Combination of beta-2 adrenergic receptor agonists and GLP-1 receptor agonists for use in the treatment of hyperglycemia.

Abstract

There is provided herein a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia, wherein the treatment and / or prophylaxis further comprises administration of: (a) insulin or a therapeutic insulin derivative; or (b) a therapeutic agent stimulating the release of insulin.

Description

1 / 138 COMBINATION OF BETA-2-ADRENERGIC RECEPTOR AGONISTS AND GLP-1 RECEPTOR AGONISTS FOR USE IN THE TREATMENT OF HYPERGLYCEMIA FIELD OF THE INVENTION

[0001] The present invention relates to methods for the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia. In particular, the invention relates to methods for the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, involving treatment and / or prophylaxis with a combination of a P2-adrenergic receptor agonist and insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release, and to compositions and kits of parts for use in such methods. BACKGROUND OF THE INVENTION

[0002] The listing or discussion of any document apparently published previously in this descriptive report should not necessarily be taken as an acknowledgment that the document is part of the state of the art or is common general knowledge.

[0003] Hyperglycemia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. If left untreated, hyperglycemia can be a serious problem, potentially leading to life-threatening conditions such as ketoacidosis. For example, chronic hyperglycemia can cause heart damage and is strongly associated with heart attacks and death in individuals without coronary artery disease or a history of heart failure. There are several causes of hyperglycemia, including diabetes and severe insulin resistance.

[0004] Severe insulin resistance (SIR) is a condition in which the patient exhibits very low levels (or, in extreme cases, no significant response) to insulin. There are several syndromes characterized by SIR, including Rabson-Mendenhall syndrome, Donohue syndrome (leprechaunism), Type A and Type B insulin resistance syndromes, and the syndrome Petition 870250079411, dated 05 / 09 / 2025, page 18 / 165 2 / 138 HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans), pseudoacromegaly, and lipodystrophy. Most of these conditions have genetic causes, such as mutations in the insulin receptor gene. The prevalence of Donohue syndrome, Rabson-Mendenhall syndrome, and type A insulin resistance syndrome ranges from about 50 recorded cases to 1 in 100,000. However, because some diseases are severe and extremely rare, it is likely that many patients will not be diagnosed before death, especially in less developed areas of the world. Therefore, it is difficult to assess the exact number of patients with these syndromes.

[0005] The current standard for treating hyperglycemia in patients with IBS is a controlled diet, supplemented with medications that affect insulin receptor sensitivity, such as metformin, or insulin supplementation. However, particularly in disorders caused by mutations in the insulin receptor gene, this treatment is not sufficiently effective and often fails.

[0006] Diabetes comprises two distinct diseases, type 1 (or insulin-dependent diabetes) and type 2 (insulin-independent diabetes), both involving malfunction of glucose homeostasis. Type 2 diabetes affects more than 400 million people worldwide, and this number is rapidly increasing. Complications of type 2 diabetes include serious cardiovascular problems, kidney failure, peripheral neuropathy, blindness, and, in the most advanced stages of the disease, even limb loss and ultimately death. Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue, and currently there is no definitive cure. Most treatments currently used focus on remedying dysfunctional insulin signaling or inhibiting glucose production by the liver, but many of these treatments have several disadvantages and side effects.Therefore, there is great interest in identifying new insulin-independent forms of treatment for type 2 diabetes.

[0007] In type 2 diabetes, the insulin signaling pathway is reduced in peripheral tissues, such as adipose tissue and skeletal muscle. The Petition 870250079411, dated 05 / 09 / 2025, page 19 / 165 3 / 138 Treatment methods for type 2 diabetes typically include lifestyle changes as well as insulin injections or oral medications to regulate glucose homeostasis. People with type 2 diabetes in the more advanced stages of the disease develop "beta cell insufficiency," meaning the pancreas is unable to release insulin in response to high blood glucose levels. In the more advanced stages of the disease, patients usually need insulin injections in combination with oral medications to control their diabetes. Furthermore, the most common medications have side effects that include downregulation or desensitization of the insulin pathway and / or promotion of lipid incorporation in adipose tissue, liver, and skeletal muscle. Therefore, there is great interest in identifying new ways to treat metabolic diseases, including type 2 diabetes, that do not include these side effects.

[0008] After a meal, the increase in blood glucose levels stimulates the release of insulin by the pancreas. Insulin mediates the normalization of blood glucose levels. Important effects of insulin on glucose metabolism include facilitating glucose uptake in skeletal muscle and adipocytes and increasing glycogen storage in the liver. Skeletal muscle and adipocytes are responsible for insulin-mediated glucose uptake and utilization in the fed state, making them very important sites for glucose metabolism.

[0009] The downstream signaling pathway of the insulin receptor has been difficult to understand in detail. In summary, the control of glucose uptake by insulin involves the activation of the insulin receptor (IR), the insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and therefore the stimulation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), the mammalian target of rapamycin (also called the mechanistic target of rapamycin, mTOR), Akt / PKB (Akt), and TBC1D4 (AS160), leading to the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Akt activation is considered necessary for GLUT4 translocation.

[0010] It should be noted that skeletal muscles Petition 870250079411, dated 05 / 09 / 2025, page 20 / 165 Skeletal muscles, comprising 4 / 138 of the body weight of mammals, play a vital role in regulating systemic glucose metabolism, accounting for up to 85% of total body glucose uptake. Glucose uptake in skeletal muscles is regulated by several intra- and extracellular signals. Insulin is the most well-studied mediator, but others also exist. For example, AMP-activated protein kinase (AMPK) functions as an energy sensor in the cell, which can increase glucose uptake and fatty acid oxidation. Due to the significant influence skeletal muscles have on glucose homeostasis, it is plausible that additional mechanisms exist. In light of the increasing prevalence of type 2 diabetes, it is of great interest to find and characterize new 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 into the body in response to different stimuli. While insulin is released in response to increased blood sugar levels (for example, after a meal), 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, glycogen formation, and triglycerides, while catecholamines are primarily catabolic.

[0012] Although insulin and catecholamines normally have opposing effects, they have been shown to have similar actions 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)) to provide muscle cells with an energy-rich substrate. Therefore, it is likely that in mammals, including humans, the adrenergic and insulin systems can function independently to regulate the energy needs of skeletal muscle in different situations. As insulin also stimulates Petition 870250079411, dated 05 / 09 / 2025, page 21 / 165 5 / 138 many anabolic processes, including some that promote undesirable effects, such as stimulating the incorporation of lipids into tissues, leading, for example, to obesity, it would be beneficial to be able to stimulate glucose uptake by other means, for example, by stimulating adrenergic receptors (ARs).

[0013] All ARs are G protein-coupled receptors (GPCRs) located in the cell membrane and characterized by an extracellular N-terminus, followed by seven transmembrane α-helices (TM-1 to TM-7) connected by three intracellular loops (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally, an intracellular C-terminus. There are three different classes of ARs, with distinct expression patterns and pharmacological profiles: αι-, α2-, and β-ARs. αι-ARs comprise the subtypes αϊA, αϊB, and αιO, while α2-ARs are divided into α2A, α2B, and α2C. Beta receptors (β-ARs) are also divided into β1, β2, and β3 subtypes, of which β2-AR is the main isoform in skeletal muscle cells. ARs are G protein-coupled receptors (GPCRs) that signal via classic secondary messengers such as cyclic adenosine monophosphate (cAMP) and phospholipase C (PLC).

[0014] Many effects that occur downstream of ARs in skeletal muscles have been attributed to classical secondary messenger signaling, such as increased cAMP levels, PLC activity, and calcium levels. Stimulation involving classical secondary messengers has many effects on different tissues. For example, it increases heart rate, blood flow, airflow in the lungs, and glucose release from the liver, which can be detrimental or considered an undesirable side effect if AR stimulation is considered a treatment for type 2 diabetes. Adverse effects of classical AR agonists include, for example, tachycardia, palpitations, tremors, sweating, agitation, and increased blood glucose levels (glucose production by the liver).Therefore, it would be beneficial to be able to activate ARs without activating these classic secondary messengers, such as cAMP, to increase glucose uptake in peripheral tissues without stimulating unwanted side effects.

[0015] Glucose uptake is primarily stimulated by facilitating glucose transporters (GLUTs) that mediate uptake. Petition 870250079411, dated 05 / 09 / 2025, page 22 / 165 6 / 138 of glucose in most cells. GLUTs are transporter proteins that mediate the transport of glucose and / or fructose across the plasma membrane down the concentration gradient. There are fourteen known members of the GLUT family, designated GLUT1-14, divided into three classes (Class I, Class II, and Class III) depending on 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 (in contrast to Class II, which also transports fructose). GLUT1 is ubiquitously expressed and is responsible for 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, for example, in the brain, kidneys, and liver. GLUT4 is the main isoform involved in insulin-stimulated glucose uptake.The mechanism by which insulin signaling increases glucose uptake occurs primarily through the translocation of GLUT4 from intracellular storage to the plasma membrane. GLUT4 translocation is known to be induced by stimulation of the β2-adrenergic receptor.

[0016] Currently, there are several treatments for diabetes and related conditions that work by increasing insulin sensitivity. They can be used in isolation, thus increasing sensitivity to natural insulin production, or in combination with therapeutic agents that work by increasing insulin levels, which may allow these agents to be used at lower doses and / or less frequently.

[0017] However, these insulin sensitization treatments are known to have a number of limitations, including an association with serious adverse events.

[0018] Therefore, there is still a need for safe and effective insulin sensitizing agents for use in the treatment of diabetes and related conditions. DESCRIPTION OF THE INVENTION

[0019] We have now discovered, surprisingly, that the Petition 870250079411, dated 05 / 09 / 2025, p. 23 / 165 7 / 138 Activation of the β2-adrenergic receptor results in increased insulin receptor sensitivity, so treatment and / or prophylaxis with β2-adrenergic receptor agonists in combination with insulin or insulin-releasing agents allows for effective treatment and / or prophylaxis of conditions characterized by high blood sugar levels (i.e., hyperglycemia), such as diabetes (e.g., type 2 diabetes). USES IN MEDICINE

[0020] In a first aspect of the invention, a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, wherein the treatment and / or prophylaxis further comprises the administration of:

[0021] (a) insulin or a therapeutic insulin derivative; or

[0022] (b) a therapeutic agent that stimulates insulin release.

[0023] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning commonly understood by a person skilled in the art to which this invention relates.

[0024] Preferences and options for a given aspect, embodiment, feature or parameter of the invention shall, unless the context indicates otherwise, be deemed to have been disclosed in combination with any and all preferences and options for all other aspects, features and parameters of the invention.

[0025] Whenever the word “about” is used herein (for example, in the context of doses of active ingredients), it will be appreciated that such variables are approximate and, as such, may vary by ± 10%, for example, ± 5% and preferably ± 2% (for example, ± 1%) of the figures specified herein.

[0026] Whenever the word “optionally” is used in relation to the resources described in this document, it will have its Petition 870250079411, dated 05 / 09 / 2025, p. 24 / 165 8 / 138 normal meaning, that is, the relevant feature may or may not be present.

[0027] In a first alternative aspect of the invention, the use of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, is provided in the manufacture of a medicament for the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, wherein the treatment and / or prophylaxis further comprises the administration of:

[0028] (a) insulin or a therapeutic insulin derivative; or

[0029] (b) a therapeutic agent that stimulates insulin release.

[0030] In a first alternative aspect of the invention, the use of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, is provided for in the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, wherein the treatment and / or prophylaxis further includes the administration of:

[0031] (a) insulin or a therapeutic insulin derivative; or

[0032] (b) a therapeutic agent that stimulates insulin release.

[0033] In a first alternative aspect of the invention, a compound is provided which is:

[0034] (a) insulin or a therapeutic insulin derivative; or

[0035] (b) a therapeutic agent that stimulates insulin release

[0036] for use in the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, wherein the use also includes the administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof. Petition 870250079411, dated 05 / 09 / 2025, page 25 / 165 9 / 138

[0037] In a first alternative aspect of the invention, the use of a compound is provided which is:

[0038] (a) insulin or a therapeutic insulin derivative; or

[0039] (b) a therapeutic agent that stimulates insulin release

[0040] in the manufacture of a medicament for the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, wherein the use also includes the administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0041] In a first alternative aspect of the invention, the use of a compound is provided which is:

[0042] (a) insulin or a therapeutic insulin derivative; or

[0043] (b) a therapeutic agent that stimulates insulin release

[0044] in the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, the use also including the administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0045] In a first alternative aspect of the invention, a combination is provided of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and a compound that is:

[0046] (a) insulin or a therapeutic insulin derivative; or

[0047] (b) a therapeutic agent that stimulates insulin release

[0048] for use in the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia.

[0049] In a first alternative aspect of the invention, it is Petition 870250079411, dated 05 / 09 / 2025, page 26 / 165 10 / 138 provided a method for the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, comprising:

[0050] (i) administration of a therapeutically effective amount of

[0051] (a) a therapeutically effective amount of insulin or of a therapeutic insulin derivative; or

[0052] (b) a therapeutically effective amount of a therapeutic agent that stimulates insulin release, and

[0053] (ii) administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof,

[0054] to a patient in need of the same.

[0055] In a first alternative aspect of the invention, a method is provided for the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, comprising administering a therapeutically effective amount of

[0056] (a) insulin or a therapeutic insulin derivative; or

[0057] (b) a therapeutic agent that stimulates insulin release

[0058] to a patient in need thereof, wherein the patient is also being treated with a therapeutically effective amount of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0059] In a first alternative aspect of the invention, a method is provided for the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, comprising administering a therapeutically effective amount of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient is also being treated with a therapeutically effective amount of Petition 870250079411, dated 05 / 09 / 2025, page 27 / 165 11 / 138

[0060] (a) insulin or a therapeutic insulin derivative; or

[0061] (b) a therapeutic agent that stimulates insulin release.

[0062] For the avoidance of doubt, the uses, methods, compositions and parts kits of other aspects of the invention, as described in this document (including all embodiments thereof), may have any of the specific features described above for the first aspect of the invention, including all combinations thereof.

[0063] For the avoidance of doubt, the treatments (and associated prophylaxis) described in this document may be referred to as “treatments of the invention” or similar.

[0064] Those skilled in the art will understand that references to the “treatment of” a particular condition (and, similarly, “to treat”) will assume their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition. In particular, the terms may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition.

[0065] As used herein, references to patients will refer to a living subject being treated, including mammalian patients (e.g., human beings). In certain embodiments of the relevant aspects of the invention (e.g., the first aspect of the invention), the treatment is performed on a mammal (e.g., a human being).

[0066] As used herein, the term therapeutically effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient. The effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of and / or feels an effect).

[0067] As used herein, the term prophylaxis includes references to the prevention (and, similarly, to the prevention) of disease or disorder (and vice versa). Petition 870250079411, dated 05 / 09 / 2025, page 28 / 165 12 / 138 versa). Thus, references to prevention can also be references to prophylaxis, and vice versa. In particular, the term can refer to achieving a reduction in the probability of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, as well as at least a 20%, 30% or 40% reduction, for example, at least a 50% reduction).

[0068] In certain embodiments, references to uses and methods for the treatment or prophylaxis of diseases and disorders, as specified in this document, refer in particular to uses and methods for the treatment of such diseases and disorders.

[0069] In one specific modality, the treatment is for a disorder (which may also be called a condition or disease) characterized by hyperglycemia.

[0070] In certain embodiments of the first aspect of the invention, the disorder is type 2 diabetes, such as type 2 diabetes of a subtype selected from the list consisting of maturity-onset diabetes in young people (MODY), adult-onset ketosis-prone diabetes, latent autoimmune diabetes in adults (LADA), and gestational diabetes.

[0071] In other forms, the disorder is type 1 diabetes, particularly when treatment also includes insulin (or a derivative and / or functional mimetic thereof).

[0072] In certain embodiments, the compounds of the invention (i.e., the compounds of formula I, including all embodiments thereof) are for use in the treatment of type 2 diabetes (or useful in the manufacture of a medicament for such treatment, or useful in a method for such treatment, as described in this document).

[0073] In other specific modalities, type 2 diabetes treatment is performed on a non-obese patient.

[0074] To avoid any doubt, those skilled in the art will understand that patients with a Body Mass Index (BMI) greater than 30 are considered obese. Petition 870250079411, dated 05 / 09 / 2025, page 29 / 165 13 / 138

[0075] In certain modalities, treatment may be for hyperglycemia in a patient at risk of developing type 2 diabetes, a condition that may be defined as prediabetes. Thus, the compounds of the invention may be useful in the prevention of type 2 diabetes (for example, in a patient with prediabetes).

[0076] As used in this document, the term prevention (and similarly, to prevent) includes references to the prophylaxis of the disease or disorder (and vice versa). In this way, references to prevention can also be references to prophylaxis, and vice versa. In particular, the term can refer to achieving a reduction in the probability of the patient (or healthy subject) developing the condition (e.g., at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g., at least a 50% reduction).

[0077] In other specific forms, type 2 diabetes is characterized by the patient having severe insulin resistance (SIR).

[0078] In other modalities, the treatment may be for hyperglycemia in a patient with type 1 diabetes. Thus, the compounds of the invention may be useful in the treatment of hyperglycemia in type 1 diabetes.

[0079] In certain modalities, the disorder characterized by hyperglycemia is type 1 diabetes or type 2 diabetes.

[0080] Those skilled in the art will understand that the compounds of the invention may be useful in the treatment of hyperglycemia in patients with impaired insulin production, such as in patients with cystic fibrosis. Thus, in other modalities, the disorder characterized by hyperglycemia is cystic fibrosis-related diabetes.

[0081] In certain modalities that may be mentioned, the disorder characterized by hyperglycemia is (or is characterized by) severe insulin resistance (SIR), which may be understood by those familiar with the technique as referring to disorders in which the individual has normal or, in some cases, increased insulin production, but sensitivity to Petition 870250079411, dated 05 / 09 / 2025, page 30 / 165 14 / 138 insulin significantly reduced. In specific cases, these patients may not be obese (for example, they may have a healthy weight). Thus, in certain modalities, these treatments are performed on patients who are not defined as obese (for example, on patients who are defined as having a healthy weight).

[0082] For example, SIR can be identified in a patient based on the fact that the patient has fasting insulin >150 pmol / L and / or a peak insulin glucose tolerance test of >1,500 pmol / L, especially in individuals with a BMI < 30 kg / m2 (who may have normal glucose tolerance).

[0083] More specifically, SIR can be characterized by the fact that the patient does not have a significant response to the presence of insulin, which may result from a defect (for example, a genetic defect) in the function of the insulin receptor.

[0084] Specific disorders that can be characterized by SIR include: Rabson-Mendenhall syndrome, Donohue syndrome (leprechaunism), Type A and Type B insulin resistance syndromes, HAIR-AN syndromes (hyperandrogenism, insulin resistance and acanthosis nigricans), pseudoacromegaly and lipodystrophy.

[0085] Other specific disorders that can be characterized by SIR include Donohue syndrome and type A insulin resistance syndrome and, even more particularly, Rabson-Mendenhall syndrome.

[0086] Those skilled in the art will understand that treatment with compounds of the first aspect of the invention may include (i.e., be combined with) other (i.e., additional / other) treatments for the same condition. In particular, treatment with the compounds of the invention may be combined with other means for the treatment of type 2 diabetes, such as treatment with one or more therapeutic agents useful in the treatment of type 2 diabetes, as known to those skilled in the art, such as therapies that require the patient to undergo a change in diet and / or exercise regimens and / or surgical procedures. Petition 870250079411, dated 05 / 09 / 2025, page 31 / 165 15 / 138 intended to promote weight loss (such as gastric band surgery).

[0087] Those skilled in the art will understand that the treatments of the first aspect of the invention may further comprise (i.e., be combined with) additional / other treatment(s) for the same condition. COMPOUNDS OF THE INVENTION

[0088] As described in this document, the present invention requires the use of a β2-adrenergic receptor agonist, examples of which are known to those skilled in the art.

[0089] Those skilled in the art will understand that the compounds mentioned in this document, such as the compounds mentioned as β2-adrenergic receptor agonists, can be supplied in the form of a pharmaceutically acceptable salt.

[0090] Pharmaceutically acceptable salts include acid addition salts and base addition salts, each of which may be in the form of salts in varying proportions of compound to counter-ion (e.g., including hemi-salts). Such salts may be formed by conventional means, for example, by the reaction of a free acid or free base form of a compound comprised in the formulations of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g., by rotary evaporation under reduced pressure, by lyophilization or by filtration). The salts may also be prepared by exchanging a counter-ion of a compound comprised in the formulations of the invention in the form of a salt with another counter-ion, for example, using a suitable ion exchange resin.

[0091] Specific acid addition salts that may be mentioned include carboxylate salts (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, hemitartrate, phenylacetate, mandelate, Petition 870250079411, dated 05 / 09 / 2025, page 32 / 165 16 / 138 phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, 1-naphthoate, 2-naphthoate, 1-hydroxy-2-naphthoate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate salts, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate), halide salts (for example, chloride, bromide or iodide salts), sulfonate salts (for example, benzenesulfonate, methyl, bromo- or chlorobenzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1,2-ethanedisulfonate, 1- or 2-naphthalenesulfonate or 1,5-naphthalenedisulfonate) or salts of sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate or nitrate and the like.

[0092] Specific base addition salts that can be mentioned include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, and lysine), and inorganic bases (such as ammonia and aluminum hydroxide). More particularly, base addition salts that can be mentioned include Mg, Ca, and, more particularly, K and Na salts.

[0093] For the avoidance of doubt, the compounds described herein may exist as solids and therefore the scope of the invention includes all amorphous, crystalline and partially crystalline forms, and may also exist as oils. When such compounds exist in crystalline and partially crystalline forms, such forms may include solvates, which are included within the scope of the invention. The compounds may also exist in solution.

[0094] Those skilled in the art will understand that references to an agonist refer to compounds suitable for acting as such when administered to a subject to be treated (i.e., a patient, for example, a human being, who needs it). Suitable compounds may include compounds that provide the required effect and compounds that are converted into compounds that provide the required effect after administration (i.e., in vivo), compounds which may be called prodrugs. The compounds Petition 870250079411, dated 05 / 09 / 2025, page 33 / 165 17 / 138 specific ones that can be mentioned are those that produce the necessary effect.

[0095] To avoid confusion, the term “agonist” can be understood as an agent (i.e., a compound) that induces the activation of the relevant receptor to produce a biological response (for example, in an individual, such as a human being), such as by binding to the relevant receptor. In this way, the term can also refer to partial agonists (which will be understood as compounds that activate a given receptor, but have only partial efficacy at the receptor in relation to a full agonist).

[0096] Agonists (and partial agonists) may exhibit, for example, maximum effective concentration (EC50) values ​​lower than about 100 μM, for example, lower than about 10 μM or lower than about 1 μM (for example, lower than about 200, about 150 or about 120 nM).

[0097] Unless otherwise indicated or if the context makes clear, references herein to agonists shall also include pharmaceutically acceptable (e.g., “protected”) derivatives of compounds that may not possess the relevant activity themselves, but which may be administered (e.g., parenterally or orally) to a patient and subsequently metabolized in the body to form compounds that possess the necessary activity, compounds that may be called prodrugs. Those skilled in the art are familiar with the appropriate prodrugs of the compounds described in this document, such as the appropriate esters (e.g., methyl or ethyl esters and the like).

[0098] For the avoidance of doubt, unless the context indicates otherwise or makes it clear, references to compounds that are agonists and their pharmaceutically acceptable salts will include compounds that are prodrugs of such agonists and their pharmaceutically acceptable salts.

[0099] Suitable e2-adrenergic receptor agonists (which may also be called e2-agonists) may include those known to those skilled in the art.

[0100] In certain modalities, the agonists of Petition 870250079411, dated 05 / 09 / 2025, page 34 / 165 18 / 138 suitable β2-adrenergic receptor compounds include those that are selective, a term known to those skilled in the art (i.e., compounds that are agonists of the relevant receptor(s) but do not cause significant activation of other β-adrenergic receptors).

[0101] Suitable β2-adrenergic receptor agonists can be identified by means of techniques known to those skilled in the art, including those described in the examples provided in this document.

[0102] Suitable β2-adrenergic receptor agonists that can be employed in various aspects of the invention include, among others, those described in the following documents: WO 2004 / 071388, EP 0 272 976, FR 2647310, DE 2 157 040, DE 2212600, DE 2015573, ZA 6705591, DE 2128258, WO 91 / 09596, GB 1 199 630, DE 4209989, BE 611502, NL 7804582, EP 0 043 807, WO 2008 / 022038, DE 2413102, US 2,308,232, BE 823841, BE 660244, WO 2000 / 075114, WO 2005 / 102350, WO 2005 / 110990, JP 56055355, AT 285583, US 4,223,137, US 3,056,836, FR 1324914, DE 638650, DD 45721, US 3,801,631, DE 2259282, DE 2300614, EP 0 290 122, US 2004 / 0266867, US 2010 / 0022658, US 2010 / 0022659, DE 2157040, GB 2133986, WO 2006 / 122788, Woo et al., Molecular Pharmacology, (2009), 75(1) 158-165, Baur et al., J. Med. Chem., (2010), 53(9), 3675-3684, Kaiser et al., J. Med. Chem. (1974), 17(1) 49-57, Baker et al., J. Pharmacology and Experimental Therapeutics, (2006), 319(1), 439-446, Engelhardt et al., Arzneimittel-Forschung, (1972), 22(5), 869-76, WO 2019 / 241744, WO 2019 / 241736, WO 2020 / 198466, WO 2021 / 003161, WO 2021 / 081292, WO 2021 / 127210 and WO 2021 / 247934, whose relevant disclosures (e.g., examples of compounds described and their pharmaceutically acceptable salts and associated preparation methods) are incorporated by reference in their entirety.

[0103] To avoid doubt, references to patent publications normally refer to the initial publication of the complete descriptive report of the patent with the relevant publication number (which may be indicated by the suffix “A1”).

[0104] Other β2-adrenergic receptor agonists Petition 870250079411, dated 05 / 09 / 2025, p. 35 / 165 19 / 138 suitable compounds that can be employed in the various aspects of the invention (whose compounds can also be identified as being suitable β2-adrenergic receptor agonists) include those described in the following publications, the content of which is incorporated herein in its entirety (in particular, the biological examples, the generic definitions of the compounds, including all their embodiments and associated definitions, and the example compounds provided, including their pharmaceutically acceptable salts and associated preparation methods):

[0105] WO 2017 / 153737

[0106] WO 2019 / 053429

[0107] WO 2019 / 053426

[0108] WO 2019 / 053425

[0109] WO 2019 / 053427

[0110] WO 2020 / 188299

[0111] WO 2020 / 188301

[0112] WO 2022 / 063895

[0113] WO 2022 / 063889

[0114] WO 2023 / 046885

[0115] WO 2023 / 046882

[0116] WO 2023 / 105035

[0117] WO 2023 / 203223

[0118] WO 2020 / 198466

[0119] A specific β2-adrenergic receptor agonist that can be mentioned is the following compound: OHH F\.^ IX% N

[0120] and its pharmaceutically acceptable salts.

[0121] Thus, a specific β2adrenergic receptor agonist that can be mentioned is (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3yl)ethan-1-ol and its pharmaceutically acceptable salts. Petition 870250079411, dated 05 / 09 / 2025, page 36 / 165 20 / 138

[0122] Specific pharmaceutically acceptable salts of the compound mentioned above (i.e., (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3yl)ethan-1-ol) that may be mentioned include the hemitartrate and dihydrochloride salts (such as the hemitartrate salt).

[0123] Another specific β2-adrenergic receptor agonist that can be mentioned is the following compound: ?HH

[0124] and its pharmaceutically acceptable salts.

[0125] Thus, a specific β2adrenergic receptor agonist that can be mentioned is (R)-2-(tert-butylamino)-1-(3fluorophenyl)ethan-1-ol and its pharmaceutically acceptable salts.

[0126] Pharmaceutically acceptable salts of (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol that may be mentioned include the HCl (hydrochloride) salt.

[0127] In certain embodiments, references to a specific stereoisomer of a compound may refer to the presence of the specific stereoisomer (for example, in a composition or formulation that includes it) in the substantial absence of the corresponding opposite stereoisomer.

[0128] As used in this document, references to the substantial absence of the corresponding opposite stereoisomer may refer to the presence of the desired stereoisomer with a purity of at least 80% (e.g., at least 90%, such as at least 95%) relative to the opposite stereoisomer. Alternatively, in such cases, compounds may be indicated as being present in the substantial absence of the compound in the other configuration, which may indicate that the compound in the relevant configuration is present in an enantiomeric excess (ee) of at least 80% (such as at least 90%, at least 95%, at least 98%, or particularly at least 99%, e.g., at least 99.9%). Petition 870250079411, dated 05 / 09 / 2025, p. 37 / 165 21 / 138

[0129] In some embodiments, the compound in the relevant configuration is present in an enantiomeric excess (ee) of at least 90% (such as at least 95%, at least 98% or, particularly, at least 99%, for example, at least 99.9%).

[0130] In certain embodiments of the invention, the β2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetharine, zinterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol, BRL-47672, trantinterol, clenproperol, clenpenterol, brombuterol, ractopamine and abediterol and pharmaceutically acceptable salts thereof.

[0131] In other embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetharine, zinterol, bamethane, (R)bamethane, clencyclohexerol, tulobuterol, BRL-47672 and trantinterol, and pharmaceutically acceptable salts thereof.

[0132] In certain embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bametane, (R)-bametane, clencyclohexerol, tulobuterol, trantinerol and abediterol and their pharmaceutically acceptable salts.

[0133] In other specific modalities, the β2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bametano, (R)-bametano, clenciclo Petition 870250079411, dated 05 / 09 / 2025, page 38 / 165 22 / 138 hexerol, tulobuterol and trantinerol and their pharmaceutically acceptable salts.

[0134] In more specific embodiments, the P2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, clenbuterol, fRJ-clenbuterol, bamethane, (7?)-bamethane and tulobuterol and their pharmaceutically acceptable salts.

[0135] In other specific embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, clenbuterol, fRJ-clenbuterol, bamethane, (7?)-bamethane and tulobuterol and their pharmaceutically acceptable salts.

[0136] To avoid any doubt, the structures of bamethane (CAS: 3703-79-5) and fR)-bamethane (CAS: 912804-58-1) are shown below. OH h OH hN Ní J 1 J HO '-2' bametano (R)-bametano

[0137] To avoid doubt, in the event of a discrepancy between the name of the compound and the structure drawn in this descriptive report, the structure shall prevail.

[0138] In other embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of formometerol, arformometerol, salmeterol, clenbuterol, tulobuterol, bambuterol, vilanterol, indacaterol, olodaterol, carmoterol and abediterol, and their pharmaceutically acceptable salts.

[0139] In other embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of salbutamol, ritodrine, colterol, hexaprenaline, tulobuterol and isoxsuprine and their pharmaceutically acceptable salts.

[0140] In certain embodiments, the β2-adrenergic receptor agonist is clenbuterol or (R)-clenbuterol, or a pharmaceutically acceptable salt.

[0141] To avoid any doubt, the compound clenbuterol can be understood as having the following structure: Petition 870250079411, dated 05 / 09 / 2025, p. 39 / 165 23 / 138 ci

[0142] In certain embodiments, the β2-adrenergic receptor agonist is tulobuterol or (R)-tulobuterol, or a pharmaceutically acceptable salt.

[0143] To avoid any doubt, the compound tulobuterol can be understood as having the following structure:

[0144] For the avoidance of doubt, the International Nonproprietary Name (INN) or drug development code (e.g., BRL-47672) of a compound generally indicates the stereochemical configuration of the compound or a specific mixture of stereoisomers (e.g., a racemate). Within the scope of the present invention, when relevant and unless the context indicates otherwise (e.g., when both the racemate and a single stereoisomer are explicitly named), these names may also be considered as encompassing separate stereoisomers that exhibit the relevant biological activity and that have not currently been assigned an alternative INN or drug development code.

[0145] In certain embodiments, the INN or drug code under development should be understood as representing the compound to which the relevant name or code has been assigned only.

[0146] When no INN or drug development code is available for a compound, it may be identified by its Chemical Abstracts Service registry number (CAS number). As mentioned in this document, the indication “CAS: XXXXXX-XX-X” (where the number of digits in the first group may vary) is used to identify these Petition 870250079411, dated 05 / 09 / 2025, page 40 / 165 24 / 138 compounds. When relevant and unless the context indicates otherwise, the CAS number of a compound may also be considered as encompassing other stereoisomers or mixtures thereof that exhibit the relevant biological activity and that have not been assigned alternative CAS numbers at present (as described above for INNs and drug development codes).

[0147] In certain embodiments, the CAS number should be understood as representing only the compound to which the relevant name or code has been assigned.

[0148] In certain modalities, the β2-adrenergic receptor agonist is selected from the group consisting of (R)-bametane, bametane, clencyclohexerol, radopamine, tulobuterol and (R)-tulobuterol.

[0149] The present invention also encompasses pharmaceutical formulations comprising isotopically labeled compounds, which are identical to the compounds described herein, except that one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number normally found in nature (or the most abundant found in nature). All isotopes of any particular atom or element, as specified in this document, are contemplated within the scope of the compounds of the invention. Therefore, the invention also encompasses pharmaceutical formulations comprising deuterated compounds, that is, in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0150] As described in this document, it will also be understood that certain compounds that act as β2-adrenergic receptor agonists are capable of activating the β2-adrenergic receptor without inducing significant cAMP production.

[0151] Thus, specific β2-adrenergic receptor agonists that can be mentioned include those capable of activating the β2-adrenergic receptor without (or with only a minimal effect on) induction of Petition 870250079411, dated 05 / 09 / 2025, p. 41 / 165 25 / 138 cAMP production.

[0152] Furthermore, in certain embodiments, the methods and uses described in this document can be carried out without inducing (or without inducing significant levels of) cAMP production.

[0153] In particular, the β2-adrenergic receptor agonist, as described in this document, can be described as being a β2-adrenergic receptor agonist that does not induce significant cAMP (i.e., levels and / or production thereof).

[0154] Those skilled in the art may determine the level of cAMP production provided by compounds, such as those mentioned in this document, using techniques known to those skilled in the art, such as those described in the examples provided in this document.

[0155] For example, the level of cAMP production induced by a given compound can be determined based on the amount induced by a defined concentration of that compound relative to the amount induced by the same concentration of a reference compound, such as isoprenaline, using techniques known to those skilled in the art (e.g., following the protocol described in the biological examples provided in WO 2019 / 053427, i.e., in cells, such as differentiated L6 myotubes, that have been stimulated with isoprenaline or the compound with a final concentration of 1x10-5M, for 15 minutes in stimulation buffer, such as HBSS supplemented with 1% BSA, 5 mM HEPES and 1 mM IBMX, at pH 7.4).

[0156] In such modalities, compounds that do not induce significant cAMP can be defined as compounds that induce less than 50% (or, in some modalities, less than 25%) of the cAMP induced by isoprenaline (e.g., according to the protocol described above).

[0157] Specific compounds that act as β2-adrenergic receptor agonists and that are capable of activating the β2-adrenergic receptor without (or with only a minimal effect on) the induction of cAMP production include those described in the following publications, the content of which is incorporated. Petition 870250079411, dated 05 / 09 / 2025, p. 42 / 165 26 / 138 in full to this document (in particular, the biological examples, the generic definitions of the compounds, including all their associated embodiments and definitions, and the example compounds provided, including their pharmaceutically acceptable salts and associated preparation methods):

[0158] WO 2017 / 153737

[0159] WO 2019 / 053429

[0160] WO 2019 / 053426

[0161] WO 2019 / 053425

[0162] WO 2019 / 053427

[0163] WO 2020 / 188299

[0164] WO 2020 / 188301

[0165] WO 2022 / 063895

[0166] WO 2022 / 063889

[0167] WO 2023 / 046885

[0168] WO 2023 / 046882

[0169] WO 2023 / 105035

[0170] WO 2023 / 203223

[0171] The compounds described in the publications referenced and incorporated in this document were investigated according to the procedures described in Biological Example 1 and Biological Example 2 of document WO 2019 / 053427. The test results are presented in Table 1. If a compound at 10 μM exhibits activity greater than 75% of that of isoproterenol at 10 μM, the activity will be indicated with +++; if it is between 75 and 50%, it will be indicated with ++; if it is between 50 and 25%, it will be indicated with +; if it is less than 25%, it will be indicated with -. The compounds are drawn as salt-free molecules in Table 1, but the tested compounds may have contained additional salt or solvent components that do not contribute to the biological activity.

[0172] In the event of a discrepancy between the nomenclature and the structure of the compounds, as graphically represented, the latter shall prevail (unless contradicted by any experimental details that Petition 870250079411, dated 05 / 09 / 2025, page 43 / 165 27 / 138 may be provided and / or unless otherwise specified in the context). Synthetic procedures and other biological data can be found in the relevant publications.

[0173] Therefore, the specific β2adrenergic receptor agonists that can be mentioned are provided in Table 1 below. TABLE 1. PARTICULAR COMPOUNDS OF THE INVENTION Structure Name Biological Example 1 from document WO 2019 / 053427 (GU) Biological Example from document WO 2019 / 053427 (cAMP) 1 °HH Γ J 2-(butylamino)-1(p-hydroxyphenyl)-1-ethanol +++ - 2 °HH Xj 2-(butylamino)-1(m-chlorophenyl)-1-ethanol + - 3 ?HHA £ϊ p-{2[(cyclopropylmethyl)amino]-1-hydroxyethyl}phenol ++ - 4 °HH AA\ / N\ / lj Τ- H 2-(tert-butylamino)-1-(p-hydroxyphenyl)-1-ethanol +++ + 5 °HH £1 | 2-(secbutylamino)-1-(phydroxyphenyl)-1ethanol ++ - 6 ?HH XX Γ T 2-[(cyclohexylmethyl)amino]1-(p-hydroxyphenyl)1-ethanol +++ - Petition 870250079411, of 05 / 09 / 2025, p. 44 / 165 28 / 138 7 ?H Η O kX 2-[(cyclohexylmethyl)amino]1 -phenyl-1 -ethanol + - 8 °HH in TT 1 -(p-hydroxyphenyl)2-(1methylbutylamino)1-ethanol ++ + 9 °HH in J (R)-2(butylamino)-l(phenyl) -++++ 10 °HHJ j O p-[2(cyclopentalamino) -1-hydroxyethyl]phenol ++ - 11 °HH Á J Ly / HO^'^ --7—7 p-[2-(1adamantanylamine o)-1hydroxyethyl]phenol + - 12 °HH Λ J . 2-(butylamino)-1(p-hydroxyphenyl)-l propanol ++ - 13 °HH in TTT HO^'^ 1 -(p-hydroxyphenyl)2-(1methylbutylamino)1-propanol ++ - 14 °HH Xk . l-(m-hydroxyphenyl)2-(1methylbutylamino)1-ethanol +++ - 15 °HH Xk 2-(butylamino)-1(m-hydroxyphenyl)-lethanol ++ - 16 °HH in JTJ 2-(2-cyclohexylethylamino)-1(p-hydroxyethanol) --ethanol ++ Petition 870250079411, of 05 / 09 / 2025, p. 45 / 165 29 / 138 17 °HH 1J H 2-(hexylamino)-1(p-hydroxyphenyl)-1ethanol + - 18 °HH 1J HO^'^ 1-(p-hydroxyphenyl)2-(octylamino)-1ethanol + - 19 °HHT j 1 1-(3-chloro-4hydroxyphenyl)-2-(1methylbutylamino)1-ethanol + - 20 °HH Λ J HO^'^ 2-(butylamino)-1(3-chloro-4hydroxyphenyl)-1ethanol + - 21 ?HH ¥¥ 1J 2-(3-cyclohexylpropylamino)1-(p-hydroxyphenyl)1-ethanol +++ - 22 °HH ¥ ¥ T Η2Ν'χ^γ Cl 1-(4-amino-3,5dichlorophenyl)-2-(1methylbutylamino)1-ethanol ++3 +HH ¥ ¥ ¥ +3 HC>V^ Cl 2-(butylamino)-1(3,5-dichloro-4hydroxyphenyl)-1ethanol - - 24 °HH Λ J v H<7 ''h p-[2-(2cyclopropylethylamine o)-1 hydroxyethyl]phenol ++ - 25 °HH Cl 1-(3,5-dichloro-4hydroxyphenyl)-2-(1methylbutylamino)1-ethanol - - 26 °HH \y OH 5-[2-(butylamino)1 hydroxyethyl]spring zero ++ - Petition 870250079411, of 05 / 09 / 2025, p. 46 / 165 30 / 138 27 °HH in YT HO^'A (R)-2-[(R)-1methylbutylamino]l-(p-hydroxyphenyl)1-ethanol +++ + 28 °HH Χγ * (R)-2-[(R)-1methylbutylamino]1-(m-hydroxyphenyl)1-ethanol ++H29 °H Η2Ν^γ Cl 1-(4-amino-3,5dichlorophenyl)-2(butylamino)-1ethanol +++ + 30 ?HHA / 3⁄4. A 1J HO^^A 2-(3cyclopropylpropyl mino)-1-(phidroxyphenyl)-1ethanol +++ - 31 °HH / ΐΐ?. Α 1J ho^'A 1-(p-hydroxyphenyl)2-(4,4,4trifluorobutylamino )-1-ethanol ++ n / a 32 F / F ?HHF XX H2N Cl 1-[4-amino-3chloro-5(trifluoromethyl)pheny l]-2-(butyno-1)++3 + FF ?HHF XX ' H2N Cl 1-[4-amino-3chloro-5(trifluoromethyl)pheny l]-2-(1methylbutylamino)1-ethanol ++ +++ 34 °HHYY ci^A 2-(butylamino)-1(4-chloro-3hydroxyphenyl)-1ethanol +H+3 °Y c / ''Ά 1-(4-chloro-3hydroxyphenyl)-2-(1methylbutylamino)1-ethanol +++ - Petition 870250079411, of 05 / 09 / 2025, p. 47 / 165 31 / 138 36 °HH H2N\^ JT 1-(3-amino-4chlorophenyl)-2(butylamino)-lethanol + - 37 °HH Η2Ν·^γ F 1-(4-amino-3,5difluorophenyl)-2(butylamino)-lethanol +++ +++ 38 Õ7 h H Ol pv OH* HH Racemic mixture of (R)-[(2S,5S)5-methyl-2pyrrolidinyl]phenylmethanol and (S)[(2R,5R)-5-methyl2pyrrolidinyl]phenylmethanol + - 39 ohh h Q r?^ õhh h Racemic mixture of (R)-[(2R,5R)5-methyl-2pyrrolidinyl]phenylmethanol and (S)[(2S,5S)-5-methyl2pyrrolidinyl]phenylm ethanol + Petition 870250079411, dated 05 / 09 / 2025, page 48 / 165 32 / 138 41 On / Ο** / I \ \ iz JJ Racemic mixture of m-{(R)[(2R,5R)-5-methyl2pyrrolidinyl]hydroxy methylphenol em{(S)-[(2S,5S)-5methyl-2pyrrolidinyl]hydroxy methylphenol 42 + HI F+ OH - OH N-{3-[2(butylamino)-lhydroxyethyl]-2,6difluorophenyl}acetate mida + - 43 I ?HH IJ 1-(3-amino-2,4difluorophenyl)-2(butylamino)-lethanol +++ - 44 °HH IJ 1-(3-amino-4-butylamino)-lethanol)-2 ++ - 45 OH u • Η H HO A? LJ (R)-[(2R,6R)-6propyl-2piperidyl](mhydroxyphenyl)methanol +++ - 46 °HHJJ (R)-2(butylamino)-l-(pfluorophenyl)-1 ethanol ++ - 47 °HHA / (R)-2(butylamino)-l(m-fluorophenol) +++4 +8 °HH il J 2-(butylamino)-1(4-pyridyl)-1-ethanol + - Petition 870250079411, of 05 / 09 / 2025, p. 49 / 165 33 / 138 49 °HHN 2-(butylamino)-1(3-pyridyl)-1-ethanol ++ - 50 °HH 44 t (R)-2-[(R)-1methylbutylamino]l-(m-fluorophenyl)1-ethanol +++ - 51 °HH F.^;;; 44 1 (R)-2-[(S)-1methylbutylamino]1-(m-fluorophenyl)1-ethanol +++ - 52 °HH in j T (R)-2-[(R)-1methylbutylamino]1-(p-fluorophenyl)1-ethanol ++ - 53 °HH in T i (R)-2-[(S)-1methylbutylamino]1-(p-fluorophenyl)1-ethanol ++ - 54 °HH 44 % (R)-2-(tercbutylamino)-1-(mfluorophenyl)-1ethanol +++ - 55 °HHF ^ 4 F 2-(butylamino)-1(3,5-difluorophenyl)1-ethanol ++ - 56 °HHJT 2-(butylamino)-1(3,4-difluorophenyl)1-ethanol ++ - 57 HO μ H 1ja...... HO^^t \ / Ky m-{(R)-[(2R,5R)5-propyl-2pyrrolidinyl]hydroxy methyl}phenol +++ ++ 58 HO μ HF^ / 4 \ / 44 (R)-[(2R,5R)-5propyl-2pyrrolidinyl](mfluorophenyl)methanol +++ + Petition 870250079411, of 05 / 09 / 2025, p. 50 / 165 34 / 138 59 OH u I Η Η (R)-[(2R,6R)-6propyl-2piperidyl](mfluorophenyl)methanol + - 60 OH u Ξ Η H ___ / (S)-[(2R,6R)-6propyl-2piperidyl](mfluorophenyl)methanol +H - 61 °H (R)-2-(1,1dimethylbutylamino) -l-(m-fluorophenyl)1-ethanol +++ - 62 o I / / z \ )—o / TZI 4-[2-(butylamino)1-hydroxyethyl]2(1 H)-pyridinone + - 63 °HH / T. / N. / HN 5-[2-(butylamino)1-hydroxyethyl]2(1 H)-pyridinone + - 64 OH ui Η H HO^ / ^ (R)-[(2R,6S)-6propyl-2piperidyl](mhydroxyphenyl)methane ol +++ - 65 OH u ξ H · Η uij. (S)-[(2R,6S)-6propyl-2piperidyl](3,4difluorophenyl)meta zero + - 66 OH ,, - Η H ψ LT F (S)-[(2R,6S)-6propyl-2piperidyl](3,5difluorophenyl)meta zero + - 67 H Fv^Al / N\X\ / ULJ (R)-[(2R,6S)-6propyl-2piperidyl](3,4difluorophenyl)meta zero + - Petition 870250079411, of 05 / 09 / 2025, p. 51 / 165 35 / 138 68 OH ,, v Η Η ÇJ r F (R)-[(2R,6S)-6propyl-2piperidyl](3,5difluorophenyl)methanol ++ - 69 OH u I Η Η (R)-[(2R,6S)-6propyl-2piperidyl](mfluorophenyl)methanol ++ - 70 OH u ξ Η H (γ kJ (S)-[(2R,6S)-6propyl-2piperidyl](mfluorophenyl)methanol ++ - 71 °HH n^A\^ h2n γ γ-1-(2-amino1,3-thiazol-4-yl)-2(butylamino)-1ethanol + - 72 °HH f3c YT (S)-2-(butylamino)-1-[2(trifluoromethyl)1,3-thiazol-4-yl]-1ethanol + - 73 °HH H2N ,N.^ Il J (S)-1-(2-amino-4pyrimidinyl)-2(butylamino)-1ethanol + - 74 \ O OH uHN%Y N-{5-[(S)-2(butylamino)-1hydroxyethyl]-1,3thiazol-2-yl}2methylpropionamide a + - 75 °HH S....A\^ Η2Νγ T (S)-1-(2-amino1,3-thiazol-5-yl)-2(butylamino)-1ethanol + - . Petition 870250079411, 05 / 09 / 2025, p. 52 / 1 36 / 1 76 ί ?H H (R)-2-(tertbutylamino)-1(2,3-difluorophenyl)1-ethanol +++ + 77 1 ?H H (R)-2(butylamino)-1(2,3-difluorophenyl)1-ethanol +++ - 78 1 ?H H (R)-2-(tertbutylamino)-1-(ofluorophenyl)-1ethanol +++ + 79 1 ?H H A-.. V XX (R)-2(butylamino)-1-(ofluorophenyl)-1ethanol +++ - 80 °H H J T b (R)-2-(tertbutylamino)-1-(4fluoro-2hydroxyphenyl)-1ethanol ++ - 81 OH H J T (R)-2(butylamino)-1-(4fluoro-2hydroxyphenyl)-1ethanol ++ - 82 °H H (R)-1-(mfluorophenyl)-2-(1methylcyclopropil mino)-1-ethanol +++ - 83 °H H p~x (R)-1-(mfluorofenil)-2-(1metilciclobutilamino)-1-ethanol +++ + 84 OH H IJ (R)-2-(tercbutilamino)-1-(4fluoro-3hydroxyfenil)-1ethanol +++ ++ Petition 870250079411, de 05 / 09 / 2025, pág. 53 / 165 37 / 138 85 OH H IJ (R)-2(butylamino)-1-(4fluoro-3hydroxyphenyl)-1ethanol +++ - 86 1 ?H H xx A (R)-2-(tertbutylamino)-1-(2fluoro-3hydroxyphenyl)-1ethanol ++ ++ 87 1 ?H H HΟ..^ xx (R)-2(butylamino)-1-(2fluoro-3hydroxyphenyl)-1ethanol +++ + 88 °H H / K / N. 0 N xXX N-{5-[(R)-2(butylamino)-1hydroxyethyl]-2pyrimidinyl}2methylpropionamide ++ - 89 OH H / k JK / η2ν ν (R)-1-(2-amino-5pyrimidinyl)-2(butylamino)-1ethanol ++ - 90 ι ?H H H2N'^ χχ (R)-1-(3-amino-2fluorophenyl)-2(butylamino)-1ethanol ++ - 91 1 ?H H χχ h (R)-1-(3-amino-2fluorophenyl)-2(tert-butylamino)1-ethanol +++ + 92 ?ην η J Τ Τ J (R)-[(2R,6S)-6propyl-2piperidyl](pfluorophenyl)methan ol + - Petition 870250079411, de 05 / 09 / 2025, pág. 54 / 165 38 / 138 93 F OH u 1 » Η H (R)-[(2R,6S)-6propyl-2piperidyl](offluorophenyl)methanol + - 94 OH uv Η H íJT j (R)-[(2R,6R)-6propyl-2piperidyl](pfluorophenyl)methane ol - 95 °H^H^ 6-[(S)-2-(tercbutylamino)-1hydroxyethyl]-3pyridinol ++ - 96 °HH f (S)-2-(tercbutylamino)-1-(5fluoro-2-pyridyl)-1ethanol ++ - 97 F OH u (Yb- (R)-[(2R,6R)-6propyl-2piperidyl](offluorophenyl)methanol ++ - 98 °HH Υ / χ / \ / Ν. / 4-[(R)-2-(tercbutylamino)-1hydroxyethyl]-1methyl-2(1H)pyridinone +++9 °H HH (R)-2-(tercbutylamino)-1-(5fluoro-3-pyridyl)-1ethanol +++ + 10 0 OH H IJ t N 5-[(R)-2-(tercbutylamino)-1hydroxyethyl]-3pyridinol +++ - 10 1 OH u , Tb H Y” ? (C)-[(R)-6,6dimethyl-2piperidyl](mfluorophenyl)methane + - Petition 870250079411, of 05 / 09 / 2025, p. 55 / 165 39 / 138 ol 10 2 OH u ¥ Η Η Ί^Γ (R)-[(R)-6,6dimethyl-2piperidyl](mfluorophenyl)methane ol ++ - 10 3 OH u Ξ Η H HO^ LA (S)-[(R)-6,6dimethyl-2piperidyl-2mhydroxymethane +] 4 OH uf HH ho Α-φ-Α / LJ LA (R)-[(R)-6,6dimethyl-2piperidyl](mhydroxyphenyl)methanol + - 10 5 ?hh H / ^ΑφΑΛχ / Jl JTJ (S)-[(2R,6S)-6propyl-2+perylphenol) - 10 6 F OH u I Ξ HH Ai LJ (C)-[(2R,6S)-6propyl-2piperidyl](ophluorophenyl)methanol + - 10 7 F OH u I Ξ Η H O........O.......... (S)-[(2R,6R)-6propyl-2piperyl-orophenyl methanol + 8 +] 1 ?HH / ^ΛΑαζ ii j A 1 (R)-2-(tercbutylamino)-1-(3fluoro-4-pyridyl)-1ethanol + - 10 9 HO HH ;% / (S)-[(R)-5,5dimethyl-2pyrrolidinyl](mfluorophenyl -) Petition 870250079411, of 05 / 09 / 2025, p. 56 / 165 40 / 138 11 0 HO H Η kJ (R)-[(R)-5,5dimethyl-2pyrrolidinyl](mfluorophenyl)methanol +++ - 11 1 ΗΟ μ Η kJ m-{(S)-[(R)-5,5dimethyl-2pyrrolidinyl]hydroxy methyl}phenol ++ - 11 2 HO Η Η ikvN\ / ηο^Ζ^<^\ m-{(RH(R)-5,5dimethyl-2pyrrolidinyl]hydroxy methyl}phenol +++ - 11 3 ΟΗ μ ξ Η Η Η°.^^ \ / jj kJ (S)-[(2S,6R)-6propyl-2piperidyl](mhydroxyphenyl)methanol ++ - 11 4 OH u = Η Η icy kJ (S)-[(2S,6R)-6propyl-2piperidyl](mchlorophenyl)methanol + - 11 5 OH ui Η Η kJ kJ (R)-[(2S,6R)-6propyl-2piperidyl](mchlorophenyl)methanol +++ - 11 6 OH μ • Η H F'-^ X^ Tj kJ (R)-[(2S,6R)-6propyl-2piperidyl](mfluorophenyl)methanol + - 11 7 °H Η 1, 3J (R)-1-(mfluorophenyl)-2(neopentylamino)1-ethanol + - 11 8 °HH Jj △ (R)-1-(mfluorophenyl)-2-[1(trifluoromethyl)cycl opropylamino]-1ethanol ++ - . Petition 870250079411, 05 / 09 / 2025, p. 57 / 1 41 / 1 11 9 OH u “ Η Η (S)-[(2S,6S)-6propyl-2piperidyl](mfluorophenyl)methanol + - 12 0 OH u ¥ Η Η (R)-[(2S,6S)-6propyl-2piperidyl](mfluorophenyl)-OH u 1 + 1 + Ξ H HO.^^^ ij (S)-[(2S,6S)-6propyl-2piperidyl](mhydroxyphenyl)methanol +++ - 12 2 OH u > Η H HO. / :^ {j Cj (R)-[(2S,6S)-6propyl-2piperidyl](mhydroxy +)methanol 12 + OH +Η H Tj yj (R)-[(2S,6S)-6propyl-2piperidyl](mclorophenyl)methanol + - 12 4 HO HH kJ (R)-[(2R,5S)-5propyl-2pyrrolidinyl](mfluorophenyl)methane ol ++ - 12 5 HO µ H HO / ^^^ kJ^ m-{(R)-[(2R,5C)5-propyl-2pyrrolidinyl]hydroxy methyl}phenol ++ - 12 6 HO HH ...... : / c \ / Ka (S)-[(2R,5R)-5propyl-2pyrrolidinyl](mfluorophenyl)methanol + - Petition 870250079411, of 05 / 09 / 2025, p. 58 / 165 42 / 138 12 7 HO H Η ...... H0..... / VZ \ / Χ-- m-{(S)-[(2R,5R)5-propyl-2pyrrolidinyl]hydroxy methyl}phenol + - 12 8 OH u ι Η Η Tj LJ (R)-[(2R,6S)-6propyl-2piperidyl](mchlorophenyl)methanol + - 12 9 OH u ξ Η H Tj LJ (S)-[(2R,6S)-6propyl-2piperidyl](mchlorophenyl)methanol + - 13 k 0 HO HH (R)-[(2C,5S)-5propyl-2pyrrolidinyl](mfluorophenyl)methanol + - 13 1 HO µ H (S)-[(2S,5S)-5propyl-2pyrrolidinyl](mfluorophenyl)methanol ++ - 13 2 HO µ HA%n ..... F.\-~ ..... u. (R)-[(2C,5R)-5propyl-2pyrrolidinyl](mfluorophenyl)methanol + - 13 3 HO μ H 7- ...... U / V \ / X Ky (S)-[(2S,5R)-5propyl-2pyrrolidinyl](mfluorophenyl)methanol ++ - OH 13 H \ ι | 4-[2-(tercbutylamino)-1hydroxyethyl]-3pyridinol +++ - 13 5 Cl OH u 1 THH CJ VJ (R)-[(2R,6S)-6propyl-2piperidyl](oclorophenyl)methanol + - Petition 870250079411, of 05 / 09 / 2025, p. 59 / 165 43 / 138 13 6 OH ui Η H ηο^^^Αξ,ν. (R)-[(2C,6R)-6propyl-2piperidyl](mhydroxyphenyl)methanol +++ - 13 7 OH H (S)-[(2R,6R)-6propyl-2piperidyl](mhydroxyphenyl)methanol + - 13 8 °HH kJ N (R)-2-(tercbutylamino)-1-(5chloro-3-pyridyl)-1ethanol +++ +++ 13 9 OH u = Η H IJ J (S)-[(2R,6S)-6propyl-2piperidyl](5-fluoro3-pyridyl)methanol - - 1 OH X 0 X XT XT Η (R)-[(2R,6S)-6propyl-2piperidyl](5-fluoro3-pyridyl)methanol - - 14 1 HO HH 1J / N\.....K ci^ / ^Y \ / kX (R)-[(2R,5R)-5propyl-2pyrrolidinyl](mclorophenyl) - HOH 14 + 2+ HOV^A) / ^ JJ m-{(R)-[(S)-5,5dimethyl-2pyrrolidinyl]hydroxy methyl}phenol + - 14 3 HO HH kJ m-{(S)-[(S)-5,5dimethyl-2pyrrolidinyl]hydroxy methyl}phenol - - 14 HO 4 Ans / HJH (P)-[(C)-5,5dimethyl-2pyrrolidinyl](mfluorophenyl)methanol - - Petition 870250079411, of 05 / 09 / 2025, p. 60 / 165 44 / 138 14 5 HO H Η vy (S)-[(S)-5,5dimethyl-2pyrrolidinyl](mfluorophenyl)methanol + - 14 6 Cl OH u 1 V n Cn (S)-2-(tercbutylamino)-1-(3chloro-2-pyridyl)-1ethanol + 14 T HH ° 14 (C)-2-(tercbutylamino)-1-(5chloro-2-pyridyl)-1ethanol + - 14 8 Cl H° Η H c? (R)-[(2R,5R)-5propyl-2pyrrolidinyl](oclorophenyl)methanol +++ - 14 9 1 ?HH JJ h (R)-1-(3-amino2,4-difluorophenyl)2-(tercbutylamino)-1ethanol +++ + 15 0 HF^U (R)-2-(tercbutylamino)-1-(3fluoro-2-tolyl)-1ethanol +++ + 15 1 Cl H? Η HC? (S)-[(R)-5,5dimethyl-2pyrrolidinyl](oclorophenyl)methanol - - 15 2 ci HLh n / Cy ^~~~ (R)-[(R)-5,5dimethyl-2pyrrolidinyl](oclorophenyl)methanol +++ - 15 μ H 3 An, HO, ci / x j^ p^ j^ y' (C)-[(P)-5,5dimethyl-2pyrrolidinyl](mchlorophenyl)methanol + - Petition 870250079411, of 05 / 09 / 2025, p. 61 / 165 45 / 138 15 4 HO H Η kJ (R)-[(R)-5,5dimethyl-2pyrrolidinyl](mchlorophenyl)methanol +++ - 15 5 OH u = HH HO.^ Xj (S)-[(2R,6S)-6propyl-2piperidyl](mhydroxyphenyl)-15 HH -UH (C)-[(R)-5,5dimethyl-2pyrrolidinyl](5fluoro-3pyridyl)methanol - - 15 7 OH F ! H IJ LX (R)-[(R)-5,5dimethyl-2pyrrolidinyl](5fluoro-3pyridyl)methanol +++ - 15 8 HO μ H \ F-^ / ^u'T / \ kJ (S)-[(R)-5,5dipropyl-2pyrrolidinyl](mfluorophenyl) - 15 HOH - 15 kJ (R)-[(R)-5,5dipropyl-2pyrrolidinyl](mfluorophenyl)methanol ++ - 16 0 HO HHF^ / U\ / UX ^N (R)-[(2R,5R)-5propyl-2pyrrolidinyl](5fluoro-3pyridyl)methanol ++1 - 16 H\H ^U^H XX ^N (S)-[(2R,5R)-5propyl-2pyrrolidinyl](5fluoro-3pyridyl)methanol + - Petition 870250079411, of 05 / 09 / 2025, p. 62 / 165 46 / 138 16 2 Cl OH I, ótf (R)-[(R)-6,6dimethyl-2piperidyl](oclorophenyl)methanol + - 16 3 Cl OH 1 = Η H kk^ (S)-[(R)-6,6dimethyl-2piperidyl](oclorophenyl) -OH 1 + 6 H + + , u + 4 kk^” (S)-[(R)-6,6dimethyl-2piperidyl](mclorophenyl)methanol ++ - 16 5 OH ui Η H Tk kkr (R)-[(R)-6,6dimethyl-2piperidyl](mclorophenyl)methanol + - 16 6 HO j \ H ^ \ N Γ 5-{(S)-[(R)-5,5dimethyl-2pyrrolidinyl]hydroxy methyl}-3-pyridinol + - 16 7 HO HH li / N / HO^ / ^X^X / ~ 1 J ^-7 5-{(R)-[(R)-5,5dimethyl-2pyrrolidin methyl-2hydroxy methyl -3-+-3-pyridinol 8 HO µ H ix (R)-{(R)-1-aza-2espiro[4.4]nonyl}( mfluorophenyl)methanol ++ + 16 9 HO µ H anã kJ (S)-{(R)-1-aza-2espiro[4.4]nonyl}( mfluorophenyl)methanol - 10 X ^ X ^ H / ^ (R)-{(R)-4-aza-5espiro[2,4]heptyl}( mfluorophenyl)methanol ++ - Petition 870250079411, of 05 / 09 / 2025, p. 63 / 165 47 / 138 17 1 HO μ H 44 (S)-{(R)-4-aza-5espiro[2,4]heptyl}( mfluorofenil)metanol + - 17 2 HO H H FZ (S)-[(R)-5,5dimethyl-2pyrrolidinyl](pfluorofenil)metanol - - 17 3 HO μ, H AavanA FZ (R)-[(R)-5,5dimethyl-2pyrrolidinyl](pfluorofenil)metanol ++ - 17 4 F HO H H (S)-[(R)-5,5dimethyl-2pyrrolidinyl](ofluorofenil)metanol - - 17 5 F HO n H <4 (R)-[(R)-5,5dimethyl-2pyrrolidinyl](ofluorofenil)metanol +++ + 17 6 ​​F OH u I = H H C4 T4 (S)-[(R)-6,6dimethyl-2piperidyl](ofluorofenil)metanol +++ + 17 7 F OH μ (R)-[(R)-6,6dimethyl-2piperidil](ofluorofenil)metan ol ++ - 17 8 _4” (S)-(mfluorofenil)(4metil-7azabiciclo[2.2.1]h ept-1-yl)methanol + - Petition 870250079411, de 05 / 09 / 2025, pág. 64 / 165 48 / 138 17 9 (R)-(mfluorophenyl)(4methyl-7azabiciclo[2.2.1]h ept-1-yl)methanol ++ - 18 0 A- (S)-(offluorophenyl)(4methyl-7azabiciclo[2.2.1]h ept-1-yl)methanol +++ 1 · 1 · 1 (R)-(ophluorophenyl)(4methyl-7azabiciclo[2.2.1]h ept-1-yl)methanol +++ - 18 2 ho / —π^ΝΗF^OM (S)-(mfluorophenyl)(4propyl-7azabiciclo[2.2.1]h ept-1-yl) -Yan 183-H (R)-(mfluorophenyl)(4propyl-7azabiciclo[2.2.1]h ept-1-yl)methanol ++ + 18 4 > FV? (S)-(5-fluoro-3pyridyl)(4-methyl-7azabiciclo[2.2.1]h ept-1-yl)methanol ++ - 18 5 HO γ 5—t^nh (R)-(5-fluoro-3pyridyl)(4-methyl-7azabiciclo[2.2.1-1-yl ept-1-yl)methanol ++) 6 HO HHY / ft, kJ (R)-{(R)-1-methyl- 2azabiciclo[2.1.1]h ex-3-yl}(mfluorophenyl)methanol +++ ++ Petition 870250079411, of 05 / 09 / 2025, p. 65 / 165 49 / 138 18 7 HO ,, Η (S)-{(R)-1-methyl- 2azabiciclo[2.1.1]h ex-3-yl}(mfluorophenyl)methanol + - 18 8 HO HH kJ (R)-{(S)-1-methyl- 2azabiciclo[2.1.13]-ex-methanophenyl}(fluorophenyl-ol}). - 18 9 HO HH j <Li+, F^ / ^X^X / ^ X^ (S)-{(S)-1-metil-2azabiciclo[2.1.1]h ex-3-il}(mfluorofenil)metan ol ++ - 19 0 OH u 1 Η H XX XX (R)-[(S)-6,6dimetil-2piperidil](mfluorofenil)metan ol +++ - 19 1 OH u 7 Η H XX XX (S)-[(S)-6,6dimetil-2piperidil](mfluorofenil)metan ol + - 19 2 F OH u 1 = Η H ex xx (S)-[(S)-6,6dimetil-2piperidil](ofluorofenil)metan ol + - 19 3 F OH , 1 T H H , CX XX (R)-[(S)-6,6dimetil-2piperidil](ofluorofenil)metan ol +++ + 19 4 <W (S)-(oclorofenil)(4metil-7- +++ - Petition 870250079411, of 05 / 09 / 2025, p. 66 / 165 50 / 138 azabiciclo[2.2.1]h ept-1-yl)methanol 19 5 ho % ti* (R)-(oclorophenyl)(4methyl-7azabiciclo[2.2.1]h ept-1-yl)methanol +++ - 19 6 ho / — / VNH (C)-(mclorophenyl)(4methyl-7azabiciclo[2.2.1]h ept-1-yl)methanol + - 19 7 H0 y / VNHCIÁJ (R)-(methyl-7azabiciclo[2.2.1]h ept-1-yl)methanol + - 19 + 8 + UNH (R)-[(R)-4,4dimethyl-2azetidinyl](mfluorophenyl)methanol +++ + 19 9 HO H mu (S)-[(S)-4,4dimethyl-2azetidinyl](mfluorophenyl)methanol + - 20 0 hoh Nh (R)-[(S)-4,4dimethyl-2azetidinyl](mfluorophenyl)methanol - - 20 1 HO UNH F^A (S)-[(R)-4,4dimethyl-2azetidinyl](mfluorophenyl)methanol - - 20 2 HO H NH F HX vu (R)-[(S)-4,4dimethyl-2azetidinyl](o- - - Petition 870250079411, of 05 / 09 / 2025, p. 67 / 165 51 / 138 fluorofenil)metanol 20 3 HO H νη F AK XC (S)-[(R)-4,4dimethyl-2azetidinyl](ofluorofenil)metanol + - 20 4 HO ί NH F (R)-[(R)-4,4dimethyl-2azetidinyl](ofluorofenil)metanol +++ + 20 5 HO H NH f / \X X / (S)-[(S)-4,4dimethyl-2azetidinyl](ofluorofenil)metanol + - 20 6 HO μ H iXv. xx (R)-{(R)-1-methyl- 2azabicyclo[2.1.1]h ex-3-yl}(mchlorophenyl)methanol +++ - 20 7 HCl μ H (S)-{(S)-1-methyl-2azabicyclo[2.1.1]h ex-3-yl}(mchlorophenyl)methanol + - 20 8 HCl μ H xx (S)-{(R)-1-methyl- 2azabicyclo[2.1.1]h ex-3-yl}(mchlorophenyl)methanol ++ - 20 9 HCl μ H iXv. xx (R)-{(S)-1-methyl- 2azabicyclo[2.1.1]hex-3-yl}(mchlorophenyl)methanol + - 21 0 p HΟ μ H (R)-{(R)-1-methyl- 2azabicyclo[2.1.1]hex-3-yl}(o- +++ +++ Petition 870250079411, de 05 / 09 / 2025, pág. 68 / 165 52 / 138 fluorophenyl)methanol 21 1 p HO HHO (S)-{(S)-1-methyl-2azabiciclo[2.1.1]h ex-3-yl}(offluorophenyl)methane ol +++ - 21 2 p HO HHO (S)-{(R)-1-methyl2azabiciclo[2.1.1]h. ex-3-yl}(offluorophenyl)methanol +++ - 21 3 P HO HHO (R)-{(S)-1-methyl2azabiciclo[2.1.1]h ex-3-yl}(offluorophenyl)methanol +++ - 21 4 F^7 N (R)-[(R)-4,4dimethyl-2azetidinyl](5fluoro-3pyridyl)methanol +++ - 21 5 HO (S)-[(S)-4,4dimethyl-2azetidinyl](5fluoro-3pyridyl)methanol + - 21 6 HO H NH (R)-[(S)-4,4dimethyl-2azetidinyl](5fluoro-3pyridyl)methanol + - 21 7 HO H n FO V- N (S)-[(R)-4,4dimethyl-2azetidinyl](5fluoro-3pyridyl)methanol + - Petition 870250079411, of 05 / 09 / 2025, p. 69 / 165 53 / 138 21 8 OH F _ ? Η χ 2 ζ Η / \ 1Ά ( 2 (S)-[(2R,7R)-7propyl-2azepanyl](5fluoro-3pyridyl)methanol - - 21 9 ΟΗ F _ r Η χ \ ζ η j \ \ / (R)-[(2R,7R)-7propyl-2azepanyl](5fluoro-3pyridyl)methanol - - 22 0 ΗΟ Η Η LZ. ~~Ά (R)-{(R)-1-methyl- 2azabicyclo[2.1.1]h ex-3-yl}(5-fluoro3-pyridyl)methanol +++ - 22 1 ΗΟ μ Η zu f.ZV\ / / \\ J ~N (S)-{(S)-1-methyl-2azabicyclo[2.1.1]h ex-3-yl}(5-fluoro3-pyridyl)methanol ++ - 22 2 HO HH FZZ VA N^ (S)-{(R)-1-methyl- 2azabicyclo[2.1.1]h ex-3-yl}(5-fluoro3-pyridyl)methanol - - 22 3 HO u H a,i+ F—Z^iV / ^ Ά (R)-{(S)-1-methyl- 2azabicyclo[2.1.1]h ex-3-yl}(5-fluoro3-pyridyl)methanol + - 22 4 θΗ H Ϊ J 'Π (R)-1-(mfluorophenyl)-2-{2[(1r,4R)-4methoxycyclohexyl]ethylamino}-1etanol + - 22 5 °HHU (R)-1-(5-fluoro-3pyridyl)-2-{2[(1r,4R)-4methoxycyclohexyl]ethylamino}-1- ++ - Petition 870250079411, 05 / 09 / 2025, pág. 70 / 165 54 / 138 ethanol 22 6 F HO HH (S)-[(R)-5,5dimethyl-2pyrrolidinyl](3amino-2fluorophenyl)methanol + - 22 7 F z (R)-[(R)-5,5dimethyl-2pyrrolidinyl](3amino-2fluorophenyl)methanol + 2+ 2 Γ H (R)-1-(mfluorophenyl)-2({[(1r,4R)-4methoxyciclohexyl]methyl}amino) -1-ethanol ++ - 22 9 ?H Η ΓΎ v XX kJ N (R)-1-(5-fluoro-3pyridyl)-2({[(1r,4R)-4methoxyciclohexyl]methyl}amino) -1-ethanol ++ - 23 0 HO H NHC|XX (R)-[(R)-4,4dimethyl-2azetidinyl](mchlorophenyl methane HOH + 1 +) ciXX (C)-[(C)-4,4dimethyl-2azetidinyl](mclorophenyl)methanol + - 23 2 HO H NH ci <J (R)-[(S)-4,4dimetil-2azetidinil](mclorofenil)metanol + - 23 3 HO H NH ciXX (S)-[(R)-4,4dimetil-2azetidinil](m- - - Petition 870250079411, of 05 / 09 / 2025, p. 71 / 165 55 / 138 clorofenil)methanol 23 4 OH J H H IANA (R)-[(2S,7S)-7propil-2azepanil](5fluoro-3pyridyl)methanol +++ - 23 5 OH ? H H . (Ar A (S)-[(2S,7S)-7propyl-2azepanyl](5fluoro-3pyridyl)methanol - - 23 6 ХО μ H aj,n^ FAA\ / Ла н2в^^\ F (S)-[(R)-5,5dimethyl-2pyrrolidinyl](4amino-3,5difluorofenil)methanol +++ + 23 7 °Х H Х Т Х 1 AA>OMe (R)-1-(mfluorofenil)-2-{2[(1s,4S)-4methoxycyclohexyl]ethylamino}-1ethanol ++ - 23 8 °Х H f^^A^A^avaa у Та N ^OMe (R)-1-(5-fluoro-3pyridyl)-2-{2[(1s,4S)-4methoxycyclohexyl]ethylamino}-1ethanol +++ - 23 9 .OMe ?Х H ХХ даа (R)-1-(mfluorophenyl)-2-{1methyl-1-[(1r,4R)4-methoxycyclohexyl]ethylamino}-1ethanol +++ - 24 0 xOMe ?H H GG FAA\ / N\ AA kJ X N (R)-1-(5-fluoro-3pyridyl)-2-{1-methyl1-[(1r,4R)-4methoxycyclohexyl]ethylamino}-1- +++ - Petition 870250079411, de 05 / 09 / 2025, pág. 72 / 165 56 / 138 ethanol 24 1 C HO µ H (R)-{(R)-1-methyl- 2azabiciclo[2.1.1]h ex-3-yl}(3-amino- 2fluorophenyl)methane ol +++ - 24 2 XZ <Ί X'V^ O 4 z CM X (S)-{(S)-{(S)-2-2. ex-3-yl}(3-amino2fluorophenyl)methanol ++ - 24 3 F HO Η H (S)-{(R)-1-methyl- 2azabiciclo[2.1.1]h ex-3-yl}(3-amino- 2fluorophenyl)methanol ++ - 24 4 F HO Ax^y^y (R)-{(S)-1-methyl- 2azabiciclo[2.1.1]h ex-3-yl}(3-amino- 2fluorophenyl)methanol ++ - 24 5 .OMe ?H η ΓΎ Fx / Ax / x / N^A^JV (R)-1-(mfluorophenyl)-2({[(1s,4S)-4methoxyciclohexyl]methyl}amino) -1-ethanol ++ - 24 6 / \ ^OMe ?H η ΓΎ FxAxA / N^Ay u N (R)-1-(5-fluoro-3pyridyl)-2({[(1s,4S)-4methoxycyclohexyl]methyl}amino) -1-ethanol ++ - Petition 870250079411, of 05 / 09 / 2025, p. 73 / 165 57 / 138 24 7 °HH Ύ j Λ Ύ 1 ^^*OMe(R)-2-{1,1-dimethyl2-[(1s,4S)-4methoxycyclohexyl]ethylamino}-1(m-fluorophenyl)-lethanol +++ - 24 8 °HH iJ χΧλ N ^OMe (R)-2-{1,1-dimethyl2-[(1s,4S)-4methoxycyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1 -ethanol +++ - 24 9 °HH fiAnk'Q (R)-2-{1,1-dimethyl- 2-[(1r,4R)-4- methoxycyclohexyl]ethylamino}-1(m-fluorophenyl)-lethanol +++ - 25 0 °HHU x Ό N ^OMe(R)-2-{1,1-dimethyl- 2-[(1r,4R)-4- methoxycyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol ++ - 25 1 .OMe ?H η ΓΎ %ζιΑ\Α\ζΑ V x (R)-1-(mfluorophenyl)-2-{1 methyl-1-[(1s,4S)4-methoxycyclohexyl]ethylamino}-1ethanol - - 25 2 .OMe ?H η ΓΎ Fkz^ / AnAA U x N (R)-1-(5-fluoro-3pyridyl)-2-{1 -methyl1-[(1s,4S)-4methoxycyclohexyl]ethylamino}-1ethanol - - 25 3 í>- (S)-(3-fluoro-4pyridyl)(4-methyl-7azabicyclo[2.2.1]h ept-1-yl)methanol - - . Petition 870250079411, 05 / 09 / 2025, p. 74 / 1 58 / 1 25 4 HO F — / Ο VNH (R)-(3-fluoro-4pyridyl)(4-metil-7azabicyclo[2.2.1]h ept-1-yl)methanol - - 25 5 °Η Η (R)-2-{1-[(1S,3R)- 3-methoxycyclohexyl]-1 methylethylamino}-1(m-fluorophenyl)-letanol +++ - 25 6 °Η Η ζ[\^'''ΌΜθ (R)-2-{1-[(1R,3S)- 3-methoxycyclohexyl]-1 methylethylamino}-1(m-fluorophenyl)-letanol +++ + 25 7 °Η Η kJ ? Ν (R)-2-{1-[(1S,3R)- 3-methoxycyclohexyl]-1 methylethylamino}-1(5-fluoro-3pyridyl)-1 -ethanol ++ - 25 8 °Η Η XX / ^.OMe (R)-1-(mfluorophenyl)-2-{3[(1s,4R)-4methoxycyclohexyl]propylamino}-1-etanol +++ ++ 25 9 °Η Η ^\oOMe (R)-1-(mfluorophenyl)-2-{3[(1r,4S)-4methoxycyclohexyl]propylamino}-1-etanol + - 26 0 °Η Η XX Ν / χ^ΟΜε (R)-1-(5-fluoro-3pyridyl)-2-{3[(1s,4R)-4methoxycyclohexyl]propylamino}-1-etanol +++ - Petition 870250079411, dated 05 / 09 / 2025, p. 75 / 165 59 / 138 26 1 λΟΜθ ?H Η O Fv^X^ / N / Z^XX (R)-1-(5-fluoro-3pyridyl)-2-{3[(1r,4S)-4methoxycyclohexyl]propylamino}-1-ethanol - - 26 2 ^ojO H / O (R)-1-(mfluorophenyl)-2({[(1s,4S)-4(benzyloxy)cyclohexyl]methyl}amino) -1-ethanol + - 26 3 qo 7 'R (R)-1-(5-fluoro-3pyridyl)-2({[(1s,4S)-4(benzylxyl)) -1-ethanol +++ - 26 4 / \ .OMe »H η <Ύ V x (R)-2-{1,1-dimethyl3-[(1s,4R)-4methoxyciclohexil]propylamino} -1-(m-fluorophenyl)1-ethanol +++ + 26 5 *XXXXX^^' XX x (R)-2-{1,1-dimethyl3-[(1r,4S)-4methoxycyclohexyl]propylamino} -1-(m-fluorophenyl)1-ethanol ++ - 26 6 / \ .OMe ?HH Cf U x N (1s,4R)-4methoxycyclohexylpropylamino}] -1-(5-fluoro-3pyridyl)-1-ethanol +++ - 26 7 / \ ,xOMe ?HH XT F'x_ / ^x / X / N'x_x / \^'XX U x N (R)-2-{1,1-dimethyl3-[(1,4S)-4methoxyclohexyl}]propyl -1-(5-fluoro-3pyridyl)-1-ethanol + - Petition 870250079411, of 05 / 09 / 2025, p. 76 / 165 60 / 138 26 8 OH u HI (R)-1-(mfluorophenyl)-2({[(1s,4S)-4hydroxycyclohexyl]methyl}amino) -1-ethanol + - 26 9 OH u N Η Γ v^>0H (R)-1-(5-fluoro-3pyridyl)-2({[(1s,4S)-4hydroxycyclohexyl]methyl}amino) -1-ethanol + - 27 0 OH F^xx u NH fz ^'OMe (R)-2-{1-[(1R,3S)3-methoxycyclohexyl]-1methylethylamino}-1(5-fluoro-3pyridyl)-1-ethanol +++ ++ 27 1 °HH 'lA' (R)-1-(mfluorophenyl)-2({[(1r,4R)-4(benzyloxy)cyclohexyl]methyl}amino) -1-ethanol + - 27 2 OH Fx / x VHI ^OH (R)-1-(mfluorophenyl)-2({[(1r,4R)-4hydroxymethylhexyl)] -1-ethanol + - 27 3 °HH IJ N oA (R)-1-(5-fluoro-3pyridyl)-2({[(1r,4R)-4(benzyloxy)ciclohexyl]methyl}amino) -1-ethanol + - 27 4 OH 'lA N Η Γ ^n^A ηηη (R)-1-(5-fluoro-3pyridyl)-2({[(1r,4R)-4hydroxycyclohexyl]methyl}amino) - - Petition 870250079411, of 05 / 09 / 2025, p. 77 / 165 61 / 138 -1-ethanol 27 5 on H (R)-1-(5-fluoro-3pyridyl)-2-{3[(1s,4R)-4(benzyloxy)cyclohexyl]propylamino} -1-ethanol ++ - 27 6 ^.o / 3 OH H u N (R)-1-(5-fluoro-3pyridyl)-2-{3[(1r,4S)-4(benzyloxy)cyclohexyl]propylamino} -1-ethanol + - 27 7 ob (R)-1-(mfluorophenyl)-2-{3[(1s,4R)-4(benzyloxy)cyclohexyl]propylamino} -1-ethanol + - 27 8 qo (R)-1-(mfluorophenyl)-2-{3[(1r,4S)-4(benzyloxy)cyclohexyl]propylamino} -1-ethanol + - 27 9 Q o 7 (R)-1-(mfluorophenyl)-2-{1 methyl-1-[(1r,4R)4-(benzyloxy)cyclohexyl]ethylamino}-1ethanol ++ - 28 0 oh H YY XiA'A1 (R)-1-(mfluorophenyl)-2-{1 methyl-1-[(1s,4S)4-(benzyloxy)cyclohexyl]ethylamino}-1ethanol +++ - 28 1 (R)-1-(5-fluoro-3- pyridyl)-2-{1 -methyl- 1-[(1r,4R)-4- ++ - Petition 870250079411, de 05 / 09 / 2025, pág. 78 / 165 62 / 138 (benzyloxy)cyclohexyl]ethylamino}-1ethanol 28 2 OH HN (R)-1-(5-fluoro-3pyridyl)-2-{1-methyl1-[(1s,4S)-4(benzyloxy)cyclohexyl]ethylamino}-1ethanol ++ - 28 3 OH ?H η Pt (R)-1-(mfluorophenyl)-2-{1methyl-1-[(1r,4R)4-hydroxycyclohexyl]ethylamino}-1ethanol ++ - 28 4 .OH ?H η pY f^^^Ax^n^A^A ux (R)-1-(mfluorophenyl)-2-{1methyl-1-[(1s,4S)4-hydroxycyclohexyl]ethylamino}-1ethanol ++ - 28 5 OH ?H η pr U Λ N. (R)-1-(5-fluoro-3pyridyl)-2-{1-methyl1-[(1r,4R)-4hydroxycyclohexyl]ethylamino}-1ethanol ++ - 28 6 ^OH ?H h PY Ρχ / ^Α^ΑχΑΑ IJ x N. (R)-1-(5-fluoro-3pyridyl)-2-{1-methyl1-[(1s,4S)-4hydroxycyclohexyl]ethylamino}-1ethanol + - 28 7 3 / od (R)-1-(mfluorophenyl)-2-{2[(1s,4S)-4(benzyloxy)cyclohexyl]ethylamino}-1ethanol++ - Petition 870250079411, 05 / 09 / 2025, p. 79 / 1 63 / 1 28 8 °HH XJ X Λ-q (R)-1-(mfluorophenyl)-2-{2[(1r,4R)-4(benzyloxy)cyclohexyl]ethylamino}-1ethanol + - 28 9 °HHXJ x N (R)-2-{1,1-dimethyl3-[(1r,4S)-4hydroxycyclohexyl]propylamino} -1-(5-fluoro-3pyridyl)-1-ethanol + - 29 0 °HHU x λΟΗ (R)-2-{1,1-dimethyl3-[(1r,4S)-4hydroxycyclohexyl]propylamino} -1-(m-fluorophenyl)1-ethanol + - 29 1 °HH ΎΫ—i N ' Aq (R)-1-(5-fluoro-3pyridyl)-2-{2[(1s,4S)-4(benzyloxy)cyclohexyl]ethylamino}-1ethanol ++ - 29 2 °HH ty—c N Aq (R)-1-(5-fluoro-3pyridyl)-2-{2[(1r,4R)-4(benzyloxy)cyclohexyl]ethylamino}-1ethanol - - 29 3 °HH kJ N ^^OH (R)-1-(5-fluoro-3pyridyl)-2-{2[(1s,4S)-4hydroxycyclohexyl]ethylamino}-1ethanol + - 29 4 °HH kJ N (R)-1-(5-fluoro-3pyridyl)-2-{2[(1r,4R)-4hydroxyclohexyl -1] Petition 870250079411, of 05 / 09 / 2025, p. 80 / 165 64 / 138 ethanol 29 5 .OH ?HHV x (R)-2-{1,1-dimethyl3-[(1s,4R)-4hydroxycyclohexyl]propylamino} -1-(m-fluorophenyl)1-ethanol +++ - 29 6 .OH ?H η ΓΎ s / v N 1JY x N (R)-2-{1,1-dimethyl3-[(1s,4R)-4hydroxycyclohexyl]propylamino} -1-(5-fluoro-3pyridyl)-1-ethanol +++ - 29 7 °HH IJ Ύ 1 X / A^*oh (R)-1-(mfluorophenyl)-2-{2[(1s,4S)-4hydroxycyclohexyl]ethylamino}-1ethanol ++ - 29 8 °HH Ύ J Ύ J (R)-1-(mfluorophenyl)-2-{2[(1r,4R)-4hydroxyheloxyl ethylamino}-1ethanol ++ 29 9 OH h à J x Là N OH (R)-2-{1,1-dimethyl2-[(1r,4R)-4hydroxycyclo- hexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol ++ - 30 0 OH H Ύ T a Ύ j (R)-2-{1,1-dimethyl2-[(1r,4R)-4hydroxycyclohexyl]ethylamino}-1(m-fluorophenyl)-1ethanol +++ - Petition 870250079411, of 05 / 09 / 2025, p. 81 / 165 65 / 138 30 1 °HHU XTA N ^OH (R)-2-{1,1-dimethyl2-[(1s,4S)-4hydroxycyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol +++ - 30 2 °HH IJ λ Ύ Ί \^*OH (R)-2-{1,1-dimethyl2-[(1s,4S)-4hydroxycyclohexyl]ethylamino}-1(m-fluorophenyl)-1ethanol ++ - 30 3 aOH °HH For M (R)-1-(mfluorophenyl)-2-{3[(1r,4S)-4S -1-ethanol ++ - 30 4 - h rr XJN (R)-1-(5-fluoro-3pyridyl)-2-{3[(1s,4R)-4hydroxycyclohexyl]propylamino} -1-ethanol ++ - 30 5 λΟΗ ?H k h ΓΊ NJ N (R)-1-(5-fluoro-3pyridyl)-2-{3[(1r,4S)-4hydroxycyclohexyl]propylamino} -1-ethanol + - 30 6 ^OH ?H h UV Fxy— (R)-1-(mfluorophenyl)-2-{3[(1R)-4R -1-ethanol + - 30 7 H °H h ry π o V N-[(1S,4s)-4{[(R)-2-(mfluorophenyl)-2hydroxyethylamino] methyl}cyclo- ++ - Petition 870250079411, of 05 / 09 / 2025, p. 82 / 165 66 / 138 hexyl]acetamide 30 8 Η ?Η η π V ΧαΧα''α / Ν''-^ ° XX N-[(1R,4r)-4{[(R)-2-(mfluorophenyl)-2hydroxyethylamino]methyl}cyclohexyl]acetamide ++ - 30 9 Η λΝ. / °Η η V FxA'a¥zNxZX / 0 Ν N-[(1R,4r)-4{[(R)-2-(5-fluoro3-pyridyl)-2hydroxyethylamino]methyl}cyclohexyl]acetamide ++ - 31 0 Η oh Η Αγ ν F\ / aXX\Z''X 0 N-[(1S,4s)-4{[(R)-2-(5-fluoro3-pyridyl)-2hydroxyethylamino]methyl}cyclohexyl]acetamide + - 31 1 \ ,ο LL (R)-1-(mfluorophenyl)-2({[(1r,4R)-4(mesylamino)cyclo - hexyl]methyl}amino); -1-ethanol ++ - 31 2 Η OH Η X γ* faAAa''^a / N'-^ θ '° XX (R)-1-(mfluorophenyl)-2({[(1s,4S)-4(mesylamino)cyclo - hexyl]methyl}amino) -1-ethanol ++ - 31 3 \ ,ο ωί τ ζΖ '° 7 7 LL(R)-1-(5-fluoro-3pyridyl)-2({[(1r,4R)-4(mesylamino)cyclo-hexyl]methyl}amino)-1-ethanol + - . Petition 870250079411, 05 / 09 / 2025, p. 83 / 1 67 / 1 31 4 9H HNH II* 1 J o 'b (R)-1-(5-fluoro-3pyridyl)-2({[(1s,4S)-4(mesylamino)cyclo - hexyl]methyl}amino) -1-ethanol ++ - 31 5 ™ H / h fl N-[(1R,4r)-4{[(R)-2-(mfluorophenyl)-2hydroxyethylamino] methyl}cyclohexyl]benzamide +++ - 31 6 XA^ « nx^-sX^X χ o N-[(1S,4s)-4{[(R)-2-(mfluorophenyl)-tihydroxylamine] methyl}cyclohexyl]benzamide ++ - 31 7 °H Η X IJ N « Π X ΑχΧ / X 0 N-[(1R,4r)-4{[(R)-2-(5-fluoro3-pyridyl)-2hydroxyethylamino] methyl}cyclohexyl]benzamide + 38 °H + H N-[(1S,4s)-4{[(R)-2-(5-fluoro3-pyridyl)-2hydroxyethylamino] methyl}cyclohexyl]benzamide ++ - 31 9 1 ?HH χΧΧχ / Ν, / χ ux X\.AH (R)-2-{1-methyl-{ 3-[(1r,4S)-4hydroxycyclohexyl]propylamino} -1-(o-fluorophenyl)1-ethanol +++ - 32 0 1 ?HHX<:X ux (R)-2-{1,1-dimethyl3-[(1s,4R)-4hydroxycyclohexyl]+++++ Petition 870250079411, of 05 / 09 / 2025, p. 84 / 165 68 / 138 -1-(o-fluorophenyl)1-ethanol 32 1 0 OH H < Y OMe (1S,4s)-8-[(R)-2(5-fluoro-3pyridyl)-2hydroxyethylamino]7-methoxy-pmentan-7-one ++ - 32 2 °HHF\ / VX\ / NYZ / A. JJS' LJ,„ ,OMe NTO (1S,4s)-4-{2-[(R)2-(5-fluoro-3pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexanocarboxylate o de methyl +++ - 32 3 o A OH H [ ] OH N (1S,4s)-8-[(R)-2(5-fluoro-3pyridyl)-2hydroxyethylamino]7-hydroxy-pmentan-7-one + ++ 32 4 °HHJJLJ·.., ,oh NY 0 acid (1S,4s)-4{2-[(R)-2-(5fluoro-3-pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexanocarboxylic o + - 32 5 H9 Η Η H FYY / o 'OMe (S)-[(2R,5S)-5{[(1r,4S)-4methoxyciclohexyl]methyl}-2pyrrolidinyl](mfluorophenyl)methanol +++ - 32 6 H2 Η Η H aJ o A Me (R)-[(2R,5S)-5{[(1r,4S)-4methoxyciclohexyl]methyl}-2- +++ - Petition 870250079411, of 05 / 09 / 2025, p. 85 / 165 69 / 138 pyrrolidinyl](mfluorophenyl)methanol 32 7 °HHLJL ¥ .OMe o (1S,4s)-4-{2-[(R)2-(m-fluorophenyl)2hydroxyethylamino]2methylpropyljcyclohexanecarboxylate of methyl +++ - 32 8 0 A OH H II OMe ^.XO (1S,4s)-8-[(R)-2(m-fluorophenyl)-2hydroxyethylamino]7-methoxy-pmenthan-7-one +++ - 32 9 ÃA F vX X (S)-(mfluorophenyl){4(methoxymethyl)-7azabicyclo[2.2.1]h ept-1-yl}methanol + - 33 0 HO v'7 (R)-(mfluorophenyl){4(methoxymethyl)-7azabicyclo[2.2.1]h ept-1-yl}methanol +++ - 33 1 °HHF \ / UzA / N ÍLJ L.¥^oh 0 acid (1S,4s)-4{2-[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyljcyclohexanecarboxylic 0 + - 33 2 HO μ Η μ ΛνΝ4\ / Τ'—\ Lí < JN 'OMe (S)-[(2R,5S)-5{[(1r,4S)-4methoxycyclohexyl]methyl}-2pyrrolidinyl](5fluoro-3pyridyl)methanol + - Petition 870250079411, dated 05 / 09 / 2025, p.86 / 165 70 / 138 33 3 HO η H H / >· ^-N '''OMe (R)-[(2R,5S)-5{[(1r,4S)-4methoxycyclohexyl]methyl}-2pyrrolidinyl](5fluoro-3pyridyl)methanol + - 33 4 H9 H H H yy Z / OMe (S)-[(2R,5R)-5{[(1r,4R)-4methoxycyclohexyl]methyl}-2pyrrolidinyl](mfluorophenyl)methanol + - 33 5 H° H H H F / Z \ yy zOMe (R)-[(2R,5R)-5{[(1r,4R)-4methoxycyclohexyl]methyl}-2pyrrolidinyl](mfluorophenyl)methanol +++ - 33 6 F H9 H H η y^y Me (S)-[(2R,5S)-5{[(1r,4S)-4methoxyciclohexyl]metil}-2pyrrolidinil](ofluorofenil)metan ol + - 33 7 F H2 H H H ÇAy (R)-[(2R,5S)-5{[(1r,4S)-4methoxyciclohexil]metil}-2pyrrolidinil](ofluorofenil)metan ol +++ - 33 8 F Hy H Cy s QUe (S)-[(2R,5R)-5{[(1r,4R)-4methoxyciclohexyl]metil}-2pyrrolidinyl](ofluorofenil)methane ++ -. Petition 870250079411, de 05 / 09 / 2025, pág. 87 / 165 71 / 138 ol 33 9 F HTH N - Cy <3 ''OMe (R)-[(2R,5R)-5{[(1r,4R)-4methoxycyclohexyl]methyl}-2pyrrolidinyl](ofluorophenyl)methane ol +++ + 34 0 HO μ. H u κ / Χ7 \ / rX < JN OMe (S)-[(2R,5R)-5{[(1r,4R)-4methoxycyclohexyl]methyl}-2pyrrolidinyl](5fluoro-3pyridyl)methanol + - 34 1 HO H Η h Fx / Y \ / rX UP XA OMe (R)-[(2R,5R)-5{[(1r,4R)-4methoxicyclohexyl]methyl}-2pyrrolidinyl](5fluoro-3pyridyl)methanol +++ - 34 2 xXCOOMe ?H h Pr FvxAx / Nv / YY U x N (1R,4r)-4-{3-[(R)2-(5-fluoro-3pyridyl)-2hidroxiethylamino]3-methylbutyl}cyclohexanocarboxylate or de methyla +++ - 34 3 sXCOOH ?H h Pr Fvx / YN\ / \ / A / U (R)-1-(5-fluoro-3pyridyl)-2-{1-methyl1-[(1r,4R)-4aminocyclohexyl]ethylamino}-1- - - Petition 870250079411, 05 / 09 / 2025, pág. 88 / 165 72 / 138 ethanol 34 5 Η °H η Ar A r' / 0 0 IJ N (R)-1-(5-fluoro-3pyridyl)-2-{1-methyl1-[(1r,4R)-4(mesylamino)cyclo-hexyl]ethylamino}1-ethanol + - 34 6 H / / aN. / ' °H h Ar AF / ZA / C^A / ^ 0 U x N N-[(1R,4r)-4-{1[(R)-2-(5-fluoro-3pyridyl)-2hydroxyethylamino]1-methylethyl}cyclohexyl]acetamide +++ - 34 7 zA ^COOH ?H Η 4Ύ f\za4^nvzax4j IJ x N acid (1S,4s)-4{3-[(R)-2-(5fluoro-3-pyridyl)-2hydroxyethylamino]3-methylbutyl}cyclohexanecarboxylic o +++ - 34 8 AA xXCOOH ?H η o acid (1R,4r)-4{3-[(R)-2-(mfluorophenyl)-2hydroxyethylamino]3-methylbutyl}cyclohexanecarboxylic o - - 34 9 AA AOOMe ?H h TT U x N (1S,4s)-4-{3-[(R)2-(5-fluoro-3pyridyl)-2hydroxyethylamino]3-methylbutyl}methyl cyclohexanecarboxylate +++ + 35 0 a\ .COOMe OH H <a u x (1r,4r)-4-{3-[(r)2-(m-fluorofenil)- 2- hidroxietilamino]3-metilbutil}ciclohexanocarboxilat o de metila +++ - petição 870250079411, 05 09 2025, pág. 89 165 73 138 35 1 -coome °h η a u (1s,4s)-4-{3-[(r)2-(m-fluorofenil)2hidroxietilamino]3-metilbutil}ciclohexanocarboxilat + 2 -cooh ?h h xv yy-a^ ácido (1s,4s)-4{3-[(r)-2-(mfluorofenil)-2hidroxietilamino]3-metilbutil}ciclohexanocarboxílic 3 h ύ t a j αχ χ 'χοομθ (1r,4r)-4-{2-[(r)2-(m-fluorofenil)2- hidroxietilamino]2metilpropil}ciclohexanocarboxilat 4 ta n 'c00me (1r,4r)-4-{2-[(r)2-(5-fluoro-3piridil)-2hidroxietilamino]2metilpropil}ciclohexanocarboxilat ++ 5 f^a \ nvzsa\ ij λ aa χα^θθπ (1r,4r)-4{2-[(r)-2-(mfluorofenil)-2hidroxietilamino]2metilpropil}ciclohexanocarboxílic 6 xla cooh (1r,4r)-4{2-[(r)-2-(5fluoro-3-piridil)-2- 90 74 hidroxietilamino]2metilpropil}ciclohexanocarboxílic 7 fx xj â zn n-[(1r,4r)-4-{2[(r)-2-(5-fluoro-3piridil)-2hidroxietilamino]2metilpropil}ciclohexil]acetamida 8 ah2 (r)-2-{1,1-dimetil3-[(1r,4r)-4aminociclohexil]propilamino} -1-(5-fluoro-3piridil)-1-etanol 9 tj xi nh2 (r)-2-{1,1-dimetil2-[(1r,4r)-4aminociclohexil]etilamino}-1(5-fluoro-3piridil)-1-etanol 36 0 -vx all θ'ρ l x (δ' (r)-2-{1,1-dimetil2-[(1r,4r)-4(mesilamino)ciclo -hexil]etilamino}1-(5-fluoro-3piridil)-1-etanol xx λν^ v 1j n-[(1r,4r)-4-{3[(r)-2-(5-fluoro-3piridil)-2hidroxietilamino]3-metilbutyl}ciclohexil]acetamida ,o ω' ã'0 ll (r)-2-{1,1-dimetil3-[(1r,4r)-4(mesilamino)ciclo hexil]propilamino} 91 75 ho μ η 'ί tz o zome (s)-[(2r,5s)-5metil-5-{[(1r,4s)4-metoxiciclohexil]metil}-2pirrolidinil](mfluorofenil)metan ol _ vaj r^x kj άμθ (r)-[(2r,5s)-5metil-5-{[(1r,4s)4-metoxiciclohexil]metil}-2pirrolidinil](mfluorofenil)metan λνντ-\ ome (s)-{(2r,5r)-5[(pmetoxifenil)metil]5-metil-2pirrolidinil}(mfluorofenil)metan λννχ-\ (r)-{(2r,5r)-5[(pmetoxifenil)metil]5-metil-2pirrolidinil}(mfluorofenil)metan .coome pt (1r,4r)-8-[(r)-2(m-fluorofenil)-2hidroxietilamino]7-metoxi-pmenthan-7-ona af χχ (1r,4r)-8-[(r)-2(m-fluorofenil)-2hidroxietilamino]7-hidroxi-pmenthan-7-ona 92 76 .cooh γύ (1s,4s)-8-[(r)-2(m-fluorofenil)-2hidroxietilamino]7-hidroxi-pmenthan-7-ona 37 ^coome γγ (1r,4r)-8-[(r)-2(5-fluoro-3piridil)-2hidroxietilamino]7-metoxi-pmenthan-7-one zz yy 'nhj (r)-2-{1,1-dimetil2-[(1r,4r)-4aminociclohexil]etilamino}-1(m-fluorofenil)-1etanol h? (s)-{(2r,5s)-5[(pmetoxifenil)metil]2-pirrolidinil}(mfluorofenil)metan h° (r)-{(2r,5s)-5[(pmetoxifenil)metil]2-pirrolidinil}(mfluorofenil)metan μι μ, p, χχθχχ (r)-{(2r,5r)-5[(pmetoxifenil)metil]2-pirrolidinil}(mfluorofenil)metan μ. xzx^ fuxj (s)-{(2r,5r)-5[(pmetoxifenil)metil]2-pirrolidinil}(mfluorofenil)metan 93 77 (r)-2-(tercbutilamino)-1-(2metil-3-piridil)-1etanol (s)-{(2r,5s)-5[(pmetoxifenil)metil]2-pirrolidinil}(5fluoro-3piridil)metanol (r)-{(2r,5s)-5[(pmetoxifenil)metil]2-pirrolidinil}(5fluoro-3piridil)metanol (r)-{(2r,5r)-5[(pmetoxifenil)metil]2-pirrolidinil}(5fluoro-3piridil)metanol 38 (s)-{(2r,5r)-5[(pmetoxifenil)metil]2-pirrolidinil}(5fluoro-3piridil)metanol «nh? ?h (r)-1-(mfluorofenil)-2-{1metil-1-[(1r,4r)4-aminociclohexil]etilamino}-1etanol o. °' zt -hexil]etilamino}1-(m-fluorofenil)1-etanol 94 78 χύί. i n-[(1r,4r)-4-{2[(r)-2-(mfluorofenil)-2hidroxietilamino]2metilpropiljciclohexil]acetamida ύχ^χύί n-[(1r,4r)-4-{2[(r)-2-(mfluorofenil)-2hidroxietilamino]2metilpropiljciclohexil]benzamida .o ω xl '° (r)-1-(mfluorofenil)-2-{1 metil-1-[(1r,4r)4(mesilamino)ciclo -hexil]etilamino}1-etanol on. π n-[(1r,4r)-4-{1[(r)-2-(mfluorofenil)-2hidroxietilamino]1-metiletil}ciclohexil]acetamida oh nc. j\k 6-[(s)-2-(tercbutilamino)-1hidroxietil]-2piridinacarbonitril —^ .nh π'^κχ'χ ,ο θ (r)-(4-benzil-7azabiciclo[2.2.1]h ept-1-il)(mfluorofenil)metan _.nh hoó χχχ, ,χ (s)-(4-benzil-7azabiciclo[2.2.1]h 95 79 39 ^cooh pa (1r,4r)-8-[(r)-2(5-fluoro-3piridil)-2hidroxietilamino]7-hidroxi-pmentan-7-ona " cl (s)-{(2r,5s)-5[(pclorofenil)metil]2-pirrolidinil}(mfluorofenil)metan h9 fta^xx (r)-{(2r,5s)-5[(pclorofenil)metil]2-pirrolidinil}(mfluorofenil)metan ho (r)-{(2r,5r)-5[(pclorofenil)metil]2-pirrolidinil}(mfluorofenil)metan (s)-{(2r,5r)-5[(pclorofenil)metil]2-pirrolidinil}(mfluorofenil)metan —-,νη i ho, va v. '—°— a3 (s)-(4-{[(pclorofenil)metoxi] metil}-7azabiciclo[2.2.1]h —_ ^nh ho^aa λ) (r)-(4-{[(pclorofenil)metoxi] 96 80 xj (s)-2-(tercbutilamino)-1-[6(trifluorometil)-2piridil]-1 -etanol λο^ [ oet acetato etila [(1r,4r)-4-{1-[(r)2-(m-fluorofenil)2hidroxietilamino]1-metiletil}ciclohexiloxi j λ ί a^>CN (1S,4s)-4-{2-[(R)2-(m-fluorophenyl)2hydroxyethylamino]2methylpropyljcyclohexanecarbonitrile a +++ + 40 0 ^x / NH hoAA, Petition 870250079411, dated 05 / 09 / 2025, p. 97 / 165 81 / 138 hexyloxy]acetic 40 3 IZ 1 (S)-{(2R,5S)-5[(pchlorophenyl)methyl]2-pyrrolidinyl}(5fluoro-3pyridyl)methanol ++ - 40 4 -\ I / ° (R)-{(2R,5S)-5[(pchlorophenyl)methyl]2-pyrrolidinyl}(5fluoro-3pyridyl)methanol +++ - 40 5 H° η Η HN Xt! (S)-{(2R,5R)-5[(pchlorophenyl)methyl]2-pyrrolidinyl}(5fluoro-3pyridyl)methanol +++ - 40 6 H° Η Η HN Cl (R)-{(2R,5R)-5[(pchlorophenyl)methyl]2-pyrrolidinyl}(5fluoro-3pyridyl)methanol +++ - 40 7 0 / χ à ^-x OH H [ 0 ethyl acetate [(1S,4s)-4-{1[(R)-2-(mfluorophenyl)-2hydroxyethylamino]1-methylethyl}cyclohexyloxy ++ - 40 8 0 A\ ^Οχ A, OH H < γ* OH Κχ,. A^Vx / U x [(1S,4s)-4{1-[(R)-2-(mfluorophenyl)-2hydroxyethylamino]1-methylethyl}cyclohexyloxy]acetic acid ++ - . Petition 870250079411, 05 / 09 / 2025, p. 98 / 1 82 / 1 40 9 0 AA Λ0. X OH HI] 0 Va N ethyl acetate [(1R,4r)-4-{1-[(R)2-(5-fluoro-3pyridyl)-2hydroxyethylamino]1-methylethyl}cyclohexyloxy +++ - 41 0 V- (C)-(mfluorophenyl)(4-{2[(1r,4R)-4methoxyciclohexyl]ethyl}-7azabiciclo[2.2.1]h ept-1-yl)methanol ++ - 41 1 / nh f TA (R)-(mfluorophenyl)(4-{2[(1r,4C)-4methoxycyclohexyl]ethyl}-7azabiciclo[2.2.1]h ept-1-yl)methanol +++ ++ 41 2 Xq HO1 / a\ XF (C)-(mfluorophenyl){4-[(pfluorophenyl)methyl]7azabiciclo[2.2.1]h ept-1-yl}methanol ++ - 41 3 NH A HO*X (R)-(mfluorophenyl){4-[(pfluorophenyl)methyl]7azabiciclo[2.2.1-yl ept-1-++}. 41 4 °HH NC. a, ΙΑ x OVA H 2-methyl-2propanocarbamate o de 4s)-4-{2[(S)-2-(6-cyano-2pyridyl)-2hydroxyethylamino]2methylpropyljcyclo- ++ - Petition 870250079411, of 05 / 09 / 2025, p. 99 / 165 83 / 138 hexila 41 5 9H H NC >x λ y xAA xY 6-[(R)-2-{1,1dimethyl-2- [(1s,4S)-4aminocyclohexyl]ethylamino}-1hidroxyethyl]-2pyridinocarbonitril a ++ - 41 7 °HH NC^ zN AA xx Y 6-[(S)-2-{1,1dimethyl-2-[(1r,4S)4-aminocyclohexyl]ethylamino}-1hidroxyethyl]-2pyridinocarbonitril a +++ + 41 8 °HH INC ,N, A. / Nx x-\ y AA A. YY YY 'nh2 6-[(S)-2-{1,1dimethyl-2- [(1s,4R)-4aminocyclohexyl]ethylamino}-1hidroxiethyl]-2pyridinocarbonitril a ++ - 41 9 o OH OH AY ΑΥΆΑ'Ύ H 2-methyl-2propanocarbamat or de (1 R,4r)-4-{2- [(R)-2-(m- ++ + Petition 870250079411, 05 / 09 / 2025, pág. 100 / 165 84 / 138 fluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl 42 1 °HH NC. .N. A^ / A. CQa H N-[(1R,4s)-4-{2[(S)-2-(6-cyano-2pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]acetamide +++ - 42 2 °HH NC .NA Ν. / A. T 1 Λ 1 1 xx XX X Χά / Sv H 6-[(S)-2-{1,1dimethyl-2[(1s,4R)-4(mesylamino)cyclo -hexyl]ethylamino}1-hydroxyethyl]-2pyridinocarbonitrile a ++ - 42 3 oH H NC, .Ν, ^A< 1J ^Qa H N-[(1S,4s)-4-{2[(R)-2-(6-cyano-2pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]acetamide - - 42 4 < TV^ ωί / '° 6-[(R)-2-{1,1dimethyl-2- [(1s,4S)-4(mesylamino)cycl -hexyl]ethylamino}1-hydroxyethyl]-2pyridinocarbonitrile a + - 42 5 °HH NC, ,N, A. ,N. / A. i / j ^O. x H N-[(1S,4r)-4-{2[(S)-2-(6-cyano-2pyridyl)-2hydroxyethylamino]2methylpropyl}cyclo- +++ + Petition 870250079411, 05 / 09 / 2025, p. 101 / 1 85 / 1 hexyl]acetamide 42 6 °HH NC. Λ / N. / K xx Ti Δ II °AAA k AH 6-[(S)-2-{1,1dimethyl-2-[(1r,4S)4(mesylamino)cyclo -hexyl]ethylamino}1-hydroxyethyl]-2pyridinocarbonitrile a +++ - 42 7 9H H NC. / N. .N. xx Xl XQ XH N-[(1R,4r)-4-{2[(R)-2-(6-cyano-2pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]acetamide - - 42 8 oH HT 1 AT 1 °A kJ kA xS. H 6-[(R)-2-{1,1dimethyl-2-[(1r,4R)4(mesylamino)cyclo -hexyl]ethylamino}1-hydroxyethyl]-2pyridinocarbonitrile a - - 42 9 °HH Yj^AO. χ Η 1 N-[(1R,4r)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]2,2dimethylpropionami da +++ + 43 0 °HHF\ / X. Αχ / N. Y Λ Ί 0 V Λ v.„x Η 1 (R)-2-{1,1-dimethyl2-[(1r,4R)-4-(3,3dimethylureido)cyclo-hexyl]ethylamino}1-(m-fluorophenyl)1-ethanol +++ ++ Petition 870250079411, 05 / 09 / 2025, p. 102 / 1 86 / 1 43 1 °HHF AN Yj a H \A N-[(1R,4r)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]cyclobutanoc arboxamide +++ ++ 43 2 °HHF y Αχ A / N. a*< ax YA o N-[(1R,4r)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]cyclopropane ocarboxamide +++ +++ 43 3 °HH r / a A yy ^xx ^a XT 1 1 x A \ Η x A\ A / yA^ H N-[(1R,4r)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]trifluoroacetate amide +++ + 43 4 °HH Αχ A / N. xs. Cv y. â NA AA \ H N-[(1R,4r)-4-{2[(R)-2-hydroxy-2(2-methyl-3pyridyl)ethylamino]2methylpropyl}cyclohexyl]acetamide +++ - 43 5 OH f H aA AA A a^< αΆ íl ATI XA XA Λ XA Λ (R)-2-{1,1-dimethyl2-[(1r,4R)-4(mesylamino)cyclo -hexyl]ethylamino}1-(2-methyl-3pyridyl)-1-ethanol + - 43 6 °HH AA A aA, AA Cv aqx NA Aa AH N-[(1C,4s)-4-{2[(R)-2-hydroxy-2(2-methyl-3pyridyl)ethylamino]- ++ - Petition 870250079411, of 05 / 09 / 2025, p. 103 / 165 87 / 138 2methylpropyljcyclohexyl]acetamide 43 7 OH J Η ÍI ATI θ θ Η (R)-2-{1,1-dimethyl2-[(1s,4S)-4(mesylamino)cyclo -hexyl]ethylamino}1-(2d-4dyl-methyl-8-1 ΝΗ Αο. ΗΟ· / AAF A (S)-(mfluorophenyl)(4-{[(pfluorophenyljmethoxy] methyl}-7azabicyclo[2.2.1]h ept-1-yl)methanol - - 43 9 ΝΗ HO* / (R)-(mfluoro]{fluorophenyl)[mfluorophenyl)[mfluorophenyl) methyl}-7azabicycle[2.2.1]h ept-1-yl)methanol +++ + 44 0 —— ,ΝΗ (S)-{4-[(pchlorophenoxy)methyl]7azabicycle[2.2.1]h ept-1 -yl}(mfluoro^4+Η+1)methane HO.Vb / Τ u 0- / Ι A (R)-{4-[(pchlorophenoxy)methyl]7azabicyclo[2.2.1]h ept-1 -yl}(mfluorophenyl)methane ol +++ - 44 2 Α°τι Ν=- gold oxy[(pphen S)- methyl}-7azabiciclo[2.2.1]h ept-1 -yl)(5-fluoro3-pyridyl)methanol + - Petition 870250079411, dated 05 / 09 / 2025, p. 104 / 165 88 / 138 44 3 NH hoA x^f N= / (R)-(4-{[(pfluorophenyl)methoxy] methyl}-7azabiciclo[2.2.1]h ept-1 -yl)(5-fluoro3-pyridyl)methanol +++ + 44 4 NH | H Ajx / An ho A (R)-(offluorophenyl){4-[2(3-pyridyl)ethyl]-7azabiciclo[2.2.1]h ept-1-yljmethanol +++ ++ 44 5 NH | N HO..... <f CAf (S)-(mfluorofenil){4-[2(3-piridil)etil]-7azabiciclo[2.2.1]h ept-1-iljmetanol +++ - 44 6 NH Γ N hoA γ (R)-(mfluorofenil){4-[2(3-piridil)etil]-7azabiciclo[2.2.1]h ept-1-iljmetanol +++ ++ 44 7 °H H Y Xf \γγ\ o ^Az N-[(1S,4s)-4-{2[(R)-2-(mfluorofenil)-2hidroxietilamino]2metilpropiljciclohexil]ciclopropan ocarboxamida +++ - 44 8 °H H X / A / N. ,-*< γ \ H VA N-[(1S,4s)-4-{2[(R)-2-(mfluorofenil)-2hidroxietilamino]2metilpropiljciclohexil]ciclobutanoc arboxamida ++ - 44 9 θΗ H F. / A / Ά Y A-γX / ΥγΧ Ο 1 L J A 1 1 A A AA AAnAqX H 2-metil-2propanocarbamat o de (1S,4s)-4-{2[(R)-2-(m- ++ - Petition 870250079411, of 05 / 09 / 2025, p. 105 / 165 89 / 138 fluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl 45 0 °HH F3C. / A / N. A*< AA 3 AA ΑΧ / X^AO 1 V Λ AA< H 2-methyl-2propanocarbamate of (1R,4s)-4(2-{(S)-2-hydroxy- 2-[6(trifluoromethyl)-2pyridyl]ethylamino}2methylpropyl)cyclohexyl - - 45 1 OH H F. aA Aa / -N / A AA II All θθ AAX k A' aa AA AA vN AA AH (R)-2-{1,1-dimethyl2-[(1r,4R)-4(propylsulfonylam no)cyclohexyl]ethylamino}-1(m-fluorophenyl)-1ethanol ++ + 45 2 OH VHF / AA Aa / N. A\ AA AA^-AH N-[(1S,4s)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]acetamide +++ - 45 3 OH 1 HF a AA AA / N. aK AA ll All θ / Ρ 4T ζ χ 4a4T'sa Η (R)-2-{1,1-dimethyl2-[(1s,4S)-4(mesylamino)cyclo -hexyl]ethylamino}1-(m-fluorophenyl)1-ethanol +++ - 45 4 °Η Η Ια aa A / Ν. / a. a-. X aa Υγ ι 0 V Λ A Η N-[(1S,4s)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclo- +++ - . Petition 870250079411, 05 / 09 / 2025, p. 106 / 1 90 / 1 hexyl]trifluoroacet amide 45 5 °HHA / A. / N. A Alx Η 1 N-[(1S,4s)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]2,2dimethylpropionami da ++ - 45 6 °HH AA A^*Nn2 (R)-2-{1,1-dimethyl2-[(1s,4S)-4aminocyclohexyl]ethylamino}-1(m-fluorophenyl)-1ethanol +++ - 45 7 °HH f. A. A / -v. ~ VY Υγ xo JA 1 1 u Αν Α^*Ν / ^ΝΜθ2 H (R)-2-{1,1-dimethyl2-[(1s,4S)-4-(3,3dimethylureido)cycl o-hexyl]ethylamino}1-(m-fluorophenyl)1-ethanol +++ + 45 8 °HH F. Η AND <A° kA x A J-',. Y AA N CF3 H (R)-2-{1,1-dimetil2-[(1r,4R)-4(trifluoromesilami no)ciclohexil]etilamino}-1(m-fluorofenil)-1etanol +++ - 45 9 °H H F,C. .N. A. .A. AJ L J a Jd H 2-metil-2propanocarbamat o de (1S,4r)-4-(2{(S)-2-hidroxi-2[6-(trifluorometil)2piridil]etilamino}2metilpropil)ciclohexila +++ - Petition 870250079411, 05 / 09 / 2025, p. 107 / 1 91 / 1 46 0 θΗ H F,C. ,N. Λ, ,N. / χ \χ Α H N-[(1S,4r)-4-(2{(S)-2-hydroxy-2[6-(trifluoromethyl)2pyridyl]ethylamino}2methylpropyl)cyclohexyl]acetamide ++ - 46 1 Ο 2 ,ο ωί / '° (S)-2-{1,1-dimethyl2-[(1r,4S)-4(mesilamino)ciclo -hexyl]ethylamino}1-[6(trifluoromethyl)-2pyridyl]-1-ethanol + - 46 2 θΗ H FoCx X, Λ ,Nx XXXXλ H N-[(1R,4s)-4-(2{(S)-2-hydroxy-2[6-(trifluoromethyl)2pyridyl]ethylamino}2methylpropyl)cyclohexyl]acetamide + - 46 3 °θ H FoCx ,N. Ah A Y Y A II °- / ° H (S)-2-{1,1-dimethyl2-[(1s,4R)-4(mesilamino)ciclo -hexyl]etilamino}1-[6(trifluorometil)-2pyridyl]-1-etanol ++ - 46 4 °H H Fx / dx / A^XAX, LJ Z\ L Yz, A Me, XZ 2 Q O (R)-2-{1,1-dimethyl2-[(1r,4R)-4(dimethylaminossulfonyl)ciclohexyl]ethylamino}-1(m-fluorofenil)-1etanol + + 46 5 °H H fAXx\ / naXA LJL \:„ ^NMe, A 'sf Q O (R)-2-{1,1-dimethyl2-[(1r,4R)-4(dimethylaminossulfonyl)cyclohexyl]ethylamino}-1(m-fluorofenil)-1ethanol + + Petition 870250079411, de 05 / 09 / 2025, pág. 108 / 165 92 / 138 hexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol 46 6 °HH fvaA\ / n\zVA kJ χΤλ (R)-2-{1,1-dimethyl2-[(1s,4S)-4aminocyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol ++ - . 46 7 °HH Fx Λ ANH N-[(1S,4s)-4-{2[(R)-2-(5-fluoro-3pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]acetamide +++ - 46 8 °HH Fx χτχ Λ Ax Η ATI OA L x L / A JsL H (R)-2-{1,1-dimethyl2-[(1s,4S)-4(mesylamino)cyclo -hexyl]ethylamino}1-(5-fluoro-3pyridyl)-1-ethanol +++ - 46 9 θΗ H Fx / XA Ax / x T ΧΤΊ ° 1 kk Λ Qa x N 0 H 2-methyl-2propanocarbamate of (1S,4s)-4-{2[(R)-2-(5-fluoro-3pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl +++ - 47 0 °HH f^aAv / ^xx / Ax ί AL ^NMe2 7sf 2 0 o (R)-2-{1,1-dimethyl2-[(1s,4S)-4(dimethylaminossul phonyl)cyclohexyl]ethylamino}-1(m-fluorophenyl)-1ethanol +++ + 47 1 FXN LA ' LA^ „NMe, N rí 6 'b (R)-2-{1,1-dimethyl2-[(1s,4S)-4(dimethylaminosul+++ ++ Petition 870250079411, 05 / 09 / 2025, p. 109 / 1 93 / 1 phonyl)cyclohexyl]ethylamino}-1 (5-fluoro-3pyridyl)-1 -ethanol 47 2 NH Z7 \ Τι Ί OO 7\ > |l JZ Ho· / zzZr' ky—F Xh (S)-[4-({p[(benzyl)-Nmesylamino}phenyl}] methyl)-7azabiciclo[2.2.1]h ept-1-yl](mfluorophenyl)methanol + - 47 3 O. / jz CL °' o (R)-[4-({p[(benzyl)-Nmesylamino]phenyl} methyl)-7azabiciclo[2.2.1]h ept-1-methanol +(mfluorophenyl) +(mfluorophenyl)ol + - 47 3 O. 4 NH Z / N li Ί 0 0 7\z 11 Λ Z HO1 / A / Jp x )—ch η (X (S)-(mfluorophenyl)(4-{[p(mesylamino)phenyl] methyl}-7azabiciclo[2.2.1]h ept-1-yl)methanol ++7 / H^Z. ί oo 7\ > |l J z H0*{ ZZp x \—VH (XF (R)-(mfluorophenyl)(4-{[p(mesylamino)phenyl] methyl}-7azabicyclo[2.2.1]h ept-1-yl)methanol ++ - 47 6 θΗ HLX / N lX 'N^ ooH ). (R)-2-{1,1-dimethyl2-[(1r,4R)-4(methylaminosulfo nil)cyclohexyl]ethylamino}-1 (m-fluorophenyl)-lethanol +++ + Petition 870250079411, of 05 / 09 / 2025, p. 110 / 165 94 / 138 47 7 θΗ H Y Y 1 Y, ,NHMe o o (R)-2-{1,1-dimethyl2-[(1s,4S)-4(methylaminossulfonyl)cyclohexyl]ethylamino}-1(m-fluorofenil)-1ethanol ++ - 47 8 θΗ H Fx / tx^Y Y xj LJ·,,,, ^NHMe N 'sf o 'o (R)-2-{1,1-dimethyl2-[(1r,4R)-4(methylaminossulfonyl)cyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol + - 47 9 ΠΟ Η Η Η *νΥ ς. N-[(1R,4s)-4({(2S,5R)-5-[(S)(mfluorofenil)hydroxy metil]-2pyrrolidinil}metil)ci clo-hexyl]-Nbenzylacetamida - - 48 0 H9 H H H Ph N-[(1R,4s)-4({(2S,5R)-5-[(R)(mfluorofenil)hydroxy metil]-2pyrrolidinil}metil)ci clo-hexyl]-Nbenzylacetamida - - 48 1 HO H H h Fx / A\ / Y\ Hy L? / ° γ N-[(1S,4r)-4({(2S,5R)-5-[(S)(mfluorofenil)hidroxi metil]-2pyrrolidinyl}metil)ci clo-hexyl]-Nbenzilacetamida - - 48 2 H° H H H f / 7 / τ^\ / ° υΎ < Ph N-[(1S,4r)-4({(2S,5R)-5-[(R)(m- - - Petition 870250079411, de 05 / 09 / 2025, pág. 111 / 165 95 / 138 fluorofenil)hidroxi metil]-2pyrrolidinil}metil)ci clo-hexyl]-Nbenzilacetamida 48 3 HO μ H μ / τ\ H N-[(1R,4s)-4({(2S,5R)-5-[(S)(mfluorofenil)hidroxi metil]-2pyrrolidinil}metil)ci clohexyl]acetamida - - 48 4 H° μ H μ / γ^*\ XT χ) ? H N-[(1R,4s)-4({(2S,5R)-5-[(R)(mfluorofenil)hidroxi metil]-2pyrrolidinil}metil)ci clohexyl]acetamida ++ - 48 5 HO μ H μ fAX\ / T-Ά XT χτ ? xT H N-[(1S,4r)-4({(2S,5R)-5-[(R)(mfluorofenil)hidroxi metil]-2pyrrolidinil}metil)ci clohexyl]acetamida ++ - 48 6 H9 H H H XX ? H N-[(1S,4r)-4({(2S,5R)-5-[(S)(mfluorofenil)hydroxy metil]-2pyrrolidinil}metil)ci clohexyl]acetamida ++ - 48 7 NH X (S)-(mfluorofenil)(4-{[(ptrifluoromethoxyfenil)metoxi]metil}-7- - - Petition 870250079411, de 05 / 09 / 2025, pág. 112 / 165 96 / 138 azabiciclo[2.2.1]h ept-1-yl)methanol 48 8 NH hoA (R)-(mfluorophenyl)(4-{[(ptrifluoromethoxyphenyl)methoxy]methyl}-7azabiciclo[2.2.1]h ept-1-yl)methanol - - 48 9 NH HOA ^^ (S)-(5-fluoro-3pyridyl)(4-{[(ptrifluoromethoxyphenyl l)methoxy]methyl}-7azabiciclo[2.2.1]h ept-1-yl)methanol - - 49 0 NH ÃXi HO-Y ^^OCFj (R)-(5-pyrofluoro-triophenyl(4)(4) l)methoxy]methyl}-7azabiciclo[2.2.1]h ept-1-yl)methanol ++ - 49 1 °HHF\ / N. ΥΎ^ΧΎΊ ? \x^ Me N-[(1R,4r)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyljciclohexyl]-Nmethylacetamide +++ - 49 2 °HH F. ,N. Me N-[(1C,4s)-4-{2[(R)-2-(mfluorophenyl)-2hydroxyethylamino]2methylpropyljcyclohexyl]-Nmethylacetamide + - 49 3 °HHF A- ,N. ,-s. ΥΎ X of °-? CA XA* xS. CF 3 H (R)-2-{1,1-dimethyl- 2-[(1s,4S)-4(trifluoromesylamino)cyclohexyl]ethylamino}-1 - + - Petition 870250079411, of 05 / 09 / 2025, p. 113 / 165 97 / 138 (m-fluorofenil)-letanol 49 4 θΗ H Fx / χ A. ,Νχ N All χ ο i A 7 χ LA* Jsí H V (R)-2-{1,1-dimethyl2-[(1s,4S)-4(ciclopropilsulfonil amino)ciclohexyl]ethylamino}-1(m-fluorofenil)-1ethanol + - 49 5 θΗ H Pχ^χΧχΑχ^ L ' L ,ΝΗΜβ N Q q (R)-2-{1,1-dimethyl2-[(1s,4S)-4(metilaminossulfonil)ciclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol ++ - 49 6 θΗ H Fx / τχ Aχ ,Νχ H ΑΤΙ Ά° i A χ AJ„z / Tsi H V (R)-2-{1,1-dimethyl2-[(1r,4R)-4(ciclopropilsulfonil amino)cyclohexyl]ethylamino}-1(m-fluorofenil)-1ethanol ++ - 49 7 θΗ Η Fx^ / χ Α. ,Νχ / χ Η Λ II °Ά Αα ΑΑΝΚχχ\ Η (R)-2-{1,1-dimethyl2-[(1s,4S)-4(propylsulfonylamino)cyclohexyl]ethylamino}-1(m-fluorofenil)-1ethanol ++ - 49 8 °Η Η Fx. / XA / Νχ / ·*< / χ Π Ατι θθ i A ζ χ L Α» Αχ χ / Me Me (R)-2-{1,1-dimethyl2-[(1s,4S)-4-(Nmesil-Nmetilamino)cyclohexyl]ethylamino}-1(m-fluorofenil)-1ethanol + - 49 9 °Η Η Fx. χ-Χχ Αχ / Νχ / ·*< / -χ Η All θθ LA ζ χ L Αχ 'Ν Me Me (R)-2-{1,1-dimethyl2-[(1r,4R)-4-(Nmesyl-Nmetilamino)ciclo- + - Petition 870250079411, of 05 / 09 / 2025, p. 114 / 165 98 / 138 hexyl]ethylamino}-1(m-fluorophenyl)-ethanol 50 0 NH HO / (S)-(mfluorophenyl){4-[(ptrifluoromethoxyphenyl l)methyl]-7azabiciclo[2.2.1]h ept-1-yl}methanol - - 50 1 NH HO» / €Xf (R)-(mfluorophenyl){4-[(ptrifluoromethoxyphenyl l)methyl]-7azabicyclo[2.2.1]h ept-1-yl}methanol - - 50 2 HO Η li Me Ph (R)-[(2R,5S)-5({(1r,4S)-4[(benzyl)-Nmesylamino]cyclohexyl}methyl)-2pyrrolidinyl](mfluorophenyl)methanol - - 50 3 Ho u H LI XJ C j 7.0 ÍTS' Me Ph (S)-[(2R,5S)-5({(1r,4S)-4[(benzyl)-Nmesylamino]cyclohexyl}methyl)-2pyrrolidinyl](mfluorophenyl)methanol - - 50 4 HO HH li X 3 Γ} o / O 'νΆ H Me (R)-[(2R,5S)-5{[(1r,4S)-4(mesylamino)cyclo -hexyl]methyl}-2pyrrolidinyl](mfluorophenyl)methanol ++ - 50 5 HO MH with Αψ-ναΧ X· X \ u 7,° Z / nSx H Me (C)-[(2R,5S)-5{[(1r,4S)-4(mesylamino)cycle - - Petition 870250079411, of 05 / 09 / 2025, p. 115 / 165 99 / 138 -hexyl]methyl}-2pyrrolidinyl](mfluorophenyl)methane ol 50 6 °HH Vj zq . â N 'N Me N-[(1R,4r)-4-{2[(R)-2-(5-fluoro-3pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]-Nmethylacetamide +++ + 50 7 °HH F- zz A\ / N. / *< / - Ir Zll Me N-[(1S,4s)-4-{2[(R)-2-(5-fluoro-3pyridyl)-2hydroxyethylamino]2methylpropyl}cyclohexyl]-Nmethylacetamide ++ - 50 8 HO u H u VA ζ Me Ph (R)-[(2R,5S)-5({(1s,4R)-4[(benzyl)-Nmesylamino]ciclohexyl}methyl)-2pyrrolidinyl](mfluorophenyl)methanol - - 50 9 H? HJ Η ζ Me Ph (S)-[(2R,5S)-5({(1s,4R)-4[(benzyl)-Nmesylamino]ciclohexyl}methyl)-2pyrrolidinyl](mfluorophenyl)methanol - - 51 0 H0 Η Η H ( J %° H Me (R)-[(2R,5S)-5{[(1s,4R)-4(mesylamino)cyclo -hexyl]methyl}-2pyrrolidinyl](m- +++ - Petition 870250079411, of 05 / 09 / 2025, p. 116 / 165 100 / 138 fluorophenyl)methanol 51 1 HO MH li xA θ / OA (S)-[(2R,5S)-5{[(1s,4R)-4(mesylamino)cyclo -hexyl]methyl}-2pyrrolidinyl](mfluorophenyl)methanol + - 51 2 R, NH I / 1 w / χ UJ> Me\ 0 HO· / (S)-[4-({m[(benzyl)-Nmesylamino]phenyl} methyl)-7azabicyclo[2.2.1]h ept-1 -yl](mfluorophenylmethane ol - - 51 3 Ph NH I / l / x / x xMe ΑΎΎ - ho Λ7-(m)(4-F) [(benzyl)-Nmesylamino]phenyl} methyl)-7azabiciclo[2.2.1]h ept-1 -yl](mfluorophenylmethane ol + - 51 4 NH H _ / | / s. ,Νχ xMe <ΓνΥΎ - AA oo H0( typ (S)-(m(mfluorophenyl)(4-{[m(m(mecylamino)phenyl] methyl}-7azabiciclo[2.2.1]h ept-1-yl)methanol ++ - 51 5 NH H / I / X / x A ^Me Az A oo HO* / (R)-(mfluorophenyl)(4-{m(m(mecylamino)phenyl)] methyl}-7azabicyclo[2.2.1]h ept-1-yl)methanol ++ + 51 6 °HHF n \ / N / % xj / ' LK x-NH, 2 o 'b (1R,4r)-4-{2-[(R)2-(m-fluorophenyl)2- hydroxyeti -+++] Petition 870250079411, of 05 / 09 / 2025, p. 117 / 165 101 / 138 2methylpropyl}cyclohexanesulfonami da 51 7 °HH ΡΧ· / ΧχΑχΝχ / ^ ί JL xL Jx ^nh2 N 'Sf Q 'b (1R,4r)-4-{2-[(R)2-(5-fluoro-3pyridyl)-2hidroxiethylamino]2methylpropyl}cyclohexanosulfonam ida ++ - 51 9 °HH ρ\ / νΑχΝχχ\ / ν LJL _T x-nh, Q 'b (1S,4s)-4-{2-[(R)2-(5-fluoro-3pyridyl)-2hidroxiethylamino]2methylpropyl}cyclohexanosulfonam ida +++ - 52 0 °HH F. / x A. ,Ν. x\ Η AT 1 °' >9 O 7 XL xA Aí Al Al Me Me (R)-2-{1,1-dimethyl2-[(1s,4S)-4-(Nmesyl-Nmethylamino)cyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-etanol ++ - 52 1 °HH Fx XX A Αχ x*< XX. η All °w° x A 7 xk Aí NN Me Me (R)-2-{1,1-dimetil2-[(1r,4R)-4-(Nmesyl-Nmetilamino)ciclohexyl]ethylamino}-1(5-fluoro-3- ++ - Petition 870250079411, 05 / 09 / 2025, pág. 118 / 165 102 / 138 pyridyl)-1-ethanol 52 2 °HHF / 3⁄4. / k YY AT 1°-? TYA zSs N CF3 H(R)-2-{1,1-dimethyl2-[(1s,4S)-4(trifluoromesylam no)cyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol +++ - 52 3 θΗ HF\ / A. / NX Η X 1 1 ° ° H (R)-2-{1,1-dimethyl2-[(1s,4S)-4(propylsulfonylam no)cyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol ++ - 52 4 °HHA / v. A. ,N. Η X 1 1 Οχ / 0 H (R)-2-{1,1-dimethyl2-[(1s,4S)-4(ethylsulfonylamino)cyclohexyl]ethylamino}-1(m-fluorophenyl)-1ethanol ++ - 52 5 °HH F. / A. T\ / N. / \ ll Ί X 1 1 ° / / 0 aa,n's\ / H (R)-2-{1,1-dimethyl2-[(1r,4R)-4(ethylsulfonylamino)cyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol ++ - 52 6 °HHR / Ά / ll All °Ά 1 XT / x X X- / , X' / L ''N 'NH(R)-2-{1,1-dimethyl2-[(1r,4R)-4(isobutylsulfonyl mino)cyclohexyl]ethylamino}-1(5-fluoro-3pyridyl)-1-ethanol ++ - . Petition 870250079411, 05 / 09 / 2025, p. 119 / 1 103 / 1 52 7 nh Γ ü HO / (C)-{4-[2-(pchlorophenyl)ethyl]-7azabiciclo[2.2.1]h ept-1 -yl}(mfluorophenyl)methanol - - 52 8 NH Γ ll ^XjA^Ax hoA vX—F (R)-{4-[2-(pchlorophenyl)ethyl]-7azabiciclo[2.2.1]h ept-1 -yl}(mfluorophenyl)methane ol - - 52 9 NH HO..... / XX fu n=7 (C)-{4-[(E)-3-phenyl- 2-propenyl]-7azabiciclo[2-1]h. -yl}(5-fluoro3-pyridyl)methanol + - 53 0 NH hoA XX Xv F n=7 (R)-{4-[(E)-3phenyl-2-propenyl]7azabiciclo[2.2.1]h ept-1 -yl}(5-fluoro3-pyridyl)methanol +++ + 53 / NH HO= L^XX7 (C)-(5-fluoro-3- pyridyl){4-(3phenylpropyl)-7azabicyclo[2.2.1]h ept-1-yljmethanol ++ - 53 2 NH hoA XX N= / (R)-(5-fluoro-3- pyridyl){4-(3phenylpropyl)-7azabiciclo-[2.2.1] ++ + 53 3 (S)-{4-[(E)-3-phenyl- 2-propenyl]-7azabiciclo[2.2.1]h ept-1 -yl}(m- - - Petition 870250079411, of 05 / 09 / 2025, p. 120 / 165 104 / 138 NH aX^XI HO' / fluorophenyl)methane ol 53 4 NH HOy fX (R)-{4-[(E)-3phenyl-2-propenyl]7azabiciclo[2.2.1]h ept-1-yl}(mfluorophenyl)methane ol +++ - 53 5 NH αΥΥΥΥΥΥF / ΥV-F (S)-(mfluorophenyl){4-(3phenylpropyl)-7azabicyclo[2.2.1]h ept-1-yl}methanol + - 53 6 NH aX'YXí ho·- / v3^f (R)-(mfluorophenyl){4-(3phenylpropyl)-7azabicyclo[2.2.1-h. + 53 7 NH Ά / xX / ~\ N Me HO^^ X <x^xf (r)-(4-{[(benzil)nmesilamino]metil} -7azabiciclo[2.2.1]h ept-1-il)(mfluorofenil)metan ol ++ + 53 8 nh %° ^ 1^. .s. n me ho^^^ xh fy f (s)-(4-{[(benzil)nmesilamino]metil} -Petition 870250079411, of 05 / 09 / 2025, p. 121 / 165 105 / 138 53 9 NH [ HO< OMe J (S)-(mfluorophenyl){4-[2(pmethoxyphenyl)ethyl]-7azabiciclo[2.2.1]h ept-1-yl}methanol - - 54 0 NH \ HO* / —f OMe ΪΓ (R)-(mfluorophenyl){4-[2(pmethoxyphenyl)ethyl]-7azabiciclo[2.2.1]h ept-1-yl}methanol ++ + 54 1 NH [ HO' / PF N= / OMe (S)-(5-fluoro-3- pyridyl){4-[2-(pmethoxyphenyl)ethyl]-7azabiciclo[2.2.1]h ept-1-yl}methanol - - 54 2 NH I HO* / OMe f (R)-(5-fluoro-3- pyridyl){4-[2-(pmethoxyphenyl)ethyl]-7azyl. ept-1-yl}methanol ++ + 54 3 NH [ HO' / chP-F N= / / OCF3 J (S)-(5-fluoro-3pyridyl){4-[2-(ptrifluoromethoxypheni l)ethyl]-7azabiciclo[2.2.1]h ept-1-yl}methanol - NH \ 4 _ _ _ _ _ HO 3 - HO J (C)-(mfluorophenyl){4-[2(ptrifluoromethoxyphenyl l)ethyl]-7azabiciclo[2.2.1]h ept-1-yl}methanol - - 54 5 NH £ | HO* / / ^Pf N= / / OCF3 (R)-(5-fluoro-3pyridyl){4-[2-(ptrifluoromethoxyphenyl l)ethyl]-7azabicyclo[2.2.1]h - - Petition 870250079411, of 05 / 09 / 2025, p. 122 / 165 106 / 138 ept-1-yl}methanol 54 6 ^^,OCF3nh Γ J HO* / (R)-(mfluorophenyl){4-[2(ptrifluoromethoxyphenyl l)ethyl]-7azabiciclo[2.2.1]h ept-1-yl}methanol - - 54 7 NH\ν / ν / ν / ν HO.....Ch (S)-(offluorophenyl){4-[2(3-pyridyl)ethyl]-7azabiciclo[2.2.1]h ept-1-yl}methanol +++ -

[0174] In certain embodiments, the P2-adrenergic receptor agonist is selected from the group consisting of:

[0175] 2-(butylamino)-1-(p-hydroxyphenyl)-1-ethanol;

[0176] 2-(terc-butylamino)-1 -(ph id roxifen yl)-1 -ethanol;

[0177] 2-[(cyclo-hexylmethyl)amino]-1 -(p-hyd roxyphenyl)-1 ethanol;

[0178] (R)-2-(butylamino)-1 -(ph id roxifen yl)-1 -ethanol;

[0179] 1-(m-hydroxyphenyl)-2-(1-methylbutylamino)-1-ethanol;

[0180] 2-(3-cyclo-hexylpropylamino)-1-(p-hydroxyphenyl)-1ethanol;

[0181] (R)-2-[(R)-1 -methylbutylamino]-1 -(ph id roxifen i I)-1 ethanol;

[0182] 1-(4-amino-3,5-dichlorophenyl)-2-(butylamino)-1 -ethanol; 2-(3-cyclopropylpropylamino)-1-(p-hydroxyphenyl)-1 ethanol; 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-2-(butylamino)-1-ethanol; 2-(Butylamino)-1-(4-chloro-3-hydroxyphenyl)-1-ethanol;

[0186] 1-(4-chloro-3-hydroxyphenyl)-2-(1-methylbutylamino)-1Petição 870250079411, de 05 / 09 / 2025, p. 123 / 165 107 / 138 ethanol;

[0187] m-{(R)-[(2R,5R)-5-methyl-2-pyrrolidinyl]hydroxymethyl}phenol and m-{(S)-[(2S,5S)-5-methyl-2-pyrrolidinyl]hydroxymethyl}phenol;

[0188] 1-(3-amino-2,4-difluorophenyl)-2-(butylamino)-1-ethanol;

[0189] (R)-[(2R,6R)-6-propyl-2-piperidyl](mhydroxyphenyl)methanol;

[0190] (R)-2-[(R)-1-methylbutylamino]-1-(m-fluorophenyl)-1-ethanol;

[0191] (R)-2-[(S)-1-methylbutylamino]-1-(m-fluorophenyl)-1-ethanol;

[0192] (R)-2-(tert-butylamino)-1-(m-fluorophenyl)-1-ethanol; (R)-[(2R,5R)-5-propyl-2-pyrrolidinyl](mfluorophenyl)methanol;

[0194] (R)-2-(1,1-dimethylbutylamino)-1-(m-fluorophenyl)-1ethanol;

[0195] (R)-[(2R,6S)-6-propyl-2-piperidyl](mhydroxyphenyl)methanol;

[0196] (R)-2-(tert-butylamino)-1-(2,3-difluorophenyl)-1-ethanol;

[0197] (R)-2-(butylamino)-1 -(2,3-difluorophenyl)-1-ethanol;

[0198] (R)-2-(tert-butylamino)-1-(o-fluorophenyl)-1-ethanol;

[0199] (R)-2-(butylamino)-1-(o-fluorophenyl)-1-ethanol;

[0200] (R)-1-(m-fluorophenyl)-2-(1-methylcyclopropylamino)-1ethanol;

[0201] (R)-1 -(m-fluorophenyl)-2-(1-methylcyclobutylamino)-1ethanol;

[0202] (R)-2-(butylamino)-1 -(4-fluoro-3-hydroxyphenyl)-1 ethanol;

[0203] (R)-2-(butylamino)-1 -(2-fluoro-3-hydroxyphenyl)-1 ethanol;

[0204] (R)-1 -(3-amino-2-fluorophenyl)-2-(tert-butylamino)-1 Petition 870250079411, dated 05 / 09 / 2025, page 124 / 165 108 / 138 ethanol;

[0205] 4-[(R)-2-(tert-butylamino)-1-hydroxyethyl]-1-methyl- 2(1H)-pyridinone;

[0206] (R)-2-(tert-butylamino)-1-(5-fluoro-3-pyridyl)-1-ethanol;

[0207] 5-[(R)-2-(tert-butylamino)-1-hydroxyethyl]-3-pyridinol;

[0208] (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](m- fluorophenyl)methanol;

[0209] m-{(R)-[(R)-5,5-dimethyl-2-pyrrolidinyl]hydroxymethyl}phenol;

[0210] (R)-[(2S,6R)-6-propyl-2-piperidyl](m- chlorophenyl)methanol;

[0211] (S)-[(2S,6S)-6-propyl-2-piperidyl](m- hydroxyfenil)methanol;

[0212] 4-[2-(tert-butylamino)-1-hydroxyethyl]-3-pyridinol;

[0213] (R)-[(2S,6R)-6-propyl-2-piperidyl](m- hydroxyfenil)methanol;

[0214] (R)-[(2R,5R)-5-propyl-2-pyrrolidinil](o- clorofenil)methanol;

[0215] (R)-1-(3-amino-2,4-difluorofenil)-2-(tert-butylamino)- 1-ethanol;

[0216] (R)-2-(tert-butylamino)-1-(3-fluoro-2-tolyl)-1-ethanol;

[0217] (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](o-chlorofenil)methanol;

[0218] (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](m-chlorofenil)methanol;

[0219] (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](5-fluoro-3-pyridyl)methanol;

[0220] (R)-[(2R,5R)-5-propyl-2-pyrrolidinyl](5-fluoro-3-pyridyl)methanol;

[0221] (S)-[(R)-6,6-dimethyl-2-piperidyl](o-chlorophenyl)methanol; Petition 870250079411, dated 05 / 09 / 2025, pages 125 / 165 109 / 138

[0222] (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](ofluorophenyl)methanol;

[0223] (S)-[(R)-6,6-dimethyl-2-piperidyl](o-fluorophenyl)methanol;

[0224] (S)-(o-fluorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1yl)methanol;

[0225] (R)-(o-fluorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1yl)methanol;

[0226] (R)-(5-fluoro-3-pyridyl)(4-methyl-7azabicyclo[2.2.1]hept-1-yl)methanol;

[0227] (R)-[(S)-6,6-dimethyl-2-piperidyl](m- fluorophenyl)methanol;

[0228] (R)-[(S)-6,6-dimethyl-2-piperidyl](o-fluorophenyl)methanol; il)methanol;

[0229] (R)-(o-chlorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1- il)methanol;

[0230] (R)-(m-chlorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1- fluorophenyl)methanol;

[0231] (R)-[(R)-4,4-dimethyl-2-azetidinyl](m- fluorophenyl)methanol;

[0232] (R)-[(R)-4,4-dimethyl-2-azetidinyl](o- chlorophenyl)methanol;

[0233] (R)-{(R)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(m- fluorophenyl)methanol;

[0234] (S)-{(S)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(o- fluorophenyl)methanol;

[0235] (S)-{(R)-1 -methyl-2-azabicyclo[2.1.1 ]hex-3-yl}(o- fluorophenyl)methanol;

[0236] (R)-{(S)-1 -methyl-2-azabicycle[2.1. 1 ]hex-3-yl}(o- pyridyl)methanol;

[0237] (R)-[(R)-4,4-dimethyl-2-azetidinyl](5-fluoro-3- Petition 870250079411, dated 05 / 09 / 2025, p. 126 / 165 110 / 138

[0238] (R)-{(R)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(5-fluoro3-pyridyl)methanol;

[0239] (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](3-amino-2fluorophenyl)methanol;

[0240] (R)-[(R)-4,4-dimethyl-2-azetidinyl](mchlorophenyl)methanol;

[0241] (R)-[(2S,7S)-7-propyl-2-azepanyl](5-fluoro-3-pyridyl)methanol;

[0242] (S)-[(R)-5,5-dimethyl-2-pyrrolidinyl](4-amino-3,5difluorophenyl)methanol;

[0243] (R)-1-(5-Fluoro-3-pyridyl)-2-{2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1-ethanol;

[0244] (R)-1-(m-fluorophenyl)-2-{1-metil-1-[(1r,4R)-4methoxycyclohexyl]ethylamino}-1-ethanol;

[0245] (R)-1-(5-fluoro-3-pyridyl)-2-{1-metil-1-[(1r,4R)-4methoxyciclo-hexyl]ethylamino}-1-ethanol;

[0246] (R)-{(R)-1-metil-2-azabiciclo[2.1.1]hex-3-yl}(3amino-2-fluorofenil)methanol;

[0247] (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0248] (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol;

[0249] (R)-2-{1,1-dimethyl-2-[(1 r ,4 R )-4-methoxycyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0250] (R)-2-{1-[(1S,3R)-3-methoxyciclo-hexyl]-1methylethylamino}-1-(m-fluorofenil)-1-ethanol;

[0251] (R)-2-{1-[(1R,3S)-3-methoxyciclo-hexyl]-1methylethylamino}-1-(m-fluorofenil)-1-ethanol;

[0252] (R)-1-(5-fluoro-3-pyridyl)-2-{3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1-ethanol; Petition 870250079411, de 05 / 09 / 2025, pág. 127 / 165 111 / 138

[0253] (R)-1-(5-fluoro-3-pyridyl)-2-({[(1s,4S)-4(benzyloxy)cyclohexyl]metil}amino)-1-ethanol;

[0254] (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1-(m-fluorophenyl)-1-ethanol;

[0255] (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol;

[0256] (R)-1-(m-fluorophenyl)-2-{1-metil-1-[(1s,4S)-4(benzyloxy)cyclohexyl]ethylamino}-1-ethanol;

[0257] (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(m-fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol;

[0259] (R)-2-{1,1-dimethyl-2-[(1R,4R)-4-hydroxycyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol; (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-hydroxycyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol; N-[(1R,4r)-4-{[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]methyl}cyclohexyl]benzamide; (R)-2-{1,1-dimethyl-3-[(1 r,4S )-4-hydroxycyclohexyl]propylamino}-1-(o-fluorophenyl)-1-ethanol;

[0263] (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(o-fluorophenyl)-1-ethanol; Methyl (1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanecarboxylate;

[0265] (S)-[(2R,5S)-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol;

[0266] (R)-[(2R,5S)-5-{[(1 r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol;

[0267] (1S,4s)-4-{2-[(R)-2-(m-fluorofenil)-2hydroxyethylamino]-2-methylpropyl}ciclo-hexanocarboxilato de methyla; Petition 870250079411, de 05 / 09 / 2025, pág. 128 / 165 112 / 138

[0268] (1S,4s)-8-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]7-methoxy-p-menthan-7-one;

[0269] (R)-(m-fluorophenyl){4-(methoxymethyl)-7-azabicyclo[2.2.1]hept-1-yl}methanol;

[0270] (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol;

[0271] (R)-[(2R,5S)-5-{[(1 r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](o-fluorophenyl)methanol;

[0272] (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](o-fluorophenyl)methanol;

[0273] (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}-2pyrrolidinyl](5-fluoro-3-pyridyl)methanol;

[0274] (1 R,4r)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylate methyl;

[0275] N-[(1R,4r)-4-{1-[(R)-2-(5-fluoro-3-pyridyl)-2hydroxyethylamino]-1-methylethyl}cyclohexyl]acetamide;

[0276] (1S,4s)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylic acid;

[0277] (1S,4s)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3-methylbutyl}methyl cyclohexanecarboxylate;

[0278] (1 R,4r)-4-{3-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylate methyl;

[0279] (1S,4s)-4-{3-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylate methyl;

[0280] (1 R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanecarboxylate methyl;

[0281] N-[(1R,4r)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2hydroxyethylamino]-2-metilpropyl}ciclo-hexyl]acetamide;

[0282] (R)-2-{1,1-dimethyl-2-[(1 r,4R)-4-aminocyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol; Petition 870250079411, de 05 / 09 / 2025, pág. 129 / 165 113 / 138

[0283] (R)-2-{1,1-dimethyl-2-[(1 r,4R)-4-(mesylamino)cyclohexyl]ethylamino}-1 -(5-fluoro-3-pyridyl)-1-ethanol;

[0284] N-[(1R,4r)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2hydroxyethylamino]-3-methylbutyl}ciclo-hexyl]acetamide;

[0285] (S)-[(2R,5S)-5-metil-5-{[(1r,4S)-4-methoxycyclohexyl]metil}-2-pyrrolidinyl](m-fluorofenil)methanol;

[0286] (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-5-methyl-2-pyrrolidinyl}(m-fluorophenyl)methanol;

[0287] (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-5-methyl-2-pyrrolidinyl}(m-fluorophenyl)methanol;

[0288] (1R,4r)-8-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]7-methoxy-p-menthan-7-one;

[0289] (1R,4r)-8-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-7-methoxy-p-menthan-7-one;

[0290] (R)-2-{1,1-dimethyl-2-[(1 r,4R)-4-aminocyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0291] (S)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol;

[0292] (R)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol;

[0293] (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol;

[0294] (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol;

[0295] (R)-2-(tert-butylamino)-1-(2-methyl-3-pyridyl)-1-ethanol;

[0296] (S)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol;

[0297] (R)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol;

[0298] (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5 Petition 870250079411, de 05 / 09 / 2025, pág. 130 / 165 114 / 138 fluoro-3-pyridyl)methanol;

[0299] (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol;

[0300] (R)-2-{1,1-dimethyl-2-[(1 r,4R)-4-(mesylamino)cyclohexyl]ethylamino}-1-(m-fluorofenil)-1-ethanol;

[0301] N-[(1R,4r)-4-{2-[(R)-2-(m-fluorofenil)-2hydroxyethylamino]-2-metilpropyl}ciclo-hexyl]acetamida;

[0302] N-[(1R,4r)-4-{1-[(R)-2-(m-fluorofenil)-2hydroxyethylamino]-1-methylethyl}ciclo-hexyl]acetamide;

[0303] 6-[(S)-2-(tert-butylamino)-1-hydroxyethyl]-2-pyridinocarbonitrile;

[0304] (R)-(4-benzyl-7-azabiciclo[2.2.1]hept-1-yl)(mfluorophenyl)methanol;

[0305] (R)-{(2R,5S)-5-[(p-chlorofenil)methyl]-2-pyrrolidinyl}(mfluorofenil)methanol;

[0306] (R)-{(2R,5R)-5-[(p-chlorofenil)methyl]-2-pyrrolidinyl}(mfluorofenil)methanol;

[0307] (R)-(4-{[(p-chlorofenil)methoxy]metil}-7azabiciclo[2.2.1]hept-1-yl)(m-fluorofenil)methanol;

[0308] (S)-2-(tert-butylamino)-1-[6-(trifluoromethyl)-2-pyridyl]1-ethanol;

[0309] ethyl acetate [(1R,4r)-4-{1-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-1-methylethyl}cyclohexyloxy]-acetate;

[0310] (1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2hydroxyethylamino]-2-methylpropyl}cyclohexanecarbonitrile;

[0311] (R)-(m-fluorophenyl){4-[(p-methoxyphenyl)methyl]-7azabicyclo[2.2.1]hept-1-yl}methanol;

[0312] (R)-{(2R,5S)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5fluoro-3-pyridyl)methanol;

[0313] (S)-{(2R,5R)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5 Petition 870250079411, dated 05 / 09 / 2025, pages 131 / 165 115 / 138 fluoro-3-pyridyl)methanol;

[0314] (R)-{(2R,5R)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5fluoro-3-pyridyl)methanol;

[0315] ethyl [(1R,4r)-4-{1-[(R)-2-(5-fluoro-3-pyridyl)-2hydroxyethylamino]-1-methylethyl}cyclohexyloxy]acetate;

[0316] (R)-(m-fluorophenyl){4-[(p-fluorophenyl)methyl]-7azabiciclo[2.2.1]hept-1-yl}methanol;

[0317] 6-[(S)-2-{1,1-dimethyl-2-[(1r,4S)-4-aminocyclohexyl]ethylamino}-1-hydroxyethyl]-2-pyridinecarbonitrile;

[0318] N-[(1R,4s)-4-{2-[(S)-2-(6-cyano-2-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide;

[0319] N-[(1S,4r)-4-{2-[(S)-2-(6-cyano-2-pyridyl)-2hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide;

[0320] 6-[(S)-2-{1,1-dimethyl-2-[(1r,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1-hydroxyethyl]-2-pyridinecarbonitrile;

[0321] N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2hydroxyethylamino]-2-methylpropyl}cyclohexyl]2,2-dimethylpropionamide;

[0322] N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2hydroxyethylamino]-2-methylpropyl}cyclohexyl]trifluoroacetamide;

[0323] N-[(1R,4r)-4-{2-[(R)-2-hydroxy-2-(2-methyl-3pyridyl)ethylamino]-2-methylpropyl}cyclohexyl]acetamide;

[0324] (R)-(m-fluorophenyl)(4-{[(p-fluorophenyl)methoxy]methyl}-7azabicyclo[2.2.1 ]hept-1 -yl)methanol;

[0325] (S)-{4-[(p-chlorophenoxy)methyl]-7-azabicyclo[2.2.1]hept1-yl}(m-fluorophenyl)methanol;

[0326] (R)-{4-[(p-chlorophenoxy)methyl]-7-azabicyclo[2.2.1 ]hept1-yl}(m-fluorophenyl)methanol;

[0327] (R)-(4-{[(p-fluorophenyl)methoxy]methyl}-7azabicyclo[2.2.1 ]hept-1 -yl)(5-fluoro-3-pyridyl)methanol;

[0328] (S)-(m-fluorophenyl){4-[2-(3-pyridyl)ethyl]-7 Petition 870250079411, 05 / 09 / 2025, pág. 132 / 165 116 / 138 azabicyclo[2.2.1 ]hept-1 -yl}methanol;

[0329] N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2hidroxiethylamino]-2-methylpropyl}cyclo-hexyl]cyclopropanecarboxamida;

[0330] N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2hidroxiethylamino]-2-methylpropyl}cyclo-hexyl]acetamida;

[0331] (R)-2-{1,1 -dimethyl-2-[(1s,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0332] N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]trifluoroacetamide;

[0333] (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-aminocyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0334] (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(3,3-dimethylureido)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0335] (R)-2-{1,1-dimethyl-2-[(1 r,4R)-4(trifluoromesylamino)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0336] (1S,4r)-4-(2-{(S)-2-hydroxy-2-[6-(trifluoromethyl)-2pyridyl]ethylamino}-2-methylpropyl)cyclohexyl 2-methyl-2-propanocarbamato;

[0337] N-[(1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide;

[0338] (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol;

[0339] (1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl 2-methyl-2-propanocarbamato;

[0340] (R)-2-{1,1-dimethyl-2-[(1s,4S)-4(dimethylaminosulfonyl)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0341] (R)-2-{1,1-dimethyl-2-[(1r,4R)-4(methylaminosulfonyl)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol;

[0342] N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2hydroxyethylamino]-2-methylpropyl}cyclohexyl]-N-methylacetamide;

[0343] N-[(1 R,4r)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2 Petition 870250079411, dated 05 / 09 / 2025, pages 133 / 165 117 / 138 hydroxyethylamino]-2-methylpropyl}cyclohexyl]-N-methylacetamide;

[0344] (R)-[(2R,5S)-5-{[(1s,4R)-4-(mesylamino)cyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol;

[0345] (1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2hydroxyethylamino]-2-methylpropyl}cyclohexanesulfonamide;

[0346] (1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2hydroxyethylamino]-2-methylpropyl}cyclohexanesulfonamide;

[0347] (R)-2-{1,1-dimethyl-2-[(1s,4S)-4(trifluoromesylamino)cyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol;

[0348] (R)-{4-[(E)-3-phenyl-2-propenyl]-7azabicyclo[2.2.1]hept-1-yl}(5-fluoro-3-pyridyl)methanol;

[0349] (R)-{4-[(E)-3-phenyl-2-propenyl]-7azabicyclo[2.2.1]hept-1-yl}(m-fluorophenyl)methanol;

[0350] (R)-(m-fluorophenyl){4-(3-phenylpropyl)-7azabicyclo[2.2.1]hept-1-yl}methanol; and

[0351] (S)-(o-fluorophenyl){4-[2-(3-pyridyl)ethyl]-7azabicyclo[2.2.1]hept-1-yl}methanol,

[0352] and its pharmaceutically acceptable salts. THERAPEUTIC AGENTS

[0353] As described in this document, the present invention relates to uses and methods comprising treatment and / or prophylaxis with:

[0354] (a) insulin or a therapeutic insulin derivative; or

[0355] (b) a therapeutic agent that stimulates insulin release.

[0356] Those skilled in the art will be aware of the various ways in which insulin can be used in the treatment and administered to, or by, patients who need it.

[0357] In a specific modality, the present Petition 870250079411, dated 05 / 09 / 2025, pages 134 / 165 118 / 138 invention relates to uses and methods comprising treatment with insulin or a therapeutic derivative of insulin.

[0358] As used in this document, the term "therapeutic insulin derivative" refers to insulin derivatives that provide an equivalent or enhanced biological response (i.e., the biological response when administered to a patient is of the same type as that obtained by administering insulin, with the effect being at a therapeutically equivalent or enhanced level, such as providing beneficially altered pharmacokinetics when compared to insulin). These derivatives may also include combinations of insulin derivatives.

[0359] Specific forms of insulin and therapeutic insulin derivatives that may be mentioned include the following:

[0360] Short-acting insulin, such as

[0361] Humulin R U-100,

[0362] Novolin R FlexPen,

[0363] Novolin R ReliOn, e

[0364] Novolin R FlexPen ReliOn;

[0365] Rapid-acting insulin, such as

[0366] inhaled insulin (e.g., Afrezza),

[0367] insulin aspart (e.g., Fiasp, Fiasp FlexTouch, Fiasp PenFill, NovoLog, NovoLog FlexPen, NovoLog FlexTouch, NovoLog PenFill, ReliOn NovoLog, ReliOn NovoLog FlexPen),

[0368] insulin glulisine (e.g., Apidra, Apidra SoloStar),

[0369] insulin lispro (e.g., Admelog, Admelog SoloStar, Humalog, Humalog KwikPen, Humalog Junior KwikPen) and

[0370] insulin lispro-aabc (e.g., Lyumjev, Lyumjev KwikPen);

[0371] Intermediate-acting insulin, such as

[0372] isophane insulin (e.g., Humulin N U-100, Petition 870250079411, dated 05 / 09 / 2025, pages 135 / 165 119 / 138 Humulin N KwikPen, Novolin N, Novolin N FlexPen, Novolin N ReliOn, Novolin N FlexPen ReliOn);

[0373] Long-acting insulin, such as

[0374] insulin degludec (e.g., Tresiba, Tresiba FlexTouch),

[0375] insulin detemir (e.g., Levemir),

[0376] insulin glargine (e.g., Basaglar KwikPen, Lantus, Lantus SoloStar, Toujeo SoloStar, Toujeo Max SoloStar),

[0377] insulin glargine-yfgn (e.g., Semglee-yfgn), and

[0378] regular concentrated insulin (e.g., Humulin R U-500, Humulin R U-500 KwikPen);

[0379] Combined (premixed) insulins, such as

[0380] protamine aspart insulin / 70 / 30 aspart insulin (e.g., NovoLog Mix 70 / 30, NovoLog Mix 70 / 30 FlexPen),

[0381] isophane insulin / regular insulin 70 / 30 (e.g., Humulin 70 / 30, Humulin 70 / 30 KwikPen, Novolin 70 / 30, Novolin 70 / 30 FlexPen, Novolin 70 / 30 FlexPen ReliOn),

[0382] insulin lispro protamine / insulin lispro 50 / 50 (e.g., Humalog Mix 50 / 50, Humalog Mix 50 / 50 KwikPen), and

[0383] insulin lispro protamine / insulin lispro 75 / 25 (e.g., Humalog Mix 75 / 25, Humalog Mix 75 / 25 KwikPen).

[0384] In a specific embodiment, the present invention relates to uses and methods comprising treatment with a therapeutic agent that stimulates insulin release.

[0385] As used in this document, the term "therapeutic agent that stimulates insulin release" refers to a therapeutic active ingredient (i.e., a drug) that, after administration to a patient (i.e., in use), stimulates the release of insulin by the pancreas (an effect that may be provided along with other biological effects). These therapeutic agents Petition 870250079411, dated 05 / 09 / 2025, pages 136 / 165 120 / 138 can also be called insulin secretagogues.

[0386] Specifically, therapeutic agents that stimulate insulin release that may be mentioned include:

[0387] Sulfonylureas, such as tolbutamide, glimerpiride, glipizide and glyburide (including micronized glyburide);

[0388] Glinides, such as repaglinide and nateglinide;

[0389] DPP-4 inhibitors, such as alogliptin, sitagliptin, saxagliptin and linagliptin;

[0390] GLP-1 receptor agonists (including GLP-1 derivatives), such as exenatide, extended-release exenatide, tirrizepatide, liraglutide, lixisenatide, semaglutide, albiglutide and dulaglutide.

[0391] Those skilled in the art will understand that GLP-1 receptor agonists, that is, glucagon-like peptide-1 receptor agonists, as well as their derivatives, mimic the action of glucagon-like peptide-1.

[0392] The GLP-1 receptor agonist may have affinity for the GIP receptor, that is, the gastric inhibitory polypeptide receptor, in addition to the GLP-1 receptor. Alternatively, the GLP-1 receptor agonist may be free or substantially free of affinity for the GIP receptor.

[0393] Those skilled in the art will understand that the GLP-1 receptor agonist may be a peptide. Furthermore, it may be supplied as a liquid or suspension, in injectable form, such as in a pre-filled injection pen, and / or as a sustained-release formulation. In one example, the GLP-1 receptor agonist may be administered subcutaneously. The GLP-1 receptor agonist may be administered once or several times daily or weekly.

[0394] The following are examples of GLP-1 receptor agonists.

[0395] Exenatide, which has CAS number 141758-74-9, is a peptide sold under the trade names Byetta and Bydureon. It can be administered subcutaneously and / or in a dosage of 5 micrograms to 2 mg. Petition 870250079411, dated 05 / 09 / 2025, pp. 137 / 165 121 / 138

[0396] Tirzepatide, which has CAS number 2023788-192, is a linear polypeptide of 39 amino acids that has been chemically modified by lipidation. It is sold under the trade name Mounjaro. It can be administered subcutaneously as an injectable solution. The dosage can be from 2.5 mg / 0.5 mL to 15 mg / 0.5 mL.

[0397] Liraglutide, which has CAS number 204656-20-2, is a peptide sold under the trade names Saxenda, Victoza, and Xultophy. It can be administered subcutaneously as an injectable solution. The dosage can be from 0.6 mg to 1.8 mg, as once daily for a week or more. For example, the dosage can be 0.6 mg, 1.2 mg, or 1.8 mg, as once daily for a week or more.

[0398] Lixisenatide, which has CAS number 320367-13-3, is sold under the trade names Lyxumia and Adlyxin. It can be administered by injection or subcutaneously. For example, it can be administered once daily. The dosage can be from 10 micrograms to 20 micrograms, for example, once a week.

[0399] Semaglutide, which has CAS number 910463-682, is a peptide sold under the brand names Ozempic, Rybelsus, and Wegovy. It can be administered in injectable form, as subcutaneously (Ozempic and Wegovy), or orally (Rybelsus). The dosage can range from 0.25 mg to 2 mg, administered weekly.

[0400] Albiglutide, which has the CAS number 782500-75-8, is a peptide sold under the trade names Eperzan and Tanzeum. It may also be called GSK-716155. It can be administered in injectable form, as well as subcutaneously. The dosage can be from 30 mg to 50 mg, for example, once a week.

[0401] Dulaglutide, which has CAS number 923950-08-7, is a peptide sold under the trade name Trulicity, among others. It can be administered via an injection pen. For example, it can be administered subcutaneously. Dulaglutide dosages can be 0.75 mg / 0.5 mL, 1.5 mg / 0.5 mL, 3 mg / 0.5 mL, or 4.5 mg / 0.5 mL. Petition 870250079411, dated 05 / 09 / 2025, pages 138 / 165 122 / 138 Pharmaceutical Formulations

[0402] Those skilled in the art will understand that both the β2-adrenergic receptor agonist, or its pharmaceutically acceptable salt, and insulin or a therapeutic derivative of insulin, or a therapeutic agent that stimulates insulin release, may be administered in the form of a pharmaceutical formulation, which may further include one or more pharmaceutically acceptable excipients.

[0403] Suitable pharmaceutical formulations may be commercially available or described in the literature, such as Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995), and Martindale - The Complete Drug Reference (35th edition), and the documents mentioned in those documents, the relevant disclosures of which are incorporated by reference in their entirety. Otherwise, the preparation of suitable formulations, and in particular, combination preparations including an β2-adrenergic receptor agonist or its pharmaceutically acceptable salts and insulin or a therapeutic insulin derivative or a therapeutic agent that stimulates insulin release, may be performed by one skilled in the art using routine techniques.

[0404] References to pharmaceutically acceptable excipients may be understood to include pharmaceutically acceptable diluents, carriers and / or adjuvants, as known to those skilled in the art.

[0405] Thus, in a second aspect of the invention, a pharmaceutical formulation is provided comprising:

[0406] (I) a compound that is

[0407] (a) insulin or a therapeutic insulin derivative; or

[0408] (b) a therapeutic agent that stimulates insulin release, and

[0409] (II) an ε2-adrenergic receptor agonist, or a Petition 870250079411, dated 05 / 09 / 2025, pages 139 / 165 123 / 138 pharmaceutically acceptable salt thereof,

[0410] and optionally one or more pharmaceutically acceptable excipients,

[0411] these formulations may be referred to as "formulations of the invention" or similar.

[0412] In a specific embodiment, the pharmaceutical formulation is for use in the treatment and / or prophylaxis of a disease or disorder.

[0413] In a third aspect of the invention, a pharmaceutical formulation is provided comprising:

[0414] (I) a compound that is

[0415] (a) insulin or a therapeutic insulin derivative; or

[0416] (b) a therapeutic agent that stimulates insulin release, and

[0417] (II) a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof,

[0418] and, optionally, one or more pharmaceutically acceptable excipients, for use in the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia.

[0419] In a third alternative aspect of the invention, a method is provided for the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, comprising administering to a patient requiring a therapeutically effective amount of a pharmaceutical formulation comprising:

[0420] (I) a compound that is

[0421] (a) insulin or a therapeutic insulin derivative; or

[0422] (b) a therapeutic agent that stimulates insulin release, and

[0423] (II) a β2-adrenergic receptor agonist, or a Petition 870250079411, dated 05 / 09 / 2025, pages 140 / 165 124 / 138 pharmaceutically acceptable salt thereof,

[0424] and optionally one or more pharmaceutically acceptable excipients.

[0425] For the avoidance of doubt, the formulations of the second and third aspects of the invention may have any of the specific features described above for the first aspect of the invention, including all combinations thereof. COMBINATIONS AND PARTS KITS

[0426] Those skilled in the art will understand that the invention may also relate to combination products comprising a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic derivative of insulin, or a therapeutic agent that stimulates insulin release, and their uses.

[0427] Those skilled in the art will understand that the combination of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic derivative of insulin, or a therapeutic agent that stimulates insulin release, may also be supplied in the form of a parts kit that includes the same.

[0428] In a fourth aspect of the invention, a combination or kit of parts is provided comprising the following components:

[0429] (A) a pharmaceutical formulation comprising a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, optionally in a mixture with one or more pharmaceutically acceptable excipients, and

[0430] (B) a pharmaceutical formulation comprising insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release, optionally in a mixture with one or more pharmaceutically acceptable excipients,

[0431] wherein components (A) and (B) are each supplied in a form suitable for administration together with each other. Petition 870250079411, dated 05 / 09 / 2025, pages 141 / 165 125 / 138

[0432] In a specific embodiment, the parts kit is for use in the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia.

[0433] In a specific embodiment, the kit of parts of the fourth aspect of the invention further includes instructions for using each component in conjunction with the other in the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

[0434] In a fourth alternative aspect of the invention, a parts kit is provided comprising:

[0435] (I) one of the components (A) or (B), as defined above, and

[0436] (II) instructions for using this component in conjunction with the other of the two components in the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

[0437] For the avoidance of doubt, the kits of parts of the fourth aspect of the invention may have any of the specific features described above for the first, second or third aspects of the invention, including all combinations thereof.

[0438] In certain embodiments, the kits of parts described herein may comprise more than one formulation, including an appropriate amount / dose of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt and / or a prodrug thereof, and / or more than one formulation, including an appropriate amount / dose of insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release, in order to permit repeat dosing. If more than one formulation (comprising any of the active compounds) is present, such formulations may be the same or may differ in terms of the dose of any compound, chemical composition(s) and / or physical form(s).

[0439] With regard to the treatments, formulations and kits of parts of the invention, as described in this document, references to Petition 870250079411, dated 05 / 09 / 2025, pp. 142 / 165 126 / 138 treatment or administration of each component refers to the fact that said component is administered together with the other. MANAGEMENT METHODS

[0440] Those skilled in the art will understand that the present invention (i.e., the pharmaceutical formulations, parts kits, compounds for use, uses and methods of treatment described herein, including all preferred embodiments and features) relates to two components, namely, a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic insulin derivative or a therapeutic agent that stimulates insulin release, administered together.

[0441] References to each component being administered in conjunction with the other will include components being administered sequentially, separately or simultaneously, as part of a medical intervention directed at treating the relevant condition. In particular, such references may include components being administered sufficiently close in time to allow a beneficial effect for the patient that is greater, during the course of treatment of the relevant condition, than if administered in the absence of the other component, during the same course of treatment.

[0442] Determining whether a combination provides a greater beneficial effect in relation to, and over the course of, treatment of a specific condition will depend on the condition being treated or prevented, but can be routinely performed by one skilled in the art.

[0443] Those skilled in the art will understand that references to the components (i.e., the P2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic derivative of insulin, or a therapeutic agent that stimulates insulin release) being administered sequentially (and therefore separately) will include that the individual doses of each component are administered (i.e., taken by the patient, as orally) within 48 hours (e.g., within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, or 10 minutes) Petition 870250079411, dated 05 / 09 / 2025, pages 143 / 165 127 / 138 apart from each other.

[0444] Similarly, references to components being administered simultaneously (which may be in a combined form or separately) will include components being administered (i.e., taken by the patient, for example, orally) at virtually the same time.

[0445] In a particular modality, the components are administered (i.e., taken by the patient, for example, orally) sequentially (and therefore as separate doses).

[0446] For example, in a given modality, the components are administered sequentially with at least a 2-hour interval (i.e., the interval between the administration of each component to the patient, for example, orally, is at least 4 hours), such as between 2 hours and 48 hours, or between 2 hours and 24 hours, or between 2 hours and 12 hours.

[0447] For the avoidance of doubt, references to components such as β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic derivative of insulin, or a therapeutic agent that stimulates insulin release, shall include references to the respective components (II) and (I) of the third aspect of the invention and to the respective components (A) and (B) of the fourth aspect of the invention.

[0448] Those skilled in the art will understand that the pharmaceutical compounds and formulations as defined herein will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, transdermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or by inhalation, in a pharmaceutically acceptable dosage form. The pharmaceutical formulations described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration and the like. Petition 870250079411, dated 05 / 09 / 2025, pages 144 / 165 128 / 138

[0449] In certain embodiments, the compounds and pharmaceutical formulations described herein are administered orally. Thus, in certain embodiments, the pharmaceutical formulations described in this document may be described as oral pharmaceutical formulations.

[0450] Thus, in certain embodiments, the pharmaceutical formulation(s) is / are provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, transdermal patches, plasters, inhalants (for example, to be applied intranasally). For the avoidance of doubt, in such embodiments, the compounds of the invention may be present as solids (for example, a solid dispersion), liquids (for example, in solution) or in other forms, such as in the form of micelles.

[0451] In more specific embodiments, the pharmaceutical formulation(s) is / are supplied in a pharmaceutically acceptable oral dosage form, including tablets or capsules, which forms may be prepared using techniques known to those skilled in the art.

[0452] For example, in the preparation of pharmaceutical formulations for oral administration, the compound may be mixed with solid and powdered ingredients such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or other suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or compressed into tablets.

[0453] Soft gelatin capsules can be prepared with capsules containing one or more active compounds (for example, compounds from the first and therefore the second and third aspects of the invention and, optionally, additional therapeutic agents), together with, for example, vegetable oil, fat or other suitable vehicle for soft gelatin capsules. Similarly, hard gelatin capsules can contain this / these compound(s) in combination with powdered solid ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, Petition 870250079411, dated 05 / 09 / 2025, pages 145 / 165 129 / 138 corn starch, amylopectin, cellulose derivatives or gelatin.

[0454] Dosage units for rectal administration may be prepared (i) in the form of suppositories containing the compound(s) mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in a mixture with vegetable oil, paraffin oil or other suitable vehicle for rectal gelatin capsules; (iii) in the form of a ready-to-use micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent immediately before administration.

[0455] Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, for example, solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, these liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent before use.

[0456] 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 ingredients and are dispensed in unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

[0457] Those skilled in the art will understand that the compounds described in this document and the formulations and kits of parts containing them can be administered (for example, as formulations described above) in varying doses, and that the appropriate doses can be readily determined by someone skilled in the art.

[0458] For example, the appropriate doses of an agonist Petition 870250079411, dated 05 / 09 / 2025, pages 146 / 165 130 / 138 of the e2-adrenergic receptor or of a pharmaceutically acceptable salt may include those discussed in the publications mentioned above, as incorporated herein by reference.

[0459] Similarly, appropriate doses of insulin, therapeutic insulin derivatives and therapeutic agents that stimulate insulin release may include those described in this document and those known to those skilled in the art (including those indicated in relevant drug formularies, such as the British National Formulary 85th Edition, the contents of which are incorporated herein by reference).

[0460] In any case, a person skilled in the art (e.g., a physician) will be able to determine the most appropriate actual dosage for an individual patient, which will likely vary with the route of administration, the type and severity of the condition being treated, as well as the species, age, weight, sex, renal function, hepatic function, and response of the specific patient being treated. The dosages mentioned above are exemplary of the average case; however, there may, of course, be individual cases where higher or lower dosage ranges are warranted, and such are included within the scope of this invention.

[0461] As described above, those skilled in the art will understand that the treatments (and methods of prophylaxis) described herein may include (i.e., be combined with) additional treatment(s) (i.e., others) for the same condition. In particular, the treatments (and methods of prophylaxis) described in this document may be combined with other means for the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

[0462] These agents will be readily identified by those skilled in the art and include, in particular, commercially available therapeutic agents (for example, agents that are the subject of a marketing authorization in one or more territories, such as a European or US marketing authorization). PREPARATION OF FORMULATIONS AND PARTS KITS

[0463] Pharmaceutical formulations and parts kits Petition 870250079411, dated 05 / 09 / 2025, pages 147 / 165 131 / 138 as described herein may be prepared in accordance with standard and / or accepted pharmaceutical practices.

[0464] Thus, in a further aspect of the invention, a process is provided for the preparation of a pharmaceutical composition / formulation, as defined above, which process comprises combining a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release, with one or more pharmaceutically acceptable excipients (for example, an adjuvant, diluent and / or carrier).

[0465] In addition, a method is provided for preparing a parts kit, as defined above, which comprises combining component (A) with component (B), making the two components suitable for administration together. Thus, references to combination will mean that the two components will be considered suitable for administration together.

[0466] Thus, with regard to the process of preparing a parts kit as defined above, when putting the two components "in association" with each other, it is contemplated that the two components of the parts kit can be:

[0467] (i) supplied as separate formulations (i.e., independently of each other), which are subsequently combined for use together in combination therapy; or

[0468] (ii) packaged and presented together as separate components of a “combination pack” for use together with each other in combination therapy.

[0469] Those skilled in the art will understand that the pharmaceutical formulations, parts kits, methods, and uses described in this document may have the advantage, in the treatment of the aforementioned conditions, of being more convenient for the physician and / or patient, more effective, less toxic, having a wider range of activity, being more potent, producing Petition 870250079411, dated 05 / 09 / 2025, pages 148 / 165 132 / 138 fewer side effects or have other useful pharmacological properties compared to similar methods (treatments) known in the state of the art, whether for use in the indications mentioned above or in other indications. In particular, these pharmaceutical formulations, parts kits, methods and uses may have the advantage of being more effective and / or exhibiting advantageous properties in vivo.

[0470] Without wanting to get bogged down in theory, it is believed that β2-adrenergic receptor agonists may act as insulin sensitizing agents, thus increasing the effect of insulin therapy, whether through insulin administration or stimulation of insulin production, in the treatment of hyperglycemia or a disorder characterized by hyperglycemia, such as type 1 and type 2 diabetes.

[0471] Furthermore, some of the compounds that act as β2-adrenergic receptor agonists, such as those described in this document, are able to activate the β2-adrenergic receptor without (or with only a minimal effect on) inducing cAMP production. This is believed to allow the therapeutic effects described in this document to be achieved with lower levels of side effects than would result from other treatments.

[0472] The combination of these therapeutic agents is therefore useful in the treatment of hyperglycemia or a disorder characterized by hyperglycemia and may have advantages over the compounds used in such methods as described in the prior art, such as the ability to administer one or more of the compounds at lower doses to obtain greater effects and / or lower levels of adverse events. BRIEF DESCRIPTION OF THE FIGURES

[0473] Figure 1 shows that glucose uptake promoted by Compound A is inhibited in a dose-dependent manner by the selective p2-adrenergic receptor antagonist ICI-118551.

[0474] Figure 2 shows the fasting blood glucose level for a control, liraglutide, Compound A, and a combination of liraglutide and Petition 870250079411, dated 05 / 09 / 2025, pages 149 / 165 133 / 138 Compound A, as described in Biological Example 2.

[0475] Figure 3 shows the fasting insulin level for a control, liraglutide, Compound A, and a combination of liraglutide and Compound A, as described in Biological Example 2.

[0476] Figure 4 shows the HOMA-IR level for a control, liraglutide, Compound A, and a combination of liraglutide and Compound A, as described in Biological Example 2.

[0477] Figure 5 shows glucose tolerance for a control, liraglutide, Compound A, and a combination of liraglutide and Compound A, as described in Biological Example 2. EXAMPLES

[0478] The present invention is illustrated by the following examples, which are not intended to limit the overall scope of the invention.

[0479] To avoid doubt, in the event of a discrepancy between the name of the compound and the structure drawn in this descriptive report, the structure shall prevail.

[0480] The mice were acquired from Scanbur (Charles River). EXAMPLE OF COMPOUNDS

[0481] The following compound, referred to here as Compound A, was used in the biological examples provided in this document in salt form, as specified (and in the context of which, references to Compound A refer to that salt form). £ H Fx / AaXa IJ %

[0482] Compound A: N

[0483] The synthesis of Compound A is described in document WO 2019 / 053427 (see Example 17), the contents of which are incorporated here by reference. Petition 870250079411, dated 05 / 09 / 2025, pp. 150 / 165 134 / 138 COMPOUND EXAMPLE 1

[0484] Compound A: (R)-2-(tert-Butylamino)-1-(5fluoropyridin-3-yl)etan-1-olOHH FvzaAx / Nv / I j YN

[0485] (a) 2-Chloro-1-(5-fluoropyridin-3-yl)ethan-1-one THE F^^Br IJ —- IJ NN

[0486] Isopropylmagnesium chloride (2 M in THF, 10.47 mL, 20.94 mmol) was added to a solution of LiCl (887.69 mg, 20.94 mmol) in THF (8 mL) at room temperature. After 15 minutes at rt, 3-bromo-5-fluoropyridine (3.35 g, 19.04 mmol) in THF (30 mL) was added dropwise at 0 °C. The mixture was stirred at rt for 2 h and cooled in an ice bath. A solution of 2-chloro-N-methoxy-N-methylacetamide (2.62 g, 19.04 mmol) in THF (30 mL) was added dropwise, and the mixture was stirred at rt for 2 h. NH4Cl (aq, 10%) was added and the mixture was extracted with Et2O. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography to obtain the subtitle compound (1.52 g, 20.94 mmol, 46%).

[0487] (b) (R)-2-Chloro-1-(5-fluoropyridin-3-yl)ethan-1-one OOH Fx^aAA / CIfvY / ¥ci IJ —~IJ NN

[0488] RhClCp*[(1S,2S)-pTsNCH(CeH5)CH(CeH5)NH2] / HCl.Et3N (68.0 mg, 87.6 μmol), prepared from the dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, (1S,2S)-(+)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine and Et3N, as described in WO 2008 / 054155, was added to a mixture of 2-chloro-1-(5-fluoropyridin-3-yl)ethan1-one (1.52 g, 8.76 mmol) in DMF (75 mL). Formic acid / Et3N (5:2, Petition 870250079411, dated 05 / 09 / 2025, pages 151 / 165 135 / 138 mL) and the mixture was stirred at room temperature for 15 minutes. H2O (60 mL) and EtOAc (60 mL) were added and the layers were separated. The aqueous layer was washed with EtOAc (2 x 60 mL) and the combined organic phases were washed with H2O, dried (Na2SO4), filtered, and concentrated. The residue was purified by chromatography to obtain the compound from the subtitle (1.35 g, 7.69 mmol, 88%, ee = 92.5%).

[0489] (c) (R)-2-(tert-Butylamino)-1-(5-fluoropyridin-3yl)ethan-1-ol OH OHu IIH Fx / y / V / Cl F^ / sJ^N.. / IJ —~ IJ nxnz

[0490] tert-butylamine (11.37 mL, 108.21 mmol) followed by NaOH (476.08 mg, 11.90 mmol) was added to a mixture of 2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-one (1.90 g, 10.82 mmol) and iPrOH (1.66 mL, 21.64 mmol) at room temperature. The mixture was heated to 75 °C for 4 h, allowed to cool, diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), and concentrated. The residue was dissolved in hot EtOAc and allowed to cool. Pentane was added, and the mixture was kept at -20 °C overnight. The solids were collected and purified by chromatography to obtain the title compound (1.43 g, 6.74 mmol, 62%, ee = 98%).

[0491] 1H NMR (400 MHz, CDCb): δ 8.43 - 8.27 (m, 2H), 7.57 - 7.42 (m, 1H), 4.62 (dd, J = 8.8, 3.7 Hz, 1H), 2.94 (dd, J = 12.1, 3.8 Hz, 1H), 2.53 (dd, J = 12.1,8.8 Hz, 1H), 1.10 (s, 9H). COMPOUND EXAMPLE 2

[0492] Hemitartrate of compound A: (R)2-(tert-Butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol hemitartrate

[0493] A solution of L-(+)-tartaric acid (6.21 g, 0.5 eq) in EtOH (175 mL) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (17.57 g) in EtOH (525 mL, 30 vol) and H2O (7 mL) at room temperature. The mixture was refluxed until all the precipitate was dissolved and then cooled. The resulting paste was stirred at rt overnight and then at 0 to 5 °C for 2 h. The solids were collected to give the salt titer of Petition 870250079411, dated 05 / 09 / 2025, pp. 152 / 165 136 / 138 (R )-2-( tert -butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (19.9 g, 83%, 100.0% purity by HPLC, 99.8% ee by HPLC).

[0494] The formation of hemitartrate was confirmed by the 1H NMR spectrum, which indicated an amine:acid ratio of 2:1. COMPOUND EXAMPLE 3

[0495] Compound A dihydrochloride: (R)-2-(tert-Butylamino)1-(5-fluoropyridin-3-yl)ethan-1-ol dihydrochloride

[0496] HCl (48 mmol, 2 M in EtzO, 24 mL) was added dropwise to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (5.10 g, 24 mmol) in Et2O (90 mL) at room temperature. After 15 minutes, the precipitate was collected, dried under vacuum, and recrystallized with MeCN (250 mL). After reaching rt, the mixture was kept in the refrigerator for 5 h, and the solid was collected and dried under vacuum over P2O5 for 5 d to give the title compound (6.41 g, 94%).

[0497] Elemental analysis found: C, 46.45%; H, 6.75%; N, 9.80%,

[0498] CiiHi9Cl2FN2 requires: C, 46.32%; H, 6.71%; N, 9.82%. BIOLOGICAL EXAMPLES

[0499] Document WO 2019 / 053427, the contents of which are incorporated herein by reference, describes biological assays demonstrating that Compound A provides significant glucose uptake without inducing significant cAMP levels (see Biological Examples 1 and 2 of that document).

[0500] In the present examples: in Biological Example 1, Compound A was used in the form of the dihydrochloride salt (2HCl); in Biological Example 2, Compound A was used in the form of the hemitartrate salt. BIOLOGICAL EXAMPLE 1: GLUCOSE UPTAKE IN THE PRESENCE OF A SELECTIVE INHIBITOR OF THE β2-ADRENERGIC RECEPTOR

[0501] L6 myoblasts were cultured in medium of Petition 870250079411, dated 05 / 09 / 2025, pp. 153 / 165 137 / 138 A modified Dulbecco's Eagle (DMEM) medium containing 1 g / L of glucose supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 50 U / mL penicillin, 50 pg / mL streptomycin, and 10 mM HEPES was used. Cells were placed at 1x10⁵ cells per mL in 24-well plates. After reaching 90% confluence, cells were cultured in medium containing 2% FBS for 7 days, at which point the cells differentiated into myotubes. The differentiated L6 myotubes were serum-deprived overnight in medium containing 0.5% fatty acid-free BSA and stimulated with Compound A at a final concentration of 1x10⁻⁵ M in the presence of the selective p2-adrenergic receptor antagonist ICI-118551. After 1 hour and 40 minutes, the cells were washed twice with warm glucose-free medium, and another portion of agonist was added to the glucose-free medium.After a further 20 minutes of incubation, the cells were exposed to 50 nM3H-2-deoxyglucose for 10 minutes before being washed three times in chilled glucose-free medium and lysed in 400 μl / well of 0.2 M NaOH for 1 ha at 60 °C. The cell lysate was mixed with 4 ml of scintillation buffer (Emulsifier Safe, Perkin Elmer) and radioactivity was detected on a β counter (Tri-Carb 4810TR, Perkin Elmer).

[0502] Figure 1 shows that glucose uptake promoted by Compound A is inhibited in a dose-dependent manner by the selective p2-adrenergic receptor antagonist ICI-118551, which proves that glucose uptake promoted by Compound A is mediated by the β2-adrenergic receptor. In this document, the antagonist ICI-118551 is understood to have CAS number 7279501-8. BIOLOGICAL EXAMPLE 2: COMBINATION OF THE COMPOUND AE LIRAGLUTIDE

[0503] Male C57Bl / 6N mice, 2.5 months old, were housed in cages (4-5 mice per cage), kept at 30 °C, and fed a high-fat, high-sucrose diet (45% fat) for 5.5 months. The mice were divided into four groups (2-3 mice per cage) according to their fasting blood glucose levels, glucose tolerance, body weight, Petition 870250079411, dated 05 / 09 / 2025, pages 154 / 165 Mice were 138 / 138 body fat and lean mass, and treated daily for 2 weeks, subcutaneously, with vehicle, liraglutide (0.1 mg / kg), Compound A (1 mg / kg), or a mixture of liraglutide (0.1 mg / kg) and Compound A (1 mg / kg). Mice were fasted for 5 hours and fasting blood glucose and serum insulin levels were recorded. Glucose (2.5 g / kg of lean mass) was injected intravenously and glucose levels were recorded after 15, 30, 60, 90, and 120 minutes. The results were used to calculate HOMA-IR (fasting glucose (mM) x fasting insulin (μμ / mL) / 22.5) and glucose tolerance (area under the curves from 0 to 120 minutes over the 5.5 mM blood glucose level).

[0504] The results obtained during the experiment period are presented below: Figure 2 shows fasting blood glucose levels; Figure 3 shows fasting insulin levels; Figure 4 shows the HOMA-IR; Figure 5 shows the result of the glucose tolerance test (measured as area under the curve at a glucose level of 5.5 mM).

[0505] Compound A had additional positive effects on glucose homeostasis (glycemia, glucose tolerance and insulin sensitivity) when added in combination with liraglutide, which illustrates that combined treatment with Compound A and GLP1-RA or insulin may be beneficial for diabetic patients. Petition 870250079411, dated 05 / 09 / 2025, pages 155 / 165

Claims

1 / 4 CLAIMS 1. An β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, characterized in that it is for use in the treatment and / or prophylaxis of hyperglycemia or of a disorder which has hyperglycemia as a particularity, wherein the treatment and / or prophylaxis further comprises the administration of: (a) insulin or a therapeutic insulin derivative; or (b) a therapeutic agent that stimulates insulin release.

2. Compound characterized in that it is: (a) insulin or a therapeutic insulin derivative; or (b) a therapeutic agent that stimulates insulin release for use in the treatment and / or prophylaxis of hyperglycemia or a disorder characterized by hyperglycemia, wherein use further includes the administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

3. Combination of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and a compound that is: (a) insulin or a therapeutic insulin derivative; or (b) a therapeutic agent that stimulates insulin release characterized in that it is for use in the treatment and / or prophylaxis of hyperglycemia or a disorder that has hyperglycemia as a particular feature.

4. Method for the treatment and / or prophylaxis of hyperglycemia or of a disorder having as a particularity hyperglycemia characterized by the fact that it comprises: (i) administration of a therapeutically effective amount of (a) insulin or a therapeutic insulin derivative; or (b) a therapeutic agent that stimulates insulin release, and (ii) administration of a therapeutically effective amount of Petition 870250079411, dated 05 / 09 / 2025, page 156 / 165 2 / 4 an β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

5. Pharmaceutical formulation characterized in that it comprises: (I) a compound that is (a) insulin or a therapeutic insulin derivative; or (b) a therapeutic agent that stimulates insulin release, and (II) a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

6. Combination or kit of parts characterized in that it comprises components: (A) a pharmaceutical formulation comprising a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, optionally in a mixture with one or more pharmaceutically acceptable excipients, and (B) a pharmaceutical formulation comprising insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release, optionally in a mixture with one or more pharmaceutically acceptable excipients, wherein components (A) and (B) are each provided in a form suitable for administration together with each other.

7. Formulation, combination or kit of parts, according to any one of claims 5 and 6, characterized in that it is for use in the treatment and / or prophylaxis of hyperglycemia or a disorder that has hyperglycemia as a particular characteristic.

8. β2-adrenergic receptor agonist for use, compound for Petition 870250079411, dated 05 / 09 / 2025, page 157 / 165 3 / 4 use, method, formulation for use, combination for use or kit of parts for use, according to any of claims 1 to 4 and 7, characterized in that the disorder has as its particularity hyperglycemia, is selected from the group consisting of type 1 diabetes, type 2 diabetes, Rabson-Mendenhall syndrome, Donohue syndrome (leprechaunism), type A and type B insulin resistance syndromes, HAIR-AN syndromes (hyperandrogenism, insulin resistance and acanthosis nigricans), pseudoacromegaly and lipodystrophy.

9. P2-adrenergic receptor agonist for use, compound for use, method, formulation, combination for use or kit of parts for use, according to any one of claims 1 to 4 and 7 and 8, characterized in that the disorder which has as its particularity hyperglycemia is, or has as its particularity, the patient presents severe insulin resistance.

10. P2-adrenergic receptor agonist for use, compound for use, method, formulation, combination for use or kit of parts for use, according to any of claims 8 and 9, characterized in that the disorder that has hyperglycemia as a particularity is type 1 diabetes or type 2 diabetes.

11. P2-adrenergic receptor agonist for use, compound for use, method, formulation, combination, parts kit, formulation for use, combination for use or parts kit for use, according to any one of claims 1 to 10, characterized in that the β2-adrenergic receptor agonist is selected from the compounds in Table 1.

12. P2-adrenergic receptor agonist for use, compound for use, method, formulation, combination, kit of parts, formulation for use, combination for use or kit of parts for use, according to any of claims 1 to 11, characterized in that the β2-adrenergic receptor agonist is: OH H fwAn\Z IX % N Petition 870250079411, dated 05 / 09 / 2025, page 158 / 165 4 / 4 or a pharmaceutically acceptable salt thereof.

13. β2-adrenergic receptor agonist for use, compound for use, method, formulation, combination, kit of parts according to, formulation for use, combination for use or kit of parts for use, according to any one of claims 1 to 12, characterized in that the therapeutic agent that stimulates insulin release is a GLP-1 receptor agonist.

14. β2-adrenergic receptor agonist for use, compound for use, method, formulation, combination, parts kit, formulation for use, combination for use or parts kit for use, according to claim 13, characterized in that the GLP-1 receptor agonist is liraglutide. Petition 870250079411, dated 05 / 09 / 2025, pp. 159 / 165

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