Cyclohexyl or heterocycloalkyl β-hydroxyalkylamines for use in the treatment of hyperglycemia and disorders characterized by hyperglycemia

Abstract

Compounds of formula I are provided herein. [Formula 1] TIFF2026514427000084.tif28165, Q 1 ~Q 5 , R 1 Rings A, Z, and n have the meanings defined herein. Their medical uses are also provided herein.

Description

[Technical Field]

[0001] This invention relates to novel compounds and compositions, and their use in medicine, for example, in the treatment of hyperglycemia and disorders characterized by hyperglycemia (e.g., type 2 diabetes). 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 via significant cAMP release. Such compounds are also used in the treatment of other diseases or disorders, which are also achieved through the activation of β2 adrenergic receptors. [Background technology]

[0002] Any listing or discussion of previously published literature in this specification should not necessarily be construed as an endorsement that such literature is 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 damage to the heart and is strongly associated with heart attacks and death in individuals 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 patients experience a very low level (or, in extreme cases, non-significant) response to insulin. Several syndromes exist that are characterized by SIR, including Rabson-Mendenhall syndrome, Donahue syndrome (Fairy syndrome), 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 genetic causes, 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. Thus, 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 (i.e., insulin-dependent diabetes mellitus) and type 2 (insulin-independent diabetes mellitus), 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 inhibiting 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," meaning 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 insulin release 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-dependent 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 muscle cells with energy-rich substrates. Thus, 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: α1-, α2-, and β-ARs, each with different expression patterns and pharmacological profiles. 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 concentration (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 GLUT4 transposition from intracellular storage to the cell membrane. It is known that GLUT4 transposition is induced by stimulation of β2-adrenergic receptors.

[0016] Thus, for treating conditions involving dysregulation of glucose homeostasis and glucose uptake in mammals, such as type 2 diabetes, one approach would be to activate β2-adrenergic receptors to move GLUT4 to the cell membrane, thereby promoting glucose uptake into skeletal muscle and normalizing systemic glucose homeostasis. Furthermore, therapies that do not involve cAMP-mediated signaling would be advantageous as they would lead to a more favorable side effect profile. [Modes for carrying out the invention]

[0017] We have surprisingly discovered that certain cyclohexyl or heterocycloalkyl β-hydroxyalkylamines that act as agonists of the β2-adrenergic receptor increase glucose uptake in skeletal muscle.

[0018] Furthermore, this effect is not mediated by significant cAMP release and it has been found that it can reduce many of the side effects (such as tachycardia, palpitations, tremors, sweating, agitation, etc.) commonly seen with conventional β2-adrenergic agonists.

[0019] The use of such compounds in medicine presents a promising strategy for the treatment of conditions described herein, such as conditions characterized by elevated blood glucose levels (i.e., hyperglycaemia), such as type 2 diabetes.

[0020] The compounds of the present invention In a first aspect of the present 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 embodiment of the present invention (for example, a compound of formula I in the first embodiment of the present invention) includes references to all embodiments and their specific features, and that further embodiments may be formed by combining those embodiments and specific features.

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

[0023] Examples of pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can 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 can 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] Examples of specific acid addition salts include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, 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, suberinate, sebacin) This includes salts (e.g., fumarates, malates, maleates, hydroxymaleates, hyperinates, phthalates, or terephthalates), halide salts (e.g., hydrochlorides, hydrobromitates, or hydroiodides), sulfonates (e.g., benzenesulfonates, methyl-, bromo-, or chlorobenzenesulfonates, 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 in relation to the hemi tartrate of the compound of formula I means that the stoichiometry of the compound of formula I and the tartrate in the salt is 1:0.5 (i.e., equivalent to 2:1).

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

[0027] Specific pharmaceutically acceptable salts that may be mentioned include hydrochloride or acetate salts, such as acetate.

[0028] More specific pharmaceutically acceptable salts include hydrochloride salts.

[0029] To avoid any doubt, it should be added that the compounds of the first aspect of the present invention may exist as solids, and therefore the scope of the present invention includes all of its amorphous, crystalline, and partially crystalline forms, and may also exist as oils. When 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.

[0030] 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 with respect to each individual double bond. All such isomers and mixtures thereof are within the scope of the present invention.

[0031] Compounds according to the first aspect of the present invention may also exhibit tautomerism. All tautomers and mixtures thereof are included within the scope of the present invention.

[0032] 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. Diastereomers may be separated using conventional techniques, e.g., chromatography or fractional crystallization. Various stereoisomers (i.e., enantiomers) may 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 may be obtained from a appropriately optically active starting material (i.e., the "chiral pool" method) under conditions that will not cause racemization or epimerization, 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 with a suitable starting material and 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.

[0033] 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).

[0034] Unless otherwise specified, C as defined herein 1-z Alkyl groups (where z is the upper limit of the range) may be linear, branched, and / or cyclic (and therefore C) if there are a sufficient number of carbon atoms (i.e., at least 3). 3-z - May form a cycloalkyl group. If a sufficient number of carbon atoms are present, such a group may also constitute part of a cyclic structure. Examples of partially cyclic alkyl groups 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) or spirocyclic.

[0035] To avoid any ambiguity, it should be added that alkyl groups may be linear (also called linear), branched (also called branched-chain), and / or cyclic. Furthermore, alkyl groups may be linear (also called linear), branched (also called branched-chain).

[0036] Unless otherwise specified, C as defined herein 2-z The alkenyl group (where z is the upper limit of the range) may be a straight chain, or it may be a branched chain if there are a sufficient number of carbon atoms (i.e., at least 3).

[0037] Unless otherwise specified, C as defined herein 2-z The alkynyl group (where z is the upper limit of the range) may be a straight chain, or it may be a branched chain if there are a sufficient number of carbon atoms (i.e., at least four).

[0038] To avoid any doubt, a person 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.

[0039] As used herein, the term heterocyclyl may refer to non-aromatic monocyclic and bicyclic heterocyclyl groups (these groups may be further cross-linked) in which at least one (e.g., 1 to 4) atoms in the ring system is non-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, forming heterocycloalkyls, or unsaturated, containing one or more carbon-carbon bonds, preferably carbon-heteroatom bonds or heteroatom-heteroatom double and / or triple bonds, e.g., C 2-z (For example C4-z ) Heterocycloalkenyl group (where z is the upper limit of the range) or C 7-z It forms a heterocycloalkynyl group. 2-z Examples 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, These include isothiazolidinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxyranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, quinuclidinyl, sulforanyl, 3-sulforenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridinyl (1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, etc.), thietanyl, thyranyl, thioranyl, tetrahydrothiopyranyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl, etc. 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, that cyclic compound may bond via a single atom on the heterocyclyl group, forming a so-called "spiro" compound. The bonding site of the heterocyclyl group may be via any atom in the ring system containing further heteroatoms (such as a nitrogen atom) where appropriate, or via an atom on a condensed carbocyclic ring that may exist as part of the ring system. The heterocyclyl group may be in N- or S-oxidized form.

[0040] As described herein, ring A represents a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl containing one or two heteroatoms (e.g., only one heteroatom) selected from N (nitrogen) or O (oxygen).

[0041] In some embodiments, when ring A represents a 4- to 7-membered heterocycloalkyl group, ring A does not contain any other heteroatoms in its ring structure; that is, the only heteroatoms in ring A are selected from N and O.

[0042] In certain embodiments, ring A represents a 4- to 7-membered heterocycloalkyl group, for example, a 5- to 6-membered heterocycloalkyl group.

[0043] Various heterocycloalkyl groups, such as dioxolanil (including 1,3-dioxolanil), dioxanil (including 1,3-dioxanil and 1,4-dioxanil), imidazolidinil, morpholinil, piperazinil, piperidinil (including 2-, 3- or 4-piperidinil), pyrazolidinil, pyrrolidinonil, pyrrolidinil (including 2- or 3-pyrrolidinil), tetrahydropyranil, and tetrahydrofuryl, will be well known to those skilled in the art.

[0044] In certain embodiments, ring A may contain one heteroatom 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.

[0045] In another 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.

[0046] 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.

[0047] Furthermore, in certain embodiments, ring A may be a six-membered heterocycloalkyl group that is optionally substituted with one or more (e.g., one) Z groups.

[0048] More specific heterocycloalkyl groups that can represent ring A include piperidinyl, for example, piperidin-3-yl or piperidin-4-yl (using the standard numbering system with the nitrogen atom at position 1).

[0049] In certain embodiments, ring A represents a 4- to 7-membered cycloalkyl group, for example, a 5- to 6-membered cycloalkyl group. In even more specific embodiments, ring A represents a 6-membered cycloalkyl group (i.e., cyclohexyl).

[0050] To avoid any doubt, it should be added that, depending on the circumstances, ring A may be substituted with a number of Z groups as defined herein. Those skilled in the art will understand that the (maximum) number and position of such substituents are determined by the properties of the ring, such as the size and degree of saturation. Furthermore, those skilled in the art will understand that such substituents may be located on preferred moieties within ring A, such as preferred C (carbon) or N (nitrogen) moieties.

[0051] In certain embodiments, the compound of formula I may be a compound of formula IX or IY. [ka] In the formula, Q 1 ~Q 5 , R 1 The rings containing , Z, and n are as defined for the compound of formula I (including all its embodiments), where X represents C (carbon) or N (nitrogen), m1 and m2 independently represent 0 to 2, m3 represents 0 to 3, and m4 represents 0 to 2.

[0052] In a particular embodiment, the sum of m1 and m2 is at least 4.

[0053] In certain embodiments, the sum of m3 and m4 is at least 4.

[0054] As described herein, Q 1 ~Q 5 A ring containing (which may be called ring Q) is phenyl, or one or more Y (i.e., one or more Y 1 Or Y 2 This represents a 5-member or 6-member heteroaryl compound that may be optionally substituted with ).

[0055] Thus, a person skilled in the art would know Q 1 ~Q 5 teeth, - Each represents a carbon atom, forming a phenyl group, or - Together, carbon atoms, one or more heteroatoms, and Q 1 ~Q 5 Those skilled in the art will understand that if the ring containing the group is five-membered, it represents either a direct bond or forms a suitable heteroaryl group known to them.

[0056] Thus, a person skilled in the art can understand Q 1 ~Q 5 When representing this, the ring contains one or more heteroatoms in addition to carbon atoms, thereby forming a suitable heteroaryl group well known to those skilled in the art. Furthermore, those 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., there is no base).

[0057] To avoid any misunderstanding, I would like to add that Q 1 ~Q 5 When a ring containing a group is depicted with a circle around its interior (for example, as in formula I), it is understood to indicate that the ring is aromatic.

[0058] To avoid any doubt, in this specification, references to heteroatoms have the usual meanings understood by those skilled in the art. Specific heteroatoms include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen, and sulfur (e.g., oxygen, nitrogen, and sulfur).

[0059] To avoid ambiguity, it should be added that references to polycyclic (e.g., bicyclic or tricyclic) groups (e.g., when used in reference to cycloalkyl groups) refer to cyclic systems in which at least two cleavages are required 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 a minimum of two cleavages are required to convert the rings into a straight chain). To avoid ambiguity, it should be added that the term bicyclic (e.g., when used in reference to 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 it may refer to a group in which two non-adjacent atoms are linked by an alkylene group, the latter of which is sometimes called a bridging group.

[0060] The present invention also includes 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 specified herein are intended to be within the scope of the compounds of the present invention. Accordingly, the compounds of the present invention also include deuterated compounds, i.e., compounds in which one or more hydrogen atoms are replaced by hydrogen isotopes of mass.

[0061] To avoid any doubt, it should be added that if two or more substituents in the compound of the present invention may be identical, the actual identity of each substituent is never 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, those halo groups may be the same or different. Similarly, one or more R a There exists a C that is independently substituted with one or more G groups. 1-6 When representing alkyl groups, the identity of each G is independent of each other.

[0062] Those skilled in the art will understand that the compounds of the present invention, which are the subject of this invention, include stable compounds. 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.

[0063] All embodiments and specific features of the present invention described herein may be adopted alone or in combination with other embodiments and / or specific features described herein (and thus describe further specific embodiments and specific features disclosed herein) without departing from the disclosure of the present invention.

[0064] In certain embodiments, there is a caveat that the compound of formula I is not as shown below. 4-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]cyclohexane-1-ol, (αR)-α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, α-[[(3-aminocyclobutyl)amino]methyl]benzenemethanol, (αR)-α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-3-pyridinemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-4-pyridinemethanol, α-[[(4-methylcyclohexyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, (αR)-α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, α-[[(trans-4-methylcyclohexyl)aminomethyl]benzenemethanol, α-[[(3-aminocyclopentyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclohexyl)amino]methyl]benzenemethanol, α-[[(3-aminocyclohexyl)amino]methyl]benzenemethanol, α-[[(4-aminocyclohexyl)amino]methyl]benzenemethanol, α-[[(3-fluorocyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]-3-pyridinemethanol, (αR)-α-[[(3-fluorocyclobutyl)amino]methyl]benzenemethanol, α-[[(4-methylcycloheptyl)amino]methyl]benzenemethanol, (αR)-α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, (αS)-α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, α-[[(4-hydroxycyclohexyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclopentyl)amino]methyl]-3-pyridinemethanol, α-[[(3-methylcyclopentyl)amino]methyl]-4-pyridinemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(4-methylcyclohexyl)amino]methyl]-4-pyridinemethanol, α-[[(3-methylcyclohexyl)amino]methyl]-4-pyridinemethanol, (αR)-α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, (αS)-α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-4-piperidinyl)amino]methyl]benzenemethanol, 5-[(2-hydroxy-2-phenylethyl)amino]cyclooctanol, α-[[(3-fluorocyclobutyl)amino]methyl]-3-pyridinemethanol, α-[[(1-methyl-3-piperidinyl)aminomethyl]benzenemethanol, α-[[(1-methyl-3-azetidinyl)amino]methyl]-3-pyridinemethanol, α-[[(Hexahydro-1-methyl-1H-azepine-4-yl)aminomethyl]benzenemethanol, α-[[(3-fluorocyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]-4-pyridinemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]-3-pyridinemethanol, α-[[(1-methyl-4-piperidinyl)amino]methyl]benzenemethanol hydrochloride, α-[[(1-methyl-3-azetidinyl)amino]methyl]-2-pyridinemethanol, 2-((1-benzylpiperidine-4-yl)amino)-1-phenylethanol, 4-(1-hydroxy-2-((1-methylpiperidine-4-yl)aminoethyl)phenol, 4-(2-((1-benzylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 4-(2-((1-butylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 3-(2-((1-butylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-((1-(2-methoxyethyl)piperidine-4-yl)aminoethyl)phenol, or 4-(1-hydroxy-2-((1-phenethylpiperidine-4-yl)aminoethyl)phenol.

[0065] In certain embodiments, the compound of formula I is not one of the following compounds, provided that the conditions (A) to (M) below are met. (A) 4-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]cyclohexane-1-ol, (B) (αR)-α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, α-[[(3-aminocyclobutyl)amino]methyl]benzenemethanol, (αR)-α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-3-pyridinemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-4-pyridinemethanol, α-[[(4-methylcyclohexyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, (αR)-α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, α-[[(trans-4-methylcyclohexyl)aminomethyl]benzenemethanol, α-[[(3-aminocyclopentyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclohexyl)amino]methyl]benzenemethanol, α-[[(3-aminocyclohexyl)amino]methyl]benzenemethanol, α-[[(4-aminocyclohexyl)amino]methyl]benzenemethanol, α-[[(3-fluorocyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]-3-pyridinemethanol, (αR)-α-[[(3-fluorocyclobutyl)amino]methyl]benzenemethanol, α-[[(4-methylcycloheptyl)amino]methyl]benzenemethanol, (αR)-α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, (αS)-α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, α-[[(4-hydroxycyclohexyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclopentyl)amino]methyl]-3-pyridinemethanol, α-[[(3-methylcyclopentyl)amino]methyl]-4-pyridinemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(4-methylcyclohexyl)amino]methyl]-4-pyridinemethanol, α-[[(3-methylcyclohexyl)amino]methyl]-4-pyridinemethanol, (αR)-α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, (αS)-α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, 5-[(2-hydroxy-2-phenylethyl)amino]cyclooctanol, α-[[(3-fluorocyclobutyl)amino]methyl]-3-pyridinemethanol, α-[[(1-methyl-3-piperidinyl)aminomethyl]benzenemethanol, α-[[(1-methyl-3-azetidinyl)amino]methyl]-3-pyridinemethanol, α-[[(Hexahydro-1-methyl-1H-azepine-4-yl)aminomethyl]benzenemethanol, α-[[(3-fluorocyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]-4-pyridinemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]-3-pyridinemethanol, α-[[(1-methyl-3-azetidinyl)amino]methyl]-2-pyridinemethanol, (C) α-[[(1-methyl-4-piperidinyl)amino]methyl]benzenemethanol, 2-((1-benzylpiperidine-4-yl)amino)-1-phenylethanol, 4-(1-hydroxy-2-((1-methylpiperidine-4-yl)aminoethyl)phenol, 4-(2-((1-benzylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 4-(2-((1-butylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 3-(2-((1-butylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-((1-(2-methoxyethyl)piperidine-4-yl)aminoethyl)phenol, or 4-(1-hydroxy-2-((1-phenethylpiperidine-4-yl)aminoethyl)phenol, (D) [ka] (E) [ka] (F) [ka] (G) [ka] (H) [ka] (J) [ka] (K)

Chem.

Chem.

Chem.

[0066] For the sake of avoiding any ambiguity, it is noted that the ring containing Q 1 ~Q 5 (also referred to herein as ring Q) represents phenyl optionally substituted with one or more Y 1 or 5- or 6-membered heteroaryl optionally substituted with one or more Y 2 .

[0067] Various heteroaryl groups, such as pyridinyl, pyridonyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, etc., 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).

[0068] In certain embodiments, when representing heteroaryl, the ring containing Q 1 ~Q 5 may contain one or more (e.g., one or two, e.g., one) heteroatoms, which may be selected from O, S, and N (e.g., from O and N, e.g., N). For example, the ring Q as defined herein may contain one heteroatom that may be selected from O, S, and N (e.g., from O and N, e.g., N).

[0069] In certain embodiments, when representing heteroaryl, the ring containing Q 1~Q 5 The ring containing Q may also be a 6-membered heteroaryl. Thus, Q 1 ~Q 5 A ring containing Y is one or more (e.g., one) Y 1 Phenyl, or one or more (e.g., one) Y which may be optionally substituted. 2 This can represent a 5-member or 6-member heteroaryl that may be optionally substituted.

[0070] Q 1 ~Q 5 A more specific heteroaryl group representing a ring containing this group is pyridinyl, for example, pyridine-3-yl (using the standard numbering system with the nitrogen atom at position 1).

[0071] In certain embodiments, Q 1 ~Q 5 The ring containing is One or more (for example, one) Y 1 Phenyl, which may be optionally substituted with, or One or more (for example, one) Y 2 This may represent pyridyl which may be optionally substituted.

[0072] Furthermore, in a specific embodiment, Q 1 ~Q 5 The ring containing is One or more (for example, one) Y 1 Phenyl, which may be optionally substituted with, or One or more (for example, one) Y 2 This may represent pyridyl-3-yl, which may be optionally substituted.

[0073] Thus, in certain embodiments, the compound of formula IX may be represented as the compound of formula IA or IB. [ka] In the formula, R 1 , Z, Y 1 , Y 2m1, m2, and n are as defined for the compound of formula IX (including all its embodiments), v represents 0 to 5, and w represents 0 to 4.

[0074] To avoid any doubt, let me add that Q provided in formulas IA and IB (and their further embodiments) 1 ~Q 5 The ring structure including can also be applied to formula I (including all its embodiments).

[0075] To avoid any misunderstanding, I would like to add that Q 1 ~Q 5 A ring containing a number of Y, as defined herein, depending on the context. 1 Base or Y 2 The ring may be substituted with a group. Those skilled in the art will understand that the (maximum) number and position of such substituents are determined by the properties of the ring, such as the ring size and degree of saturation. Furthermore, those skilled in the art will understand that such substituents may be located on a suitable moiety within the ring Q, for example, a suitable carbon (C) moiety.

[0076] In certain embodiments, Q 1 ~Q 5 The ring containing may have up to two (i.e., 0 to 2) Y elements as needed. 1 Base or Y 2 It is substituted with the base.

[0077] Furthermore, in a specific embodiment, Q 1 ~Q 5 The ring containing may have up to one (i.e., zero or one) Y elements as needed. 1 Base or Y 2 It is substituted with the base.

[0078] Furthermore, in a specific embodiment, Q 1 ~Q 5 The ring containing one Y may, if necessary 1 Base or Y 2substituted with a base (i.e., it is necessary to be substituted) (i.e., in the compound of formula IA, v is 1, and in the compound of formula IB, w is 1).

[0079] In certain embodiments, the point of attachment to the essential -CH(OH)- moiety is taken as the 1-position, and at least one (or, if there is only one such group, that) Y 1 group or Y 2 group may, optionally, be located at the 2-position or 3-position (which may also be referred to as the ortho- and meta- positions, respectively).

[0080] In certain embodiments, the ring containing Q 1 ~Q 5 may represent phenyl substituted with one or more (e.g., one) Y groups, or 1 6-membered heteroaryl substituted with one or more (e.g., one) Y groups. 2

[0081] In a more particular embodiment, the ring containing Q 1 ~Q 5 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​Thus, in certain embodiments, compounds of formula IA and IB may be represented as compounds of formula IA' and IB', respectively.

[0084] [ka] In the formula, R 1 , Z, Y 2 n, m1, and m2 are as defined for compounds of formula IX (such as compounds of formulas IA and IB; including all embodiments thereof), where Y 1a and Y 1b On the other hand (especially Y 1b ) is Y 1 One represents , and the other represents H.

[0085] In a particular embodiment, each Y 1 R is independent of R a1 , halo (for example, F or Cl), -CN,-N(R b1 )R c1 , or -OR d1 It represents.

[0086] In a particular embodiment, R a1 C may be 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.

[0087] Furthermore, in a specific embodiment, R a1 R represents a C1 alkyl group (e.g., methyl) which may be optionally substituted by one or more halos. For example, R a1 This may represent -CH3 or -CF3.

[0088] Furthermore, in a specific embodiment, each Y 1 Independently, a halo (e.g., F or Cl) or - Represents CN

[0089] Furthermore, in a specific embodiment, each Y 1 It independently represents either Cl or F.

[0090] Furthermore, in a specific embodiment, each Y 1 It independently represents F.

[0091] Furthermore, in a specific embodiment, each Y 1 This independently represents -CN.

[0092] In a particular embodiment, one or more (e.g., each) Y 1 is -OR d1 This represents R d1 This represents H.

[0093] In a particular embodiment, one or more (e.g., each) Y 1 -NR b1 R c1 This represents R b1 represents H. Furthermore, in certain embodiments, R c1 is H or C 1-4 It represents an alkyl group, for example, H.

[0094] In a particular embodiment, each Y 2 R is independent of R a2 , halo (for example, F or Cl), -CN, -N(R b2 )R c2 , or -OR d2 It represents.

[0095] In a particular embodiment, R a2 C may be 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.

[0096] Furthermore, in a specific embodiment, R a2R represents a C1 alkyl group (e.g., methyl) which may be optionally substituted by one or more halos. For example, R a1 This may represent -CH3 or -CF3.

[0097] Furthermore, in a specific embodiment, each Y 2 It independently represents either Cl or F.

[0098] Furthermore, in a specific embodiment, each Y 2 It independently represents F.

[0099] In a particular embodiment, R d2 This represents H.

[0100] In a particular embodiment, R b2 represents H, and / or (for example, and) R c2 is H or C 1-4 Alkyl, for example, represents H.

[0101] To avoid any doubt, the embodiments of the present invention, as described herein, include combinations of the embodiments described herein.

[0102] In a particular embodiment, each Y 1 and Y 2 R is independent of R a1 It represents a halo (e.g., F or Cl) or -CN.

[0103] For example, in a particular embodiment that can be illustrated, Each Y 1 R is independent of R a1 , represents a halo (e.g., F or Cl), or -CN, R a1 C may be 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. Each Y 2 R is independent of Ra2 , represents a halo (e.g., F or Cl), or -CN, R a2 C may be 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.

[0104] In a particular embodiment, each Y 1 and Y 2 It independently represents Cl or F (especially F).

[0105] In certain embodiments, n represents at least 1 (i.e., there is a requirement that at least one Z group is present). In further embodiments, n represents up to 5, for example, up to 4, up to 3, or up to 2.

[0106] In a particular embodiment, If ring A represents a cycloalkyl group, then n represents 1 to 5 (e.g., 1 to 3, e.g., 1 or 2, e.g., 1), If ring A represents a heterocycloalkyl group, then n represents 0 to 5 (e.g., 0 to 3, e.g., 0, 1 or 2, e.g., 1).

[0107] In further embodiments, If ring A represents a cycloalkyl group, then n represents 1 to 3 (e.g., 1 or 2, e.g., 1). When ring A represents a heterocycloalkyl group, n represents 1 to 3 (e.g., 1 or 2, e.g., 1).

[0108] For example, in a particular embodiment, n represents 1 to 4, for example, 1 to 3.

[0109] Furthermore, in certain embodiments, n represents 1 or 2.

[0110] Furthermore, in certain embodiments, n represents 1.

[0111] In a particular embodiment, R1 is H or C 1-4 Alkyl (C such as methyl) 1-2 Represents alkyl groups, etc.

[0112] In a particular embodiment, R 1 In another embodiment, R 1 represents methyl.

[0113] In certain embodiments, the sum of m1 and m2 is 1 or 2.

[0114] Furthermore, in certain embodiments, the sum of m1 and m2 is 2.

[0115] In a particular embodiment, both m1 and m2 represent 1.

[0116] In certain embodiments, X represents C (carbon).

[0117] Furthermore, in certain embodiments, X represents C (carbon), and m1 and m2 represent 1. Thus, in such embodiments, ring A (for example, the ring containing X) represents cyclohexyl.

[0118] Thus, in some embodiments, the compound of formula I may exist as the compound of formula IC. [ka] In the formula, R 1 Q 1 ~Q 5 The rings, Z, and n, including the rings, 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).

[0119] In certain embodiments, X represents N (nitrogen).

[0120] Furthermore, in certain embodiments, X represents N (nitrogen), and m1 and m2 represent 1. Thus, in such embodiments, ring A (for example, the ring containing X) represents piperidine-4-yl.

[0121] Thus, in some embodiments, the compound of formula I may exist as the compound of formula ID. [ka] In the formula, R 1 Q 1 ~Q 5 The ring, Z, and n are as described herein (i.e., as described in the first aspect of the invention, including all embodiments and specific features, and combinations thereof). To avoid any doubt, one Z group may be present on the N of the piperidine ring.

[0122] In certain embodiments (for example, formula IX in which n represents 1 and m1 and m2 represent 1), the Z group is located at the 3rd or 4th position (relative to the bonding site to the essential skeleton of the compound) of the ring containing the X group.

[0123] Thus, in a particular embodiment, ring A can be depicted as follows. [ka] In the formula, the wavy line indicates the bonding point to the essential skeleton of the compound, Z 1 and Z 2 One of them represents Z, and the other represents H.

[0124] For example, in a particular embodiment that can be illustrated, Z 2 This represents Z, 1 This represents H. Thus, in a particular embodiment, the compound of formula I may be the compound of formula IE. [ka] In the formula, R 1 Q 1 ~Q5 The rings, Z, and X, including the rings, are as described herein (i.e., as described in the first aspect of the invention, including all embodiments and specific features, and combinations thereof).

[0125] In certain embodiments, if Z is present on a carbon atom, then R is independent. 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.

[0126] Furthermore, in certain embodiments, if each Z is present on a carbon atom, R is independent. a3 -CN, -N(R b3 )R c3 , -OR d3 , -S(O) q N(R f3 )R g3 , -N(R h3 )S(O) t R i3 , or = represents O.

[0127] Furthermore, in certain embodiments, if each Z is present on a carbon atom, R is independent. a3 , -N(R b3 )R c3 , -OR d3 , -N(R h3 )S(O) t R i3 , or = represents O.

[0128] Furthermore, in certain embodiments, if each Z is present on a carbon atom, R is independent. a3 , -N(R b3 )R c3 , -OR d3 , -N(R h3)S(O) t R i3 This represents, for example, R a3 It represents.

[0129] In a particular embodiment, each t represents 2.

[0130] In a particular embodiment, R a3 However, when representing a Z group present on a carbon atom, one or more (for example, one or two, for example, one) G 1 C may be optionally substituted by the group. 1-6 Alkyl (for example, C2 or C4 alkyl) 1-4 Represents alkyl.

[0131] For example, in a particular such embodiment, Z 2 is R a3 It represents one or more Gs (for example, one or two, for example, one) 1 Z may be optionally substituted by the element, 1 This represents H.

[0132] In a particular such embodiment, G 1 is -N(R b4 )R c4 or -N(R h4 )S(O) r R i4 It represents.

[0133] In certain such embodiments, R b4 represents H, and / or (for example, and) R c4 C may be optionally replaced by one or more halos or =O. 1-2 This represents an alkyl group, for example, a C2 alkyl group which may be optionally substituted with =O.

[0134] In certain such embodiments, R h4 represents H, and / or (for example, and) R i4 C may be optionally substituted with one or more halos such as C1 alkyl groups.1-2 Represents alkyl.

[0135] In certain embodiments, r represents 2.

[0136] For example, in a particular such embodiment, for instance, if the substituent is on a Z group located on a carbon atom, then G 1 This represents -NH(O)Me or -NHS(O)2Me.

[0137] In a specific embodiment, R b3 and / or (for example, or) R c3 This represents H.

[0138] In a particular embodiment, R b3 and / or (for example, or) R c3 is Halo and G 2 C may be optionally substituted by one or more groups selected from the above. 1-6 Represents alkyl. In certain such embodiments, G 2 R a4 Alternatively, it may represent =O.

[0139] In a particular embodiment, R d3 is Halo and G 2 C may be optionally substituted by one or more groups independently selected from 1-6 Alkyl (C 1-2 This represents alkyl groups (for example, methyl or ethyl). In certain such embodiments, G 2 R a4 , -OH, or =O may also be used to represent this.

[0140] In a particular embodiment, R h3 This represents H.

[0141] In a particular embodiment, R i3 is Halo and G 2 C may be optionally substituted by one or more groups independently selected from 1-6 Alkyl (C1-2 This represents alkyl groups (for example, methyl or ethyl).

[0142] As described herein, if Z is present on the nitrogen atom, R independently a3 , -S(O) p R e3 , or -S(O) q N(R f3 )R g3 It represents.

[0143] In a particular embodiment, if Z is present on a nitrogen atom, then independently, R a3 , or -S(O) p R e3 It represents.

[0144] In a particular embodiment, R a3 However, when representing a Z group present on a nitrogen atom, one or more (for example, one or two) G 1 C may be optionally substituted by the group. 1-6 Alkyl (for example, C1 or C2 alkyl) 1-4 Represents alkyl. For example, G 1 These are, independently, -OR d4 (-OMe or -OH, etc.), -N(R b4 )R c4 (-NMe2, etc.) or =O may also be represented.

[0145] For example, in a particular such embodiment, Z 2 is R a3 It represents one or more Gs (for example, one or two). 1 Z may be optionally substituted by the element, 1 This represents H.

[0146] In a particular such embodiment, G 1 represents = O.

[0147] In certain embodiments, -S(O) p R e3However, when representing the Z group present on a nitrogen atom, S(O) p R e3 This represents R e3 C 1-4 This represents alkyl, for example, methyl.

[0148] In certain embodiments, p represents 2.

[0149] For example, if Z is present on a nitrogen atom, it may independently represent -CH2C(O)OMe, -CH2C(O)OH, -C(O)Me, -S(O)2CH2C(O)OMe, -S(O)2CH2C(O)OH, -S(O)2nBu, or -S(O)2Me, such as -C(O)Me or -S(O)2Me.

[0150] To avoid any ambiguity, "when located on a carbon (or possibly nitrogen) atom" means when Z is located on a carbon (or possibly nitrogen) atom of ring A (including all embodiments thereof).

[0151] Those skilled in the art will recognize specific R that can be exemplified. 1 It will be understood that the groups X, m1, m2, ring Q, and substituents thereon, as well as the Z group (including any substituents thereon), include those present in the examples provided herein.

[0152] Specific compounds of the first embodiment of the present invention that may be exemplified include the compounds of the examples provided herein and their pharmaceutically acceptable salts.

[0153] 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, certain such optical isomers and / or diastereomers have been found to be of greater utility in the treatment of the conditions described herein, such as hyperglycemia or disorders characterized by hyperglycemia (e.g., type 2 diabetes).

[0154] Thus, the compound of formula I may also exist as compounds of formulas IF and IG. [ka] In the formula, R 1 Q 1 ~Q 5 The rings, Z, X, n, m1, and m2, including the rings Z, X, n, m1, and m2, 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).

[0155] In certain embodiments, the compound of formula I is the compound of formula IF.

[0156] To avoid any doubt, it should be added that the stereochemistry described for compounds of formulas IF and IG may apply to all embodiments of the compound of formula I.

[0157] Those skilled in the art will understand that, in addition to the carbon having the essential hydroxyl group, the compounds of the present invention may contain further stereocenters. To avoid doubt, unless otherwise specified, the stereochemistry of all stereocenters (including those located at positions other than the carbon having the essential hydroxyl group) may be in any configuration (i.e., R configuration or S configuration), or may be present in the compound as a mixture thereof (e.g., a racemic mixture).

[0158] Thus, in certain embodiments, the compound of formula IF may be a compound of formula IH or IJ. [ka] In the formula, R 1 The rings Q, Z, X, n, m1, and m2 are as described herein (i.e., as described in the First Aspect of the Invention, including all embodiments and specific features, and combinations thereof).

[0159] Furthermore, in certain embodiments, when X represents C (carbon), the compound of formula IH is the compound of formula IK or formula IL, and the compound of formula IJ is the compound of formula IM or formula IN. [ka] In the formula, R 1 Rings Q, Z, m1, and m2 are as described herein (i.e., as described in the First Aspect of the Invention, including all embodiments and specific features, as well as combinations thereof).

[0160] Furthermore, in certain embodiments, the compound of formula IF is the compound of formula IO, or the compound of formula IP. [ka] In the formula, R 1 , Y 1a , Y 1b , Y 2 Z, X, n, m1, and m2 are as described herein (i.e., as described in the First Aspect of the Invention, including all embodiments and specific features, and combinations thereof).

[0161] Those skilled in the art will understand that when referring to a specific stereoisomer(s) of a compound of formula I (for example, in the case of a compound of formula I, where the carbon having the essential -OH group by substitution is in the R configuration), it refers to a specific stereoisomer that exists in a substantially nonexistent manner from other (corresponding) stereoisomers(s) (for example, in the case of a compound of formula I, where the carbon having the essential -OH group by substitution is in the opposite configuration, i.e., the S configuration).

[0162] In this specification, the reference to “substantially absent corresponding opposite stereoisomers” means that the desired stereoisomer (e.g., in the case of a compound of formula I, where the carbon having the essential -OH group by substitution is in the (R) configuration) exists with at least 80% purity (e.g., at least 90%, e.g., at least 95%) compared to the other (e.g., opposite) stereoisomer (e.g., in the case of a compound of formula I, where the carbon having the essential -OH group by substitution is in the S configuration). Alternatively, in such cases, it may be shown that the compound exists in a substantially absent state of the other configuration (i.e., the (S) configuration), which may indicate that the compound of the relevant configuration exists in an enantiomer excess (ee). Alternatively, if two or more stereocenters are defined, it may be shown that the compound exists in a diastereomer excess (de) of at least 80% (e.g., at least 90%, at least 95%, at least 98%, in particular at least 99%, e.g., at least 99.9%).

[0163] In some embodiments, the compound in the relevant configuration may be shown to exist in an enantiomer excess (ee), or, if two or more stereocenters are defined, in a diastereomer excess (de) of at least 90% (e.g., at least 95%, at least 98%, particularly at least 99%, e.g., at least 99.9%).

[0164] To avoid any ambiguity, it should be added that when multiple stereochemistry positions are specified, the compound exists in a state where all other diastereomers are substantially absent.

[0165] To avoid any doubt, it should be added that, unless a specific position is specified, the compounds of the present invention include compounds in which that position has any of the available stereochemical configurations, and mixtures thereof (e.g., racemic mixtures). Thus, a compound referred to as having a specific position (for example, in the case of a compound of formula I, where the carbon having the essential -OH group by substitution is in the R configuration) may also have stereochemistry at one or more other positions, and therefore may exist as a mixture of enantiomers or diastereomers in relation to the stereochemistry at those positions.

[0166] medical use As described herein, the compounds of the present invention, and therefore compositions and kits containing them, are useful as pharmaceuticals.

[0167] Accordingly, according to a second aspect of the present invention, the compound of the first aspect of the present invention as defined above (i.e., the compound defined in the first aspect including all of its embodiments and specific features) is used in medicine (i.e., used as a pharmaceutical, which may be expressed as pharmaceutical use).

[0168] In the embodiment of the second aspect, the compound is as defined in the first aspect, except that proviso (B) is not attached.

[0169] 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 this activity may be confirmed to be mediated by activation of the β2 receptor by observing that such activity is prevented or reduced in the presence of a (e.g., selective) β2 adrenergic receptor antagonist (as in the biological examples provided herein).

[0170] Accordingly, a third aspect of the present invention provides a compound of the first aspect of the present invention for use in treating a disease or disorder that is mediated through the activation of β2-adrenergic receptors, as defined above.

[0171] In an alternative third aspect of the present invention, the use of a compound according to the first aspect of the present invention is provided in the manufacture of a pharmaceutical for use in the treatment of a disease or disorder mediated by the activation of β2-adrenergic receptors.

[0172] In a further alternative third aspect of the present invention, a method is provided for treating a disease or disorder via activation of β2-adrenergic receptors, comprising administering a therapeutically effective amount of a compound of the first aspect of the present invention to a patient in need thereof.

[0173] To avoid any doubt, references to compounds defined in the first embodiment of the present invention include references to compounds of formula I (including all embodiments thereof) and their pharmaceutically acceptable salts.

[0174] In the third embodiment, the compound is as defined in the first embodiment, except that the provisos (B) to (M) are not applied.

[0175] 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.

[0176] In a specific embodiment of a third aspect of the present invention, a compound of the first aspect of the present invention is provided for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia, as defined above.

[0177] In another embodiment of a third aspect of the present invention, the use of a compound of the first aspect of the present invention in the manufacture of a pharmaceutical for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia is provided.

[0178] In yet another embodiment of a third aspect of the present invention, a method for treating hyperglycemia or a disorder characterized by hyperglycemia is provided, comprising administering a therapeutically effective amount of a compound of the first aspect of the present invention to a patient in need thereof.

[0179] To avoid any doubt, it will be understood by those skilled in the art that, as used herein, the term “hyperglycemia” refers to a condition in which an excess amount of glucose is circulating in the plasma of the subject experiencing it. 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 (e.g., higher than about 11.1 mmol / L, e.g., higher than about 15 mmol / L), or to a subject (e.g., a human subject) having a blood glucose concentration higher than about 7 mmol / L for a prolonged period (e.g., longer than 24 hours, e.g., longer than 48 hours).

[0180] Those skilled in the art will understand that references to the treatment of a particular condition (or similarly, the act of treating that condition) have the usual meaning in the field of medicine. In particular, this 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, this may refer to achieving a reduction in blood glucose levels. In certain embodiments, when treating hyperglycemia or a condition characterized by hyperglycemia, this term may refer to achieving a reduction in blood glucose levels (e.g., to about 10.0 mmol / mL or less (e.g., from about 4.0 mmol / L to about 10.0 mmol / L), e.g., to about 7.5 mmol / mL 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)).

[0181] As used herein, a patient refers to a living organism being treated, including a mammalian patient (e.g., human). Thus, in certain embodiments of the first aspect of the present invention, the treatment is in a mammal (e.g., human).

[0182] 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. Such an effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of an effect and / or feels an effect).

[0183] Compounds of the first aspect of the present invention may have pharmacological activity on their own, or certain pharmaceutically acceptable (e.g., “protected”) derivatives of the compounds of the present invention that do not have such activity may exist or be prepared, which 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, but such activity is considerably lower than that of the active compound after metabolism) may be described as “prodrugs” of the compounds of the present invention.

[0184] As used herein, a reference to a prodrug will include 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.

[0185] To avoid any doubt, it should be added that 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), the term which will be readily understood by those skilled in the art (as described herein).

[0186] In certain embodiments, treatment is the treatment of a disorder (which may also be called a condition or disease) characterized by hyperglycemia.

[0187] 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.

[0188] 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).

[0189] 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, as described herein, useful in the manufacture of a medicament for such treatment or useful in a method for such treatment).

[0190] In a further specific embodiment, the treatment of type 2 diabetes is carried out in non-obese patients.

[0191] 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.

[0192] 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).

[0193] As used herein, the terms prevention (and similarly, the act of prevention) include references to prophylaxis of disease or disorder (and vice versa). Thus, a reference to prevention may also be a reference 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%).

[0194] Furthermore, in certain embodiments, type 2 diabetes is characterized by patients exhibiting severe insulin resistance (SIR).

[0195] 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.

[0196] 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.

[0197] In particular, in certain embodiments that may be mentioned, a disorder characterized by hyperglycemia is (or is characterized by) severe insulin resistance (SIR), and typically refers 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).

[0198] 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 level (these patients may have normal glucose tolerance).

[0199] Furthermore, SIR may be characterized in patients who do not have a significant response to the presence of insulin, which may be due to defects in insulin receptor function (e.g., gene deficiencies).

[0200] Specific disorders that may be characterized by SIR include Rabson-Mendenhall syndrome, Donahue syndrome (fairy syndrome), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.

[0201] More specific disorders that may be characterized by SIR include Donahue syndrome and insulin-resistant type A syndrome, and more specifically, Rabson-Mendenhall syndrome.

[0202] Those skilled in the art will understand that a treatment using 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, a treatment using a compound according to the present invention may be combined with other means for the treatment of type 2 diabetes, for example, a treatment using 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 a therapy that involves requiring the patient to make dietary changes and / or follow an exercise program, and / or a surgical procedure designed to promote weight loss (e.g., gastric band surgery).

[0203] In particular, treatment using the compounds of the present invention may be carried out in combination with one or more (e.g., one) additional compounds (i.e., therapeutic agents) (e.g., even in patients being treated with them), and the compounds to be combined are (i) It can lower blood sugar levels, and / or (ii) an insulin sensitizer, and / or (iii) It enhances insulin release, All of these are described below in this specification.

[0204] In another embodiment, 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).

[0205] Non-alcoholic fatty liver disease (NAFLD) is defined as an excessive accumulation of fat in the liver in the form of triglycerides (steatosis), histologically specified as an accumulation of more than 5% of liver cells. It is the most common liver disease in developed countries (for example, about 30% of adults in the United States are affected), and most patients are asymptomatic. If left untreated, the condition gradually worsens and can eventually lead to cirrhosis. NAFLD is particularly common in obese patients, with an estimated 80% of them having the disease.

[0206] A subgroup of NAFLD patients (e.g., 2–5% of US adults) exhibit liver cell damage and inflammation in addition to excessive fat accumulation. This condition is called non-alcoholic steatohepatitis (NASH) and is histologically almost indistinguishable from alcoholic steatohepatitis. While the simple steatosis seen in NAFLD does not directly correlate with increased short-term morbidity or mortality, progression from 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 cirrhosis of unknown cause) in developed countries.

[0207] The exact cause of NASH is still unknown and is not the same for all patients. It is most closely associated with insulin resistance, obesity, and metabolic syndromes (including type 2 diabetes, insulin resistance, central (Thorn) 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, effective treatment is clearly needed.

[0208] 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, as described herein, useful in the manufacture of a medicament for such treatment or useful in a method for such treatment).

[0209] 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. Thus, in certain embodiments of the first aspect of the present invention, treatment or prevention is the treatment or prevention of fatty liver disease characterized by steatosis.

[0210] In steatosis, excess lipids accumulate in vesicles, replacing the cytoplasm of cells. Over time, these vesicles can grow large enough to distort the nucleus; this condition is known as macrovesicular steatosis. Otherwise, the condition may be called microvesicular 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 mellitus, protein malnutrition, hypertension, obesity, anoxia, sleep apnea, and the presence of intracellular toxins.

[0211] 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).

[0212] 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 disorder, Weber-Christian disease, acute fatty liver disease during pregnancy, and steatosis. Non-alcohol-related factors associated with fatty liver disease include malnutrition, complete parenteral nutrition, severe weight loss, refeeding syndrome, jejunal bypass surgery, gastric bypass surgery, polycystic ovary syndrome, and diverticulosis.

[0213] The compounds of the present invention have been found to be particularly useful in the treatment or prevention of NAFLD, sometimes referred to as non-alcohol-related fatty liver disease. “Non-alcohol-related” fatty liver disease can be diagnosed when a patient’s alcohol consumption is not considered a major causative factor. Typical thresholds for diagnosing fatty liver disease as “non-alcohol-related” are less than 20g for female subjects and less than 30g for male subjects.

[0214] If left untreated, individuals with fatty liver disease may begin to experience inflammation of the liver (hepatitis). One possible cause of this inflammation is thought to be lipid peroxidation damage to the membranes of hepatocytes. Since inflammation of fatty liver can lead to many serious conditions, it is desirable to treat or prevent fatty liver disease before inflammation occurs. Therefore, in certain embodiments of the first aspect of the present invention, the treatment or prevention is the treatment or prevention of NAFLD associated with inflammation.

[0215] 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 leads 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. Naturally, the compounds of the present invention are also useful in the treatment or prevention of NASH. Therefore, in a further embodiment of the first aspect of the present invention, the treatment or prevention is for non-alcoholic steatohepatitis (NASH).

[0216] Those skilled in the art will understand that a treatment using 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, a treatment using a compound according to the present invention may be combined, as described herein, with other means for the treatment of fatty liver disease, for example, a treatment using one or more other therapeutic agents useful for treating fatty liver disease that are known to those skilled in the art, such as a therapy that involves requiring the patient to make changes to their diet and / or to follow an exercise program, and / or a surgical procedure designed to promote weight loss (e.g., gastric band surgery).

[0217] In particular, therapies using the compounds of the present invention may be carried out in combination with one or more (e.g., one) additional compounds (i.e., therapeutic agents) that have the ability to lower lipid levels (such as triglycerides) in the liver (e.g., even in patients being treated with such agents).

[0218] Treatment of fatty liver disease may also refer to a therapeutically significant reduction in fat (triglycerides, etc.) within liver cells (a reduction of at least 5% by weight, for example, at least 10% by weight, or at least 20% by weight, or even 25% by weight).

[0219] As described herein, the compounds of the present invention are also used to treat diseases or disorders that are caused by the activation of β2-adrenergic receptors.

[0220] In certain embodiments, a compound according to the first aspect of the present invention may be understood to positively modulate the β2-adrenergic receptor, and such compound may be called a β2-adrenergic receptor agonist.

[0221] 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 any doubt, adrenergic receptors are a class of G protein-coupled receptors activated by endogenous ligands, catecholamines, adrenaline and noradrenaline. Adrenergic receptors are classified into five subtypes: 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. While this invention relates to the β2-adrenergic receptor, compounds may interact with one or more other adrenergic receptors (e.g., one or more other β-adrenergic receptors).

[0222] The term "positively modulates β2-adrenergic receptor activity" is understood to mean that the compound can alter the signaling pathway of the receptor.

[0223] 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 exhibit some agonism to other adrenergic receptors. In this application, the terms “β2 adrenergic receptor agonist,” “β2AR agonist,” “β2AR agonist,” and “β2 agonist” may be used interchangeably.

[0224] Therefore, in certain embodiments, reference to a β2 agonist may include both selective and non-selective agonists.

[0225] In certain embodiments, reference to a β2 agonist may include, but not limited to, full agonists 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.

[0226] As used herein, the term "mediated by activation of β2-adrenergic receptors" is used to indicate that the activation of a receptor modulates or elicits a physiological response which in turn provides a biological effect corresponding to (or leading to) the treatment of a disease or disorder.

[0227] As used herein, references to the treatment of diseases and disorders “made via activation of β2-adrenergic receptors” may, in particular, refer to diseases and disorders (and their treatments in particular) that “relate to,” “are via,” “are affected by,” “are regulated by,” “are modulated by,” and “are associated with” β2-adrenergic receptors.

[0228] As described herein, diseases or disorders treated through the activation of β2-adrenergic receptors will be known to those skilled in the art. Therefore, 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 referred to below herein (which are incorporated herein by reference).

[0229] In addition to those described herein, specific diseases or disorders that may be treated via activation of β2 adrenergic receptors may be mentioned: Neurodegenerative diseases (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 degeneration), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, EKS (wet Lnicke-Korsakoff syndrome, normal pressure hydrocephalus, hypersomnia (sleep attacks), 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 (e.g., muscle injury, muscle wasting, muscle atrophy, muscle degeneration, or sclerosis), Kidney diseases, such as CKD (chronic kidney disease), ESRD (end-stage renal disease), and diabetic nephropathy, Inflammation or inflammation-characterized disorders (e.g., sepsis, psoriasis, dermatitis, psoriasis-like dermatitis, lacerations, or HDF (human dermal fibroblasts)) including those associated with endotoxemia and local acute inflammation such as acute lung injury (ALI), and further including inflammation-related respiratory diseases (e.g., asthma and other lung disorders, e.g., chronic obstructive pulmonary disease (COPD)), Autoimmune diseases (for example, SLE (systemic lupus erythematosus), RA (rheumatoid arthritis), MG (myasthenia gravis), MS, and GD (Graves' disease)) are examples.

[0230] 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 (e.g., the literature cited herein) (it is understood that the entirety of such literature, in particular the experimental results presented, is incorporated herein by reference).

[0231] In particular, the suitability of β2 adrenergic receptor agonists for treating certain diseases and disorders referred to herein may be specified in the disclosures of International Publication No. 2020 / 198466A1 and International Publication No. 2021 / 003161A1, and in some examples may be confirmed therein (these are incorporated herein by reference, in particular in the examples provided therein, to avoid any doubt).

[0232] In certain embodiments, compounds according to a first aspect of the present invention are provided for use in the treatment of neurodegenerative diseases, as defined above.

[0233] 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 degeneration), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, EK The following conditions are selected: S (Wernicke-Korsakoff syndrome), normal pressure hydrocephalus, hypersomnia (sleep attacks), 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).

[0234] Mittal. S., et al., Science., 357(6354), 891-898 (2017) describes how β2-adrenergic receptor agonists promote dopamine neuron health by reducing SNCA expression via H2K27 deacetylation and mitochondrial free radicals. This may be beneficial for substantia nigra dopamine neurons, which are prone to mitochondrial bioenergetics dysfunction in the early stages of Lewy body neuropathy. β2-adrenergic receptor agonists are expressed in the substantia nigra and cortex, areas progressively affected by Parkinson's disease (PD). Therefore, β2-adrenergic receptor agonists may be used to reduce the risk and effects of PD.

[0235] Hishida, R., The Lancet, 870 (1992) describes that β2 adrenergic receptor agonists may have beneficial effects on the wearing-off phenomenon in Parkinson's disease patients receiving long-term levodopa therapy.

[0236] Uc, EY, et al., Clin. Neuropharmacol., 26(4), 207-212 (2003) describes how albuterol, a β2 adrenergic receptor agonist, benefits PD patients through two mechanisms: increased response to levodopa and increased muscle mass.

[0237] O'Neill, et al., Br.J.Pharmacol., 177, 282-297 (2019) described how β2-adrenergic receptor agonists restrict microglial activation, preventing the onset and progression of dopaminergic neuronal loss and associated motor disorders caused by central nervous system or systemic inflammation. Therefore, targeting β2-adrenergic receptors with β2-adrenergic receptor agonists provides an interprophylactic mechanism to protect against the progression of neurodegeneration and motor function decline associated with exacerbated systemic and central inflammation. As a result, β2-adrenergic receptor agonists may be beneficial in the treatment of inflammation-induced Parkinson's disease (PD)-related neurological and motor disorders.

[0238] In another embodiment, a compound according to the first aspect of the present invention is provided for use in the treatment of muscular dystrophy or a disorder characterized by muscular dystrophy, as defined above.

[0239] In certain such embodiments, muscular dystrophy is muscle damage, muscle wasting, muscle atrophy, muscle degeneration, or sclerosis.

[0240] Jiang, G., et al., ISRN Pharma., 2011, 1-7 (2011) described how β2-AR agonists improve denervation, amyotrophic lateral sclerosis, muscular dystrophy, disuse, aging, and debilitation in animals in myocardial no-load 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 have been found to promote myocardial recovery in patients with myocardial unloading atrophy resulting from the application of left ventricular assist devices.

[0241] 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.

[0242] In another embodiment, a compound according to the first aspect of the present invention is provided for use in the treatment of kidney disease, as defined above.

[0243] In certain such embodiments, the kidney disease is selected from CKD (chronic kidney disease), ESRD (end-stage renal disease), and diabetic nephropathy.

[0244] 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 their potential use as a treatment for diabetic nephropathy (DN).

[0245] Jesinkey, SR, et al., J.Am.Soc.Nephrol., 25, 1157-1162 (2014) describes the need for mitochondrial biosynthesis as an adaptive response to meet the increased metabolic and energy demands during organ recovery after 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 followed by the accumulation of harmful waste products in the body.

[0246] In another embodiment, compounds according to the first aspect of the present invention are provided for use in the treatment of inflammation or inflammation-characterized disorders, as defined above.

[0247] In certain embodiments, inflammation is (or characterized by) sepsis, psoriasis, dermatitis, psoriasis-like dermatitis, laceration, or HDF (human dermal fibroblasts).

[0248] 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 inflammatory and anti-inflammatory mediators, the removal of dead cells, and the containment of pathogens.

[0249] Those skilled in the art will know that inflammation can also be a cause of respiratory conditions such as asthma, and lung disorders such as chronic obstructive pulmonary disease (COPD).

[0250] 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.

[0251] Agac, D., et al., Brain, Behaviour and Immunity, 74, 176-185 (2018) states that a unique synergistic pathway exists that converts acute inflammatory signals into anti-inflammatory responses, and is likely to explain various phenomena known to be involved in immunosuppression via β2-adrenergic receptor agonists. 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.

[0252] Liu, F., et al., Cells, 511(9), 1-17 (2020) reported that β2 adrenergic receptor agonists showed significant antipsoriatic effects, suggesting that this may involve the regulation of Th17 / Tregs axis balance and glycerophospholipid metabolism in response to imiquimod (IMQ)-induced psoriasis.

[0253] Provost, GS, et al., J. Investig. Dermatol., 135, 279-288 (2015) reported that β2-adrenergic receptor agonists reduce the differentiation of human dermal fibroblasts (HDFs) and decrease scar formation in patients with lacerations or open wounds.

[0254] In another embodiment, a compound according to the first aspect of the present invention is provided for use in the treatment of an autoimmune disease, as defined above.

[0255] 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).

[0256] Wu, et al., Front. Pharmacol., 1313(9), 1-9 (2018) states that β2-adrenergic receptor agonists may be targeted therapies for autoimmune diseases (AD) such as SLE (systemic lupus erythematosus), RA (rheumatoid arthritis), MG (myasthenia gravis), MS, and GD (Grebe's disease).

[0257] Pharmaceutical composition As described herein, the compounds of the first, and therefore the second and third, aspects of the present invention are useful as pharmaceuticals. Such compounds may be administered alone or via known pharmaceutical compositions / formulations.

[0258] 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.

[0259] Those skilled in the art will understand that the references herein to compounds of the first aspect of the present invention for specific uses (as well as similarly to uses and methods of use relating to the compounds of the present invention) may also be applied to pharmaceutical compositions comprising the compounds of the present invention as described herein.

[0260] 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 defined in the first aspect of the present invention and optionally one or more pharmaceutically acceptable adjuvants, diluents and / or carriers.

[0261] 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.

[0262] 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.

[0263] Those skilled in the art will understand that compounds of the first (and therefore second and third) aspects of the present invention can act systemically and / or topically (i.e., at specific sites).

[0264] 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, rectal, skin, nasal cavity, trachea, bronchi, sublingual, intranasal, topical, any other parenteral route, or by inhalation. The pharmaceutical compositions described herein may 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, if such compounds of the present invention act topically, the pharmaceutical compositions may be formulated for topical administration.

[0265] Accordingly, in certain embodiments of the fourth and fifth aspects of the present invention, the pharmaceutical formulations are provided in pharmaceutically acceptable dosage forms, including tablets or capsules, liquids administered orally or by injection, suppositories, creams, gels, effervescent agents, inhalants (e.g., applied nasally), 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.

[0266] For example, in the preparation of pharmaceutical formulations for oral administration, the compound may be mixed with a solid powder component such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable component, and 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.

[0267] Soft gelatin capsules can be prepared using capsules containing one or more active compounds (e.g., compounds of the first, and consequently, second and third embodiments of the present invention, and optionally additional therapeutic agents) together with, for example, vegetable oil, fat, or other vehicles 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.

[0268] 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 microenemas that are reconstituted in a suitable solvent immediately before administration.

[0269] Liquid preparations for oral administration may be prepared in the form of a solution or suspension containing, for example, a syrup or suspension, containing 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. If desired, 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 reconstituted with a suitable solvent before use.

[0270] 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.

[0271] Those skilled in the art will understand that the compounds of the present invention and pharmaceutically acceptable salts may be administered in variable doses (e.g., as the formulations described above), and that preferred doses can be easily determined by those skilled in the art. Oral, pulmonary, and topical doses (as well as subcutaneous doses, although these doses may be relatively lower) may range from about 0.01 μg / kg body weight / day (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 involve the administration of formulations typically 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(s). For intravenous administration, the most preferred dose is in the range of about 0.001 to about 10 μg / kg / hour during constant-rate infusion. Advantageously, treatment may involve administering such compounds and compositions once daily, or the total daily dose may be divided into two, three, or four doses per day (for example, twice daily, in relation to the doses described herein, such as doses of 10 mg, 20 mg, 30 mg, or 40 mg twice daily, or doses of 10 μg, 20 μg, 30 μg, or 40 μg twice daily).

[0272] 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 above dosages are examples for the average case, 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.

[0273] As described herein, those skilled in the art will understand that treatment with compounds of the first embodiment 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 the treatment of hyperglycemia or hyperglycemia-characterized disorders (such as type 2 diabetes as defined herein), for example, treatment with one or more other therapeutic agents useful for the treatment of hyperglycemia or hyperglycemia-characterized disorders (such as type 2 diabetes as defined herein).

[0274] 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.

[0275] In particular embodiments, one or more additional therapeutic agents include metformin, sulfonylurea (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)), and dipeptidyl These are agents for the treatment of type 2 diabetes known to those skilled in the art, such as lupeptidase-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.

[0276] Those skilled in the art will understand that combinations of therapeutic agents may be described as combination products and / or offered as kit products.

[0277] In a sixth aspect of the present invention, (A) A compound defined in the first embodiment 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.

[0278] In a seventh aspect of the present invention, (a) A compound (or a pharmaceutical composition containing the same) as defined in the first (or second and / or third) aspect of the present invention, or a pharmaceutical composition as defined in the fourth or fifth aspect of the present invention, (b) comprising one or more other therapeutic agents, optionally mixed with one or more pharmaceutically acceptable adjuvants, diluents or carriers, A kit product is further provided, wherein components (a) and (b) are provided in a form suitable for administration together with the other.

[0279] 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 (for example, type 2 diabetes), as is known to those skilled in the art (for example, as described herein).

[0280] For example, in certain embodiments of the fourth to fifth aspects of the present invention, an additional therapeutic agent is: (i) It can lower blood sugar, and / or (ii) is an insulin sensitizer, and / or (iii) A drug that can promote insulin secretion, The above-mentioned drugs are readily identifiable by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g., drugs that are subject to marketing authorization in one or more regions, such as in Europe or the United States).

[0281] 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 its blood level by at least 10% (e.g., 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 the blood glucose level before treatment with the compound in question.

[0282] In other 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), the agents being readily identifiable by those skilled in the art and, in particular, including 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).

[0283] In other embodiments of the sixth and seventh aspects of the present invention, additional therapeutic agents are agents that treat diseases or disorders by activation of β2-adrenergic receptors, the diseases and disorders being described herein, the agents being readily identifiable to those skilled in the art, and in particular including such therapeutic agents that are commercially available (e.g., agents subject to marketing authorization in one or more regions, such as marketing authorization in Europe or the United States).

[0284] 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 practices.

[0285] Accordingly, in a further aspect of the present invention, a process for preparing a pharmaceutical composition / formulation as defined above is provided, comprising associating a compound of the present invention with one or more pharmaceutically acceptable adjuvants, diluents, or carriers as defined above.

[0286] In a further aspect of the present invention, a process is provided for preparing the combination product or kit product as defined above, comprising associating the compound of the present invention or a pharmaceutically acceptable salt thereof with other therapeutic agents useful for treating hyperglycemia or a disorder characterized by hyperglycemia (e.g., type 2 diabetes), and at least one pharmaceutically acceptable adjuvant, diluent, or carrier.

[0287] As used herein, reference to association will mean that the two components are suitable for administration in combination with each other.

[0288] Therefore, with respect to the process for preparing the kit product as defined above, by "associating" the two components with each other, the two components of the kit product are: (i) They may be provided as separate formulations (i.e., independently of each other) and then combined for use in combination therapy, or (ii) This includes the possibility that the components may be packaged and presented together as separate components in a “combination pack” for use in combination therapy.

[0289] The compounds defined in the first embodiment of the present invention (i.e., the compounds of the present invention) may be prepared according to techniques well known to those skilled in the art, as described in the examples provided below.

[0290] For example, R 1 A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, wherein is H and the other substituents are as defined in the first embodiment of the present invention, (i) Compound of formula II [ka] In the formula, rings A and R 1 Z and n are as defined herein, and M 1 This represents a compound that is a suitable metal or metal halide, and a compound of formula III. [ka] And in the formula, Q 1 ~Q 5 (Therefore, ring Q) is as defined herein, and reacts with the compound under conditions known to those skilled in the art. (ii) Compounds of formula IV [ka] And in the formula, Q 1 ~Q 5 M is as defined herein. 2 This represents a compound that is a suitable metal or metal halide, and a compound of formula V. [ka] In the formula, rings A and R 1 A process is provided comprising the reaction of a compound, where Z and n are as defined herein, under conditions known to those skilled in the art.

[0291] The compounds of formulas II, III, IV, and V are commercially available or known in the literature and may be obtained from readily available starting materials (e.g., appropriately substituted benzaldehyde, styrene, or phenacyl bromide (or phenacyl chloride, etc.)) using appropriate reagents and reaction conditions, following standard techniques, in a manner similar to or conventionally used in the processes described herein. In this regard, those skilled in the art may refer in particular to “Comprehensive Organic Synthesis” by 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.

[0292] The substituents Y and Z defined above may be modified one or more times after or during the process described above for preparing the compound 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 to the group defined in formula I. Those skilled in the art may also refer to “Comprehensive Organic Functional Group Transformations” by AR Katritzky, O. Meth-Cohn and CWRees, Pergamon Press, 1995, and / or “Comprehensive Organic Transformations” by RC Larock, Wiley-VCH, 1999.

[0293] Such compounds can be isolated from the reaction mixture and, if necessary, purified using prior art 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).

[0294] 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.

[0295] 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 scheme described above.

[0296] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and the techniques 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 to achieve the synthesis. The use of protecting groups is described in full in “Protective Groups in Organic Synthesis”, 3rd edition, TW Greene & P. ​​G.M. Wutz, Wiley-Interscience (1999).

[0297] The compounds described herein (in particular, the compounds defined in the first, and therefore the second and third, embodiments of the present invention) may have the advantage of being more potent, 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), as well as / or other useful pharmacological, physical or chemical properties, compared to compounds known in the prior art, whether for use in the indications described above. In particular, such compounds may have the advantage of being more potent and / or exhibiting favorable properties in vivo.

[0298] While we do not wish to be bound by theory, the compounds described herein are thought to be potent agonists of the β2-adrenergic receptor, enabling increased glucose uptake in skeletal muscle cells.

[0299] In addition, the compounds described herein are considered to be β2 adrenergic receptor agonists that do not induce cAMP production (or have only 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 occur with other therapies. 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]

[0300] The present invention is illustrated by the following embodiments.

[0301] Chemicals and reagents were obtained from commercial suppliers and used as received unless otherwise noted. All reactions involving moisture-sensitive reagents were carried out under positive pressure of nitrogen or argon in an oven or flame-dried glassware.

[0302] Abbreviation The abbreviations used herein will be familiar to those skilled in the art. In particular, the following abbreviations may be used herein. atm (atmosphere) aq Aqueous (Note: Translated as "aqueous solution" or "water layer" depending on the context) Pd-C (Palladium on carbon) rt Room temperature sat saturated

[0303] Examples of 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).

[0304] Example 1: N-(1-((cis)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)-2-methylpropan-2-yl)acetamide [ka]

[0305] (a) tert-butyl((cis)-4-(hydroxymethyl)cyclohexyl)carbamate [ka] (cis)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (1.00 g, 4.11 mmol) was slowly added dropwise to an ice-cold THF (30 mL) solution to a boranedimethyl sulfide complex (2.42 mL, 25.48 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 3 hours. MeOH (5 mL) was added and the mixture was concentrated. MeOH (1 mL) was added to the residue and the mixture was concentrated. This procedure was repeated two more times. NaOH (aqueous solution, 2 M) was added to the residue and extracted with ethyl acetate. The combined extract was washed with brine, dried, and concentrated with (Na2SO4) to obtain the subtitle compound (1.88 g, 99%), which was used in the next step without further purification.

[0306] (b)((cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate [ka] Methanesulfonyl chloride (0.70 mL, 9.00 mmol) was added dropwise to a stirred, ice-cold mixture of tert-butyl((cis)-4-(hydroxymethyl)cyclohexyl) carbamate (1.88 g, 8.18 mmol), triethylamine (1.48 mL, 10.63 mmol), and CH2Cl2 (50 mL). The mixture was stirred at 0°C for 2 hours, and H2O was added. The layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phase was washed with H2O and brine, dried, and concentrated with (Na2SO4) to obtain the subtitle compound (2.50 g, 99%), which was used in the next step without further purification.

[0307] (c) tert-butyl((cis)-4-(cyanomethyl)cyclohexyl)carbamate [ka] ((cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate (2.50 g, 8.13 mmol) was dissolved in DMSO (20 mL) and NaCN (1.20 g, 24.40 mmol) was added. The mixture was stirred at 90 °C for 4 hours and then cooled to room temperature. Brine was added and the mixture was extracted with RINKAN. The combined extract was washed with brine, dried, and concentrated in (Na2SO4). The residue was purified by chromatography to obtain the subtitle compound (1.66 g, 85%).

[0308] (d) tert-butyl((cis)-4-(2-amino-2-methylpropyl)cyclohexyl)carbamate [ka] A mixture of CeCl3 (4.99 g, 20.25 mmol) and THF (34) was vigorously stirred at room temperature for 45 minutes. The suspension was cooled to -78°C, and MeLi (1.6 M in Et2O, 12.66 mL, 20.25 mmol) was added dropwise. The mixture was stirred at -78°C for 30 minutes, and a solution of tert-butyl((cis)-4-(cyanomethyl)cyclohexyl) carbamate (0.95 g, 4.00 mmol) in THF (8 mL) was added dropwise. The mixture was stirred at -78°C for 30 minutes and then at -65°C for 3 hours. NH3 (aqueous solution, saturated) was added dropwise at -65°C, the mixture was warmed to room temperature, filtered through a Celite pad, and washed with CH2Cl2. The combined filtrate was dried and concentrated (Na2SO4). The residue was dissolved in CH2Cl2 (40 mL), and AcOH (1.15 mL, 20 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 30 minutes and concentrated. CH2Cl2 was added to the residue and the mixture was concentrated. This procedure was repeated three times. The residue was ground with MeCN, sonicated, and filtered. The residue was partitioned between CH2Cl2 and NaHCO3 (aqueous solution, saturated), the layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phase was washed with brine, dried, and concentrated (Na2SO4) to obtain the subtitle compound (0.72 g, 66%).

[0309] (e)tert-butyl((cis)-4-(2-acetamido-2-methylpropyl)cyclohexyl)carbamate [ka] Et3N (134 μL, 0.96 mmol), followed by acetyl chloride (58 μL, 0.81 mmol), was added at 0°C to a solution of tert-butyl((cis)-4-(2-amino-2-methylpropyl)cyclohexyl)carbamate (200 mg, 0.74 mmol) in CH2Cl2 (5 mL). The mixture was stirred at 0°C for 1 hour and diluted with CH2Cl2. NaHCO3 (aqueous solution, saturated) was added, the layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography to obtain the subtitle compound (218 mg, 94%).

[0310] (f)N-(1-((cis)-4-aminocyclohexyl)-2-methylpropan-2-yl)acetamide [ka] Amberlyst15 resin (300 mg) was washed with MeOH and added to a stirred solution of tert-butyl(cis)-4-(2-acetamido-2-methylpropyl)cyclohexyl)carbamate (100 mg, 0.32 mmol) in CH2Cl2 (1 mL). The mixture was stirred overnight at room temperature. Another 200 mg of Amberlyst15 resin was added, and the mixture was stirred at room temperature for 2 days. The resin was filtered and washed with MeOH. The washed resin was placed in 1 mL of 7N NH3 sol in MeOH. The mixture was stirred for 30 minutes. The resin was then filtered, washed with MeOH, and the filtrate was concentrated to obtain the sub-compound (51 mg, 75%), which was used in the next step without further purification.

[0311] (g)N-(1-((cis)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)-2-methylpropan-2-yl)acetamide [ka] A mixture of N-(1-((cis)-4-aminocyclohexyl)-2-methylpropan-2-yl)acetamide (45 mg, 0.21 mmol), (R)-2-(3-fluorophenyl)oxirane (38 mg, 0.28 mmol), and iPrOH (0.5 mL) was stirred at 80°C for 16 hours. The mixture was concentrated, and the residue was purified by chromatography to obtain the subject compound (30 mg, 40%). 1 H NMR(400MHz,CDCl3)δ7.34-7.26(m,1H),7.15-7.07(m,2H),6.95(tdd,J=8.5,2 .6,1.1Hz,1H),5.18(s,1H),4.66(dd,J=9.0,3.6Hz,1H),2.96(dd,J=12.2,3.6H z,1H),2.70-2.63(m,1H),2.60(dd,J=12.2,9.0Hz,1H),1.90(s,3H),1.70-1.6 6(m,2H),1.66-1.56(m,2H),1.56-1.44(m,5H),1.44-1.36(m,2H),1.31(s,6H).

[0312] Example 2: N-(1-((cis)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)-2-methylpropan-2-yl)methanesulfonamide [ka]

[0313] (a)N-(1-((cis)-4-aminocyclohexyl)-2-methylpropan-2-yl)methanesulfonamide [ka] In step (e), a mixture of tert-butyl((cis)-4-(2-methyl-2-(methylsulfonamidopropyl)propyl)cyclohexyl) carbamates prepared according to the procedure of Example 1 using methanesulfonyl chloride (0.100 g, 0.287 mmol), NaI (0.056 g, 0.373 mmol), CeCl3*7H2O (0.16 g, 0.43 mmol), and MeCN (2 mL) was stirred at 80°C for 4 hours. CHCl3 (10 mL) and NaOH (aqueous solution, 1 M, 15 mL) were added, and the mixture was shaken until it became colorless. The layers were separated, and the organic phase was washed with water. The combined aqueous phase was extracted with iPrOH / CHCl3 (1 / 4), the organic phase was combined, dried, and concentrated in (Na2SO4). The residue was purified by reverse-phase chromatography to obtain the subtitle compound (55 mg, 77%).

[0314] (b) N-(1-((cis)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)-2-methylpropan-2-yl)methanesulfonamide [ka] In Example 1, the subject compound was prepared from N-(1-((cis)-4-aminocyclohexyl)-2-methylpropan-2-yl)methanesulfonamide according to the procedure of step (g). 1 H NMR(400MHz,CDCl3)δ7.33-7.27(m,1H),7.14-7.08(m,2H),6.95(tdd,J=8.5,2.6,1.1Hz,1H),4.71(dd,J=9.1,3.5Hz,1H),4.22(s,1H),3.02(s,3H), 2.97(dd,J=12.2,3.6Hz,1H),2.74-2.68(m,1H),2.63(dd,J=12.2,9.1Hz, 1H),1.69-1.59(m,3H),1.59-1.50(m,6H),1.50-1.40(m,2H),1.37(s,6H).

[0315] Example 3: N-(1-((cis)-4-(((R)-2-(5-fluoropyridine-3-yl)-2-hydroxyethyl)amino)cyclohexyl)-2-methylpropan-2-yl)acetamide [ka] In step (g), (R)-3-fluoro-5-(oxiran-2-yl)pyridine was used to prepare the subject compound according to the procedure of Example 1. 1 H NMR(400MHz,CDCl3)δ8.40-8.37(m,1H),8.36(d,J=2.8Hz,1H),7.55-7.43(m,1H),5.22(s,1H),4.69(dd,J=9.2,3.6Hz,1H),2.98(dd,J=12.3,3 .7Hz,1H),2.69-2.62(m,1H),2.58(dd,J=12.3,9.2Hz,1H),1.89(s,3H) ,1.72-1.65(m,2H),1.65-1.43(m,7H),1.43-1.34(m,2H),1.30(s,6H).

[0316] Example 4: N-(1-((cis)-4-(((R)-2-(5-fluoropyridine-3-yl)-2-hydroxyethyl)amino)cyclohexyl)-2-methylpropane-2-yl)methanesulfonamide [ka] The subject compound was prepared according to the procedure of Example 1, using methanesulfonyl chloride in step (e) and (R)-2-(3-fluorophenyl)oxirane in step (g). 1H NMR(400MHz,CDCl3)δ8.44-8.39(m,1H),8.38(d,J=2.8Hz,1H),7.55-7.46(m,1H),4.76(dd,J=9.2,3.5Hz,1H),4.21(s,1H),3.07-2 .98(m,4H),2.76-2.69(m,1H),2.62(dd,J=12.3,9.2Hz,1H),1.70-1.59(m,3H),1.59-1.50(m,6H),1.50-1.41(m,2H),1.38(s,6H).

[0317] Example 5: (R)-1-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)ethane-1-one [ka]

[0318] (a) tert-butyl(1-acetyl-4-methylpiperidine-4-yl)carbamate [ka] Et3N (0.33 mL, 2.34 mmol), followed by acetyl chloride (0.14 mL, 1.98 mmol), was added at 0°C to a solution of tert-butyl(4-methylpiperidine-4-yl)carbamate (0.385 g, 1.80 mmol) in CH2Cl2 (5 mL). The mixture was stirred at 0°C for 1 hour and diluted with CH2Cl2. NaHCO3 (aqueous solution, saturated) was added, the layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography to obtain the subtitle compound (0.36 g, 77%).

[0319] (b) 1-(4-amino-4-methylpiperidine-1-yl)ethane-1-one [ka] Amberlyst15 resin (0.5 g) was washed with MeOH and added to a stirred solution of tert-butyl (1-acetyl-4-methylpiperidine-4-yl)carbamate (0.10 g, 0.39 mmol) in CH2Cl2 (1 mL). The mixture was stirred at room temperature for 48 hours. The resin was washed with CH2Cl2 and treated with NH3 (7 M in MeOH, 1 mL), and the slurry was stirred at room temperature for 30 minutes. The resin was filtered, washed with MeOH, and the combined filtrate was concentrated to obtain the sub-subject compound (0.50 g, 82%).

[0320] (d)(R)-1-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)ethane-1-one [ka] A mixture of 1-(4-amino-4-methylpiperidine-1-yl)ethane-1-one (43 mg, 0.28 mmol), (R)-2-(3-fluorophenyl)oxirane (49 mg, 0.36 mmol), and iPrOH (0.63 mL) was stirred at 80°C for 16 hours. The mixture was concentrated, and the residue was purified by chromatography to obtain the subject compound (36 mg, 44%). 1 H NMR(400MHz,CDCl3)δ7.35-7.27(m,1H),7.24-7.16(m,2H),7.03-6.92(m,1H),5.35(dd,J=10.4,2.0Hz,1H),3.18(dd,J=12.1,2.1Hz,1H),3 .05-2.96(m,1H),2.96-2.83(m,7H),1.97-1.89(m,1H),1.89-1.79(m ,4H),1.79-1.65(m,4H),1.65-1.51(m,2H),1.47(s,3H),1.44(s,3H).

[0321] Example 6: (R)-1-(3-fluorophenyl)-2-((4-methyl-1-(methylsulfonyl)piperidine-4-yl)amino)ethane-1-ol [ka] In step (a), methanesulfonyl chloride was used to prepare the subject compound according to the procedure of Example 5. 1 H NMR(400MHz,CDCl3)δ7.35-7.27(m,1H),7.15-7.06(m,2H),6.96(tdd,J=8.4,2.5,1.2Hz,1H),4.65(dd,J=8.1,3.8Hz,1H),3.38-3.2 1(m,2H),3.21-3.04(m,2H),2.86(dd,J=11.7,3.8Hz,1H),2.75(s,3H),2.58(dd,J=11.7,8.2Hz,1H),1.72-1.52(m,4H),1.12(s,3H).

[0322] Example 7: (R)-1-(4-((2-(5-fluoropyridine-3-yl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)ethane-1-one [ka] In step (d), (R)-3-fluoro-5-(oxiran-2-yl)pyridine was used to prepare the subject compound according to the procedure of Example 5. 1 H NMR(300MHz,CDCl3)δ8.50-8.24(m,2H),7.59-7.37(m,1H),4.70(dd,J=8.7,3.7Hz,1H),3.76-3.59(m,1H),3.58-3.24 (m,3H),2.95(ddd,J=11.9,4.8,3.7Hz,1H),2.58(dt,J=11.9,8.9Hz,1H),2.08(s,3H),1.58-1.45(m,4H),1.14(s,3H).

[0323] Example 8: (R)-1-(5-fluoropyridine-3-yl)-2-((4-methyl-1-(methylsulfonyl)piperidine-4-yl)amino)ethane-1-ol dihydrochloride [ka] Using methanesulfonyl chloride in step (a) and (R)-3-fluoro-5-(oxiran-2-yl)pyridine in step (d), the free base of the subject compound was prepared according to the procedure of Example 1 and dissolved in CH2Cl2. HCl (2M in Et2O) was added, and the mixture was concentrated to obtain the dihydrochloride salt. 1 H NMR(400MHz,CDCl3)δ8.57-8.49(m,1H),8.46(d,J=2.7Hz,1H),7.86-7.75(m,1H),5.08(dd,J=9.9,3.1Hz,1H),3.76-3.62( m,2H),3.29(d,J=3.3Hz,1H),3.15(dd,J=12.4,9.9Hz,1H),3.07-2.97(m,2H),2.89(s,3H),2.04-1.88(m,4H),1.46(s,3H).

[0324] Example 9: Ethyl 2-(((trans)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)oxy)acetate [ka]

[0325] (a) Ethyl 2-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)acetate [ka] Ethyl diazoacetate (0.59 mL, 4.88 mmol) was slowly added at room temperature to a stirred mixture of tert-butyl ((trans)-4-hydroxycyclohexyl) carbamate (0.50 g, 2.32 mmol), rhodium acetate dimer (31 mg, 70 μmol), and CH2Cl2 (25 mL). The mixture was stirred at room temperature for 15 minutes and then concentrated. The residue was purified by chromatography to obtain the subtitle compound (0.55 g, 79%).

[0326] (b) Ethyl 2-(((trans)-4-aminocyclohexyl)oxy)acetate [ka] CF3CO2H (1.41 mL, 18.4 mmol) was added at room temperature to a stirred solution of ethyl 2-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy) acetate (0.55 g, 1.84 mmol) in CH2Cl2 (2.5 mL). The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in CH2Cl2 and washed with H2O. The layers were separated, and NaHCO3 (aqueous solution, saturated) was added to the aqueous phase and extracted with iPrOH:CH2Cl2 (1:3). The combined organic phase was dried (Na2SO4) and concentrated to obtain the subtitle compound (0.33 g, 90%).

[0327] (c) Ethyl 2-(((trans)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)oxy)acetate [ka] Following the procedure of step (d) of Example 1, 85 mg (42%) of the subject compound was prepared from ethyl 2-(((trans)-4-aminocyclohexyl)oxy)acetate (0.12 g, 0.60 mmol), (R)-2-(3-fluorophenyl)oxirane (38 mg, 0.28 mmol), and iPrOH (0.5 mL). 1 H NMR(300MHz,CDCl3)δ7.36-7.27(m,1H),7.16-7.02(m,2H),6.95(tdd,J=8.5 ,2.6Hz,1H),4.68(dd,J=9.0,3.6Hz,1H),4.21(q,J=7.2Hz,2H),4.08(s,2H), 3.37-3.25(m,1H),2.97(dd,J=12.2,3.6Hz,1H),2.73-2.59(m,1H),2.52(tt, J=10.3,3.6Hz,1H),2.14-1.86(m,4H),1.41-1.24(m,5H),1.22-1.02(m,2H).

[0328] Example 10: 2-(((trans)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)oxy)acetic acid [ka] A solution of LiOH·H2O (31 mg, 0.73 mmol) in H2O (3 mL) was added at 0°C to an ice-cold THF (3 mL) stirred solution of ethyl 2-(((trans)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)aminocyclohexyl)oxy) acetate (62 mg, 0.18 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 16 hours. AcOH (52 μl, 0.91 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered through a cotton plug and rinsed with H2O:MeCN (1:1). The combined filtrate was concentrated, and the residue was purified by reverse-phase chromatography to obtain the subject compound (40 mg, 70%). 1 H NMR(300MHz,CD3OD)δ7.49-7.37(m,1H),7.31-7.15(m,2H),7.06(td,J=8.5,2.6Hz,1H),4.97(dd,J=10.3,3.0Hz,1H),3.91(s,2 H),3.48-3.36(m,1H),3.25(dd,J=12.6,3.0Hz,1H),3.17-3.01(m,2H),2.33-2.07(m,4H),1.60-1.41(m,2H),1.41-1.19(m,2H).

[0329] Example 11: N-((cis)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)acetamide [ka] The subject compound was prepared from tert-butyl((cis)-4-aminocyclohexyl)carbamate according to the procedure of Example 5. [α] D 25 =-11.3(c1.00,MeOH) 1 H NMR(400MHz,CD3OD)δ7.43-7.29(m,J=1H),7.24-7.10(m,2H),7.05-6.93(m,1H),4.78(dd,J=9.1,3.8Hz,1H),3.92-3.79(m,1H), 2.82(dd,J=12.1,3.8Hz,1H),2.73(dd,J=12.1,9.1Hz,1H),2.72-2.62(m,1H),1.96(s,3H),1.77-1.65(m,4H),1.65-1.46(m,4H).

[0330] Example 12: N-((cis)-4-(((R)-2-(5-fluoropyridine-3-yl)-2-hydroxyethyl)amino)cyclohexyl)acetamide [ka] Following the procedure of Example 5, the subject compound was prepared from tert-butyl((cis)-4-aminocyclohexyl)carbamate using (R)-3-fluoro-5-(oxiran-2-yl)pyridine in step (d). [α] D 25 = -19.3(c1.10, MeOH). 1 H NMR(400MHz,CD3OD)δ8.49-8.41(m,1H),8.40-8.33(m,1H),7.77-7.60(m,1H),4.86-4.83(m,1H),3.92-3.73(m,1H),2.86( dd,J=12.2,4.0Hz,1H),2.77(dd,J=12.1,8.7Hz,1H),2.72-2.61(m,1H),1.95(s,3H),1.77-1.64(m,4H),1.64-1.50(m,4H).

[0331] Example 13: N-((cis)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)methanesulfonamide hydrochloride [ka] In step (a), methanesulfonyl chloride was used, and the subject compound was prepared from tert-butyl((cis)-4-aminocyclohexyl)carbamate according to the procedure of Example 5. The free base was dissolved in CH2Cl2, HCl (2M in Et2O) was added, and the precipitate was collected and dried to obtain the subject hydrochloride. [α] D 25 = -9.8(c0.81,CHCl3). 1 H NMR(400MHz,CDCl3)δ:9.43(br s,1H),8.28(br s,1H),7.32-7.22(m,1H),7.20-7.12(m,2H),6.99-6.91(m,1H),6.49(d,J=6.7Hz,1H),5.65-5.53(m,1H),5.41(d,J =10.1Hz,1H),3.68-3.58(m,1H),3.37-3.21(m,1H),3.21-3.04(m,2H),2.98(s,3H),2.28-1.94(m,6H),1.64(s,2H).

[0332] Example 14: N-((cis)-4-(((R)-2-(5-fluoropyridine-3-yl)-2-hydroxyethyl)amino)cyclohexyl)methanesulfonamide [ka] The subject compound was prepared from tert-butyl((cis)-4-aminocyclohexyl)carbamate according to the procedure of Example 5, using methanesulfonyl chloride in step (a) and (R)-3-fluoro-5-(oxiran-2-yl)pyridine in step (d). [α] D 25 = -21.3(c0.80, MeOH). 1H NMR(400MHz,CD3OD)δ8.52-8.43(m,1H),8.43-8.35(m,1H),7.78-7.63(m,1H),4.95(dd,J=9.3,3.6Hz,1H),3.57-3.50(m,1H),3 .02(dd,J=12.3,3.6Hz,1H),2.95(s,3H),2.91(dd,J=12.3,9.3Hz,1H),2.87-2.80(m,1H),1.92-1.75(m,4H),1.75-1.55(m,4H).

[0333] Example 15: N-((trans)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)acetamide [ka] The subject compound was prepared from tert-butyl((trans)-4-aminocyclohexyl)carbamate according to the procedure of Example 5. [α] D 25 = -8.3(c1.62, MeOH). 1 H NMR(400MHz,CD3OD)δ7.40-7.29(m,1H),7.23-7.09(m,2H),7.05-6.93(m,1H),4.76(dd,J=9.2,3.6Hz,1H),3.70-3.53(m,1H),2 .83(dd,J=12.1,3.7Hz,1H),2.72(dd,J=12.1,9.2Hz,1H),2.59-2.42(m,1H),2.03-1.91(m,4H),1.91(s,3H),1.36-1.14(m,4H).

[0334] Example 16: N-((trans)-4-(((R)-2-(5-fluoropyridine-3-yl)-2-hydroxyethyl)amino)cyclohexyl)acetamide [ka] Following the procedure of Example 5, the subject compound was prepared from tert-butyl((trans)-4-aminocyclohexyl)carbamate using (R)-3-fluoro-5-(oxiran-2-yl)pyridine in step (d). [α] D 25 = -14.7(c1.22, MeOH). 1 H NMR(400MHz,CD3OD)δ8.47-8.41(m,1H),8.40-8.36(m,1H),7.76-7.61(m,1H),4.86-4.81(m,1H),3.69-3.53(m,1H),2.91(dd,J=12. 2,3.8Hz,1H),2.80(dd,J=12.2,9.0Hz,1H),2.62-2.46(m,1H),2.09-1.97(m,2H),1.97-1.92(m,2H),1.91(s,3H),1.36-1.17(m,4H).

[0335] Example 17: N-((trans)-4-(((R)-2-(3-fluorophenyl)-2-hydroxyethyl)amino)cyclohexyl)methanesulfonamide [ka] In step (a), methanesulfonyl chloride was used, and the subject compound was prepared from tert-butyl((trans)-4-aminocyclohexyl)carbamate according to the procedure of Example 5. [α] D 25 = -8.9(c1.12, MeOH). 1 H NMR(400MHz,CD3OD)δ7.41-7.30(m,1H),7.24-7.08(m,2H),7.07-6.91(m,1H),4.76(dd,J=9.2,3.7Hz,1H),3.20(tt,J=11.5,4.0Hz,1H),2 .95(s,3H),2.83(dd,J=12.1,3.7Hz,1H),2.73(dd,J=12.1,9.2Hz,1H),2.50(tt,J=10.8,3.7Hz,1H),2.12-1.91(m,4H),1.46-1.14(m,4H).

[0336] Example 18: N-((trans)-4-(((R)-2-(5-fluoropyridine-3-yl)-2-hydroxyethyl)amino)cyclohexyl)methanesulfonamide [ka] The subject compound was prepared from tert-butyl((trans)-4-aminocyclohexyl)carbamate according to the procedure of Example 5, using methanesulfonyl chloride in step (a) and (R)-3-fluoro-5-(oxiran-2-yl)pyridine in step (d). [α] D 25 = -11.8(c0.84, MeOH). 1 H NMR(400MHz,CD3OD)δ8.47-8.41(m,1H),8.41-8.33(m,1H),7.73-7.62(m,1H),4.86-4.82(m,1H),3.20(tt,J=11.5,3.9Hz,1H),2.95( s,3H),2.88(dd,J=12.1,3.9Hz,1H),2.77(dd,J=12.1,8.9Hz,1H),2.50(tt,J=10.7,3.7Hz,1H),2.11-1.93(m,4H),1.43-1.15(m,4H).

[0337] Example 19: Methyl(R)-2-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)acetate dihydrochloride [ka]

[0338] (a) Methyl 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)acetate [ka] Methyl bromoacetate (0.48 mL, 5.1 mmol) and K2CO3 (1.29 g, 9.3 mmol) were added to a solution of tert-butyl(4-methylpiperidine-4-yl)carbamate (1.00 g, 4.7 mmol) in DMF (10 mL) at room temperature, and the mixture was stirred at room temperature for 18 hours. H2O was added, and the mixture was extracted with phenylethylamine. The combined extract was dried (Na2SO4) and concentrated to obtain the sub-subject compound (0.64 g, 48%), which was used in the next step without further purification.

[0339] (b) Methyl(R)-2-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)acetate dihydrochloride [ka] In Example 5, the subject compound was prepared from methyl 2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)acetate according to the procedures of steps (b) and (c). HCl (4M in dioxane) was added to the free base in MeCN, the solid was collected, washed with Et2O, and dried to obtain the dihydrochloride salt. [α] D 20 -30.3 (c0.69, MeOH). 1 H NMR(400MHz,CD3OD)δ7.42(td,J=8.0,5.8Hz,1H),7.33-7.24(m,2H),7.12-7.04(m,1H),5.05(d,J=10.2Hz,1H),4.21(s,2H),3.87(s,3H),3. 78-3.68(m,2H),3.44-3.33(m,2H),3.29(d,J=2.9Hz,1H),3.13(dd,J=12.3,10.5Hz,1H),2.44-2.28(m,2H),2.27-2.10(m,2H),1.57(s,3H).

[0340] Example 20: (R)-2-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)acetate [ka] A solution of LiOH (11 mg, 0.46 mmol) in H2O (3 mL) was slowly added at room temperature to a solution of methyl(R)-2-(4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl) acetate (225 mg, 1.21 mmol) in THF (3 mL), and the mixture was stirred at room temperature for 18 hours. AcOH (1 mL) was added, and the mixture was concentrated. The residue was dissolved in MeCN / H2O and purified by preparative HPLC (Atlantis T3, (10 × 100 mm, 5 μm), H2O:MeCN mixture containing 0.01% AcOH, 100:0~50:50) to obtain the subject compound (33 mg, 96%). [α] D 20 -17.8 (c0.71, MeOH). 1 H NMR(400MHz,CD3OD)δ7.37(td,J=8.0,5.8Hz,1H),7.24-7.14(m,2H),7.01(tdd,J=8.2,2.7,1.0Hz,1H),4.75(dd,J =7.7,4.5Hz,1H),3.45(s,2H),3.24-3.05(m,4H),2.85-2.72(m,2H),1.98(s,3H),1.91-1.71(m,4H),1.22(s,3H).

[0341] Example 21: Methyl(R)-2-((4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)sulfonyl)acetate hydrochloride [ka] Using methyl 2-(chlorosulfonyl)acetate in step (a), the free base of the subject compound was prepared from tert-butyl(4-methylpiperidine-4-yl)carbamate according to the procedure of Example 5. The hydrochloride salt was prepared by treating the CHCl3 solution of the free base with HCl (4M in dioxane), adding heptane, removing the CHCl3 in an argon stream, recovering the solid, and drying it. [α] D 20 -17.6 (c1.00, MeOH). 1 H NMR(400MHz,CD3OD)δ7.42(td,J=8.0,5.8Hz,1H),7.31-7.23(m,2H),7.10-7.03(m,1H),4.98(dd,J=10.3,2.9Hz,1H),4.1 9(s,2H),3.86-3.79(m,2H),3.78(s,3H),3.27(dd,J=12.4,3.0Hz,1H),3.19-3.05(m,3H),2.03-1.90(m,4H),1.48(s,3H).

[0342] Example 22: (R)-2-((4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)sulfonyl)acetic acid [ka] The subject compound was prepared from methyl(R)-2-((4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-yl)sulfonyl) acetate according to the procedure of Example 20. [α] D 20 -16.7(c0.60,DMSO-d6 / MeOH=1:1). 1H NMR(400MHz,DMSO-d6)δ7.39(td,J=8.0,6.0Hz,1H),7.29-7.21(m,2H),7.12-7.04(m,1H),4.81(dd,J=9.4,3.3Hz,1H),3.95-3.81(m,2H), 3.42-3.34(m,2H),3.18-3.09(m,2H),3.00-2.90(m,1H),2.74(dd,J=11.8,9.5Hz,1H),1.85-1.70(m,2H),1.69-1.56(m,2H),1.18(s,3H).

[0343] Example 23: (R)-2-((1-(butylsulfonyl)-4-methylpiperidine-4-yl)amino)-1-(3-fluorophenyl)ethane-1-ol acetate [ka]

[0344] (a)tert-butyl(R)-4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-carboxylate [ka] In Example 1, the subtitle compound was prepared from tert-butyl 4-amino-4-methylpiperidine-1-carboxylate and (R)-2-(3-fluorophenyl)oxirane according to the procedure in step (g).

[0345] (b)(R)-1-(3-fluorophenyl)-2-((4-methylpiperidine-4-yl)amino)ethane-1-ol [ka] HCl (aqueous solution, 4M, 0.39 mL, 0.16 mmol) was slowly added at room temperature to a MeOH (1 mL) stirred solution of tert-butyl(R)-4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-4-methylpiperidine-1-carboxylate, and the mixture was stirred at room temperature for 18 hours. CH2Cl2 (5 mL) and NaOH (aqueous solution, 1M, 5 mL) were added, and the mixture was stirred at room temperature for 15 minutes. The layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined extract was washed with brine, dried (Na2SO4), and concentrated to obtain the subtitle compound (33 mg, 84%).

[0346] (c)(R)-2-((1-(butylsulfonyl)-4-methylpiperidine-4-yl)amino)-1-(3-fluorophenyl)ethane-1-ol [ka] 1-Butanesulfonyl chloride (8 μL, 60 μmol) was slowly added at -18°C to a stirred mixture of (R)-1-(3-fluorophenyl)-2-((4-methylpiperidine-4-yl)amino)ethane-1-ol (15 mg, 60 μmol), Et3N (10 μL, 70 μmol), and MeCN (1 mL). The mixture was stirred at -18°C for 1 hour. AcOH (0.1 mL) and H2O (0.5 mL) were added. The mixture was stirred at room temperature for 5 minutes, filtered (0.2 μM filter), and purified by preparative HPLC (Atlantis T3 (10 × 100 mm, 5 μm), H2O:MeCN containing 0.01% AcOH, 100:0~50:50) to obtain the subject compound (15 mg, 58%). [α] D 20 -17.8 (c1.40, MeOH). 1H NMR(400MHz,CD3OD)δ7.38(td,J=8.0,5.8Hz,1H),7.27-7.17(m,2H),7.03(tdd,J= 8.2,2.7,1.0Hz,1H),4.86-4.83(m,1H),3.58-3.48(m,2H),3.16-3.07(m,2H),3.0 5(dd,J=12.0,3.5Hz,1H),3.02-2.97(m,2H),2.92(dd,J=12.0,9.4Hz,1H),1.94(s ,3H),1.88-1.69(m,6H),1.48(h,J=7.5Hz,2H),1.33(s,3H),0.97(t,J=7.4Hz,3H).

[0347] Example 24: (R)-4-((2-(3-fluorophenyl)-2-hydroxyethyl)amino)-N,N,4-trimethylpiperidine-1-carboxamide acetate [ka] In step (c), dimethylcarbamoyl chloride was used, and the subject compound was prepared according to the procedure of Example 23. 1 H NMR(400MHz,CD3OD)δ7.40(td,J=8.1,5.9Hz,1H),7.29-7.19(m,2H),7.08-7.01(m,1H),4.93-4.90(m,1H),3.6 3-3.54(m,2H),3.18-3.03(m,2H),3.02-2.95(m,2H),2.85(s,6H),1.94(s,3H),1.90-1.73(m,4H),1.41(s,3H).

[0348] 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 to 24) with a suitable amount of a suitable excipient. The resulting mixture is formed into tablets. Optionally, a suitable coating is applied to the tablets.

[0349] Biological examples L6 myoblasts were grown in Dulbecco's Modified Eagle Medium (DMEM) containing 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.

[0350] Biological Example 1: Glucose Uptake Differentiated L6-myotubes were serum-deficient overnight in a medium containing 0.5% fatty acid-free BSA, resulting in a final concentration of 1x10⁶. -5 Cells were stimulated with a 50 nM agonist. After 1 hour and 40 minutes, cells were washed twice with warm glucose-free medium or PBS, and another agonist was added to the glucose-free medium. After 20 minutes, cells were stimulated with a 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 400 μL / well of 0.2 M NaOH 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 with a β-counter (Tri-Carb4810TR, Perkin Elmer). The activity of each compound was compared to the activity of isoproterenol. If the compound showed activity greater than 75% of the activity of 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 -.

[0351] Biological Example 2: Measurement of Intracellular cAMP Concentration Differentiated cells were kept serum-deficient overnight and then immersed in a stimulation buffer (HBSS with 1% BSA, 5 mM HEPES, and 1 mM IBMX, pH 7.4) to a final concentration of 1 × 10⁶. -5Cells were stimulated with an M agonist 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 stored overnight at -20°C. The EtOH was evaporated, and 500 μL of lysis buffer (1% BSA, 5 mM HEPES, 0.3% Tween-20, pH 7.4) was added to each well. The plate was stored at -80°C for 30 minutes, and then stored at -20°C until the detection day when the samples were thawed. Intracellular cAMP levels were detected using the AlphaScreen cAMP kit (Perkin Elmer 6760635D). The activity of each compound was compared to the activity of isoproterenol. If the compound showed activity greater than 75% of the activity of 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 -.

[0352] The following results were obtained using the assays described in Biological Examples 1 and 2. [Table 1]

[0353] Biological Example 3: Glucose uptake in the presence of the β2 antagonist ICI-118,551 The fact that glucose uptake is mediated by the activation of β2-adrenergic receptors can be confirmed by observing a decrease (or disappearance) of glucose uptake in the presence of a β2 antagonist (ICI-118,551).

[0354] Differentiated L6-myotubes were serum-deficient overnight in a medium containing 0.5% fatty acid-free BSA, resulting in a final concentration of 1 × 10⁶. -5 Incubate M cells with the β2-adrenergic receptor antagonist ICI-118,551 for 30 minutes. The cells reach a final concentration of 1 × 10⁶. -5 The cells are stimulated with the compound of the present invention at M. After 1 hour and 40 minutes, the cells are washed twice with warm glucose-free medium or PBS, and additional amounts of the compound of the present invention and the antagonist are added. After 20 minutes, the cells are stimulated with 50 nM 3Expose the cells to H-2-deoxyglucose for 10 minutes, then wash three times with ice-cold glucose-free medium or PBS, and lyse in 400 μL / well of 0.2 M NaOH at 60°C for 1 hour. Mix the cell lysate with 4 mL of scintillation buffer (Emulsifier Safe, Perkin Elmer) and detect radioactivity with a β-counter (Tri-Carb4810TR, Perkin Elmer). Compare the activity of each compound to the activity of isoproterenol. If the compound shows more than 75% of the activity of 10 μM isoproterenol, the activity is indicated as +++; if it is between 75% and 50%, as ++; if it is between 50% and 25%, as +; and if it is less than 25%, as -.

Claims

1. Compound of formula I 【Chemistry 1】 Or, a pharmaceutically acceptable salt thereof In the formula, R １ is H or C １－６ Represents alkyl, Q １ ~Q ５ Each of these independently represents a carbon atom, a heteroatom, or a direct bond, Q １ ~Q ５ A ring containing, One or more Y １ Phenyl, which may be optionally substituted with, or One or more Y ２ This represents a five-membered or six-membered heteroaryl which may be optionally substituted, Each Y １ independently represents halo, R ａ１ , -CN, -N ３ , -N(R ｂ１ )R ｃ１ , or -OR ｄ１ and represents Each Y ２ However, they became independent, Hello, R ａ２ -CN, -N ３ , -N(R ｂ２ ) R ｃ２ , or -OR ｄ２ This represents, Ring A represents a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl containing one or two heteroatoms selected from N or O. n represents a value between 0 and 5. If each Z is present on a carbon atom, then independently, 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, If each Z is present on a nitrogen atom, R is independent. ａ３ , -S(O) ｐ R ｅ３ , or -S(O) ｑ N(R) ｆ３ ) R ｇ３ This represents, Each R ａ１ and R ａ２ However, C may be optionally substituted by one or more halos independently. １－６ Represents alkyl, Each R ａ１ and R ａ２ However, C may be optionally substituted by one or more halos independently. １－６ Represents alkyl, Each R ａ３ , R ｅ３ , and R ｉ３ However, independently, Halo and G １ C may be optionally substituted by one or more groups independently selected from 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 may be optionally substituted by one or more groups independently selected from each of them. １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Representing Alkinnil, Alternatively, R ｂ３ and R ｃ３ , and / or R ｆ３ and R ｇ３ Any of these may bond together with the nitrogen atom to which they are bonded to form a 4- to 6-membered ring, which may optionally contain one further heteroatom, and which may optionally be substituted by a halo, or one or more halos. １－３ It may be optionally substituted with one or more groups independently selected from alkyl and =O groups. Each G １ and G ２ However, R ａ４ -CN, -N ３ , -N(R ｂ４ ) R ｃ４ , -OR ｄ４ This represents -S(O) ｐ R ｅ４ , -S(O) ｑ N(R) ｆ４ ) R ｇ４ , -N(R ｈ４ ) S(O) ｒ R ｉ４ , or = represents O, Each R ａ４ independently represents phenyl or a 5- or 6-membered heteroaryl, each of which is 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 may be optionally substituted. Each R ｂ４ , R ｃ４ , R ｄ４ , R ｆ４ , R ｈ４ , and R ｇ４ However, C may be independently and optionally substituted by H, or one or more halos, -CN, or =O. １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Representing Alkinnil, Each R ｅ４ and R ｉ４ C may be independently and optionally replaced by one or more halos or -CNs. １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Representing Alkinnil, Alternatively, R ｂ４ and R ｃ４ , and / or R ｆ４ and R ｇ４ Any of these may bond together with the nitrogen atom to which they are bonded to form a 4- to 6-membered ring, which may optionally contain one further heteroatom, and which may optionally be substituted by a halo, or one or more halos. １－３ It may be optionally substituted with one or more groups independently selected from alkyl and =O groups. Each R ａ５ , R ｅ５ , and R ｉ５ However, independently, C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Represents alkynyl, and the C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Each alkynyl may be optionally substituted with a halo or one or more halos. １－３ It may be optionally substituted with one or more groups independently selected from alkyl and =O groups. Each R ｂ５ , R ｃ５ , R ｄ５ , R ｆ５ , R ｇ５ , and R ｈ５ Each of them operates independently. H, or C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Represents alkynyl, and the C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Each alkynyl may be optionally substituted with a halo or one or more halos. １－３ It may be optionally substituted with one or more groups independently selected from alkyl and =O groups. Alternatively, R ｂ５ and R ｃ５ , and / or R ｆ５ and R ｇ５ Any of these may bond together with the nitrogen atom to which they are bonded to form a 4- to 6-membered ring, which may optionally contain one further heteroatom, and which may optionally be substituted by a halo, or one or more halos. １－３ It may be optionally substituted with one or more groups independently selected from alkyl and =O groups. Each p independently represents 0, 1, or 2. Each q independently represents either 1 or 2. Each r independently represents either 1 or 2, Each t independently represents either 1 or 2, However, the compound of formula I is as follows, in accordance with the conditions (A) to (C) below. (A) 4-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]cyclohexane-1-ol, (B) (αR)-α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)aminomethyl]benzenemethanol, α-[[(3-aminocyclobutyl)amino]methyl]benzenemethanol, (αR)-α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-3-pyridinemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-4-pyridinemethanol, α-[[(4-methylcyclohexyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, (αR)-α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, α-[[(trans-4-methylcyclohexyl)aminomethyl]benzenemethanol, α-[[(3-aminocyclopentyl)aminomethyl]benzenemethanol, α-[[(3-methylcyclopentyl)aminomethyl]benzenemethanol, α-[[(3-methylcyclohexyl)aminomethyl]benzenemethanol, α-[[(3-aminocyclohexyl)amino]methyl]benzenemethanol, α-[[(4-aminocyclohexyl)amino]methyl]benzenemethanol, α-[[(3-fluorocyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]-3-pyridinemethanol, (αR)-α-[[(3-fluorocyclobutyl)amino]methyl]benzenemethanol, α-[[(4-methylcycloheptyl)aminomethyl]benzenemethanol, (αR)-α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-3-azetidinyl)aminomethyl]benzenemethanol, (αS)-α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, α-[[(4-hydroxycyclohexyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclopentyl)amino]methyl]-3-pyridinemethanol, α-[[(3-methylcyclopentyl)amino]methyl]-4-pyridinemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(4-methylcyclohexyl)amino]methyl]-4-pyridinemethanol, α-[[(3-methylcyclohexyl)amino]methyl]-4-pyridinemethanol, (αR)-α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, (αS)-α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-3-pyrrolidinyl)aminomethyl]benzenemethanol, 5-[(2-hydroxy-2-phenylethyl)amino]cyclooctanol, α-[[(3-fluorocyclobutyl)amino]methyl]-3-pyridinemethanol, α-[[(1-methyl-3-piperidinyl)aminomethyl]benzenemethanol, α-[[(1-methyl-3-azetidinyl)amino]methyl]-3-pyridinemethanol, α-[[(Hexahydro-1-methyl-1H-azepine-4-yl)aminomethyl]benzenemethanol, α-[[(3-fluorocyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]-4-pyridinemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]-3-pyridinemethanol, α-[[(1-methyl-4-piperidinyl)aminomethyl]benzenemethanol hydrochloride, α-[[(1-methyl-3-azetidinyl)amino]methyl]-2-pyridinemethanol, (C) α-[[(1-methyl-4-piperidinyl)aminomethyl]benzenemethanol, 2-((1-benzylpiperidine-4-yl)amino)-1-phenylethanol, 4-(1-hydroxy-2-((1-methylpiperidine-4-yl)aminoethyl)phenol, 4-(2-((1-benzylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 4-(2-((1-butylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 3-(2-((1-butylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 4-(1-hydroxy-2-((1-(2-methoxyethyl)piperidine-4-yl)aminoethyl)phenol, or A compound that does not fall under any of the following categories: 4-(1-hydroxy-2-((1-phenethylpiperidine-4-yl)aminoethyl)phenol.

2. Furthermore, according to the following conditions (D) to (M), the compound of formula I is as follows: (D) 【Chemistry 2】 (E) 【Transformation 3】 (F) 【Chemistry 4】 (G) 【Transformation 5】 (H) 【Transformation 6】 (J) 【Transformation 7】 (K) 【Transformation 8】 (L) 【Chemistry 9】 (M) 【Chemistry 10】 The compound according to claim 1, which does not fall under any of the above.

3. Q １ ~Q ５ The ring including, One or more Y １ Phenyl, which may be optionally substituted, One or more Y ２ The compound according to claim 1 or 2, comprising pyridyl which may be optionally substituted.

4. Each Y １ R ａ１ A compound according to any one of the preceding claims, representing a halo or -CN.

5. Each Y ２ However, R ａ２ A compound according to any one of the preceding claims, representing a halo or -CN.

6. Each Y １ and Y ２ A compound according to any one of the preceding claims, wherein F represents the compound.

7. If each Z is present on a carbon atom, then independently, halo, R ａ３ , -CN, -N(R ｂ３ ) R ｃ３ , -OR ｄ３ , or -N(R ｈ３ ) S(O) ｔ R ｉ３ A compound according to any one of the preceding claims 1, which represents the compound.

8. If each Z is present on a carbon atom, then independently, R ａ３ , -N(R ｂ３ ) R ｃ３ , -OR ｄ３ , or -N(R ｈ３ ) S(O) ｔ R ｉ３ This represents, for example, R ａ３ A compound according to any one of the preceding claims, representing the above.

9. A compound according to any one of the preceding claims, wherein t represents 2.

10. A compound according to any one of the preceding claims, wherein n represents 1.

11. The compound of formula I is the compound of formula IX, 【Chemistry 11】 During the ceremony, Q １ ~Q ５ , R １ n and Z are as defined in any of the prior claims, X represents C or N, The compound according to any one of the preceding claims, wherein m1 and m2 independently represent 0 to 2.

12. The compound of formula IX is the compound of formula IE, 【Chemistry 12】 Q １ ~Q ５ , R １ The compound according to claim 11, wherein Z is as defined in any of the prior claims, and X is as defined in claim 11.

13. A compound as defined in any one of claims 1 to 12, for use in medicine.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, and one or more pharmaceutically acceptable adjuvants, diluents, and / or carriers, optionally selected from among them.

15. A compound as defined in any one of claims 1 to 12, for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

16. Use of a compound as defined in any one of claims 1 to 12 for the manufacture of a medicament for the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

17. A method for treating hyperglycemia or a disorder characterized by hyperglycemia, comprising administering a therapeutically effective amount of a compound defined in any one of claims 1 to 12 to a patient in need thereof.

18. A compound, method, or use according to any one of claims 15 to 17, wherein hyperglycemia or a disorder characterized by hyperglycemia is characterized by or by a patient exhibiting severe insulin resistance.

19. A compound, method, or use for use according to any one of claims 15 to 18, wherein the disorder characterized by hyperglycemia is selected from the group consisting of type 2 diabetes, Rabson-Mendenhall syndrome, Donahue syndrome (fairy syndrome), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.

20. A compound as defined in any one of claims 1 to 12, for use in the treatment of non-alcoholic fatty liver disease.

21. Use of the compound according to any one of claims 1 to 12 in the manufacture of a pharmaceutical product for the treatment or prevention of non-alcoholic fatty liver disease.

22. A method for treating non-alcoholic fatty liver disease, comprising administering a therapeutically effective amount of a compound defined in any one of claims 1 to 12 to a patient in need thereof.

23. Said β ２ A compound as defined in any one of claims 1 to 12, used for the treatment of a disease or disorder mediated by the activation of adrenaline receptors.

24. Said β ２ Use of a compound as defined in any one of claims 1 to 12 in the manufacture of a pharmaceutical product for use in the treatment of a disease or disorder mediated by the activation of adrenaline receptors.

25. Said β ２ A method for treating a disease or disorder by activation of adrenaline receptors, comprising administering a therapeutically effective amount of a compound defined in any one of claims 1 to 12 to a patient in need thereof.

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