anti-inflammatory cytokine IL-10. These results suggest the use of β2AR agonists in the treatment of inflammatory disorders such as sepsis.

[0235] Liu, F., et al., Cells, 511(9), 1-17 (2020) described the remarkable antipsoriatic effect of β2-adrenergic receptor agonists, which may be involved in regulating the Th17 / Tregs axis balance and glycerophospholipid metabolism in response to imiquimod (IMQ)-induced psoriasis.

[0236] Provost, GS, et al., J. Investig. Dermatol., 135, 279-288 (2015) describes how β2-adrenergic receptor agonists reduce human dermal fibroblast (HDF) differentiation and, therefore, reduce scarring in patients with lacerations or open wounds.

[0237] In alternative embodiments, compounds of the first aspect of the present invention, as defined herein, are provided for use in the treatment of autoimmune diseases.

[0238] In certain such embodiments, the autoimmune disease is selected from SLE (systemic lupus erythematosus), RA (rheumatoid arthritis), MG (myasthenia gravis), MS, and GD (Graves' disease).

[0239] Wu, et al., Front. Pharmacol., 1313(9), 1-9 (2018) describes that β2-adrenergic receptor agonists may be a targeted therapy for autoimmune diseases (AD) such as SLE (systemic lupus erythematosus), RA (rheumatoid arthritis), MG (myasthenia gravis), MS, and GD (Graves' disease).

[0240] Pharmaceutical composition As described herein, the compounds of the first, and therefore the second and third embodiments of the present invention are useful as pharmaceuticals. Such compounds may be administered alone or via known pharmaceutical compositions / formulations.

[0241] A fourth aspect of the present invention provides a pharmaceutical composition comprising a compound defined in a second or third aspect of the present invention and optionally one or more pharmaceutically acceptable adjuvants, diluents, and / or carriers.

[0242] Those skilled in the art will understand that references herein to compounds of the first aspect of the present invention for specific uses (and similarly, uses and methods of use related to the compounds of the present invention) may also apply to pharmaceutical compositions comprising the compounds of the present invention as described herein.

[0243] A fifth aspect of the present invention provides a pharmaceutical composition for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia (such as type 2 diabetes as defined herein), comprising a compound as defined in the first aspect of the present invention and optionally one or more pharmaceutically acceptable adjuvants, diluents, and / or carriers.

[0244] In an alternative fifth aspect of the present invention, a pharmaceutical composition for use in the treatment or prevention of non-alcoholic fatty liver disease is provided, as defined herein.

[0245] In an alternative fifth aspect of the present invention, a pharmaceutical composition for use in the treatment or prevention of non-alcoholic fatty liver disease is provided, as defined herein.

[0246] Those skilled in the art will understand that compounds according to the first (and therefore second and third) aspects of the present invention may act systemically and / or topically (i.e., at specific sites).

[0247] Those skilled in the art will understand that the compounds and compositions described in the first to fifth aspects of the present invention are typically administered in pharmaceutically acceptable dosage forms by oral, intravenous, subcutaneous, buccal mucosa, rectal, skin, nasal cavity, trachea, bronchi, sublingual, intranasal cavity, topical, any other parenteral route, or by inhalation. The pharmaceutical compositions described herein 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. Alternatively, particularly when such compounds of the present invention act topically, the pharmaceutical compositions may be formulated for topical administration.

[0248] Accordingly, in certain embodiments of the fourth and fifth aspects of the present invention, the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g., applied intranasally), or forms suitable for topical administration. To avoid doubt, in such embodiments, the compounds of the present invention may exist in other forms, such as solids (e.g., solid dispersions), liquids (e.g., in solutions), or micelles.

[0249] For example, in the preparation of pharmaceutical formulations for oral administration, the compound may be mixed with solid powder components such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable components, as well as with disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol wax. The mixture may then be processed into granules or compressed into tablets.

[0250] Soft gelatin capsules can be prepared in which one or more active compounds (e.g., compounds of the first, and therefore second and third embodiments of the present invention, and optionally additional therapeutic agents) are contained together with, for example, vegetable oil, fat, or other vehicle suitable for soft gelatin capsules. Similarly, hard gelatin capsules can contain such compounds(s) in combination with solid powder components such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.

[0251] Dosage units for rectal administration may be prepared in the form of (i) suppositories containing the compound(s) mixed with a neutral lipid base, (ii) gelatin rectal capsules containing the active substance in a mixture with vegetable oil, paraffin oil, or other vehicle suitable for gelatin rectal capsules, (iii) ready-made microenemas, or (iv) dried microenema preparations that are reconstituted in a suitable solvent immediately before administration.

[0252] Liquid preparations for oral administration may be prepared in the form of a solution or suspension containing, for example, a syrup or suspension, the compound(s), a sugar or sugar alcohol, and the remainder of a formulation consisting of a mixture of ethanol, water, glycerol, propylene glycol, and polyethylene glycol. Optionally, such liquid preparations may contain colorants, flavorings, saccharin, and carboxymethylcellulose or other thickeners. Liquid preparations for oral administration may also be prepared in the form of a dry powder that is reconstituted with a suitable solvent before use.

[0253] 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 and / or buffering components 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 that is reconstituted improvisationally with a suitable solvent before use.

[0254] Those skilled in the art will understand that the compounds of the present invention and their pharmaceutically acceptable salts may be administered in variable doses (e.g., as formulations described earlier herein), and that preferred doses can be easily determined by those skilled in the art. Oral, pulmonary, and topical doses (and subcutaneous doses, although these may be relatively low) may range from about 0.01 μg / kg body weight (μg / kg / day) to about 200 μg / kg / day, preferably about 0.01 to about 10 μg / kg / day, more preferably about 0.1 to about 5.0 μg / kg / day. For example, when administered orally, treatment with such compounds may typically involve the administration of formulations containing about 0.01 μg to about 2000 mg, e.g., about 0.1 μg to about 500 mg, or 1 μg to about 100 mg (e.g., about 20 μg to about 80 mg) of the active ingredient. When administered intravenously, the most preferred dose is in the range of about 0.001 to about 10 μg / kg / hour during a constant rate infusion. Advantageously, treatment may involve administering such compounds and compositions in a once-daily dose, or the total daily dose may be administered in two, three, or four divided doses per day (e.g., 10 mg, 20 mg, 30 mg, or 40 mg twice daily, or 10 μg, 20 μg, 30 μg, or 40 μg twice daily, as described herein).

[0255] In any case, a person skilled in the art (e.g., a physician) can determine the most appropriate actual dosage for an individual patient, which is likely to vary depending on the route of administration, the type and severity of the condition being treated, and the race, age, weight, sex, renal function, hepatic function, and response of the particular patient being treated. The dosages mentioned above are examples of average cases, and naturally, there may be individual cases where a higher or lower dosage range is appropriate, and such cases are within the scope of the present invention.

[0256] As described above in this specification, those skilled in the art will understand that treatment with compounds of the first aspect of the present invention may further include (i.e., be combined with) further (i.e., additional / other) treatments for the same condition. In particular, treatment with compounds of the present invention may be combined with other means for treatment with one or more other therapeutic agents useful for treating hyperglycemia or disorders characterized by hyperglycemia (such as type 2 diabetes as defined herein).

[0257] In specific embodiments of the fourth and fifth aspects of the present invention, the pharmaceutical composition may further comprise one or more additional (i.e., other) therapeutic agents.

[0258] In more specific embodiments, one or more additional therapeutic agents include metformin, sulfonylureas (e.g., carbatamide, acetohexamide, chlorpropamide, tolbutamide, glipizide (glucotol), gliclazide, glibenclamide, glibride (Micronase), glibornelide, gliquidone, glisoxepide, glycopyramide, glimeprid (Amaryl), glimiprim, JB253 or JB558), thiazolidinediones (e.g., pioglitazone, rosiglitazone (Avandia), robeglitazone (Duvie), and troglitazone (Rezulin)), dipeptidyl peptide These are agents for the treatment of type 2 diabetes known to those skilled in the art, such as tidase-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin, and omaligliptin), SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, cergliflozin etabonate, remogliflozin etabonate, and erzgliflozin), and glucagon-like peptide-1 (GLP-1) analogues.

[0259] Those skilled in the art will understand that combinations of therapeutic agents may also be described as combination products and / or offered as kits of parts.

[0260] In a sixth aspect of the present invention, (A) A compound defined in the first aspect of the present invention, (B) comprising one or more additional therapeutic agents, A combination product is provided in which each of components (A) and (B) is optionally mixed with one or more pharmaceutically acceptable adjuvants, diluents, or carriers to form a formulation.

[0261] In a seventh aspect of the present invention, (a) A compound as defined in the first (or second and / or third) aspect of the present invention (or a pharmaceutical composition containing the same), or a pharmaceutical composition as defined in the fourth or fifth aspect of the present invention, (b) comprising one or more other therapeutic agents, which are optionally mixed with one or more pharmaceutically acceptable adjuvants, diluents, or carriers, A kit of parts is provided, wherein components (a) and (b) are provided in forms suitable for administration together with the other.

[0262] In certain embodiments (for example, the sixth and seventh aspects of the present invention), the additional therapeutic agent is a therapeutic agent useful for treating hyperglycemia or a disorder characterized by hyperglycemia (e.g., type 2 diabetes), as is known to those skilled in the art (such as those described herein).

[0263] For example, in certain embodiments of the fourth and fifth aspects of the present invention, an additional therapeutic agent is: (i) A drug that can lower blood sugar levels, and / or (ii) Drugs that are insulin sensitizers, and / or (iii) A drug that can enhance insulin release, Such drugs are readily identifiable by those skilled in the art and include, in particular, commercially available therapeutic agents (e.g., drugs that are subject to marketing authorization in one or more regions, such as marketing authorization in Europe or the United States).

[0264] Those skilled in the art will understand that reference to a therapeutic agent capable of lowering blood glucose levels may refer to a compound capable of lowering blood glucose levels by at least 10% (at least 20%, at least 30%, or at least 40%, e.g., at least 50%, at least 60%, at least 70%, or at least 80%, e.g., at least 90%) compared to blood glucose levels before treatment with the compound in question.

[0265] In alternative embodiments of the sixth and seventh aspects of the present invention, additional therapeutic agents are agents for the treatment or prevention of non-alcoholic fatty liver disease (such as NASH), which will be readily identifiable to those skilled in the art, and in particular include commercially available therapeutic agents (e.g., agents subject to marketing authorization in one or more regions, such as marketing authorization in Europe or the United States).

[0266] In alternative embodiments of the sixth and seventh aspects of the present invention, the additional therapeutic agent is a drug for treating a disease or disorder in which the treatment is mediated by the activation of β2-adrenergic receptors, the disease and disorder including those described herein, the drug being readily identifiable to those skilled in the art, and in particular including such therapeutic agents that are commercially available (e.g., drugs subject to marketing authorization in one or more territories, such as marketing authorization in Europe or the United States).

[0267] Preparation of compounds / compositions The pharmaceutical compositions / formulations, combination products, and kits described herein may be prepared in accordance with standard and / or acceptable pharmaceutical regulations.

[0268] Accordingly, further embodiments of the present invention provide a process for preparing a pharmaceutical composition / formulation as defined herein, the process comprising associating a compound of the present invention as defined herein with one or more pharmaceutically acceptable adjuvant diluents or carriers.

[0269] In further aspects of the present invention, a process is provided for the preparation of a combination product or kit of parts as defined herein earlier, the process comprising associating a compound of the present invention as defined herein earlier, or a pharmaceutically acceptable salt thereof, with other therapeutic agents useful for the treatment of hyperglycemia or a disorder characterized by hyperglycemia (e.g., type 2 diabetes), and at least one pharmaceutically acceptable adjuvant, diluent, or carrier.

[0270] As used herein, a reference to association means that the two components are suitable for administration together.

[0271] Therefore, with respect to the process for preparing a kit of parts as defined herein, by "associating" the two components of the kit of parts with each other, (i) They may be provided as separate formulations (i.e., independently of each other) and then combined for use in combination therapy, or (ii) may be packaged and presented together as separate components of a “combination pack” for use in combination therapy.

[0272] The compounds defined in the first aspect of the present invention (i.e., the compounds of the present invention) can be prepared according to techniques well known to those skilled in the art, such as those described in the examples provided below.

[0273] For example, a process is provided for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, where R 1represents H, and the remaining substituents are as defined in the first aspect of the present invention, and the process is (i) A compound of formula II, [ka] In the formula, rings A, n, m, and r are as defined herein, and in the formula, M 1 However, a compound of formula II and a compound of formula III that represent a suitable metal or metal halide, [ka] In the formula, Q 1 ~Q 5 (Therefore, ring Q) reacts with a compound of formula III as defined herein under conditions known to those skilled in the art, (ii) Compounds of formula IV, [ka] In the formula, Q 1 ~Q 5 However, as defined herein, in the formula, M 2 However, a compound of formula IV and a compound of formula V that represent a suitable metal or metal halide, [ka] The reaction includes a reaction with a compound of formula V, wherein rings A, n, m, Z, and r are as defined herein under conditions known to those skilled in the art.

[0274] The compounds of formulas II, III, IV, and V can be obtained from commercially available, literature-known, or readily available starting materials (e.g., appropriately substituted benzaldehyde, styrene, or phenacyl bromide (or phenacyl chloride, etc.)) using standard techniques and appropriate reagents and reaction conditions, either by the process described herein or by conventional synthetic procedures. In this regard, those skilled in the art may refer, in particular, to “Comprehensive Organic Synthesis” BMTrost and I. Fleming, Pergamon Press, 1991. Further references that may be used include “Science of Synthesis”, Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0275] Substituents Y and Z, as defined herein, may be modified one or more times after or during the processes described above for the preparation of compounds of formula I, by methods well known to those skilled in the art. Examples of such methods include substitution, reduction, oxidation, dehydrogenation, alkylation, dealkylation, acylation, hydrolysis, esterification, etherification, halogenation, and nitration. The precursor group may be changed at any point in the reaction sequence to a different such group or a group defined in formula I. Those skilled in the art may also refer to “Comprehensive Organic Functional Group Transformations” ARKatritzky, O. Meth-Cohn and CWRees, Pergamon Press, 1995 and / or “Comprehensive Organic Transformations” RCLarock, Wiley-VCH, 1999.

[0276] Such compounds can be isolated from the reaction mixture and, if necessary, purified using conventional techniques known to those skilled in the art. Accordingly, the process for preparing the compounds of the present invention as described herein may, as a final step, include isolation and optional purification of the compounds of the present invention (e.g., isolation and optional purification of the compound of formula I).

[0277] Those skilled in the art will understand that compounds of formula I having a specific stereochemistry can be provided by reacting suitable starting materials having the required stereochemistry in the process described herein. Furthermore, those skilled in the art will understand that suitable starting materials having the required stereochemistry can be prepared in the same manner as in the process described herein.

[0278] Those skilled in the art will understand that in the processes described above and below, it may be necessary to protect the functional groups of the intermediate compound with protecting groups. Protection and deprotection of functional groups may be carried out before or after the reaction in the schemes mentioned above.

[0279] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and those described below. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemical reaction involved will determine the need and type of protecting group, as well as the sequence for achieving the synthesis. The use of protecting groups is fully described in “Protective Groups in Organic Synthesis”, 3rd edition, TW Greene & P. ​​G.M. Wutz, Wiley-Interscience (1999).

[0280] The compounds described herein (in particular, the compounds defined in the first, and therefore, second and third embodiments of the present invention) may have advantages over compounds known in the prior art, whether for use in the aforementioned conditions, such as being more effective, less toxic, longer-acting, more potent, having fewer side effects, being more readily absorbed, and / or having a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or other useful pharmacological, physical, or chemical properties. In particular, such compounds may have the advantage of being more effective and / or exhibiting advantageous properties in vivo.

[0281] While we do not wish to be bound by theory, the compounds described herein are thought to be potent agonists of β2-adrenergic receptors that enable increased glucose uptake in skeletal muscle cells.

[0282] In addition, the compounds described herein are considered to be β2-adrenergic receptor agonists that do not induce cAMP production (or have minimal effect in inducing it). This is thought to enable effects such as increased glucose uptake in skeletal muscle cells with a lower level of side effects than those that may result from other treatments. Furthermore, combining the compounds described herein with other therapeutic agents, such as those that can lower blood glucose levels, is thought to provide an effective combination therapy. [Examples]

[0283] The present invention is illustrated through the following embodiments.

[0284] Chemicals and reagents were obtained from suppliers and used in the condition received, unless otherwise noted. All reactions involving hygroscopic reagents were carried out under positive pressure of nitrogen or argon in oven-dried or flame-dried glassware.

[0285] Abbreviation The abbreviations used herein are known to those skilled in the art. In particular, the following abbreviations may be used herein: aq aqueous solution Pd-C Palladium Carbon rt room temperature sat saturation

[0286] Example Compounds In the event of any discrepancy between the nomenclature and the structure of a compound shown in a diagram, the latter takes precedence (unless it contradicts any experimental details that may be given and / or is not clear from the context).

[0287] Example 1: (R)-(3-fluorophenyl)((2R,5S)-5-(piperidine-4-ylmethyl)pyrrolidine-2-yl)methanol dihydrochloride [ka] (a) Methyl(R)-2-((tert-butoxycarbonyl)amino)-6-(dimethoxyphosphoryl)-5-oxo-hexanoate [ka] n-butyllithium (2.5 M in toluene, 1.73 mL, 4.32 mmol) was added at -78°C to a solution of dimethylmethylphosphonate (0.46 mL, 4.32 mmol) in toluene (50 mL). The mixture was stirred at -78°C for 20 minutes and added dropwise at -78°C to a solution of 1-(tert-butyl)2-methyl(R)-5-oxopyrrolidine-1,2-dicarboxylate (1.00 g, 4.11 mmol) in toluene (20 mL). After 1 hour, the cooling bath was removed and the stirred mixture was allowed to rise to room temperature for 30 minutes. NH4Cl (aqueous solution, saturated) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic phases were washed with brine, dried to (Na2SO4), and concentrated to obtain the sub-subject compound (1.40 g, 93%), which was used in the next step without further purification.

[0288] (b)tert-butyl(R)-4-(5-((tert-butoxycarbonyl)amino)-6-methoxy-2,6-dioxohexylidene)piperidine-1-carboxylate [ka] A mixture of methyl(R)-2-((tert-butoxycarbonyl)amino)-6-(dimethoxyphosphoryl)-5-oxohexanoate (400 mg g, 1.09 mmol), 1-tert-butoxycarbonylpiperidine-4-one (434 mg, 2.18 mmol), K2CO3 (602 mg, 4.36 mmol), and MeCN (8 mL) was stirred at 70°C for 16 hours, cooled to room temperature, and concentrated. The residue was treated with H2O and extracted with CH2Cl2. The combined extract was dried (Na2SO4) and concentrated. The residue was purified by chromatography to obtain the subtitle compound (380 mg, 79%).

[0289] (c) 1-(tert-butyl)2-methyl(2R,5S)-5-((1-(tert-butoxycarbonyl)piperidine-4-yl)-methyl)pyrrolidine-1,2-dicarboxylate [ka] Pd-C (10%, 87 mg, 0.08 mmol) was added all at once to tert-butyl(R)-4-(5-((tert-butoxycarbonyl)amino)-6-methoxy-2,6-dioxohexylidene)piperidine-1-carboxylate (360 mg, 0.82 mmol) in MeOH (5 mL), followed by dropwise addition of Et3SiH (1.30 mL, 8.17 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes and filtered. The filter was washed with MeOH, and the combined filtrate was concentrated. The residue was dissolved in CH2Cl2 (7 mL), sodium triacetoxyborohydride (693 mg, 3.27 mmol) was added, and the mixture was cooled in an ice bath. Me3SiCl (830 μL, 6.54 mmol) was added dropwise, the ice bath was removed, and the mixture was stirred at room temperature for 16 hours. H2O was added, and the mixture was extracted with ELISA. The combined extracts were washed with H2O and brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography to obtain the subtitle compound (320 mg, 92%).

[0290] (d) tert-butyl 4-(((2S,5R)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate [ka] LiBH4 (4M in THF, 703 μL, 2.81 mmol) was added dropwise at 0°C to a solution of 1-(tert-butyl)2-methyl(2R,5S)-5-((1-(tert-butoxycarbonyl)piperidine-4-yl)methyl)pyrrolidine-1,2-dicarboxylate (300 mg, 0.70 mmol) in THF (8 mL). The stirred mixture was slowly brought to room temperature over 16 hours, cooled in an ice bath, quenched with H2O, and extracted with Et2O. The combined extracts were washed with brine, dried, and concentrated in (MgSO4). Purification by chromatography yielded the subtitle compound (220 mg, 79%).

[0291] (e)tert-butyl 4-(((2S,5R)-1-(tert-butoxycarbonyl)-5-formylpyrrolidine-2-yl)-methyl)piperidine-1-carboxylate [ka] Dess-Martin periodinane (255 mg, 0.60 mmol) in CH2Cl2 (5 mL) was added via syringe to a solution of tert-butyl 4-(((2S,5R)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)-pyrrolidine-2-yl)methyl)piperidine-1-carboxylate (200 mg, 0.50 mmol) in CH2Cl2 (15 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. NaOH (aqueous solution, 1 M, 10 mL) was added, and the mixture was vigorously stirred for 10 minutes. The layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phase was dried (Na2SO4), concentrated to obtain the subtitle compound (180 mg, 91%), which was used in the next step without further purification.

[0292] (f)tert-butyl 4-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((R)-(3-fluorophenyl)-(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate and tert-butyl 4-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((S)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate [ka] Freshly prepared magnesium 3-fluorophenylbromide (1 M in THF, 1.36 mL, 1.36 mmol) was added dropwise at 0°C to a stirred solution of tert-butyl 4-(((2S,5R)-1-(tert-butoxy-carbonyl)-5-formylpyrrolidine-2-yl)methyl)piperidine-1-carboxylate (180 mg, 0.45 mmol) in THF (4 mL). The mixture was stirred at 0°C for 30 minutes and at room temperature for 16 hours, then quenched with NH4Cl (aqueous solution, saturated). The mixture was extracted with Et2O, the combined extract was dried and concentrated with (Na2SO4). The residue was purified by chromatography on silica gel to obtain the sub-subject compounds, yielding 58 mg (26%) of the (R) isomer and 43 mg (19%) of the (S) isomer.

[0293] (g)(R)-(3-fluorophenyl)((2R,5S)-5-(piperidine-4-ylmethyl)pyrrolidine-2-yl)methanol dihydrochloride [ka] HCl (4M in dioxane, 500 μL, 2.00 mmol) was added to tert-butyl 4-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((R)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)-piperidine-1-carboxylate (48 mg, 0.10 mmol). The solution was stirred at room temperature for 1 hour and concentrated to dryness. The residue was ground with Et2O and air-dried to obtain the title compound (29 mg, 82%).

[0294] 1 H NMR(400MHz,CD3OD) δ 7.47-7.38(m,1H),7.33-7.21(m,2H),7.13-7.04(m,1H),4.84(d,J=8.4Hz,1H),3.82(q,J=8.5Hz,1H),3.77-3.65(m,1 H),3.46-3.37(m,2H),3.13-2.93(m,2H),2.35-2.21(m,1H),2.13-1.96(m,2H),1.95-1.68(m,6H),1.58-1.39(m,2H).

[0295] Example 2: (S)-(3-fluorophenyl)((2R,5S)-5-(piperidine-4-ylmethyl)pyrrolidine-2-yl)methanol dihydrochloride [ka] The title compound was prepared from tert-butyl 4-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((S)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate (see Example 1, step (f)) according to the procedure of Example 1, step (g).

[0296] 1 H NMR(400MHz,CD3OD) δ 7.48-7.35(m,1H),7.33-7.17(m,2H),7.10-6.97(m,1H),5.13(d,J=3.6Hz,1H),3.93(td,J=8.0,3.5Hz,1H),3.79-3.65(m,1H) ,3.46-3.34(m,2H),3.02(tt,J=13.0,3.6Hz,2H),2.24-2.05(m,3H),2.03-1.94(m,1H),1.92-1.67(m,5H),1.54-1.37(m,2H).

[0297] Example 3: (R)-(3-fluorophenyl)((2R,5S)-5-(((S)-piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol dihydrochloride [ka] (a) tert-butyl 3-(((2S,5R)-1-(tert-butoxycarbonyl)-5-formylpyrrolidine-2-yl)-methyl)piperidine-1-carboxylate [ka] The subtitle compound was prepared according to the procedure of steps (a) to (e) of Example 1, using tert-butyl 3-oxopiperidine-1-carboxylate in step (b).

[0298] (b) A: tert-butyl(R)-3-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((S)-(3-fluorophenyl)-(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate, B: tert-butyl(S)-3-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((S)-(3-fluorophenyl)-(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate, C:tert-butyl(R)-3-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((R)-(3-fluorophenyl)-(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate, and D:tert-butyl(S)-3-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((R)-(3-fluorophenyl)-(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate [ka] The subtitle compound was prepared from tert-butyl 3-(((2S,5R)-1-(tert-butoxy-carbonyl)-5-formylpyrrolidine-2-yl)methyl)piperidine-1-carboxylate according to the procedure of Step (f) of Example 1. The isomers were separated by chromatography on silica gel (eluate Et2O), followed by preparative chiral chromatography (DAICEL CHIRALPAK IC 250×30 mm-5 μm, 40 mL / min, iPrOH / heptane (1 / 4), λ262 nm, 210 nm).

[0299] Isomer A (Rt=5.0 min): [a] D 20 = +58.0 (c=1.0, CHCl3)

[0300] 1 H NMR (400MHz, CDCl3) δ 7.34-7.17(m,1H),7.16-7.01(m,2H),6.98-6.85(m,1H),5.72(br s,1H),4.88(br s,1H),4.19(br s,1H),4.04-3.67(m,3H),2.76-2.48(m,1H),2.30-2.03(m,1H),2.00-1.69(m,3H),1 .61-1.46(m,11H),1.46-1.25(m,12H),1.21-1.02(m,1H),1.02-0.75(m,1H),0.28(br s,1H).

[0301] Heterogeneous entity B (Rt=6.6 points): [a] D 20 =+30.7 (c=1.0, CHCl3)

[0302] 1 H NMR (400MHz, CDCl3) δ 7.32-7.17(m,1H),7.15-6.98(m,2H),6.97-6.86(m,1H),6.31-5.41(m,1H),4.84(br s,1H),4.46-4.07(m,1H),4.08-3.28(m,3H),2.73(br s,1H),2.05-1.59(m,5H),1.59-1.40(m,19H),1.40-1.06(m,3H),0.96-0.56(m,2H),0.33(br s,1H).

[0303] Heterogeneous entity C (Rt=8.3 points): [a] D 20 =+26.0 (c=1.0, CHCl3).

[0304] 1H NMR(400MHz,CDCl3) δ 7.34-7.25(m,1H),7.15-7.03(m,2H),7.02-6.87(m,1H),6.12(br s,1H),4.49-4.39(m,1H),4.30-3.81(m,4H),2.68(td,J=12.6,3.0Hz,1H),2.35(br s,1H),2.00-1.77(m,2H),1.49(d,J=26.5Hz,25H),1.28-1.00(m,2H).

[0305] Isomer D (Rt=10.2 min):[a] D 20 = +6.0 (c=1.0, CHCl3).

[0306] 1 H NMR(400MHz,CDCl3) δ 7.34-7.22(m,1H),7.18-7.05(m,2H),7.02-6.89(m,1H),6.14(s,1H),4.54-4.38(m,1H),4.11-3.95(m ,2H),3.94-3.54(m,2H),3.12-2.36(m,2H),1.97-1.73(m,2H),1.70-1.32(m,25H),1.31-1.02(m,2H).

[0307] (c)(S)-(3-fluorophenyl)((2R,5S)-5-(((R)-piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol dihydrochloride [ka] The title compound was prepared from tert-butyl(R)-3-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((S)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate according to the procedure of Example 1, step (g).

[0308] H NMR(400MHz,CD3OD) δ 7.51-7.37(m,1H),7.34-7.19(m,2H),7.12-6.98(m,1H),5.16(d,J=3.6Hz,1H),4.00-3.90(m,1H),3.80-3.70(m,1H),3.44- 3.35(m,2H),2.94(td,J=12.8,3.4Hz,1H),2.73(t,J=12.1Hz,1H),2.28-2.04(m,3H),2.04-1.67(m,7H),1.38-1.21(m,1H).

[0309] Example 4: (S)-(3-fluorophenyl)((2R,5S)-5-(((S)-piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol dihydrochloride [ka] The title compound was prepared from tert-butyl(S)-3-(((2S,5R)-1-(tert-butoxycarbonyl)-5-((S)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate according to the procedure of Example 1, step (g).

[0310] H NMR(400MHz,CD3OD) δ 7.52-7.34(m,1H),7.34-7.16(m,2H),7.12-6.96(m,1H),5.12(d,J=3. 5Hz,1H),4.01-3.86(m,1H),3.81-3.62(m,1H),3.53-3.42(m,1H),3.4 2-3.31(m,1H),2.93(td,J=12.8,3.2Hz,1H),2.77-2.64(m,1H),2.25- 2.05(m,2H),2.01-1.89(m,3H),1.89-1.66(m,5H),1.39-1.22(m,1H).

[0311] Example 5: (R)-(3-fluorophenyl)((2R,5S)-5-(((R)-piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol dihydrochloride [ka] The title compound was prepared from tert-butyl(R)-3-(((2S,5R)-1-(tert-butoxy-carbonyl)-5-((R)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate according to the procedure of Step (g) of Example 1.

[0312] H NMR(400MHz,CD3OD) δ 7.48-7.37(m,1H),7.33-7.21(m,2H),7.12-7.03(m,1H),4.83(d,J=8.5Hz,1H),3.80(q,J=8.5Hz,1H),3.75-3.63(m,1H),3.4 4-3.33(m,2H),2.93(td,J=12.8,3.4Hz,1H),2.71(t,J=11.9Hz,1H),2.36-2.20(m,1H),2.11-1.62(m,9H),1.38-1.21(m,1H).

[0313] Example 6: (R)-(3-fluorophenyl)((2R,5S)-5-(((S)-piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol dihydrochloride [ka] The title compound was prepared from tert-butyl(S)-3-(((2S,5R)-1-(tert-butoxy-carbonyl)-5-((R)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-carboxylate according to the procedure of Example 1, step (g).

[0314] H NMR(400MHz,CD3OD) δ 7.46-7.37(m,1H),7.30-7.20(m,2H),7.12-7.04(m,1H),4.78(d,J=8.3Hz,1H),3.80(q,J=8.5Hz,1H),3.71-3.63(m,1H),3.45-3 .32(m,2H),2.93(td,J=12.8,3.2Hz,1H),2.73(dd,J=12.4,11.3Hz,1H),2.33-2.19(m,1H),2.07-1.67(m,9H),1.38-1.22(m,1H).

[0315] Example 7: (R)-(3-fluorophenyl)((2R,5S)-5-((1-(methylsulfonyl)piperidine-4-yl)-methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] (a) Methyl(R)-6-(1-benzylpiperidine-4-ylidene)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate [ka] NaH (60% in mineral oil, 345 mg, 8.62 mmol) was added all at once at 0°C to a solution of methyl(R)-2-((tert-butoxycarbonyl)amino)-6-(dimethoxyphosphoryl)-5-oxo-hexanoate (see Example 1, step (a)) (2.64 g, 7.19 mmol) in THF (20 mL). The mixture was stirred at 0°C for 30 minutes, and 1-benzylpiperidine-4-one (2.57 mL, 14.37 mmol) was slowly added. The mixture was stirred at room temperature for 17 hours, quenched with NH4Cl (aqueous solution, saturated), and extracted with ethyl acetate. The combined extract was washed with brine, dried, filtered, and concentrated. The residue was purified by chromatography to obtain the subtitle compound (1.98 g, 64%).

[0316] (b) tert-butyl(2R,5S)-2-methyl(2R,5S)-5-((1-(methylsulfonyl)piperidine-4-yl)-methyl)pyrrolidine-1,2-dicarboxylate [ka] Pd-C (10%, 156 mg, 0.15 mmol) was added all at once, followed by ammonium formate (309 mg, 4.90 mmol) in a solution of methyl(R)-6-(1-benzylpiperidine-4-ylidene)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (422 mg, 0.98 mmol) in MeOH. The mixture was stirred at 60°C for 30 minutes, cooled, and filtered through Celite. The filtrate was concentrated and dissolved in CH2Cl2. Sodium triacetoxyborohydride (831 mg, 3.92 mmol) was added all at once, and the mixture was cooled to 0°C. Trimethylsilyl chloride (995 μL, 7.84 mmol) was added dropwise at 0°C. After 5 minutes, the cooling bath was removed, and the mixture was stirred at room temperature for 21 hours. It was then quenched with H2O and NaOH (aqueous solution, 1M) and extracted with ethyl acetate. The combined extract was dried (Na2SO4) and concentrated. The residue was dissolved in CH2Cl2 (4.5 mL) and Et3N (273 μL, 1.96 mmol) was added. The mixture was cooled to 0°C, and mesyl chloride (152 μL, 1.96 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour and diluted with CH2Cl2 (20 mL). NaHCO3 (aqueous solution, saturated) was added, and the layers were separated. The aqueous phase was extracted with CH2Cl2, and the combined extract was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography to obtain the subtitle compound (210 mg, 53%).

[0317] (c) tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)(hydroxy)methyl)-5-((1-(methyl-sulfonyl)piperidine-4-yl)methyl)pyrrolidine-1-carboxylate and tert-butyl(2R,5S)-2-((S)-(3-fluorophenyl)(hydroxy)methyl)-5-((1-(methylsulfonyl)-piperidine-4-yl)methyl)pyrrolidine-1-carboxylate [ka] The subtitle compound was prepared according to the procedure of steps (d) to (f) of Example 1, separated by chromatography on silica gel, and subsequently obtained the (R) isomer (34%) and the (S) isomer (22%) by chiral HPLC (CHIRALPAK IH column, elution system 65% heptane, 30% CH2Cl2, 5% iPrOH).

[0318] (d)(R)-(3-fluorophenyl)((2R,5S)-5-((1-(methylsulfonyl)piperidine-4-yl)methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] The title compound was prepared from tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)(hydroxy)methyl)-5-((1-(methyl-sulfonyl)piperidine-4-yl)methyl)pyrrolidine-1-carboxylate according to the procedure of Example 1, step (g).

[0319] 1 H NMR(400MHz,CD3OD) δ 7.46-7.38(m,1H),7.30-7.22(m,2H),7.12-7.05(m,1H),4.77(d,J=8.3Hz,1H),3.82-3.61(m,4H),2.82(s,3 H),2.74(tt,J=12.1,3.0Hz,2H),2.30-2.20(m,1H),1.94-1.66(m,7H),1.61-1.47(m,1H),1.37-1.24(m,2H).

[0320] Example 8: (S)-(3-fluorophenyl)((2R,5S)-5-((1-(methylsulfonyl)piperidine-4-yl)-methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] The title compound was prepared from tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)(hydroxy)methyl)-5-((1-(methyl-sulfonyl)piperidine-4-yl)methyl)pyrrolidine-1-carboxylate (see Example 7, step (c)) according to the procedure of Example 7, step (d), followed by the procedure of Example 1, step (g).

[0321] 1 H NMR(400MHz,CD3OD) δ 7.46-7.38(m,1H),7.29-7.18(m,2H),7.09-7.01(m,1H),5.08(d,J=3.5Hz,1H),3.90(td,J=7.9,3.6Hz,1H),3.76-3.65(m,3H),2.8 2(s,3H),2.75(tdd,J=12.1,5.5,2.6Hz,2H),2.24-2.05(m,2H),1.97-1.64(m,6H),1.62-1.50(m,1H),1.31(qd,J=12.1,4.1Hz,2H).

[0322] Example 9: 1-(4-(((2S,5R)-5-((R)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-yl)ethane-1-one hydrochloride [ka] The title compound was prepared according to the procedure of Example 7, with acetyl chloride used in step (b), diastereomers separated by chromatography on silica gel, followed by reverse-phase preparative HPLC (XBridge Prep C18 5μm OBD column (30×100mm), 10% MeCN / 90% (0.01% AcOH in H2O) to 95% MeCN / 5% (0.01% AcOH in H2O) to form the salt according to the procedure of Example 1, step (g).

[0323] 1 1H NMR (400MHz, CD3OD) δ 7.42(td,J=7.9,5.9Hz,1H),7.31-7.21(m,2H),7.08(td,J=8.5,2.6Hz,1H) ,4.77(d,J=8.2Hz,1H),4.52(d,J=13.3Hz,1H),3.94(d,J=13.3Hz,1H),3.82 -3.72(m,1H),3.71-3.51(m,2H),3.15(d,J=13.1Hz,1H),2.66(d,J=13.1Hz ,1H),2.31-2.19(m,1H),2.12(s,3H),1.93-1.61(m,7H),1.33-1.05(m,2H).

[0324] Example 10: 1-(4-(((2S,5R)-5-((S)-(3-fluorophenyl)(hydroxy)methyl)pyrrolidine-2-yl)methyl)piperidine-1-yl)ethane-1-one hydrochloride [ka] The title compound was prepared according to the procedure of Example 7, with acetyl chloride used in step (b), diastereomers separated by chromatography on silica gel, followed by reverse-phase preparative HPLC (XBridge Prep C18 5μm OBD column (30×100mm), 10% MeCN / 90% (0.01% AcOH in H2O) to 95% MeCN / 5% (0.01% AcOH in H2O) to form the salt according to the procedure of Example 1, step (g).

[0325] 1H NMR(400MHz,CD3OD) δ 7.42(td,J=8.0,5.8Hz,1H),7.29-7.18(m,2H),7.05(td,J=8.5,2.6Hz,1 H),5.09(d,J=3.5Hz,1H),4.53(d,J=13.2Hz,1H),3.98(d,J=13.2Hz,1H), 3.91(td,J=7.9,3.7Hz,1H),3.78-3.67(m,1H),3.26-3.13(m,1H),2.75(t ,J=12.8Hz,1H),2.24-2.05(m,5H),1.99-1.63(m,7H),1.35-1.09(m,2H).

[0326] Examples 11 to 14 (a) Methyl(R)-6-(1-benzylpiperidine-3-ylidene)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate [ka] A mixture of methyl(R)-2-((tert-butoxycarbonyl)amino)-6-(dimethoxyphosphoryl)-5-oxohexanoate (see Example 1, step (a)) (1.06 g, 2.89 mmol), 1-benzylpiperidine-3-one (956 mg, 5.05 mmol), K2CO3 (1.60 g, 11.54 mmol), and MeCN (3.5 mL) was stirred at 50°C for 19 hours, cooled to room temperature, and concentrated. The residue was treated with NH4Cl (aqueous, saturated) and extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography to obtain the subtitle compound (698 mg, 56%).

[0327] (b) 1-(tert-butyl)2-methyl(2R,5S)-5-(piperidine-3-ylmethyl)pyrrolidine-1,2-dicarboxylate [ka] Pd-C (10%, 240 mg, 1.50 mmol) was added all at once to a solution of methyl(R)-6-(1-benzylpiperidine-3-ylidene)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (646 mg, 1.50 mmol) in 2,2,2-trifluoroethanol (7 mL). The stirred mixture was hydrogenated at 4 atm at room temperature for 19 hours, filtered through Celite, and concentrated. The residue was dissolved in CH2Cl2 (5 mL), sodium triacetoxyborohydride (607 mg, 2.86 mmol) was added, and the mixture was cooled in an ice bath. Me3SiCl (727 μL, 5.72 mmol) was added dropwise, the ice bath was removed, and the mixture was stirred at room temperature for 20 hours. NaOH (0.1 M in saturated aqueous solution of Na2CO3, 20 mL) was added, and the mixture was extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated. The residue was dissolved in ethyl acetate, washed three times with NaOH (0.1 M in saturated aqueous solution of Na2CO3), dried (Na2SO4), and concentrated. The residue was purified by chromatography to obtain the subtitle compound (698 mg, 56%).

[0328] (c) 1-(tert-butyl)2-methyl(2R,5S)-5-((1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1,2-dicarboxylate [ka] Mesyl chloride (83 μL, 1.07 mmol) was added dropwise at 0°C to a stirred mixture of 1-(tert-butyl)2-methyl(2R,5S)-5-(piperidine-3-ylmethyl)pyrrolidine-1,2-dicarboxylate (292 mg, 0.89 mmol), Et3N (150 μL, 1.07 mmol), and CH2Cl2 (3 mL). The mixture was stirred at 0°C for 1 hour and diluted with CH2Cl2. NaHCO3 (aqueous, saturated) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2, the combined extract was washed with brine, dried, and concentrated with (Na2SO4). The residue was purified by chromatography to obtain the subtitle compound (279 mg, 77%).

[0329] (d) tert-butyl(2R,5S)-2-((S)-(3-fluorophenyl)(hydroxy)methyl)-5-(((R)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1-carboxylate, tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)(hydroxy)methyl)-5-(((R)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1-carboxylate, tert-butyl(2R,5S)-2-((S)-(3-fluorophenyl)(hydroxy)methyl)-5-(((S)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1-carboxylate, and tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)(hydroxy)methyl)-5-(((S)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1-carboxylate [ka] The subtitle compound was prepared from 1-(tert-butyl)2-methyl(2R,5S)-5-((1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1,2-dicarboxylate according to the procedure of Example 1, steps (d) to (f). The isomers were separated using preparative chiral HPLC (DAICEL CHIRALPAK ID 250×30mm-5μm, 40mL / min, 10% iPrOH, 20% CH2Cl2, 70% heptane, λ262nm, 210nm).

[0330] Example 11: (S)-(3-fluorophenyl)((2R,5S)-5-(((R)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] The title compound was prepared from tert-butyl(2R,5S)-2-((S)-(3-fluorophenyl)-(hydroxy)methyl)-5-(((R)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1-carboxylate according to the procedure of Step (g) of Example 1.

[0331] [α] D 20 +21.7 (c1.0, MeOH).

[0332] 1 H NMR(400MHz,CD3OD) δ 7.42(td,J=7.9,5.8Hz,1H),7.27-7.18(m,2H),7.06(td,J=8.5,2.6Hz,1H),5.06(d,J=3.7Hz,1H),3.90(td,J=8.0,3.7Hz,1H),3.76-3.64(m, 1H),3.60-3.47(m,2H),2.92-2.84(m,1H),2.83(s,3H),2.63(dd,J=11. 7,9.1Hz,1H),2.26-2.03(m,2H),2.00-1.57(m,8H),1.27-1.16(m,1H).

[0333] Example 12: (R)-(3-fluorophenyl)((2R,5S)-5-(((R)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] The title compound was prepared from tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)-(hydroxy)methyl)-5-(((R)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1-carboxylate according to the procedure of Example 1, step (g).

[0334] [α] D 20 -35.3 (c1.0, MeOH).

[0335] 1H NMR(400MHz,CD3OD) δ 7.42(td,J=7.9,5.8Hz,1H),7.29-7.22(m,2H),7.08(td,J=8.5,2.6Hz,1H),4.76(d,J=8.2Hz,1H),3.78(q,J=8.4Hz,1H),3.70-3.60(m,1H) ,3.58-3.47(m,2H),2.91-2.84(m,1H),2.83(s,3H),2.61(dd,J=11.7,9.1Hz,1H),2.31-2.20(m,1H),1.97-1.57(m,9H),1.28-1.15(m,1H).

[0336] Example 13: (S)-(3-fluorophenyl)((2R,5S)-5-(((S)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] The title compound was prepared from tert-butyl(2R,5S)-2-((S)-(3-fluorophenyl)-(hydroxy)methyl)-5-(((S)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1-carboxylate according to the procedure of Example 1, step (g).

[0337] [α] D 20 +45.0 (c1.0, MeOH).

[0338] 1H NMR(400MHz,CD3OD) δ 7.42(td,J=7.9,5.8Hz,1H),7.28-7.19(m,2H),7.06(td,J=8.5,2.6Hz,1H),5.0 7(d,J=3.7Hz,1H),3.89(td,J=8.0,3.8Hz,1H),3.74-3.64(m,1H),3.62-3.56(m, 1H),3.54-3.46(m,1H),2.92-2.84(m,1H),2.83(s,3H),2.64(dd,J=11.6,8.3Hz, 1H),2.23-2.04(m,2H),1.92-1.70(m,7H),1.68-1.56(m,1H),1.32-1.17(m,1H).

[0339] Example 14: (R)-(3-fluorophenyl)((2R,5S)-5-(((S)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] The title compound was prepared from tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)-(hydroxy)methyl)-5-(((S)-1-(methylsulfonyl)piperidine-3-yl)methyl)pyrrolidine-1-carboxylate according to the procedure of Example 1, step (g).

[0340] [α] D 20 -18.7 (c0.5, MeOH).

[0341] 11H NMR (400MHz, CD3OD) δ δ 7.42(td,J=8.1,5.9Hz,1H),7.30-7.21(m,2H),7.08(td,J=8.5,2.6Hz,1H),4. 75(d,J=8.2Hz,1H),3.77(q,J=8.5Hz,1H),3.69-3.60(m,1H),3.59-3.53(m,1H) ,3.53-3.46(m,1H),2.92-2.84(m,1H),2.83(s,3H),2.64(dd,J=11.6,8.3Hz,1 H),2.30-2.19(m,1H),1.93-1.68(m,8H),1.68-1.56(m,1H),1.30-1.16(m,1H).

[0342] Examples 15 and 16 (a) tert-butyl(2R,5S)-2-((S)-(3-fluorophenyl)(hydroxy)methyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxylate and tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)(hydroxy)methyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxylate [ka] The subtitle compound was prepared from methyl(R)-2-((tert-butoxycarbonyl)-amino)-6-(dimethoxyphosphoryl)-5-oxohexanoate and tetrahydro-4H-pyran-4-one according to the procedure of Example 1, steps (b) to (f). The isomers were separated using preparative chiral HPLC (DAICEL CHIRALPAK IC 250×30 mm-5 μm, 40 mL / min, 15% iPrOH, 85% heptane, λ261 nm, 210 nm).

[0343] Example 15: (S)-(3-fluorophenyl)((2R,5S)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] The title compound was prepared from tert-butyl(2R,5S)-2-((S)-(3-fluorophenyl)(hydroxy)methyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxylate according to the procedure of Step (g) of Example 1.

[0344] 1 H NMR(400MHz,CD3OD) δ 7.39-7.25(m,1H),7.22-7.07(m,2H),7.03-6.90(m,1H),4.98(d,J=3.7Hz,1H),3.89-3.75(m,3H ),3.67-3.53(m,1H),3.40-3.27(m,2H),2.17-1.91(m,2H),1.76-1.50(m,7H),1.29-1.10(m,2H).

[0345] Example 16: (R)-(3-fluorophenyl)((2R,5S)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-2-yl)methanol hydrochloride [ka] The title compound was prepared from tert-butyl(2R,5S)-2-((R)-(3-fluorophenyl)(hydroxy)methyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine-1-carboxylate according to the procedure of Step (g) of Example 1.

[0346] 1 H NMR(400MHz,CD3OD) δ 7.50-7.36(m,1H),7.33-7.20(m,2H),7.14-7.01(m,1H),4.77(d,J=8.3Hz,1H),3.98-3.88(m,2H),3.77(q,J =8.5Hz,1H),3.71-3.60(m,1H),3.47-3.37(m,2H),2.30-2.18(m,1H),1.90-1.58(m,8H),1.38-1.20(m,2H).

[0347] Formulation Examples The pharmaceutical composition is obtained by mixing a therapeutically effective amount of the compound of formula I (such as the compounds of Examples 1-16) with a suitable amount of a suitable excipient. The resulting mixture is molded to form a tablet. Optionally, a suitable coating is applied to the tablet.

[0348] Biological examples L6 myoblasts were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 50 U / mL penicillin, 50 μg / mL streptomycin, and 1 g / L glucose supplemented with 10 mM HEPES. The cells were placed in 24-well plates at a rate of 1 × 10⁶ cells. 5 Cells were seeded at a concentration of cells / mL. After reaching 90% confluence, the cells were grown in a medium containing 2% FBS for 7 days to differentiate them into myotubes.

[0349] Biological Example 1: Glucose Uptake Differentiated L6-myotubes were subjected to serum starvation overnight in a medium containing 0.5% fatty acid-free BSA, resulting in a final concentration of 1 × 10⁶. -5 The cells were stimulated with M agonist. After 1 hour and 40 minutes, the cells were washed twice with warm glucose-free medium or PBS, and the other portion of the agonist was added to glucose-free medium. After 20 minutes, the cells were stimulated with 50 nM agonist. 3 After further exposure to H-2-deoxyglucose for 10 minutes, the cells were washed three times with ice-cold glucose-free medium or PBS and lysed in 0.2 M NaOH (400 μL / well) at 60°C for 1 hour. The cell lysates were mixed with 4 mL of scintillation buffer (Emulsifier Safe, Perkin Elmer), and radioactivity was detected using a β-counter (Tri-Carb 4810TR, Perkin Elmer). The activity of each compound was compared to the activity of isoproterenol. If a 10 μM compound showed more than 75% of the activity of 10 μM isoproterenol, the activity was indicated as +++; if it was between 75% and 50%, it was indicated as ++; if it was between 50% and 25%, it was indicated as +; and if it was less than 25%, it was indicated as -.

[0350] Biological Example 2: Measurement of Intracellular cAMP Levels Differentiated cells were subjected to serum starvation overnight and then injected into a stimulation buffer (HBSS supplemented with 1% BSA, 5 mM HEPES, and 1 mM IBMX, pH 7.4) to a final concentration of 1 × 10⁶. -5 Cells were stimulated with agonist M for 15 minutes. The culture medium was aspirated, and 100 μL of 95% EtOH was added to each well of a 24-well plate. Cells were maintained overnight at -20°C. The EtOH was evaporated, and 500 μL of lysis buffer (1% BSA, 5 mM HEPES, and 0.3% Tween-20, pH 7.4) was added to each well. The plates were maintained at -80°C for 30 minutes, then at -20°C, until detection day when the samples were thawed. Intracellular cAMP levels were detected using the AlphaScreen cAMP kit (6760635D from Perkin Elmer). The activity of each compound was compared to the activity of isoproterenol. If a 10 μM compound exhibits more than 75% of the activity of 10 μM isoproterenol, the activity is indicated as +++; if it is between 75% and 50%, it is indicated as ++; if it is between 50% and 25%, it is indicated as +; and if it is less than 25%, it is indicated as -.

[0351] The following results were obtained using the assays described in Biological Examples 1 and 2. [Table 1]

[0352] Biological Example 3: Glucose uptake in the presence of the β2-antagonist ICI-118,551 Confirmation that glucose uptake is mediated by the activation of β2-adrenergic receptors can be provided by observing a reduction (or absence) of glucose uptake in the presence of a β2-antagonist (ICI-118,551).

[0353] Differentiated L6-myotubes were subjected to serum starvation overnight in a medium containing 0.5% fatty acid-free BSA, resulting in a final concentration of 1 × 10⁶. -5 Cells were incubated with the M β2-adrenergic receptor antagonist ICI-118,551 for 30 minutes. The cells were then incubated at a final concentration of 1 × 10⁶.-5 The cells were stimulated with the compound of the present invention (M). After 1 hour and 40 minutes, the cells were washed twice with warm glucose-free medium or PBS, and the additional portion of the compound of the present invention and the antagonist were added. After 20 minutes, the cells were 50 nM 3 After exposure to H-2-deoxyglucose for 10 minutes, the cells are washed three times with ice-cold glucose-free medium or PBS, and lysed in 0.2 M NaOH (400 μL / well) at 60°C for 1 hour. The cell lysates are mixed with 4 mL of scintillation buffer (Emulsifier Safe, Perkin Elmer), and radioactivity is detected with a β-counter (Tri-Carb 4810TR, Perkin Elmer). The activity of each compound is compared to the activity of isoproterenol. If the compound shows activity greater than 75% of the activity of 10 μM isoproterenol, the activity is indicated as +++; if it is between 75% and 50%, it is indicated as ++; if it is between 50% and 25%, it is indicated as +; and if it is less than 25%, it is indicated as -.

Claims

1. Compound of formula I 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, Q １ ~Q ５ Each of these independently represents a carbon atom, a heteroatom, or a direct bond, and therefore Q １ ~Q ５ A ring containing, One or more Y １ Phenyl, which is optionally substituted, or One or more Y ２ This represents a 5-membered or 6-membered heteroaryl that is optionally substituted, Each Y １ independently represents halo, R ａ１ , -CN, -N ３ , -NR ｂ１ R ｃ１ , or -OR ｄ１ and represents Each Y ２ However, they became independent, Hello, R ａ２ -CN, -N ３ , -NR ｂ２ R ｃ２ , or -OR ｄ２ This represents, Ring A represents a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms selected from N and O. When present on the carbon atoms of ring A, each Z independently forms a halo, R ａ３ , CN, -N ３ , -N(R ｂ３ ) R ｃ３ , -OR ｄ３ , -S(O) ｐ R ｅ３ , -S(O) ｑ N(R) ｆ３ ) R ｇ３ , -N(R ｈ３ ) S(O) ｔ R ｉ３ , or = represents O, When present on the nitrogen atom of ring A, each Z independently has R ａ３ , -S(O) ｐ R ｅ３ , or -S(O) ｑ N(R) ｆ３ ) R ｇ３ This represents, Each R ａ１ , R ａ２ , R ａ３ , R ｅ３ , and R ｉ３ However, Halo and G １ C is independently substituted by one or more elements, each of which is arbitrarily substituted. １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Representing Alkinnil, Each R ｂ１ , R ｂ２ , R ｂ３ , R ｃ１ , R ｃ２ , R ｃ３ , R ｄ１ , R ｄ２ , R ｄ３ , R ｆ３ , R ｇ３ , and R ｈ３ However, they became independent, H, or Halo and G ２ C is independently substituted by one or more elements, each of which is arbitrarily substituted. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Does it represent alkinyl? Alternatively, R ｂ１ and R ｃ１ , R ｂ２ and R ｃ２ , R ｂ３ and R ｃ３ , and / or R ｆ３ and R ｇ３ Any of these can be linked together to form a 4-6 membered ring with the nitrogen atom to which they are linked, the ring optionally containing one further heteroatom, and the ring optionally substituted by a halo or one or more halos. １－３ It is optionally substituted with one or more groups independently selected from alkyl and =O, Each G １ and G ２ However, R ａ４ -CN, -N ３ , -N(R ｂ４ ) R ｃ４ , -OR ｄ４ , -S(O) ｐ R ｅ４ , -S(O) ｑ N(R) ｆ４ ) R ｇ４ , or = represents O, Each R ａ４ is independently optionally substituted by one or more groups selected from halo, R ａ５ , -CN, -N ３ , -N(R ｂ５ )R ｃ５ , -OR ｄ５ , -S(O) ｐ R ｅ５ , -S(O) ｑ N(R ｆ５ )R ｇ５ , or -N(R ｈ５ )S(O) ｔ R ｉ５ and represents phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by one or more groups selected from​ Each R ｂ４ , R ｃ４ , R ｄ４ , R ｆ４ , and R ｇ４ However, C is independently and optionally substituted by H, or one or more halos or -CNs. １－６ Alkyl, C ２－６ Alkenil, or C ２－６ Representing Alkinnil, Each R ｅ４ However, each is independently and optionally substituted by one or more halos or -CNs, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Does it represent alkinyl? Alternatively, R ｂ４ and R ｃ４ And / or R ｆ４ and R ｇ４ Any of these can be linked together to form a 4-6 membered ring with the nitrogen atom to which they are linked, the ring optionally containing one further heteroatom, and the ring optionally substituted by a halo or one or more halos. １－３ It is optionally substituted with one or more groups independently selected from alkyl and =O, Each R ａ５ , R ｅ５ , and R ｉ５ However, C is independently and optionally substituted by one or more halos. １－３ C is optionally substituted with one or more groups independently selected from alkyl and =O. １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Representing Alkinnil, Each R ｂ５ , R ｃ５ , R ｄ５ , R ｆ５ , R ｇ５ , and R ｈ５ However, they became independent, H, or C is optionally replaced by one or more halos. １－３ C is optionally substituted with one or more groups independently selected from alkyl and =O. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Does it represent alkinyl? Alternatively, R ｂ５ and R ｃ５ , and / or R ｆ５ and R ｇ５ Any of these can be linked together to form a 4-6 membered ring with the nitrogen atom to which they are linked, the ring optionally containing one further heteroatom, and the ring optionally substituted by a halo or one or more halos. １－３ It is optionally substituted with one or more groups independently selected from alkyl and =O, Each p independently represents 0, 1, or 2. Each q independently represents either 1 or 2. Each t independently represents either 1 or 2. m represents a value between 0 and 3. n represents a value between 0 and 2. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein r represents 0 to 6.

2. Each Y １ and Y ２ However, R ａ１ The compound according to claim 1, representing a halo or -CN.

3. Each Y １ and Y ２ However, the compound according to any one of the prior claims, which independently represents F.

4. Q １ ~Q ５ The ring including, One or more Y １ Phenyl, which is optionally substituted, or One or more Y ２ A compound according to any one of the prior claims, representing a six-membered heteroaryl that is optionally substituted with .

5. Q １ ~Q ５ The ring including, One or more Y １ Phenyl, which is optionally substituted, or One or more Y ２ A compound according to any one of the prior claims, representing a pyridyl optionally substituted with a pyridyl.

6. A compound according to any one of the prior claims, wherein r represents 0.

7. A compound according to any one of the prior claims, wherein n represents 1.

8. A compound according to any one of the prior claims, wherein m represents 1.

9. A compound according to any one of claims 1 to 8 for use in medical applications.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, and optionally one or more pharmaceutically acceptable adjuvants, diluents, and / or carriers.

11. A compound according to any one of claims 1 to 8, for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

12. Use of the compound according to any one of claims 1 to 8 for the manufacture of a drug for the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

13. A method for treating hyperglycemia or a disorder characterized by hyperglycemia, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 8 to a patient in need thereof.

14. A compound, method, or use for use according to any one of claims 11 to 13, wherein the hyperglycemia or disorder characterized by hyperglycemia is in a patient exhibiting severe insulin resistance, or is characterized by a patient exhibiting severe insulin resistance.

15. A compound, method, or use for use according to any one of claims 11 to 14, wherein the disorder characterized by hyperglycemia is selected from the group consisting of type 2 diabetes, Rabson-Mendenhall syndrome, Donahue syndrome (dwarfism), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.

16. A compound according to any one of claims 1 to 8, for use in the treatment of non-alcoholic fatty liver disease.

17. Use of the compound according to any one of claims 1 to 8 in the manufacture of a drug for the treatment or prevention of non-alcoholic fatty liver disease.

18. A method for treating or preventing non-alcoholic fatty liver disease, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 8 to a patient in need thereof.

19. Treatment is β ２ A compound according to any one of claims 1 to 8, for use in the treatment of a disease or disorder mediated by the activation of adrenaline receptors.

20. Treatment is β ２ Use of the compound according to any one of claims 1 to 8 in the manufacture of a drug for use in the treatment of a disease or disorder mediated by the activation of adrenaline receptors.

21. Treatment is β ２ A method for treating a disease or disorder mediated by the activation of adrenaline receptors, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 8 to a patient in need thereof.

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