EA041181B1 - BETA-3 ADRENERGIC RECEPTOR MODULATOR USED TO TREAT OR PREVENT DISORDERS ASSOCIATED WITH THIS RECEPTOR - Google Patents

Description

Technical field

This invention relates to compounds of formula (Ia) and their pharmaceutical compositions, which modulate the activity of the beta-3-adrenergic receptor. The compounds of the invention and their pharmaceutical compositions are directed to methods useful in the treatment of beta3 adrenergic receptor mediated disorders such as heart failure; performance of the heart in heart failure; mortality, re-infarction and / or hospitalization due to heart failure; acute heart failure; acute decompensated heart failure; chronic heart failure; severe chronic heart failure; organ damage associated with heart failure (eg, kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; mortality from cardiovascular diseases due to myocardial infarction; mortality from cardiovascular disease in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; class II heart failure using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; heart failure class IV using the New York Heart Association (NYHA) classification system; left ventricular ejection fraction (LVEF) <40% on radionuclide ventriculography; LVEF <35% by echocardiography or ventricular contrast angiography and related conditions.

State of the art

Acute heart failure is a rapid deterioration in the functioning of the heart, which can cause oxygen starvation of tissues (especially the brain), leading to death. Acute heart failure may occur in previously asymptomatic patients (eg, patients with pulmonary edema or cardiogenic shock) or in patients with an acute exacerbation of chronic heart failure.

In a healthy heart, the actions of beta-1 and beta-2 adrenergic receptors are dominant and act by Gs-coupling to increase the force and frequency of cardiac muscle contraction, while beta-3-adrenergic receptors act by Gi-coupled eNOS to exert a weak negative inotropic effect. . With beta-1 and beta-2 heart failure, the number of adrenergic receptors is reduced or their susceptibility is reduced, which causes an increase in the expression level of beta-3 adrenergic receptors, thereby increasing the negative manifestations of beta-3 agonism in relation to cardiac contractility. Morimoto, Am J Physiol Heart Circ Physiol, 286: H2425-H2433, 2004; Kulandavelu, J Am College Cardiology 59(22): 1988-90, 2012

In patients suffering from acute heart failure, the short-term goal is to increase contractility and improve hemodynamic status. The current standard of care for acute heart failure involves the administration of inotropes, agents that alter the force or energy of heart contractions. These agents are typically administered in an intensive care setting by continuous injection. Examples of such agents include: epinephrine, dobutamine, dopamine, levosimendan and norepinephrine. However, the initial improvement in contractility provided by these agents may be accompanied by early mortality. Katz AM and Konstam MA, Heart Failure: Pathophysiology, Molecular Biology and Clinical Management, Lippincott, Williams & Wilkins, 2nd Edition, 1999. Increased mortality following administration of these agents has been associated with increased tachycardia and increased myocardial oxygen consumption, resulting in to arrhythmia and myocardial ischemia. Francis et al., J Am College of Cardiology 63(20): 2069-2078, 2014

The essence of the invention

One aspect of this invention encompasses specific 1-oxa-8azaspiro[4.5]decan-3-yl-aminopropanyl ether derivatives selected from compounds of formula (Ia) and their pharmaceutically acceptable salts, solvates and hydrates.

(la) R ^3c where

X is -SO ₂ -, -C(=O)- or -CH ₂ C(=O)-;

W is absent or is C1- _C3 alkylene;

R ¹ is aryl or heteroaryl, each optionally substituted with one or more substituents selected from C _r C ₆ alkoxy, C ₁ -C ₆ alkyl, amino, cyano, C ₃ -C ₇ cycloalkyl, C1 -C6 haloalkyl, halogen, hydroxyl, oxo and sulfamoyl; and wherein said C1-C6 alkyl and _C3 - _C7 cycloalkyl are each optionally substituted with one or more substituents selected from amino, C1-C6 alkoxy, C1-Q alkylcarboxamide, _-YC3 - _C7 -cycloalkyl, -YC ₁ -C ₆ alkylene-g, C1-C6 alkylamino, C1-C6 haloalkylamino and heterocyclyl;

Y is independently selected from -O-, -NH- and -N-(C ₁ -C ₄ -alkyl)-;

Z is independently selected from hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino and C2-C6 dialkylamino;

R2 is selected from C2-C6 alkenyl, C1-C6 alkyl, _C3 - _C7 cycloalkyl, heterocyclyl and C1-C6 haloalkyl; each optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkylene hydroxyl, amino, aryl, C ₃ -C ₇ cycloalkyl, cyano, C ₃ -C ₇ halocycloalkyl, hydroxyl and oxo; and R ^3a , R ^3b , R ^3c and R ^3d are each independently H or halogen.

One aspect of this invention relates to pharmaceutical products selected from pharmaceutical composition, dosage form and formulation, dosage form with a single dose and kit; each of which contains a compound of the invention.

One aspect of this invention relates to pharmaceutical compositions containing a compound of the invention and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to methods for preparing pharmaceutical compositions comprising the step of mixing a compound of the invention with a pharmaceutically acceptable carrier.

One aspect of the invention relates to methods for treating or preventing a beta-3 adrenergic receptor mediated disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention; or a pharmaceutical composition according to the invention.

One aspect of the invention relates to methods for treating or preventing heart failure in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention.

One aspect of the present invention relates to methods of treating a patient suffering from arterial hypotension, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention.

One aspect of this invention relates to methods of treating a patient who is on the verge of arterial hypotension, including administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention.

One aspect of this invention relates to methods of treating a patient with normal blood pressure, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention.

One aspect of the present invention relates to methods of treating a patient suffering from arterial hypertension, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention.

One aspect of the invention relates to methods of treating a patient following a myocardial infarction comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention.

One aspect of the present invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a beta-3 adrenergic receptor mediated disorder in a patient.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of heart failure in a patient.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient suffering from arterial hypotension.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient on the brink of hypotension.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient with normal blood pressure.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient suffering from arterial hypertension.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient following a myocardial infarction.

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One aspect of this invention relates to the compounds of the invention; a pharmaceutical product of the invention or a pharmaceutical composition of the invention for use in a method of treating a human or animal body through therapy.

One aspect of this invention relates to the compounds of the invention; pharmaceutical products of the invention or pharmaceutical compositions of the invention for use in a method for treating or preventing a beta-3 adrenergic receptor mediated disorder in a patient.

One aspect of this invention relates to the compounds of the invention; pharmaceutical products of the invention or pharmaceutical compositions of the invention for use in a method for treating or preventing heart failure in a patient.

One aspect of this invention relates to the compounds of the invention; pharmaceutical products of the invention or pharmaceutical compositions of the invention for use in a method of treating a patient suffering from arterial hypotension.

One aspect of this invention relates to the compounds of the invention; pharmaceutical products according to the invention or pharmaceutical compositions according to the invention for use in a method of treating a patient who is on the verge of arterial hypotension.

One aspect of this invention relates to the compounds of the invention; pharmaceutical products of the invention or pharmaceutical compositions of the invention for use in a method of treating a patient with normal blood pressure.

One aspect of this invention relates to the compounds of the invention; pharmaceutical products of the invention or pharmaceutical compositions of the invention for use in a method of treating a patient suffering from arterial hypertension.

One aspect of this invention relates to the compounds of the invention; pharmaceutical products of the invention or pharmaceutical compositions of the invention for use in a method of treating a patient after myocardial infarction.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is selected from the list consisting of: heart failure; performance of the heart in heart failure; mortality, re-infarction and / or hospitalization due to heart failure; acute heart failure; acute decompensated heart failure; chronic heart failure; severe chronic heart failure; organ damage associated with heart failure (eg, kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; mortality from cardiovascular diseases due to myocardial infarction; mortality from cardiovascular disease in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; heart failure class II using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; heart failure class IV using the New York Heart Association (NYHA) classification system; LVEF <40% on radionuclide ventriculography; and LVEF <35% on echocardiography or ventricular contrast angiography.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is a decrease in cardiac performance in heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is mortality, re-infarction, and/or hospitalization due to heart failure.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is acute heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is acute decompensated heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is chronic heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is severe chronic heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is an organ injury associated with heart failure (eg, kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage).

In some embodiments, the beta-3 adrenergic receptor mediated disorder is heart failure due to left ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is heart failure with a normal ejection fraction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is cardiovascular death due to myocardial infarction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is left ventricular failure.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is left ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is class II heart failure using the New York Heart Association (NYHA) classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is class III heart failure using the New York Heart Association (NYHA) classification system.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is class IV heart failure using the New York Heart Association (NYHA) classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is a left ventricular ejection fraction (LVEF) <40% on radionuclide ventriculography.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is a left ventricular ejection fraction (LVEF) <35% on echocardiography or ventricular contrast angiography.

This document describes beta-3 adrenergic receptor antagonists that are useful for increasing cardiac contractility. These compounds are selective for the beta-3 adrenergic receptor and have a distinct mechanism of action that differs from currently prescribed inotropes with known cardiotoxic effects.

Since increased activity of beta-3 adrenergic receptors is known to inhibit contractility in heart failure, studies have been conducted to evaluate the effect of beta-3 adrenergic receptor antagonists on contractile function. As described herein, these studies show that inhibition of the beta-3 adrenergic receptor by beta-3 adrenergic receptor antagonists improves contractile function and hemodynamic status in heart failure. There is a need for new agents that increase cardiac contractility while avoiding cardiotoxic effects.

These and other aspects of the invention disclosed herein will be set forth in more detail later in the disclosure of this patent.

Brief description of graphic materials

In FIG. 1 illustrates a general synthetic scheme for the preparation of intermediates used in the preparation of compounds of formula (Ia), where PG ¹ (i.e., protecting group 1) can be a variety of protecting groups known to those skilled in the art, such as a benzyloxycarbamate group.

In FIG. 2 illustrates a general synthetic scheme for the preparation of intermediates used in the preparation of compounds of formula (Ia), where PG ¹ (protecting group 1) and PG ² (protecting group 2) can be a variety of protecting groups known to a person skilled in the art, for example , a benzyloxycarbamate group (Cbz) and a tert-butoxycarbonyl (BOC) group. In some cases, PG ¹ and PG ² are different and are orthogonal protecting groups, for example PG ¹ is Cbz and PG ² is BOC.

In FIG. 3 illustrates the general synthesis scheme for the preparation of compounds of formula (Ia). It is understood that one or more chiral intermediates can be used in the scheme to obtain chiral compounds of formula (Ia).

In FIG. 4 illustrates the general synthesis scheme for the preparation of compounds of formula (Ia). It is understood that one or more chiral intermediates may be used in a scheme to prepare chiral compounds of formula (Ia). PG ¹ and PG ² are protecting groups, eg BOC (tert-butyloxycarbonyl), Cbz (carboxybenzyl or alternative name benzyloxycarbamate) and the like.

In FIG. 5 illustrates the general synthesis scheme for the preparation of compounds of formula (Ia). It is understood that one or more chiral intermediates can be used in the scheme to obtain chiral compounds of formula (Ia).

In FIG. 6 illustrates a general synthetic scheme for the preparation of compounds of formula (Ia) using a chiral oxirane.

In FIG. Figure 7 illustrates a general synthetic scheme for the preparation of compounds of formula (Ia) using a chiral oxirane and a chiral amine intermediate (see Figure 2).

In FIG. 8 illustrates a general synthetic scheme for the preparation of compounds of formula (Ia) using a chiral oxirane and a chiral amine intermediate (see FIG. 2).

In FIG. Figure 9 illustrates a general synthetic scheme for the preparation of compounds of formula (Ia) using a chiral oxirane and a chiral amine intermediate (see Figure 2).

In FIG. 10 illustrates a general synthetic scheme for the preparation of compounds of formula (Ia) using a chiral oxirane and a chiral amine intermediate (see FIG. 2).

In FIG. 11 illustrates the general synthesis scheme for the preparation of compounds of formula (Ia). It is understood that one or more chiral intermediates can be used in the scheme to obtain chiral compounds of formula (Ia).

In FIG. 12 illustrates the general synthesis scheme for the preparation of compounds of formula (Ia). It is understood that one or more chiral intermediates can be used in the scheme to obtain chiral compounds of formula (Ia).

In FIG. 13 illustrates the general synthesis scheme for the preparation of compounds of formula (Ia). It is understood that one or more chiral intermediates can be used in the scheme to obtain chiral compounds of formula (Ia).

In FIG. 14 illustrates three general synthetic schemes for the preparation of specific compounds of formula (Ia) wherein X is -SO ₂ -, -C(=O)- and -CH ₂ C(=O)-. It is understood that intermediates may be chiral, given the chiral compounds of formula (Ia).

In FIG. 15 illustrates a general synthetic scheme for the preparation of specific intermediates used in the preparation of compounds of formula (Ia).

In FIG. 16 illustrates a general synthetic scheme for the preparation of specific intermediates used in the preparation of compounds of formula (Ia).

In FIG. 17 illustrates a general synthetic scheme for the preparation of specific intermediates used in the preparation of compounds of formula (Ia).

In FIG. 18 illustrates a general synthetic scheme for the preparation of specific intermediates used in the preparation of compounds of formula (Ia).

In FIG. 19 illustrates the general synthesis scheme for obtaining specific compounds of formula (Ia), where R ¹ represents -Ar ¹ -Ar ² . It is understood that Ar ¹ and Ar ² may optionally be substituted with one or more groups as described herein.

In FIG. 20 illustrates a general synthesis scheme for obtaining specific compounds of formula (Ia), where R ¹ represents -Ar ¹ -Ar ² . In particular, the diagram illustrates that Ar ² is substituted with at least -CH2OH or -CH2NH-C1-C6 alkyl. It is understood that Ar ¹ and Ar ² (excluding the ring atom for Ar ² which is bonded to -CH2OH or -CH2NH-C1-C6 alkyl) may optionally be substituted with one or more groups as described herein.

In FIG. 21 illustrates a general synthesis scheme for obtaining specific compounds of formula (Ia), where R ¹ represents -Ar ¹ -Ar ² . In particular, the scheme illustrates that Ar ² is substituted with at least -CH2NH2. It is understood that Ar ¹ and Ar ² (excluding the ring atom for Ar ² which is associated with -CH2NH ₂ ) may optionally be substituted with one or more groups as described herein.

In FIG. 22 illustrates a general synthesis scheme for obtaining specific compounds of formula (Ia), where R ¹ represents -Ar ¹ -Ar ² . In particular, the diagram illustrates that Ar ² is substituted with at least -C(=O)H or -CH2NH-C1-C6 alkyl.

It will be appreciated that Ar ¹ and Ar ² (excluding the ring atom for Ar ² which is bonded to -C(=O)H or -CH2NHCi-C ₆ alkyl) may optionally be substituted with one or more groups as described herein. document.

In FIG. 23 illustrates the general synthesis scheme for obtaining specific compounds of formula (Ia), where R ¹ represents 4-hydroxyquinolin-3-yl (or a tautomer close to it, for example 4-oxo-1,4-dihydroquinolin-3-yl) or 1 -(C1-C6-alkyl)-4-oxo-1,4-dihydroquinolin-3-yl, for example 1-ethyl4-oxo-1,4-dihydroquinolin-3-yl. It is understood that R ^23a , R ^23b , R ^23c and R ^23d may be C1-C6 alkoxy, C1-C6 alkyl, amino, cyano, C3- _C7 cycloalkyl, C1-C6 haloalkyl, halogen, hydroxyl, oxo and sulfamoyl, moreover, C 1 -C 6 alkyl and C ₃ -C ₇ cycloalkyl, each optionally may be substituted by one or more substituents selected from: amino, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylcarboxamide,

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-YC ₃ -C ₇ -cycloalkyl, -YC ₁ -C6-alkylene-Z, Ci-C ₆ alkylamino, Ci-C ₆ haloalkylamino and heterocyclyl, with Y and Z being as defined herein.

In FIG. 24 illustrates a general synthetic scheme for introducing R ² into compounds of formula (Ia) where W is a chemical bond.

In FIG. 25 illustrates a scheme for administering compounds of the invention to healthy rats in Example 4.

In FIG. 26 illustrates a scheme for administering compounds of the invention to heart failure rats in Example 4.

In FIG. 27 illustrates the inhibition of negative BRL manifestations against LVP in healthy rats due to the administration of Compound 123 (example 4).

In FIG. 28 illustrates the inhibition of negative BRL manifestations against LVP in healthy rats due to the administration of Compound 310 (example 4).

In FIG. 29 illustrates the inhibition of negative BRL manifestations against LVP in healthy rats due to the administration of Compound 163 (example 4).

In FIG. 30 illustrates the inhibition of negative BRL manifestations against LVP in healthy rats due to the administration of Compound 154 (example 4).

In FIG. 31 illustrates the inhibition of negative BRL manifestations against LVP in healthy rats due to the administration of Compound 88 (example 4).

In FIG. 32 illustrates the inhibition of negative BRL manifestations against LVP in a rat with heart failure due to the administration of Compound 88 (example 4).

In FIG. 33A illustrates an exemplary effect of Compound 88 in a dog prior to heart failure.

In FIG. 33B illustrates an exemplary effect of Compound 88 on a dog following heart failure. The horizontal dotted line in the graphs represents baseline LV pressure indicating the presence of heart failure (compare lower LV pressures in Figure 33A and baseline LV pressure in Figure 33B).

In FIG. 34 illustrates the effect of Compound 88 on hemodynamics and LV contractility in healthy dogs (n=4).

Detailed Description of the Invention Definitions

For clarity and consistency, the following definitions will be used throughout this patent document.

As used herein, the term administration refers to the provision of a compound of the invention or other therapy, drug, or treatment to a patient in need of treatment in a form that can be administered to that patient in a therapeutically useful form and in a therapeutically useful amount, including, but without limitation: oral dosage forms, such as tablets, capsules, syrups, suspensions, etc.; injectable dosage forms, for example BB, IM or intra-abdominal, etc.; transdermal dosage forms, including creams, jellies, powders or patches; buccal dosage forms; inhalation powders, sprays, suspensions, etc.; and rectal suppositories. The practitioner may directly provide the compound to the patient in sample form, or may indirectly provide the compound to the patient by providing an oral or written prescription for said compound. In addition, for example, the patient can receive the compound himself without the participation of a medical practitioner. If the compound is administered to a patient, then the body is somehow transformed by the compound. When a compound of the invention is provided in combination with one or more other agents, administration is intended to include administering the compound and other agents at the same time or at different times. If the agents of the combination are administered at the same time, they may be administered together in the same composition, or they may be administered separately.

As used herein, the term antagonist refers to a moiety that can competitively bind to a _β3 -adrenergic receptor as an agonist (e.g., an endogenous ligand), but does not activate or significantly reduce an intracellular response compared to an agonist, and thus may inhibit intracellular responses by an agonist or partial agonist. The antagonist does not reduce the original intracellular response or does so to a small extent in the absence of the agonist or partial agonist.

The term composition refers to a compound or its crystalline form, including, but not limited to: salts, solvates and hydrates of a compound of the invention in combination with at least one additional component, for example, a composition obtained/produced during synthesis, prior to giving it a medicinal form, during testing (i.e. samples by TLC, HPLC, NMR), etc.

As used herein, the term hydrate means a compound of the invention, or a salt thereof, which additionally contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

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The term in need of treatment and the term in need of it, when referring to treatment, is used interchangeably to refer to a judgment made by a nursing professional (i.e. a doctor, nurse, paramedic, etc. in the case of humans; a veterinarian in the case of animals, including non-human mammals) that the patient or animal needs or from which the patient or animal will receive treatment. This judgment is based on a variety of factors that are within the purview of the healthcare professional, but which include the knowledge that the patient or animal is ill or will become ill as a result of the disease, condition or disorder that is treatable with the compounds of the invention. Accordingly, the compounds of the invention may be used in a protective or preventive manner; or the compounds of the invention may be used to alleviate, inhibit or eliminate a disease, condition or disorder.

The term patient refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the term patient refers to humans.

The term pharmaceutical composition refers to a specific composition containing at least one active ingredient; including, but not limited to, salts, solvates, and hydrates of the compounds of the invention, whereby the composition is amenable to study for a specific, effective result in a mammal (eg, without limitation, a human).

Those skilled in the art will understand and appreciate methods suitable for determining whether an active ingredient has the desired effective result based on the needs of the skilled artisan.

The phrase pharmaceutically acceptable salts, solvates and hydrates, when referring to a compound/compounds as described herein, encompasses pharmaceutically acceptable solvates and/or hydrates of the compound/compounds, pharmaceutically acceptable salts of the compound/compounds, as well as pharmaceutically acceptable solvates and/or hydrates of pharmaceutically acceptable salts of the compound/compounds. It is also understood that when the phrase pharmaceutically acceptable solvates and hydrates or the phrase pharmaceutically acceptable solvate or hydrate is used when referring to a compound/compounds as described herein that are salts, it encompasses pharmaceutically acceptable solvates and/or hydrates of such salts. . Those skilled in the art will appreciate that hydrates are a subset of solvates.

The term prescribing refers to the order, authorization, or recommendation to use a drug or other therapy, drug, or treatment. In some embodiments, a healthcare provider verbally advises, recommends, or authorizes the use of a compound, drug regimen, or other treatment for a patient. A healthcare provider may or may not provide a written prescription for a formulation, drug regimen, or treatment. In addition, the healthcare provider may or may not provide the compound or treatment to the patient. For example, a healthcare provider, without providing a compound, may advise a patient where to obtain said compound. In some embodiments, a healthcare provider may provide a written prescription for a compound, a drug regimen, or treatment for a patient. The recipe can be written on paper or recorded on electronic media. In addition, a prescription may be requested (verbally) or faxed (in writing) to a pharmacy or prescription department. In some embodiments, a sample of the compound or method of treatment is provided to the patient. As used herein, providing a sample compound is an implicit recipe for a compound. Different health systems throughout the world use different methods of prescribing and administering compounds or treatments, and these methods are covered by the disclosure in this document.

The term health care provider may include, for example, a physician, nurse, paramedic, or other healthcare professional who may prescribe or administer compounds (drugs) for the disorders described herein. In addition, the term health care provider may include anyone who may recommend, prescribe, administer, or prevent a patient from receiving a compound or drug, including, for example, an insurance provider.

The terms avoidance, prevention, and prophylaxis refer to the elimination or reduction of the occurrence or onset of one or more of the symptoms associated with a particular disorder. For example, the terms avoidance, prevention, and prophylaxis may refer to the use of therapy on a prophylactic or precautionary basis for a patient who may eventually develop at least one symptom of the disorder, but who has not yet. Such patients can be identified based on risk factors known to correlate with subsequent onset of the disease, such as the presence of a biomarker. Alternatively, prophylactic therapy may be administered as a prophylactic measure without prior identification of a risk factor. Delaying the onset of at least one attack and/or symptom of a disorder may also be considered a warning.

- 7 041181 or prevention.

As used herein, the term solvate means a compound of the invention, or a salt thereof, which additionally contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and/or acceptable for administration to humans in trace amounts.

The terms treat, treatment, and method/agent for treatment refer to the administration of therapy to a patient who is already exhibiting or who has previously exhibited at least one symptom of a disease, disorder, condition, addiction, or behavior. For example, the term treatment may include any of the following in relation to a disease, disorder, condition, addiction, or behavior: partial relief of symptoms, alleviation of pain, reduction of the intensity of symptoms, normalization of the condition, inhibition (for example, suppression of development), alleviation or reduction of pain, or inducing remission. The term treatment may also include treatment of symptoms, prevention of additional symptoms, prevention of underlying physiological causes of symptoms, or termination of symptoms (prophylactically and/or therapeutically) of a disease, disorder, condition, addiction, or behavior. For example, the term treatment in relation to a disorder means reducing the severity of one or more symptoms associated with a particular disorder. Therefore, treating a disorder does not necessarily mean reducing the severity of all symptoms associated with the disorder, and does not necessarily mean completely reducing the severity of one or more of the symptoms associated with the disorder.

The term therapeutically effective amount refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, or human being sought by a patient, researcher, veterinarian, physician, or other healthcare professional or healthcare professional who may include one or more of the following:

(1) preventing a disorder, such as preventing a disease, condition, or disorder in a patient who may be predisposed to the disease, condition, or disorder, but does not yet experience or exhibit the corresponding pathology or symptom;

(2) inhibition of the disorder, eg, inhibition of the disease, condition, or disorder in a patient who is experiencing or exhibiting the associated pathology or symptom (ie, stopping further development of the pathology and/or symptom); and (3) amelioration of symptoms, eg, amelioration of symptoms of a disease, condition, or disorder in a patient who is experiencing or exhibiting the associated pathology or symptom (ie, reversal of pathology and/or symptomatology).

Chemical group, molecular fragment or radical

The term C ₂ -C6 alkenyl denotes a radical containing from 2 to 6 carbon atoms in which at least one carbon-carbon double bond is present. In some embodiments, the invention contains from 2 to 5 carbon atoms. In some embodiments, the invention contains from 2 to 4 carbon atoms. In some embodiments, the invention contains from 2 to 3 carbon atoms. In some embodiments, the invention contains 2 carbon atoms (ie -CH=CH ₂ ). Both E and Z isomers are encompassed by the term alkenyl. In addition, the term alkenyl includes di- and tri-alkenyls.

The terms C ₁ -C ₆ alkylene and C ₁ -C ₄ alkylene refer to a linear or branched saturated aliphatic divalent radical having a specified number of carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms, respectively. In some embodiments, the invention contains from 1 to 2 carbon atoms. In some embodiments, the invention contains from 1 to 5 carbon atoms. In some embodiments, the invention contains from 1 to 4 carbon atoms. In some embodiments, the invention contains from 1 to 3 carbon atoms. In some embodiments, the invention contains 1 or 2 carbon atoms. In some embodiments, the invention contains 1 carbon atom (ie -CH ₂ -). Examples include, but are not limited to: methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, t-butylene, pentylene, isopentylene, t-pentylene, neopentylene, 1-methylbutylene [i.e. CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ], 2-methylbutylene [i.e. CH ₂ CH(CH ₃ ) CH2CH3], n-hexylene, etc.

The term amino refers to the -NH2 group.

The term aryl refers to a ring system containing from 6 to 12 carbon atoms, which may contain one ring, two fused rings or two rings connected via a single bond (i.e. biphenyl) and at least one ring is aromatic. Examples include phenyl, biphenyl, indanyl, tetrahydronaphthalenyl, naphthalenyl, and the like. Examples of biphenyl include [1,1'-biphenyl]-2-yl (i.e. biphenyl-2-yl), [1,1'-biphenyl]-3-yl (i.e. biphenyl-3yl) , or [1,1'-biphenyl]-4-yl (i.e. biphenyl-4-yl) with the following structures, respectively:

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If a substituent is present on the aryl ring, then the substituent can be linked to any additional

foot carbon atom in the ring.

The term C1-C6 alkoxy refers to a radical containing a C1-C ₆ alkyl group attached directly to an oxygen atom, C1-C ₆ alkyl having the same definition as used herein. In some embodiments, the invention contains from 1 to 5 carbon atoms (ie, C1-C5 alkoxy). In some embodiments, the invention contains from 1 to 4 carbon atoms (ie, C1-C4 alkoxy). In some embodiments, the invention contains from 1 to 3 carbon atoms (ie, C1-C3 alkoxy). In some embodiments, the invention contains 1 or 2 carbon atoms. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, sec-butoxy, and the like.

The term C1-C6 alkyl refers to a linear or branched carbon radical containing from 1 to 6 carbon atoms. Some embodiments of the invention are from 1 to 5 carbon atoms (i.e. C1-C5 alkyl), some embodiments of the invention are from 1 to 4 carbon atoms (i.e. C1-C4 alkyl), some embodiments of the invention are 1 to 3 carbon atoms (ie C1-C ₃ alkyl) and some embodiments of the invention are 1 or 2 carbon atoms. Examples of alkyl include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, isopentyl, t-pentyl, neo-pentyl, 1-methylbutyl [those. CH(CH ₃ )CH ₂ CH ₂ CH ₃ ], 2-methylbutyl [i.e. CH2CH (CH ₃ ) CH ₂ CH ₃ ], n-hexyl, etc.

The term C1- _C6 alkylamino refers to a radical containing one C1- _C6 alkyl group attached to an NH group, with C1- _C6 alkyl having the same meaning as described herein. Some embodiments of the invention are C1-C2 alkylamino. Some examples include methylamino, ethylamino, n-propylamino, isopropylamino, nbutylamino, sec-butylamino, isobutylamino, t-butylamino, and the like.

The term C1- _C6 alkylcarboxamide refers to a single C1-C6 alkyl group attached to the carbon or nitrogen of an amide group, with C1- _C6 alkyl having the same definition as used herein. The C1-C6 alkylcarboxamido group can be represented as follows:

O H ^X^Ci-Ce alkyl ^a|k U n o

Examples include N-methylcarboxamide, N-ethylcarboxamide, N-n-propylcarboxamide, N-isopropylcarboxamide, N-n-butylcarboxamide, N-sec-butylcarboxamide, N-isobutylcarboxamide, Nt-butylcarboxamide, and the like.

The term cyano refers to the -CN group.

The term C ₃ -C 7 cycloalkyl refers to a saturated ring radical containing 3 to 7 carbon atoms. In some embodiments, the invention contains from 3 to 6 carbon atoms. In some embodiments, the invention contains from 3 to 5 carbon atoms. In some embodiments, the invention contains from 5 to 7 carbon atoms. In some embodiments, the invention contains from 3 to 4 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term C ₂ -C ₆ dialkylamino refers to a radical containing an amino group substituted with two alkyl groups, said alkyl groups being the same or different, provided that the two alkyl groups do not exceed a total of 6 carbon atoms between the two alkyl groups. Some embodiments of the invention are C2-C4 dialkylamino. Some examples include dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylbutylamino, methylpentylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino, and the like.

The term C1- _C6 haloalkylamino refers to a radical containing one C1-C6 haloalkyl group attached to an NH group, with C1- _C6 haloalkyl having the same meaning as described herein. Some embodiments of the invention are C1-C2 haloalkylamino. Some examples include 2-fluoroethylamino, 2,2,2-trifluoroethylamino, (1,1,1trifluoropropan-2-yl)amino, 3,3,3-trifluoropropylamino, 2,2,2-trifluoropropylamino, and the like.

The term C1-C6 haloalkyl refers to a radical containing a C1- _C6 alkyl group substituted with one or more halogen atoms, C1-C6 alkyl having the same definition as used herein. C1-C6 haloalkyl may be fully substituted, in which case it may be represented by the formula CnL2 _n+i where L is halogen and n is 1, 2, 3, 4, 5, or 6. If present more than one halogen, they may be the same or different and are selected from: fluorine, chlorine, bromine and iodine. In some embodiments, the haloalkyl contains from 1 to 5 carbon atoms (ie, C ₁ -C ₅ haloalkyl). In some embodiments, the haloalkyl contains from 1 to 4 carbon atoms (ie, C1-C4 haloalkyl). In some embodiments, the haloalkyl contains from 1 to 3 carbon atoms (ie, C1-C3 haloalkyl). In some embodiments, the implementation of the haloalkyl contains 1 or 2 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and the like.

The term C ₃ -C ₇ halocycloalkyl refers to a radical containing a C ₃ -C ₇ cycloalkyl group substituted with one or more halogen atoms, with C ₃ -C ₇ cycloalkyl having the same definition as used herein. Examples of halocycloalkyl groups include 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 4,4-difluorocyclohexyl, and the like.

The term halogen refers to the group of fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

The term heteroaryl refers to a ring system containing from 5 to 14 ring atoms, which may contain one ring, two fused rings, two rings connected by a single bond, or three fused rings, and at least one ring atom is a heteroatom, for example O, S and N, where N is optionally substituted with H, C1-C4 acyl or C1-C4 alkyl and at least one ring is aromatic. If the heteroaryl group is substituted with an oxo group, then the oxo group can be on any available ring atom, for example, on a ring carbon to form a carbonyl group, on a ring nitrogen to form an IV-oxide, and on a ring sulfur to form a sulfoxide (i.e. - S(=O)-) or a sulfone (i.e. -S(=O) ₂ -)-. In some embodiments, the invention contains 5-6 ring atoms, for example, furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and so on. In some embodiments, the invention contains from 8 to 14 ring atoms, for example, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran, 2,3-dihydrobenzofuranyl, 4H-benzo[1,3]dioxinyl, 3,4-dihydro-1H-isoquinolinyl, 1, 4,6,7-tetrahydroimidazo[4,5-c]pyridinyl, 7,8-dihydro-5H-[1,6]naphthyridinyl, 5,6-dihydro-8H[1,2,4]triazolo[4,3 -a]pyrazinyl, benzo[1,3]dioxolyl, pyrazolo[1,5-a]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, and the like. If heteroaryl is a ring system containing two rings connected by a single bond, then it is clear that the two rings can be associated with any available carbon ring or available nitrogen atom. Some embodiments of the invention include 3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 5phenylthiophen-2-yl, 3- (pyridin-3-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 5-(phenyl)pyridin-3-yl, 5-(1Hpyrazol-4-yl)pyridin-3-yl, 4-(pyridine -3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(pyridin-2-yl)phenyl (corresponding to the following chemical structures), and the like.

In some embodiments, heteroaryl is selected from the group (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3,4tetrahydropyrido[3,2-b]pyrazinyl, 1,2 -dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3b]pyridinyl , 1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro 1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-III-pyrrolo[2,3b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro -2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2Hpyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4 ]oxazinyl, 3H-imido[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3- yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, chromanyl, isoquinolinyl, isoxazolyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl and thiazolyl. In some embodiments, iso

- 10 041181 brevity heteroaryl is selected from the group 1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,2-dihydroquinolin-6-yl, benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H- pyrazol-4-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin- 6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl , 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -7-yl, 1,4-dihydroquinolin-3-yl, 2,3-dihydro-1H-pyrrolo[2,3b]pyridin-5-yl, 2,3-dihydrobenzofuran-5-yl, 3-(1H- pyrazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl , 3,4-dihydro-2H-benzo [b] [ 1,4] oxazin-6-yl, 3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl, 3,4-dihydro -2H-pyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl, 3H-imidazo[4, 5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 4-(pi ridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1Hpyrazol-4-yl)pyridin-3-yl, 5-(phenyl) pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenylthiophen-2yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[ c][1,2,5]oxadiazol-4-yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, isoxazol-4-yl , pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl, quinolin-7-yl and thiazol-4-yl . When referring to a heteroaryl group, the terms thiophenyl, thiophen-2-yl, thiophen-3-yl, and the like are understood to be refer to the following heteroaryl groups respectively

The term heterocyclyl refers to a non-aromatic ring radical containing from 3 to 8 ring atoms, wherein one, two or three ring atoms are heteroatoms selected from, for example, O, S and N, where N is optionally substituted with H, C1-C4 acyl or C1-C4 alkyl. In some embodiments, heterocyclyl refers to a non-aromatic ring radical containing 3 to 8 ring atoms, where one or two ring atoms are heteroatoms selected from, for example, O, S, and NH. Examples of the heterocyclic group include aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, imidazolidinyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, [1,4]oxazepanyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and the like.

The term hydroxyl refers to the -OH group.

The term C1-C6 alkylene hydroxyl refers to a radical consisting of a hydroxyl group linked to a Ci-C6 alkylene radical, with hydroxyl and C1-C6 alkylene having the same definitions as described herein. Examples include hydroxymethyl, 2-hydroxyethyl, 1hydroxyethyl, and the like.

The term oxo refers to the diradical =O.

The term sulfamoyl refers to the -S(=O) ₂ NH ₂ group.

Compounds of the invention

One aspect of the present invention encompasses, inter alia, specific 1-oxa8-azaspiro[4.5]decan-3-yl-aminopropanyl ether derivatives selected from the compounds of formula (Ia), as well as their pharmaceutically acceptable salts, solvates and hydrates.

(la) _R 3c where R ¹ (as well as Y and Z, which are both associated with R ¹ ), X, W, R ² , R ^3a , R ^3b , R ^3c and R ^3d have the same definitions as described in this document above and below. It is understood that specific features of the present invention, which, for clarity, are described in the context of separate embodiments of the invention, can also be offered in combination in one embodiment of the invention. On the contrary, various features of the present invention, which, for brevity, are described in the context of one embodiment of the invention, can also be offered separately or in any suitable subcombination. All combinations of embodiments of the invention relating to the chemical groups represented by variables (for example, R ¹ , X, W, R ² , R ^3a , R ^3b , R ^3c and R ^3d ; and R ⁴ , R ^5a , R ^5b , R ^5c and R ^5d ) contained in the general chemical formulas described herein, for example, formulas (Ia), (Ia ¹ ), (Ia ² ), (Ia ³ ), (Ia ⁴ ), (Ib), ( Ic), (Ie), (Ig), (li) and the formulas disclosed in the figures are specifically covered by this invention, just as if each combination were individually and explicitly described to the extent that such combinations cover compounds that leads to the formation of stable compounds (ie, compounds that can be isolated, characterized and tested for biological activity). In addition, all subcombinations of chemical groups listed in the embodiments of the invention describing such variables, as well as all subcombinations of use and medical indications described herein, are also specifically covered by this invention in the same way as if each subcombination of chemical groups and

- 11 041181 subcombination of application and medical indications has been individually and explicitly stated in this document.

As used herein, the term "substituted" means that at least one hydrogen atom of a chemical group is replaced by a non-hydrogen substituent or group, said non-hydrogen substituent or group being monovalent or divalent. If a substituent or group is divalent, then it is understood that this group is additionally substituted with another substituent or group. If a chemical group in the context of this invention is substituted, then it may have a full degree of substitution; for example, the methyl group may be substituted with 1, 2, or 3 substituents, the methylene group may be substituted with 1 or 2 substituents, the phenyl group may be substituted with 1, 2, 3, 4, or 5 substituents, and the naphthyl group may be substituted with 1, 2, 3 , 4, 5, 6 or 7 substituents, and the like. Likewise, the phrase substituted with one or more substituents refers to the substitution of a group substituted with one substituent up to the total number of substituents physically permitted by the group. In addition, if a group is substituted by more than one group, they may be identical or may be different.

The compounds of the invention may also include tautomeric forms such as ketoenol tautomers and the like. The tautomeric forms may be in equilibrium or spatially locked into one form through an appropriate substitution. It is understood that various tautomeric forms are within the scope of the compounds of this invention. One example relates to compounds containing a group described herein as 4-oxo-1,4-dihydroquinolin-3-yl, for example, Compound 326. Although a single tautomer is shown for the compound, as illustrated in Table. And, it is understood that the connection covers all such tautomers; below are two typical tautomers of 4-oxo-1,4-dihydroquinolin-3-yl o he

It is understood and appreciated that the compounds of formula (Ia) and related formulas may have one or more chiral centers and therefore may exist as enantiomers and/or diastereoisomers. The invention is intended to extend to and cover all such enantiomers, diastereoisomers, and mixtures thereof, including, but not limited to, racemates.

In some embodiments, the compounds of this invention may have the following defined stereochemistry as illustrated in formula (Ia ¹ )

where R ¹ , X, W, R ² , R ^3a , R ^3b , R ^3c and R ^3d have the same definitions as described above and below in this document, and the carbon designated as C(3) oxaazaspiro[4.5 The ] decanyl group bound to the nitrogen has (R) stereochemistry, and the carbon designated C(2) of the propyl group bound to the hydroxyl group has (S) stereochemistry.

In some embodiments, the compounds of this invention may have the following defined stereochemistry as illustrated in formula (Ia ² )

where: R ¹ , X, W, R ² , R ^3a , R ^3b , R ^3c and R ^3d have the same definitions as described above and below in this document, and the carbon designated as C(3) oxaazaspiro[ 4.5] of the nitrogen-bonded decanyl group has (R) stereochemistry, and the carbon designated C(2) of the hydroxyl-bonded propyl group has (R) stereochemistry.

In some embodiments, the compounds of this invention may have the following defined stereochemistry as illustrated in formula (Ia ³ )

where R ¹ , X, W, R ² , R ^3a , R ^3b , R ^3c and R ^3d have the same definitions as described above and below in this document, and the carbon designated as C(3) oxaazaspiro[ 4.5] of the nitrogen-bonded decanyl group has (S) stereochemistry, and the carbon designated as C(2) of the hydroxyl-bonded propyl group has (S) stereochemistry.

In some embodiments, the compounds of this invention may have the following defined stereochemistry as illustrated in formula (Ia ⁴ )

- 12 041181

where R ¹ , X, W, R ² , R ^3a , R ^3b , R ^3c and R ^3d have the same definitions as described above and below in this document, and the carbon designated as C(3) oxaazaspiro[4.5 The ] decanyl group bound to the nitrogen has (S) stereochemistry, and the carbon designated C(2) of the propyl group bound to the hydroxyl group has (R) stereochemistry.

It is understood that any formulas described herein for which the stereochemistry is not specifically illustrated may be written to specifically show the stereochemistry as (R) and (S), (R) and (R), (S) and (S ) OR (S) and (R) for C(3) and C(2), respectively, in the same way as in the formulas (Ia ¹ ), (Ia ² ), (Ia ³ ) and (Ia ⁴ ) the corresponding stereochemistry for formula (Ia), see above. Likewise, any formulas described herein for which the stereochemistry is not specifically illustrated may alternatively be defined using the formulation described for formulas (Ia ¹ ), (Ia ² ), (Ia ³ ) and (Ia ⁴ ), above, to define stereochemistry as (R) and (S), (R) and (R), (S) and (S), and (S) and (R) respectively.

Accordingly, in some embodiments, the stereochemistry of the C(3) carbon of the oxaazaspiro[4.5]decanyl group bonded to the nitrogen is (R) and the stereochemistry of the C(2) carbon of the propyl group bonded to the hydroxyl group is (S) . In some embodiments, the stereochemistry of the C(3) carbon of the oxaazaspiro[4.5]decanyl group associated with the nitrogen is (R) and the stereochemistry of the C(2) carbon of the propyl group associated with the hydroxyl group is (R). In some embodiments, the stereochemistry of the C(3) carbon of the oxaazaspiro[4.5]decanyl group bonded to the nitrogen is (S) and the stereochemistry of the C(2) carbon of the propyl group bonded to the hydroxyl group is (S). In some embodiments, the stereochemistry of the C(3) carbon of the oxaazaspiro[4.5]decanyl group bonded to the nitrogen is (S) and the stereochemistry of the C(2) carbon of the propyl group bonded to the hydroxyl group is (R).

It is understood that the compounds of formula (Ia) and the formulas used in this disclosure are all individual enantiomers and mixtures thereof, unless specifically stated or shown otherwise.

Group X

In some embodiments, X is -SO2-, -C(=O)-, or -CH2C(=O)-.

In some embodiments of the invention, X is -SO ₂ —.

In some embodiments of the invention, X is -C(=O)-.

In some embodiments of the invention, X is -CH ₂ C(=O)-.

W ring

In some embodiments, W is absent or is C1-C3 alkylene.

In some embodiments of the invention, W is absent.

In some embodiments, W is C1-C3 alkylene.

In some embodiments, W is -CH ₂ -.

Y and Z groups

The Y and Z groups refer to specific substituents on R ¹ , wherein the substituent is selected from C 1 -C 6 alkyl and C ₃ -C ₇ cycloalkyl, and each optionally may be further substituted with one or more substituents selected from the group consisting of the following which contain a group Y or both groups Y and Z: -Y-C ₃ -C ₇ -cycloalkyl and -Y-C ₁ -C ₆ -alkylene-Z.

In some embodiments, Y is independently selected from -O-, -NH-, and -N-(C ₁ -C ₄ alkyl).

In some embodiments, Z is independently selected from hydroxyl, C ₁ -C ₆ alkoxy, amino, C 1 -C 6 alkylamino, and C 2 -C 6 dialkylamino.

It is understood that if more than one -YC ₃ -C ₇ -cycloalkyl and/or -YC ₁ -C ₆ alkylene-Z group is present, then Y and Z may be the same or different.

In some embodiments, Y is -O-.

In some embodiments, Y is -NH-.

In some embodiments, Y is -N-(C ₁ -C ₄ alkyl)-.

In some embodiments, Z is independently selected from C1-C6 alkoxy, amino, and C1-C6 alkylamino.

In some embodiments, Z is hydroxyl.

In some embodiments, Z is C1-C6 alkoxy.

In some embodiments, Z is amino.

In some embodiments, Z is C1-C6 alkylamino.

In some embodiments, Z is a C2-C6 dialkylamino.

- 13 041181

Group R ¹ (aryl and heteroaryl)

In some embodiments, R ¹ is aryl or heteroaryl, each optionally substituted with one or more substituents selected from: C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, amino, cyano, C3 -C7 cycloalkyl, C ₁ -C ₆ haloalkyl, halogen, hydroxyl, oxo and sulfamoyl; and wherein C ₁ -C ₆ alkyl and C 3 -C 7 cycloalkyl are each optionally substituted with one or more substituents selected from amino, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarboxamide, -YC ₃ -C ₇ -cycloalkyl, -YC ₁ -C ₆ -alkylene-Z, C ₁ -C ₆ alkylamino, C ₁ -C ₆ haloalkylamino and heterocyclyl.

In some embodiments, R ¹ is aryl or heteroaryl, each optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkyl, amino, cyano, _C3 - _C7 cycloalkyl, C1-C6 haloalkyl, halogen, hydroxyl, oxo and sulfamoyl; and wherein C1-C6 alkyl and _C3 - _C7 cycloalkyl are each optionally substituted with one or more substituents selected from amino, C1-C6 alkoxy, C1-C6 alkylcarboxamide, -NH- _C3 - _C7 cycloalkyl, -NH-C ₁ -C ₆ -alkylene-NH ₂ , -NH-C ₁ -C ₆ -alkylene-O-C ₁ -C ₆ -alkyl, -NH-C ₁ -C ₆ -alkylene-NH-C ₁ -C ₆ -alkyl, C1-C6 alkylamino, C1-C6 haloalkylamino and heterocyclyl.

In some embodiments, R ¹ is selected from (1H-pyrazolyl)phenyl, (1Hpyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3,4-tetrahydropyrido[3,2b]pyrazinyl, 1,2 -dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b ]pyridinyl, 1Hpyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-imidazo[4,5b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4 -dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro- 5H-pyrrolo[3,4b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, biphenyl, chromanyl, isoquinolinyl, isoxazolyl, naphthalenyl, phenyl, phenylthiophenyl, pyride inyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl and thiazolyl; each optionally substituted with one or more substituents selected from: 2-methylpropan-2-yl, amino, bromine, chlorine, cyclopropyl, ethoxy, ethyl, fluorine, hydroxy, isopropoxy, methoxy, methyl, oxo, propane- 2-yl, propan-1-yl, sulfamoyl and trifluoromethyl; and wherein said 2-methylpropan-2-yl, cyclopropyl, ethyl, methyl and propan-2-yl are each optionally substituted with one or more substituents selected from 2,2,2trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino, 3 -aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methoxy, methylamino, morpholino, propylamino, t-butylamino and t-pentylamino.

In some embodiments, R ¹ is selected from (1H-pyrazolyl)phenyl, (1Hpyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3,4-tetrahydropyrido[3,2b]pyrazinyl, 1,2 -dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b ]pyridinyl, 1Hpyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-imidazo[4,5b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4 -dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro- 5H-pyrrolo[3,4b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, biphenyl, chromanyl, isoquinolinyl, isoxazolyl, naphthalenyl, phenyl, phenylthiophenyl, pyride inyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl and thiazolyl; each optionally substituted with one or more substituents selected from (2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl, (2-methoxyethylamino)methyl, (3-aminopropylamino)methyl, (butylamino) methyl, (cyclobutylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl, 1-amino- 2-methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl, 2-methoxyethyl, amino, aminomethyl, azetidin-1-ylmethyl, bromine, chlorine, cyano, cyclopropyl, ethoxy, ethyl, fluorine, hydroxy, isopropoxy, methoxy, methyl, morpholinomethyl, oxo, propan-1-yl, sulfamoyl and trifluoromethyl.

In some embodiments, R ¹ is selected from 1,2,3,4-tetrahydropyrido[3,2b]pyrazin-7-yl, 1,2-dihydroquinolin-6-yl, 1,4-dihydroquinolin-3-yl, 1H -benzo[d]imidazol-5-yl, 1Nindazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H -pyrazol-4-yl, 1Н-pyrazolo[4,3-b]pyridin-6-yl, 1Н-pyrrolo[2,3-b]pyridin-3-yl, 1Н-pyrrolo[3,2-b]pyridin-6 -yl, 2,3dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2, 3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydro-1Hpyrrolo[2,3-b]pyridin-5-yl, 2,3-dihydrobenzofuran-5-yl, 3-(1H-pyrazol-4-yl)phenylc, 3-(pyridin-2yl) phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3,4-dihydro2H-benzo[b][1,4] oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 3,4-dihydro-2H-pyrano[2,3

- 14 041181

b]pyridin-6-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl, 3H-imidazo[4,5-b]pyridin-3-yl , 3Nimidazo[4,5-b]pyridin-6-yl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5- (1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydroquinolin- 3-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl , benzofuran-2-yl, benzofuran-5-yl, biphenyl-3-yl, biphenyl-4-yl, chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, isoxazol-4-yl, naphthalene -2-yl, phenyl, pyridin-2yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl, quinolin-7-yl and thiazole -4-silt; each optionally substituted with one or more substituents selected from (2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl, (2-methoxyethylamino)methyl, (3-aminopropylamino)methyl, (butylamino) methyl, (cyclobutylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl, 1-amino- 2-methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl, 2-methoxyethyl, amino, aminomethyl, azetidin-1-ylmethyl, bromine, chlorine, cyano, cyclopropyl, ethoxy, ethyl, fluorine, hydroxy, isopropoxy, methoxy, methyl, morpholinomethyl, oxo, propan-1-yl, sulfamoyl and trifluoromethyl.

In some embodiments, R ¹ is selected from: (R)-1,3-dimethyl-2,3-dihydro-1Hpyrido[2,3-b][1,4]oxazin-7-yl, (S)-1 ,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]oxazin-7-yl, 1-(2methoxyethyl)-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-7-yl, 1,3,3-trimethyl-2,3-dihydro-1Н-pyrido[2,3-b][1,4]oxazin-6-yl , 1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,6-dimethyl-2,3dihydro-1H-pyrido[2,3-b][ 1,4]oxazin-7-yl, 1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7yl, 1-ethoxynaphthalen-2-yl, 1 -ethyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]oxazin-7-yl, 1-ethyl-4-oxo-1,4dihydroquinolin-3-yl, 1-ethyl- 5-methyl-1 H-pyrazol-4-yl, 1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3 yl, 1-ethyl-6-methyl-4-oxo-1,4- dihydroquinolin-3-yl, 1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1 ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazole -5-yl, 1H-indazol-5-yl, 1Nin dol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1Hpyrrolo[2, 3-b]pyridin-3-yl, 1Н-pyrrolo[3,2-b]pyridin-6-yl, 1-methyl-2,3-dihydro-1Н-pyrido[2,3b][1,4]oxazine -7-yl, 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 2,3-dihydro[1,4]duoxino[2,3-b]nurudin-7-yl, 2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydrobenzofuran-5-yl, 2-aminothiazol-4-yl, 2-oxo-2,3- dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-(1-cyclopropyl -1 H-pyrazol-4-yl)phenyl, 3-(1-ethyl-1 H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1-methyl -1 H-pyrazol-4-yl)phenyl, 3-(1-propyl-1 H-pyrazol-4-yl)phenyl, 3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridine- 2-yl)phenyl, 3-(4-methylpyridin-2-yl)phenyl, 3-(5methylpyridin-2-yl)phenyl, 3-(6-(trifluoromethyl)pyridin-2-yl)phenyl, 3-(6 -aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridine -3yl)phenyl, 3-(pyridin-4-yl)ph enyl, 3-(pyrimidin-5-yl)phenyl, 3-(trifluoromethyl)phenyl, 3,4-dihydro2H-pyrano[2,3-b]pyridin-6-yl, 3,5-dimethylisoxazol-4-yl, 3-bromo-2-methylphenyl, 3-bromo-4-methoxyphenyl, 3-bromophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-methyl-3Nimidazo[4,5-b]pyridine- 5-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4 '-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-aminoethylamino)methyl)biphenyl-3-yl, 4'-((2-methoxyethylamino)methyl)biphenyl- 3-yl, 4'-((3-aminopropylamino)methyl)biphenyl-3-yl, 4'-((butylamino)methyl)biphenyl-3-yl, 4'-((cyclobutylamino)methyl)biphenyl3-yl, 4 '-((ethylamino)methyl)biphenyl-3-yl, 4'-((isobutylamino)methyl)biphenyl-3-yl, 4'-((isopropylamino)methyl)biphenyl-3-yl, 4'-((methylamino )methyl)biphenyl-3-yl, 4'-((propylamino)methyl)biphenyl-3yl, 4'-((tert-butylamino)methyl)biphenyl-3-yl, 4'-((tert-pentylamino)methyl) biphenyl-3-yl, 4'-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl, 4'-(1-amino-2-methylpropan-2-yl)b iphenyl-3-yl, 4'(1-aminocyclopropyl)-2-methylbiphenyl-3-yl, 4'-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl)-6-fluorobiphenyl -3-yl, 4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl)biphenyl-3-yl, 4'-(2-acetamidoethyl)-4-ethoxy-biphenyl -3-yl, 4'-(2-acetamidoethyl)biphenyl-3-yl, 4'-(2-aminoethyl)-4-ethoxybiphenyl-3-yl, 4'-(2-aminoethyl)-6-methoxybiphenyl-3 -yl, 4'-(2-aminoethyl)biphenyl-3-yl, 4'-(2-aminopropan-2-yl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-2methoxybiphenyl-3-yl , 4'-(aminomethyl)-2-methylbiphenyl-3-yl, 4'-(aminomethyl)-3'-fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxy-3'-fluorobiphenyl-3- yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-4-fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-isopropoxybiphenyl-3-yl, 4'- (aminomethyl)-5methoxybiphenyl-3-yl, 4'-(aminomethyl)-6-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-6-fluorobiphenyl-3-yl, 4'-(aminomethyl)-6-methoxybiphenyl -3-yl, 4'-(aminomethyl)biphenyl-3-yl, 4'-(aminomethyl)biphenyl-4yl, 4'-(azetidin-1-ylme tyl)biphenyl-3-yl, 4'-(morpholinomethyl)biphenyl-3-yl, 4-(pyridin-2yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl , 4'-(sulfamoyl)biphenyl-3-yl, 4-bromo-3methylphenyl, 4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3-yl, 4-hydroxy-6-methylquinolin-3-yl, 4hydroxy-7-methylquinolin-3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4methoxyquinolin-3-yl, 4-methyl-2-oxo-1,2-dihydroquinolin- 6-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1, 4]oxazin-7-yl, 4-methyl-3,4-dihydro-2Н

- 15 041181 pyrido[3,2-b] [ 1,4]oxazin-7-yl, 4'-methylbiphenyl-3-yl, 4-oxo-1,4-dihydroquinolin-3-yl, 5-(1 - methyl1H-pyrazol-4-yl)pyridin-3-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5,6,7,8-tetrahydronaphthalen-2yl, 5,6,7,8- tetrahydroquinolin-3-yl, 5-bromo-6-chloropyridin-3-yl, 5-bromopyridin-3-yl, 5-chloronaphthalen-2-yl, 5-oxo-6,7-dihydro-5H-pyrrolo[3, 4-b]pyridin-3-yl, 5-phenylthiophen-2-yl, 6-chloronaphthalen-2-yl, 6-fluoro-4-hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5 ]oxadiazol-4-yl, 7-fluoro-4hydroxyquinolin-3-yl, 8-fluoro-4-hydroxyquinolin-3-yl, benzofuran-2-yl, benzofuran-5-yl, chroman6-yl, chroman-7-yl , isoquinolin-5-yl, m-tolyl, naphthalen-2-yl, phenyl, pyridin-2-yl, pyridin-3yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinoline -6-yl and quinolin-7-yl.

In some embodiments, R ¹ is (R)-1,3-dimethyl-2,3dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R ¹ is (S)-1,3-dimethyl-2,3dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R ¹ is 1-(2-methoxyethyl)-2,3dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R ¹ is 1,3,3-trimethyl-2,3dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl.

In some embodiments, R ¹ is 1,4-dimethyl-1,2,3,4tetrahydropyrido[3,2-b]pyrazin-7-yl.

In some embodiments, R ¹ is 1,6-dimethyl-2,3dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R ¹ is 1,8-dimethyl-2,3dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R ¹ is 1-ethoxynaphthalen-2-yl.

In some embodiments, R ¹ is 1-ethyl-2,3-dihydro-Spirido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R ¹ is 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 1-ethyl-5-methyl-1Hpyrazol-4-yl.

In some embodiments, R ¹ is 1-ethyl-6-fluoro-4-oxo1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 1-ethyl-6-methyl-4-oxo1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 1-ethyl-7-fluoro-4-oxo1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 1-ethyl-7-methyl-4-oxo1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 1-ethyl-8-fluoro-4-oxo1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 1-ethyl-8-methyl-4-oxo1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 1H-benzo[d]imidazol-5yl.

In some embodiments, R ¹ is 1H-indazol-5-yl.

In some embodiments, R ¹ is 1H-indol-2-yl.

In some embodiments, R ¹ is 1H-indol-3-yl.

In some embodiments, R ¹ is 1H-indol-5-yl.

In some embodiments, R ¹ is 1H-indol-6-yl.

In some embodiments, R ¹ is 1H-pyrazolo[4,3b]pyridin-6-yl.

In some embodiments, R ¹ is W-pyrrolo[2,3b]pyridin-3-yl.

In some embodiments, R ¹ is W-pyrrolo[3,2b]pyridin-6-yl.

In some embodiments, R ¹ is 1-methyl-2,3-dihydro 1 H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R ¹ is 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-yl.

In some embodiments, R ¹ is 2,3-dihydro-Spirido[2,3-b][1,4]oxazin-7-yl.

- 16 041181

In some embodiments, R ¹ is 2,3-dihydrobenzofuran5-yl.

In some embodiments, R ¹ is 2-aminothiazol-4-yl.

In some embodiments, R ¹ is 2-oxo-2,3-dihydro-Shimidazo[4,5-b]pyridin-6-yl.

In some embodiments, R ¹ is 2-oxo-2,3-dihydro-Spyrrolo[2,3-b]pyridin-5-yl.

In some embodiments, R ¹ is 3-(1-cyclopropyl-Spyrazol-4-yl)phenyl.

In some embodiments, R ¹ is 3-(1-ethyl-1H-pyrazol-4yl)phenyl.

In some embodiments, R ¹ is 3-(III-pyrazol-4yl)phenyl.

In some embodiments, R ¹ is 3-(1-methyl-1H-pyrazol4-yl)phenyl.

In some embodiments, R ¹ is 3-(1-propyl-III-pyrazol4-yl)phenyl.

In some embodiments, R ¹ is 3-(2-methylpyridin-4yl)phenyl.

In some embodiments, R ¹ is 3-(3-fluoropyridin-2yl)phenyl.

In some embodiments, R ¹ is 3-(4-methylpyridin-2yl)phenyl.

In some embodiments, R ¹ is 3-(5-methylpyridin-2yl)phenyl.

In some embodiments, R ¹ is 3-(6-(trifluoromethyl)pyridin-2-yl)phenyl.

In some embodiments, R ¹ is 3-(6-aminopyridin-3yl)phenyl.

In some embodiments, R ¹ is 3-(6-fluoropyridin-2yl)phenyl.

In some embodiments, R ¹ is 3-(6-methylpyridin-2yl)phenyl.

In some embodiments, R ¹ is 3-(pyridin-2-yl)phenyl.

In some embodiments, R ¹ is 3-(pyridin-3-yl)phenyl.

In some embodiments, R ¹ is 3-(pyridin-4-yl)phenyl.

In some embodiments, R ¹ is 3-(pyrimidin-5yl)phenyl.

In some embodiments, R ¹ is 3-(trifluoromethyl)phenyl.

In some embodiments, R ¹ is 3,4-dihydro-2Hpyrano[2,3-b]pyridin-6-yl.

In some embodiments, R ¹ is 3,5-dimethylisoxazol-4yl.

In some embodiments, R ¹ is 3-bromo-2-methylphenyl.

In some embodiments, R ¹ is 3-bromo-4-methoxyphenyl.

In some embodiments, R ¹ is 3-bromophenyl.

In some embodiments, R ¹ is 3-chlorophenyl.

In some embodiments, R ¹ is 3-cyanophenyl.

In some embodiments, R ¹ is 3-fluorophenyl.

In some embodiments, R ¹ is 3-methoxyphenyl.

In some embodiments, R ¹ is 3-methyl-3-Nimidazo[4,5-b]pyridin-5-yl.

In some embodiments, R ¹ is 3-methyl-3-Nimidazo[4,5-b]pyridin-6-yl.

In some embodiments, R ¹ is 3-oxo-3,4-dihydro-2Hbenzo[b] [ 1,4]oxazin-6-yl.

In some embodiments, R ¹ is 4'-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((2-aminoethylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((2methoxyethylamino)methyl)biphenyl-3-yl.

- 17 041181

In some embodiments, R ¹ is 4'-((3-aminopropylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((butylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((cyclobutyl amino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((ethylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((isobutylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((isopropylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((methylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((propylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((tert-butylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-((tert-pentylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-(1-amino-2methylpropan-2-yl)-4-ethoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(1-aminocyclopropyl)-6-fluorobiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(1-aminocyclopropyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-(2-acetamidoethyl)-4ethoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(2-acetamidoethyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-(2-aminoethyl)-4ethoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(2-aminoethyl)-6methoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(2-aminoethyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-(2-aminopropan-2yl)-4-ethoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-2methoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-2-methylbiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-3'fluorobiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-4ethoxy-3'-fluorobiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-4ethoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-4fluorobiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-4isopropoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-5methoxybiphenyl-3-yl.

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In some embodiments, R ¹ is 4'-(aminomethyl)-6ethoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-6fluorobiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)-6methoxybiphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-(aminomethyl)biphenyl-4-yl.

In some embodiments, R ¹ is 4'-(azetidin-1ylmethyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4'-(morpholinomethyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4-(pyridin-2-yl)phenyl.

In some embodiments, R ¹ is 4-(pyridin-3-yl)phenyl.

In some embodiments, R ¹ is 4-(pyridin-4-yl)phenyl.

In some embodiments, R ¹ is 4'-(sulfamoyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4-bromo-3-methylphenyl.

In some embodiments, R ¹ is 4-ethoxy-4'((isopropylamino)methyl)biphenyl-3-yl.

In some embodiments, R ¹ is 4-hydroxy-6-methylquinolin-3-yl.

In some embodiments, R ¹ is 4-hydroxy-7-methylquinolin-3-yl.

In some embodiments, R ¹ is 4-hydroxy-8-methylquinolin-3-yl.

In some embodiments, R ¹ is 4-hydroxyquinolin-3yl.

In some embodiments, R ¹ is 4-methoxyquinolin-3-yl.

In some embodiments, R ¹ is 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl.

In some embodiments, R ¹ is 4-methyl-3,4-dihydro-2Hbenzo[b][1,4]oxazin-6-yl.

In some embodiments, R ¹ is 4-methyl-3,4-dihydro-2Hbenzo[b] [ 1,4]oxazin-7 -yl.

In some embodiments, R ¹ is 4-methyl-3,4-dihydro-2Hpyrido[3,2-b][1,4]oxazin-7-yl.

In some embodiments, R ¹ is 4'-methylbiphenyl-3-yl.

In some embodiments, R ¹ is 4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R ¹ is 5-(1-methyl-1H-pyrazol4-yl) pyridin-3-yl.

In some embodiments, R ¹ is 5-(4-(aminomethyl)phenyl)pyridin-3-yl.

In some embodiments, R ¹ is 5,6,7,8-tetrahydronaphthalen-2-yl.

In some embodiments, R ¹ is 5,6,7,8-tetrahydroquinolin-3-yl.

In some embodiments, R ¹ is 5-bromo-6-chloropyridin3-yl.

In some embodiments, R ¹ is 5-bromopyridin-3-yl.

In some embodiments, R ¹ is 5-chloronaphthalene-2-yl.

In some embodiments, R ¹ is 5-oxo-6,7-dihydro-5Hpyrrolo[3,44e]pyridin-3-yl.

In some embodiments, R ¹ is 5-phenylthiophen-2-yl.

In some embodiments, R ¹ is 6-chloronaphthalene-2-yl.

In some embodiments, R ¹ is 6-fluoro-4-hydroxyquinolin-3-yl.

In some embodiments, R ¹ is 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl.

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In some embodiments, R ¹ is 7-fluoro-4-hydroxyquinolin-3-yl.

In some embodiments, R ¹ is 8-fluoro-4-hydroxyquinolin-3-yl.

In some embodiments, R ¹ is benzofuran-2-yl.

In some embodiments, R ¹ is benzofuran-5-yl.

In some embodiments, R ¹ is chroman-6-yl.

In some embodiments, R ¹ is chroman-7-yl.

In some embodiments, R ¹ is isoquinolin-5-yl.

In some embodiments, R ¹ is m-tolyl.

In some embodiments, R ¹ is naphthalene-2-yl.

In some embodiments, R ¹ is phenyl.

In some embodiments, R ¹ is pyridin-2-yl.

In some embodiments, R ¹ is pyridin-3-yl.

In some embodiments, R ¹ is pyrrolo[1,2-a]pyrimidin-3-yl.

In some embodiments, R ¹ is quinolin-3-yl.

In some embodiments, R ¹ is quinolin-6-yl.

In some embodiments, R ¹ is also quinolin-7-yl.

Group R ¹ (aryl)

In some embodiments, R ¹ is aryl, each optionally substituted with one or more substituents selected from Ci-C ₆ alkoxy, C1C ₆ alkyl, amino, cyano, C ₃ -C ₇ cycloalkyl, C1-C6 haloalkyl, halogen, hydroxyl, oxo and sulfamoyl; and while C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl, each optionally substituted with one or more substituents selected from amino, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylcarboxamide, -YC ₃ - C ₇ cycloalkyl, -YC ₁ -C ₆ alkylene-Z, C 1 -C 6 alkylamino, C 1 -C 6 haloalkylamino and heterocyclyl.

In some embodiments, R ¹ is aryl, optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkyl, cyano, _C3 - _C7 cycloalkyl, C1-C6 haloalkyl, halo, and sulfamoyl; and wherein said C1-C6 alkyl and _C3 - _C7 cycloalkyl are each optionally substituted with one or more substituents selected from amino, C1-C6 alkylcarboxamide, -NH- _C3 - _C7 cycloalkyl, -NH-C ₁ -C ₆ -alkylene-NH2, -NHC ₁ -C ₆ -alkylene-O-C ₁ -C ₆ -alkyl, C1-C6 alkylamino, C1-C6 haloalkylamino and heterocyclyl.

In some embodiments, R ¹ is selected from 5,6,7,8-tetrahydronaphthalenyl, biphenyl, naphthalenyl, and phenyl; each optionally substituted with one or more substituents selected from 2-methylpropan-2-yl, bromine, chlorine, cyano, cyclopropyl, ethoxy, ethyl, fluorine, isopropoxy, methoxy, methyl, propan-2-yl, sulfamoyl and trifluoromethyl; and wherein said 2-methylpropan-2-yl, cyclopropyl, ethyl, methyl and propan-2-yl are each optionally substituted with one or more substituents selected from 2,2,2-trifluoroethylamino, 2aminoethylamino, 2-methoxyethylamino, 3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methylamino, morpholino, propylamino, t-butylamino and t-pentylamino.

In some embodiments, R ¹ is selected from 5,6,7,8-tetrahydronaphthalenyl, biphenyl, naphthalenyl, and phenyl; each optionally substituted with one or more substituents selected from: (2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl, (2methoxyethylamino)methyl, (3-aminopropylamino)methyl, (butylamino)methyl , (cyclobutylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl, 1-amino-2 -methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl, aminomethyl, azetidin1-ylmethyl, bromine, chlorine, cyano, ethoxy, fluorine, isopropoxy, methoxy, methyl, morpholinomethyl , sulfamoyl and trifluoromethyl.

In some embodiments, R ¹ is selected from 5,6,7,8-tetrahydronaphthalen-2-yl, biphenyl-3-yl, biphenyl-4-yl, naphthalen-2-yl, and phenyl; each optionally substituted with one or more substituents selected from (2,2,2-trifluoroethylamino)methyl, (2aminoethylamino)methyl, (2-methoxyethylamino)methyl, (3-aminopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl, 1amino-2-methylpropane- 2-yl, 1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2yl, aminomethyl, azetidin-1-ylmethyl, bromine, chlorine, cyano, ethoxy, fluorine, isopropoxy, methoxy, methyl, morpholinomethyl, sulfamoyl and trifluoromethyl.

In some embodiments, R ¹ is selected from 1-ethoxynaphthalen-2-yl, 3(trifluoromethyl)phenyl, 3-bromo-2-methylphenyl, 3-bromo-4-methoxyphenyl, 3-bromophenyl, 3-chlorophenyl, 3-cyanophenyl , 3-fluorophenyl, 3-methoxyphenyl, 4'-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4'-20 041181 ((2-aminoethylamino)methyl)biphenyl-3-yl, 4 '-((2-methoxyethylamino)methyl)biphenyl-3-yl, 4'-((3-aminopropylamino)methyl)biphenyl-3-yl, 4'-((butylamino)methyl)biphenyl-3-yl, 4' -((cyclobutylamino)methyl)biphenyl-3-yl, 4'-((ethylamino)methyl)biphenyl-3-yl, 4'-((isobutylamino)methyl)biphenyl-3-yl, 4'-((isopropylamino)methyl )biphenyl-3-yl, 4'-((methylamino)methyl)biphenyl-3-yl, 4'-((propylamino)methyl)biphenyl-3-yl, 4'-((tert-butylamino)methyl)biphenyl- 3-yl, 4'-((tert-pentylamino)methyl)biphenyl-3-yl, 4'-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl, 4'-( 1-amino-2-methylpropan-2-yl)biphenyl-3-yl, 4'-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl, 4'-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl )-6-fluorobiphenyl-3-yl, 4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl)biphenyl-3-yl, 4'-(2-acetamidoethyl)- 4ethoxybiphenyl-3-yl, 4'-(2-acetamidoethyl)biphenyl-3-yl, 4'-(2-aminoethyl)-4-ethoxybiphenyl-3-yl, 4'(2-aminoethyl)-6-methoxybiphenyl-3 -yl, 4'-(2-aminoethyl)biphenyl-3-yl, 4'-(2-aminopropan-2-yl)-4ethoxybiphenyl-3-yl, 4'-(aminomethyl)-2-methoxybiphenyl-3-yl , 4'-(aminomethyl)-2-methylbiphenyl-3-yl, 4'-(aminomethyl)-3'-fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxy-3'-fluorobiphenyl-3- yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-4-fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-isopropoxybiphenyl-3-yl, 4'- (aminomethyl)-5-methoxybiphenyl-3-yl, 4'-(aminomethyl)-6-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-6-fluorobiphenyl-3-yl, 4'-(aminomethyl)-6 -methoxybiphenyl-3-yl, 4'-(aminomethyl)biphenyl-3-yl, 4'-(aminomethyl)biphenyl-4-yl, 4'-(azetidin-1-ylmethyl)biphenyl-3-yl, 4'- (morpholinomethyl)biphenyl-3-yl, 4'-(sulfamoyl)biphenyl-3-yl, 4-bromo-3-methylphenyl, 4-ethoxy-4'-((isopropylamino )methyl)biphenyl-3-yl, 4'-methylbiphenyl-3-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5-chloronaphthalen2-yl, 6-chloronaphthalen-2-yl, m-tolyl, naphthalen-2-yl and phenyl.

Group R ¹ (heteroaryl)

In some embodiments, R ¹ is heteroaryl, each optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkyl, amino, cyano, _C3 - _C7 cycloalkyl, C1-C ₆ haloalkyl, halogen, hydroxyl, oxo and sulfamoyl, while C1-C6 alkyl and C ₃ -C ₇ cycloalkyl, each optionally substituted with one or more substituents selected from amino, C1-C6 alkoxy, C1-C6 alkylcarboxamide, - YC ₃ -C ₇ -cycloalkyl, -YC ₁ -C ₆ -alkylene-Z, C1-C6 alkylamino, C1-C6 haloalkylamino and heterocyclyl.

In some embodiments, R ¹ is heteroaryl optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkyl, amino, _C3 - _C7 cycloalkyl, C1-C6 haloalkyl, halogen, hydroxyl, and oxo; and wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from amino and C1-C6 alkoxy.

In some embodiments, R ¹ is selected from (1H-pyrazolyl)phenyl, (1Hpyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3,4-tetrahydropyrido[3,2b]pyrazinyl, 1,2 -dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b ]pyridinyl, 1Hpyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-imidazo[4,5b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4 -dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b] pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, chromanil, isoquinolinyl, isoxazolyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl and thiazolyl; each optionally substituted with one or more substituents selected from amino, bromine, chlorine, cyclopropyl, ethyl, fluorine, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl; and wherein said ethyl and methyl are each optionally substituted with one or more substituents selected from amino and methoxy.

In some embodiments, R ¹ is selected from (1H-pyrazolyl)phenyl, (1Hpyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3,4-tetrahydropyrido[3,2b]pyrazinyl, 1,2 -dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1H-pyrazol[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl , 1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b] pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl, 3 ,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2Hpyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b] pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, chromanil, isoquinolinyl, isoxazolyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl and thiazolyl; each optionally substituted with one or more substituents selected from 2-methoxyethyl, amino, aminomethyl, bromine, chlorine, cyclopropyl, ethyl, fluorine, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl.

In some embodiments, R ¹ is selected from 1,2,3,4-tetrahydropyrido[3,2

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b]pyrazin-7-yl, 1,2-dihydroquinolin-6-yl, 1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1Nindazol-5-yl, 1H-indol- 2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazol-4-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 2,3dihydro-[1,4]dioxino[2,3-b]pyridine -7-yl, 2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2 ,3-dihydrobenzofuran-5-yl, 3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-2yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4- yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-benzo[b][ 1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][ 1 ,4]oxazin-7-yl, 3,4-dihydro-2H-pyrano[2,3b]pyridin-6-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4] oxazin-7-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3Nimidazo[4,5-b]pyridin-6-yl, 4-(pyridin-2-yl)phenyl, 4-( pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1H-pyrazole -4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5phenylthiophen-2-yl, 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman -7-yl, isoquinolin-5-yl, isoxazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinoline -6-yl, quinolin-7yl and thiazol-4-yl; each optionally substituted with one or more substituents selected from 2-methoxyethyl, amino, aminomethyl, bromine, chlorine, cyclopropyl, ethyl, fluorine, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl.

In some embodiments, R ¹ is selected from (R)-1,3-dimethyl-2,3-dihydro-1Hpyrido[2,3-b][1,4]oxazin-7-yl, (S)-1, 3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]oxazin-7-yl, 1-(2methoxyethyl)-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazin-7-yl, 1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 1,4-dimethyl-1,2,3,4-tetrahydronurudo[3,2-b]nurazin-7-ula, 1,6-dimethyl-2,3dihydro-1H-pyrido[2,3-b][1 ,4]oxazin-7-yl, 1,8-dimethyl-2,3-dihydro-1H-pirudo[2,3-b][1,4]oxazin-7yl, 1-ethyl-2,3-dihydro- 1 H-pyrido[2,3-b] [1,4]oxazin-7-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 1 ethyl-5-methyl-1H-pyrazole -4-yl, 1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-6-methyl-4-oxo1,4-dihydroquinolin-3-yl, 1-ethyl -7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-7-methyl-4-oxo-1,4dihydroquinolin-3-yl, 1-ethyl-8-fluoro-4-oxo -1,4-dihydroquinolin-3-yl, 1-ethyl-8-methyl-4-oxo-1,4dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl , 1Н-indol-2-yl, 1Н-indol-3-yl, 1 H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H- pyrrolo[3,2-b]pyridin-6-yl, 1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-methyl-4oxo -1,4-dihydroquinolin-3-yl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-pyrido[2,3-b ][1,4]oxazin-7-yl, 2,3-dihydrobenzofuran-5-yl, 2-aminothiazol-4-yl, 2-oxo-2,3-dihydro1H-imidazo[4,5-b]pyridine- 6-yl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl, 3- (1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1methyl-1H-pyrazol-4-yl)phenyl, 3-(1 -propyl-1 H-pyrazol-4-yl)phenyl, 3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl, 3-(4-methylpyridin-2-yl )phenyl, 3-(5-methylpyridin-2-yl)phenyl, 3-(6(trifluoromethyl)pyridin-2-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridine -2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4yl)phenyl , 3-(pyrimidin-5-yl)pheni la, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl, 3,5-dimethylisoxazol-4-yl, 3-methyl-3H-imidazo[4,5-b]pyridine- 5-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4 -(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4(pyridin-4-yl)phenyl, 4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-7-methylquinoline -3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4-methoxyquinolin-3-yl, 4-methyl-2-oxo-1,2dihydroquinolin-6-yl, 4 -methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl , 4-methyl-3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazin-7-yl, 4-oxo-1,4-dihydroquinolin-3-yl, 5-(1 -methyl-1H-pyrazol-4-yl)pyridin-3-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-bromo -6-chloropyridin-3-yl, 5-bromopyridin-3-yl, 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylthiophen-2-yl , 6-fluoro-4-hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7-fluoro-4-hydroxyquinolin-3-yl, 8-fluoro p-4-hydroxyquinolin-3yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, pyridin-2yl, pyridin-3-yl, pyrrolo[ 1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl and quinolin-7-yl.

Group R ²

In some embodiments, R ² is selected from C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkyl, C ₃ C ₇ cycloalkyl, heterocyclyl, and C ₁ -C ₆ haloalkyl; each optionally substituted with one or more substituents selected from C 1 -C 6 alkoxy, C ₁ -C ₆ alkylene hydroxyl, amino, aryl, C ₃ -C ₇ cycloalkyl, cyano, C ₃ -C ₇ halocycloalkyl, hydroxyl and oxo.

In some embodiments, R ² is selected from 1,1-difluoroethyl, 1-fluoroethyl, 2methylpropan-2-yl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, azetidin-3-yl, cyclobutyl, cyclopentyl , cyclopropyl, ethyl, fluoromethyl, isobutyl, isopentyl, isopropyl, methyl, oxetan-3-yl, propan-1-yl, sec-butyl and vinyl; each optionally substituted with one or more substituents selected from 2,2-difluorocyclopropyl, amino, cyano, cyclobutyl, cyclohexyl, cyclopropyl, ethoxy, hydroxy, hydroxymethyl, methoxy, oxo and phenyl.

In some embodiments, R ² is selected from (2,2-difluorocyclopropyl)methyl,

- 22 041181

-(hydroxymethyl)cyclobutyl, 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-amino2-methyl-1-oxopropan-2-yl, 1-ethoxy-2-methyl-1-oxopropan-2 -yl, 1-fluoroethyl, 1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl, 2-aminoethyl, 2-hydroxyethyl, 3,3,3-trifluoropropyl, 3-amino-3oxopropyl, 3 -hydroxycyclobutyl, 3-hydroxypropyl, 3-methoxypropyl, 4,4,4-trifluorobutyl, azetidin-3-yl, benzyl, carboxymethyl, cyanomethyl, cyclobutyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, ethyl, fluoromethyl, isobutyl, isopentyl , isopropyl, methoxymethyl, methyl, oxetan-3-yl, propan-1-yl, sec-butyl and vinyl.

In some embodiments, R ² is selected from 1-(hydroxymethyl)cyclobutyl, 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-fluoroethyl, 1-hydroxy-2-methylpropan2-yl, 2-amino -2-oxoethyl, 2-hydroxyethyl, 3-amino-3-oxopropyl, 3-hydroxypropyl, 3-methoxypropyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isobutyl, isopropyl, methoxymethyl, methyl and propan-1-yl.

In some embodiments, R ² is (2,2-difluorocyclopropyl)methyl.

In some embodiments, R ² is 1-(hydroxymethyl)cyclobutyl.

In some embodiments, R ² is 1-(hydroxymethyl)cyclopropyl.

In some embodiments, R ² is 1,1-difluoro-2hydroxyethyl.

In some embodiments, R ² is 1-amino-2-methyl-1oxopropan-2-yl.

In some embodiments, R ² is 1-ethoxy-2-methyl-1oxopropan-2-yl.

In some embodiments, R ² is 1-fluoroethyl.

In some embodiments, R ² is 1-hydroxy-2-methylpropan-2-yl.

In some embodiments, R ² is 2-amino-2-oxoethyl.

In some embodiments, R ² is 2-aminoethyl.

In some embodiments, R ² is 2-hydroxyethyl.

In some embodiments, R ² is 3,3,3-trifluoropropyl.

In some embodiments, R ² is 3-amino-3-oxopropyl.

In some embodiments, R ² is 3-hydroxycyclobutyl.

In some embodiments, R ² is 3-hydroxypropyl.

In some embodiments, R ² is 3-methoxypropyl.

In some embodiments, R ² is 4,4,4-trifluorobutyl.

In some embodiments, R ² is azetidin-3-yl.

In some embodiments, R ² is benzyl.

In some embodiments, R ² is carboxymethyl.

In some embodiments, R ² is cyanomethyl.

In some embodiments, R ² is cyclobutyl.

In some embodiments, R ² is cyclobutylmethyl.

In some embodiments, R ² is cyclohexylmethyl.

In some embodiments, R ² is cyclopentyl.

In some embodiments, R ² is cyclopropyl.

In some embodiments, R ² is cyclopropylmethyl.

In some embodiments, R ² is ethyl.

In some embodiments, R ² is fluoromethyl.

In some embodiments, R ² is isobutyl.

In some embodiments, R ² is isopentyl.

In some embodiments, R ² is isopropyl.

In some embodiments, R ² is methoxymethyl.

In some embodiments, R ² is methyl.

In some embodiments, R ² is oxetan-3-yl.

In some embodiments, R ² is propan-1-yl.

In some embodiments, R ² is sec-butyl.

In some embodiments, R ² is vinyl. Groups R ^3a , R ^3b , R ^3c and R ^3d

In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are each independently H or halogen.

In some embodiments, R ^3a is H or halo;

R ^3b is H;

- 23 041181

R ^3c is H or halogen and

R ^3d is H.

In some embodiments, R ^3a is halo;

R ^3b is H;

R ^3c is H or halogen and

R ^3d is H.

In some embodiments, R ^3a is H;

R ^3b is H; R ^3c is halogen; and R ^3d is H.

In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are each independently H or F.

In some embodiments, R ^3a is H or F;

R ^3b is H; R ^3c is H or F; and R ^3d is H.

In some embodiments, R ^3a is F;

R ^3b is H;

R ^3c is H and

R ^3d is H.

In some embodiments, R ^3a is H;

R ^3b is H;

R ^3c is F and

R ^3d is H.

In some embodiments, R ^3a , R ^3b , R ^3c , and R ^3d are each H.

In some embodiments, R ^3a is halogen.

In some embodiments, R ^3b is halo.

In some embodiments, R ^3c is halo.

In some embodiments, R ^3d is halo.

In some embodiments, R ^3a is F.

In some embodiments, R ^3b is F.

In some embodiments, R ^3c is F.

In some embodiments, R ^3d is F.

In some embodiments, R ^3a is H.

In some embodiments, R ^3b is H.

In some embodiments, R ^3c is H.

In some embodiments, R ^3d is H.

Specific Combinations

One aspect of this invention relates to compounds of formula (Ib) and their pharmaceutically acceptable salts, solvates and hydrates

(lb) _R 3C where R ¹ (as well as Y and Z, which are both associated with R ¹ ), X, W, R ² , R ^3a , R ^3b , R ^3c and R ^3d have the same definitions as described in this document above and below.

One aspect of this invention relates to compounds of formula (Ic) and their pharmaceutically acceptable salts, solvates and hydrates

Where

W is absent or represents -CH ₂ -;

R ¹ is aryl or heteroaryl, each optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkyl, amino, cyano, _C3 - _C7 cycloalkyl, C1-C6 haloalkyl, halogen , hydroxyl, oxo and sulfamoyl; and wherein said C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl are each optionally substituted with one or more substituents selected from: amino, C1-C6 alkoxy, C1-C6 alkyl carboxamide, -NH-C ₃ - C ₇ -cycloalkyl, -NH-C1-C6 alkylene-NH ₂ , -NH-C ₁ -C ₆ -alkylene-O-C ₁ -C ₆ -alkyl, -NH-C ₁ -C ₆ -alkylene-NH-C ₁ - _C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkylamino and heterocyclyl;

R ² is selected from C ₂ -C ₆ alkenyl, C 1 -C 6 alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl and C 1 -C 6 haloalkyl; each optionally substituted with one or more substituents selected from: C1-C6 alkoxy, C1-C6 alkylene hydroxyl, amino, aryl, C ₃ -C ₇ cycloalkyl, cyano, C ₃ -C ₇ halocycloalkyl, hydroxyl and oxo; and R ^3a , R ^3b , R ^3c and R ^3d are each independently H or halogen.

One aspect of this invention relates to compounds of formula (Ic) and their pharmaceutically acceptable salts, solvates and hydrates.

- 24 041181

Where

W is absent or represents -CH ₂ -;

R ¹ is selected from (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,34-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[b]imidazolyl, 1H-indazolyl, 1H-indolyl, 1-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H- pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3b]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro- 2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b][1, 4]oxazinyl, 3Nimidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3 ,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, biphenyl, chromanyl, isoquinolinyl, isoxazolyl, naphthalenyl, phenyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2-a] pyrimidinyl, quinolinyl and thiazolyl; each optionally substituted with one or more substituents selected from: 2-methylpropan-2-yl, amino, bromine, chlorine, cyclopropyl, ethoxy, ethyl, fluorine, hydroxy, isopropoxy, methoxy, methyl, oxo, propane- 2yl, propan-1-yl, sulfamoyl and trifluoromethyl; and wherein said 2-methylpropan-2-yl, cyclopropyl, ethyl, methyl and propan-2-yl are each optionally substituted with one or more substituents selected from 2,2,2-trifluoroethylamino, 2-aminoethylamino, 2- methoxyethylamino, 3aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methoxy, methylamino, morpholino, propylamino, t-butylamino and t-pentylamino;

R ² is selected from 1,1-difluoroethyl, 1-fluoroethyl, 2-methylpropan-2-yl, 3,3,3-trifluoropropyl, 4,4,4trifluorobutyl, azetidin-3-yl, cyclobutyl, cyclopentyl, cyclopropyl, ethyl, fluoromethyl, isobutyl, isopentyl, isopropyl, methyl, oxetan-3-yl, propan-1-yl, sec-butyl and vinyl; each optionally substituted with one or more substituents selected from 2,2-difluorocyclopropyl, amino, cyano, cyclobutyl, cyclohexyl, cyclopropyl, ethoxy, hydroxy, hydroxymethyl, methoxy, oxo and phenyl; and R ^3a , R ³ b , R ^3c and R ^3d are each independently H or F.

One aspect of this invention relates to compounds of formula (Ic) and their pharmaceutically acceptable salts, solvates and hydrates

Where

W is absent or represents -CH2-;

R ¹ is selected from (R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, (S)-1,3-dimethyl -2,3dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl, 1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 1, 4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]oxazin-7-yl, 1,8dimethyl-2,3-dihydro-1 H-pyrido [2,3-b][1,4]oxazin-7-yl, 1-ethyl-2,3-dihydro -1 H-pyrido [2,3-b][1,4]oxazin-7-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-5-methyl-1 H-pyrazol-4-yl, 1-ethyl-6-fluoro-4oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-7-fluoro-4-oxo1,4-dihydroquinolin-3-yl, 1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-8-fluoro- 4-oxo-1,4dihydroquinolin-3-yl, 1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol- 5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo [4,3b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-methyl-2,3dihydro -1 H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 2,3-dihydro[1,4 ]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydrobenzofuran-5- yl, 2-aminothiazol-4-yl, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2-oxo2,3-dihydro-1H-pyrrolo [2 ,3-b]pyridin-5-yl, 3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl, 3-(1-ethyl-1Hpyrazol-4-yl)phenyl, 3-(1H- pyrazol-4-yl)phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1Hpyrazol-4-yl)phenyl, 3-(2-methylpyridin-4- yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl, 3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl, 3-(6-(trifluoromethyl ) pyridin-2-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3-(pyridine -2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3,4dihydro-2H-pyrano[2, 3-b]pyridine- 6-yl, 3,5-dimethylisoxazol-4-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine- 6-yl, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6yl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl , 4-(pyridin-4-yl)phenyl, 4-hydroxy-6-methyl

- 25 041181 quinolin-3-yl, 4-hydroxy-7-methylquinolin-3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4-methoxyquinolin-3-yl, 4 -methyl-2-oxo-1,2-dihydroquinolin-6-yl, 4-methyl-3,4dihydro-2H-benzo[b] [1,4]oxazin-6-yl, 4-methyl-3,4- dihydro-2H-benzo[b][1,4]oxazin-7-yl, 4-methyl3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl, 4- oxo-1,4-dihydroquinolin-3-yl, 5-(1-methyl-1Hpyrazol-4-yl)pyridin-3-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5.6 ,7,8-tetrahydroquinolin-3-yl, 5-bromo-6-chloropyridin-3-yl, 5-bromopyridin-3-yl, 5-oxo-6,7-dihydro-5H-pyrrolo [3,4-b ]pyridin-3yl, 5-phenylthiophen-2-yl, 6-fluoro-4-hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7fluoro-4-hydroxyquinoline -3-yl, 8-fluoro-4-hydroxyquinolin-3-yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, pyridin-2 -yl, pyridin-3-yl, pyrrolo[1,2a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl and quinolin-7-yl;

R ² is selected from: (2,2-difluorocyclopropyl)methyl, 1-(hydroxymethyl)cyclobutyl, 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-amino-2-methyl-1-oxopropane- 2-yl, 1-ethoxy-2methyl-1-oxopropan-2-yl, 1-fluoroethyl, 1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl, 2aminoethyl, 2-hydroxyethyl, 3, 3,3-trifluoropropyl, 3-amino-3-oxopropyl, 3-hydroxycyclobutyl, 3-hydroxypropyl, 3-methoxypropyl, 4,4,4-trifluorobutyl, azetidin-3-yl, benzyl, carboxymethyl, cyanomethyl, cyclobutyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, ethyl, fluoromethyl, isobutyl, isopentyl, isopropyl, methoxymethyl, methyl, oxetan-3-yl, propan-1-yl, sec-butyl and vinyl; and

R ^3a , R ^3b , R ³ c and R ^3d are each independently H or F.

One aspect of this invention relates to compounds of formula (Ie) and their pharmaceutically acceptable salts, solvates and hydrates

(Ie) _R 3c where

R ¹ is aryl or heteroaryl, each optionally substituted with one or more substituents selected from C1- _C6 alkoxy, C1- _C6 alkyl, amino, cyano, _C3 - _C7 cycloalkyl, C1-C6 haloalkyl , halogen, hydroxyl, oxo and sulfamoyl; and wherein said C1-C6 alkyl and _C3 - _C7 cycloalkyl are each optionally substituted with one or more substituents selected from amino, C1-C6 alkoxy, C1- _C6 alkylcarboxamide, -NH- _C3 - _C7 -cycloalkyl, -NH-C1-C6 alkylene-NH ₂ , -NH-C ₁ -C ₆ -alkylene-O-C ₁ -C ₆ -alkyl, -NH-C ₁ -C ₆ -alkylene-NH-C ₁ - C ₆ alkyl, C 1 -C ₆ alkylamino, C 1 -C ₆ haloalkylamino and heterocyclyl;

R ² is selected from C ₂ -C ₆ alkenyl, C 1 -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl and C 1 -C ₆ haloalkyl; each optionally substituted with one or more substituents selected from C1- _C6 alkoxy, C1-C6 alkylene hydroxyl, amino, aryl, _C3 - _C7 cycloalkyl, cyano, _C3 - _C7 halocycloalkyl, hydroxyl and oxo; and R ^3a and R ^3c are each independently H or halogen.

One aspect of this invention relates to compounds of formula (Ie) and their pharmaceutically acceptable salts, solvates and hydrates

(ie) _R 3c where

R ¹ is selected from (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2- dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[b]imidazolyl, 1H-indazolyl, 1H-indolyl, 1-n-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1Hpyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl , 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4- dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b][ 1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5Hpyrrolo [3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, biphenyl, chromanyl, isoquinolinyl, isoxazolyl, naphthalenyl, phenyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2- a] pyrimidinyl, quinolinyl and thiazolyl; each optionally substituted with one or more substituents selected from 2-methylpropan-2-yl, amino, bromine, chlorine, cyclopropyl, ethoxy, ethyl, fluorine, hydroxy, isopropoxy, methoxy, methyl, oxo, propane-2 -yl, propan-1-yl, sulfamoyl and trifluoromethyl; and wherein said 2-methylpropan-2-yl, cyclopropyl, ethyl, methyl and propan-2-yl are each optionally substituted with one or more substituents selected from 2,2,2trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino , 3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methoxy, methylamino, morpholino, propylamino, t-butylamino and t-pentylamino;

- 26 041181

R ² is selected from 1,1-difluoroethyl, 1-fluoroethyl, 2-methylpropan-2-yl, 3,3,3-trifluoropropyl, 4,4,4trifluorobutyl, azetidin-3-yl, cyclobutyl, cyclopentyl, cyclopropyl, ethyl, fluoromethyl, isobutyl, isopentyl, isopropyl, methyl, oxetan-3-yl, propan-1-yl, sec-butyl and vinyl; each optionally substituted with one or more substituents selected from 2,2-difluorocyclopropyl, amino, cyano, cyclobutyl, cyclohexyl, cyclopropyl, ethoxy, hydroxy, hydroxymethyl, methoxy, oxo and phenyl; and R ^3a and R ^3c are each independently H or F.

One aspect of this invention relates to compounds of formula (Ie) and their pharmaceutically acceptable salts, solvates and hydrates

(le) _R 3c where

R ¹ is selected from (R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, (S)-1,3-dimethyl -2,3dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl, 1,3,3-trimethyl-2,3-dihydro-1H-nirido[2,3-b][1,4]oxazin-6-yl, 1, 4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]oxazin-7-yl, 1,8dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-ethyl-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-5-methyl-1H-pyrazole -4-yl, 1-ethyl-6-fluoro-4oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl -7-fluoro-4-oxo1,4-dihydroquinolin-3-yl, 1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-8-fluoro-4-oxo -1,4dihydroquinolin-3-yl, 1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl , 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-nirazolo[4,3b]pyridium n-6-yl, 1H-n-pyrrolo[2,3-b]pyridin-3-yl, 1H-n-pyrrolo[3,2-b]pyridin-6-yl, 1-methyl-2,3dihydro-1 H-pyrido [2,3-b][1,4]oxazin-7-yl, 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 2,3-dihydro[1,4]dioxino[2, 3-b]pyridin-7-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydrobenzofuran-5-yl, 2-aminothiazole -4-yl, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2-oxo2,3-dihydro-1H-pyrrolo[2,3-b]pyridine -5-yl, 3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl, 3-(1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl , 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1Hpyrazol-4-yl)phenyl, 3-(2-methylpyridin-4-yl)phenyl, 3-( 3-fluoropyridin-2-yl)phenyl, 3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl, 3-(6-(trifluoromethyl)pyridin-2-yl) phenyl, 3-(6aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3,4dihydro-2H-pyrano[2,3-b]pyridin-6 -yl, 3,5-dimethyl isoxazol-4-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6yl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4- yl)phenyl, 4-hydroxy-6methylquinolin-3-yl, 4-hydroxy-7-methylquinolin-3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4-methoxyquinolin- 3-yl, 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl, 4-methyl-3,4dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methyl -3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 4-methyl-3,4dihydro-2H-pyrido[3,2-b][1,4]oxazin-7 -yl, 4-oxo-1,4-dihydroquinolin-3 -yl, 5-(1-methyl-1 H-pyrazol4-yl)pyridin-3-yl, 5-(4-(aminomethyl)phenyl)pyridin-3 -yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-bromo6-chloropyridin-3-yl, 5-bromopyridin-3-yl, 5-oxo-6,7-dihydro-5H-pyrrolo[3 ,4-b]n-pyridin-3-yl, 5phenylthiophen-2-yl, 6-fluoro-4-hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7- fluoro-4hydroxyquinolin-3-yl, 8-fluoro-4-hydroxyquinolin-3-yl, benzofuran-2-yl, benzofuran -5-yl, chroman6-yl, chroman-7-yl, isoquinolin-5-yl, pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3 -yl, quinolin-6-yl and quinolin-7-yl;

R ² is selected from (2,2-difluorocyclopropyl)methyl, 1-(hydroxymethyl)cyclobutyl, 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-amino-2-methyl-1-oxopropan-2 -yl, 1-ethoxy-2methyl-1-oxopropan-2-yl, 1-fluoroethyl, 1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl, 2-aminoethyl, 2-hydroxyethyl, 3.3 ,3-trifluoropropyl, 3-amino-3-oxopropyl, 3-hydroxycyclobutyl, 3hydroxypropyl, 3-methoxypropyl, 4,4,4-trifluorobutyl, azetidin-3-yl, benzyl, carboxymethyl, cyanomethyl, cyclobutyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentyl , cyclopropyl, cyclopropylmethyl, ethyl, fluoromethyl, isobutyl, isopentyl, isopropyl, methoxymethyl, methyl, oxetan-3-yl, propan-1-yl, sec-butyl and vinyl; and

R ^3a and R ^3c are each independently H or F.

One aspect of this invention relates to compounds of formula (Ig) and their pharmaceutically acceptable salts, solvates and hydrates

(lg) R ^3c where

- 27 041181

Ar ¹ and Ar ² are independently 1H-pyrazolyl, phenyl, pyridinyl, pyrimidinyl and thiophenyl, each optionally substituted with one or more substituents selected from: Ci-C ₆ alkoxy, Ci-C ₆ alkyl, amino, C ₃ -C 7 cycloalkyl, Ci-C ₆ haloalkyl, halogen and sulfamoyl; and wherein said C1-C6 alkyl and _C3 -C7 cycloalkyl are each optionally substituted with one or more substituents selected from: amino, C1-C6 alkylcarboxamide, -NH- _C3 - _C7 cycloalkyl, -NH- _C1 -C ₆ -alkylene-NH ₂ , -NH-C ₁ -C ₆ -alkylene-O-C ₁ -C ₆ -alkyl, C1-C6 alkylamino, C1-C6 haloalkylamino and heterocyclyl;

R ² is selected from C1-C6 alkyl, C ₃ -C ₇ cycloalkyl and C1-C6 haloalkyl;

each optionally substituted with one or more substituents selected from C ₁ C ₆ alkoxy, C ₁ -C ₆ alkylene hydroxyl, amino, hydroxyl and oxo; and R ^3a , R ^3b , R ^3c and R ^3d are each independently H or halogen.

One aspect of this invention relates to compounds of formula (Ig) and their pharmaceutically acceptable salts, solvates and hydrates where

Ar ¹ and Ar ² together form a group selected from (1H-pyrazolyl)phenyl, (1Hpyrazolyl)pyridinyl, (phenyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, biphenyl and phenylthiophenyl, each optionally substituted with one or more substituents selected from 2-methylpropan-2-yl, amino, cyclopropyl, ethoxy, ethyl, fluorine, isopropoxy, methoxy, methyl, n-propyl, propan-2-yl, sulfamoyl and trifluoromethyl; and wherein said 2methylpropan-2-yl, cyclopropyl, ethyl, methyl and propan-2-yl are each optionally substituted with 2,2,2trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino, 3-aminopropylamino, acetamido, amino, azetidine 1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, isopropylamino, methylamino, morpholino, propylamino, t-butylamino and t-pentylamino;

R ² is selected from 1,1-difluoroethyl, 2-methylpropan-2-yl, cyclopropyl, ethyl, isopropyl and methyl; each optionally substituted with one or more substituents selected from amino, hydroxy, hydroxymethyl, methoxy and oxo; and R ^3a , R ^3b , R ^3c and R ^3d are each H.

One aspect of this invention relates to compounds of formula (Ig) and their pharmaceutically acceptable salts, solvates and hydrates

Ar ¹ —Ar ² —S—N where

Ar ¹ and Ar ² together form a group selected from 3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-2yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4 -yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 4-(pyridin2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-( 1H-pyrazol-4-yl)pyridin-3-yl, 5(phenyl)pyridin-3-yl, 5-phenylthiophen-2-yl, biphenyl-3-yl and biphenyl-4-yl, each optionally substituted with one more substituent selected from (2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl, (2-methoxyethylamino)methyl, (3-aminopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl, 1-amino-2-methylpropan-2-yl, 1 -aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl, amino, aminomethyl, azetidin-1-ylmethyl, cyclopropyl, ethoxy, ethyl, fluorine, isopropoxy, methoxy, methyl, morpholinomethyl, propyl, su famoyl and trifluoromethyl;

R ² is selected from 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-hydroxy-2methylpropan-2-yl, 2-amino-2-oxoethyl, 2-hydroxyethyl, cyclopropyl, ethyl, isopropyl, methoxymethyl and methyl; and

R ^3a , R ^3b , R ^3c and R ^3d are each H.

One aspect of this invention relates to compounds of formula (Ig) and their pharmaceutically acceptable salts, solvates and hydrates where

Ar ¹ and Ar ² together form a group selected from 3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl, 3-(1ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol- 4-yl)phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1propyl-1H-pyrazol-4-yl)phenyl, 3-(2-methylpyridin-4-yl)phenyl , 3-(3-Fluoropyridin-2-yl)phenyl, 3-(4

- 28 041181 methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl, 3-(6-(trifluoromethyl)pyridin-2-yl)phenyl, 3-(6-aminopyridin-3-yl) )phenyl, 3-(6-fluoropyridin-2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 4((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-aminoethylamino) methyl)biphenyl-3-yl, 4'-((2methoxyethylamino)methyl)biphenyl-3-yl, 4'-((3-aminopropylamino)methyl)biphenyl-3-yl, 4'-((butylamino)methyl)biphenyl -3-yl, 4'-((cyclobutylamino)methyl)biphenyl-3-yl, 4'-((ethylamino)methyl)biphenyl-3yl, 4'-((isobutylamino)methyl)biphenyl-3-yl, 4' -((isopropylamino)methyl)biphenyl-3-yl, 4'-((methylamino)methyl)biphenyl-3-yl, 4'-((propylamino)methyl)biphenyl-3-yl, 4'-((tert- butylamino)methyl)biphenyl-3-yl, 4'-((tert-pentylamino)methyl)biphenyl-3-yl, 4'-(1-amino-2-methylpropan-2-yl)-4ethoxybiphenyl-3-yl, 4'-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl, 4'-(1-aminocyclopropyl)-2methylbiphenyl-3-yl, 4'-(1-a minocyclopropyl)-4-ethoxybiphenyl-3 -yl, 4'-(1-aminocyclopropyl)-6fluorobiphenyl-3-yl, 4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl )biphenyl-3-yl, 4'-(2-acetamidoethyl)-4-ethoxy-biphenyl-3-yl, 4'-(2-acetamidoethyl)-biphenyl-3-yl, 4'-(2-aminoethyl)- 4-ethoxybiphenyl-3-yl, 4'-(2-aminoethyl)-6-methoxybiphenyl-3-yl, 4'-(2-aminoethyl)biphenyl-3-yl, 4'-(2-aminopropan-2-yl )-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-2-methoxybiphenyl-3-yl, 4'-(aminomethyl)-2-methylbiphenyl-3-yl, 4'-(aminomethyl)-3-fluorobiphenyl -3-yl, 4'(aminomethyl)-4-ethoxy-3'-fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)4-fluorobiphenyl-3 -yl, 4'-(aminomethyl)-4-isopropoxybiphenyl-3-yl, 4'-(aminomethyl)-5-methoxybiphenyl-3-yl, 4'-(aminomethyl)-6-ethoxybiphenyl-3-yl, 4' -(aminomethyl)-6-fluorobiphenyl-3-yl, 4'(aminomethyl)-6-methoxybiphenyl-3-yl, 4'-(aminomethyl)biphenyl-3-yl, 4'-(aminomethyl)biphenyl-4-yl , 4'-(azetidin-1-ylmethyl)biphenyl-3-yl, 4'-(morpholinomethyl)biphenyl-3yl, 4-(pyridin-2- yl)phenyl, 4(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4'-(sulfamoyl)biphenyl-3-yl, 4-ethoxy-4'((isopropylamino)methyl)biphenyl -3-yl, 4'-methylbiphenyl-3 -yl, 5-(1-methyl-1H-pyrazol-4-yl)pyridin3-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl and 5-phenylthiophen-2-yl;

R ² is selected from 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-hydroxy-2methylpropan-2-yl, 2-amino-2-oxoethyl, 2-hydroxyethyl, cyclopropyl, ethyl, isopropyl, methoxy methyl and methyl; and

R ^3a , R ^3b , R ^3c and R ^3d are each H.

One aspect of this invention relates to compounds of formula (Ii) and their pharmaceutically acceptable salts, solvates and hydrates

Where

R ² is selected from C1-C6 alkyl, C ₃ -C ₇ cycloalkyl and C _r C ₆ haloalkyl; each optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkylene hydroxyl and hydroxyl;

R ^3a , R ^3b , R ^3c and R ^3d are each independently H or halogen;

R ⁴ is H or C1-C6 alkyl; and

R ^5a , R ^5b , R ^5c and R ^5d are independently H, C1-C6 alkyl and halo.

One aspect of this invention relates to compounds of formula (Ii) and their pharmaceutically acceptable salts, solvates and hydrates

Where

R ² is selected from 1,1-difluoroethyl, 2-methylpropan-2-yl, cyclopropyl, ethyl, 1-fluoroethyl, isopropyl and methyl; each optionally substituted with one or more substituents selected from hydroxy, hydroxymethyl and methoxy;

R ^3a , R ^3b , R ^3c and R ^3d each represents H;

R ⁴ is selected from H, methyl and ethyl and

R ^5a , R ^5b , R ^5c and R ^5d are independently H, methyl and fluorine.

One aspect of this invention relates to compounds of formula (Ii) and their pharmaceutically acceptable salts, solvates and hydrates

Where

R ² is selected from 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-fluoroethyl, 1-hydroxy-2-methylpropan-2-yl, cyclopropyl, isopropyl, methoxymethyl and methyl;

R ^3a , R ^3b , R ^3c and R ^3d each represents H;

R ⁴ is selected from: H, methyl and ethyl;

R5 ^a , R5 ^b and R5 ^c are independently H, methyl and fluoro; and

^R5d is H.

Some embodiments of this invention include any combination of one or more compounds and their pharmaceutically acceptable salts, solvates and hydrates selected from the following group, shown in table. A.

Table A

Chemical Name

88 .OH n ^ ⁿ o G l \=/ χ XT Ϊ T ° o '- ^z o-^ CHU (5)-1-(3-(2- hydroxyethylsulfonyl)phenoxy) -3-( (SCH-8- (quinolin-3ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3- ylamino)propan2-ol 123 O^in ₂ n ^ ⁿ _{o h} J u\=/ u XT Г Ϊ ° 2-(3-((5)-2hydroxy-3- ( (Yu -8- (quinoline-3- ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3- ylamino) propox i) phenylsulfonyl l)acetamide 136 Ο=ω=Ο Ζ ° / ΖΙ \ABOUT / I o 0. .OT /—O (5)-1-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)3-((R)-8- (quinolin-3ylsulfonyl) - 1 - oxa-8- azaspiro[4.5]de can-3- ylamino)propan2-ol

- 30 041181

154 A ⁿ L 0 Η 9 ^H °H^l)SG tt ° (5)-1-(3- (cyclopropylsulfonyl)phenoxy) -3-(((^)-8-(1methyl-2,3dihydro-ΙΗpyrido [2,3 - b][1,4]oxazin7-ylsulfonyl)1-oxa-8azaspiro[4.5]decan-3- ylamino)propan2-ol 161 /. jQT^ Οι ο^γ ο=ω=Ο ζ ° / ζτ ^.Ο ο 0. before' Ο' \__ Ή 41 Ο τ (5)-1-( (A-8- (4 ' - (aminomethyl)-4ethoxybiphenyl3-ylsulfonyl)1-oxa-8- azaspiro[4.5]decan-3-ylamino)3-(3-(1,1difluoro-2- hydroxyethylsulfonyl)phenoxy)propan-2-ol 163 νη ₂ <0Ч it V. Ο Η ? ^Η 0χ <Нl Χ0 ΥΎ ° 0 '' Q,- ¹ CD °Λ (5)-1-( (5)-8- (4 ' - (aminomethyl)-4ethoxybiphenyl3-ylsulfonyl)1-oxa-8- azaspiro[4.5]de can-3-ylamino)-

- 31 041181

3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol 169 nh ₂ Q ι ^Η 0 H ? ^H <>< W“® vXT TT ° F (S)-1-((R)-8- (4 ' - (aminomethyl)-4fluorobiphenyl-3ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3-ylamino)3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol 199 △^NH ₂ O? ⁿ _ H ° ^H O _x <^ ° \ Y )?L λΎ rT 0 '-' O '-/ OJ %% (S)-1-((R)-8- (4'- (1- aminocyclopropyl) -6- methoxybiphenyl3-ylsulfonyl)1-oxa-8- azaspiro[4.5]de can-3-ylamino)3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol

- 32 041181

210 ψ " Ο=ω=ο - ΖΙ /Ό / I ο 0. before' Ο' \__ Ή -Π Ο (S)-1-((S)-8- ( 4 ’ - (2aminoethyl) biphenyl-3- ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3-ylamino)3- (3-(1,1- difluoro-2- hydroxyethylsulfonyl)phenoxy)propan-2-ol 211 ^ΝΗ ₂ / ^- ) he “V ο _ Η ? ^Η _η 0X1 cgch Xj ΥΥο (S)-1-((S)-8- (4'- (2aminoethyl) biphenyl-3- ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3-ylamino)3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol 217 △g-YNz cY he Υ o n 9 ^H 0χ] χΎ ΥΎ ъ O '—' CX (S)-1-((R)-8- (4'- (1- aminocyclopropyl l)-6- fluorobiphenyl-3ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3-ylamino)-

- 33 041181

3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol 220 nh ₂ < F O ? ⁿ ο Η ? ^Η q^ won Xj ΤΥ'° °Λ (3)-1-((3)-8- (4 ' - (aminomethyl)-4ethoxy-3'- fluorobiphenyl-3ylsulfonyl) - 1 - oxa-8- azaspiro[4.5]de can-3-ylamino)3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol 225 χχ$ ¢/ ο=ω=ο ί ΖΙ Υό /το X /—Q> °Χ (3)-1-((3)-8- (4'- (1- aminocyclopropyl) -6- methoxybiphenyl3-ylsulfonyl)1-oxa-8- azaspiro[4.5]de can-3-ylamino)3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol

- 34 041181

227 <Lo zW 0 ABOUT T / ABOUT/ ΙΖ δ ο=ω=ο £ ί 7 Τ (S)-1-((S)-8- (4 ' - (aminomethyl)-6methoxybiphenyl3-ylsulfonyl)1-oxa-8- azaspiro[4.5]de can-3-ylamino)3- (3- (cyclopropylsulfonyl) phenoxy) propan-2-ol 229 νη ₂ ο 0 Η 9 ^Η CL WV Π GT° )—' o '—' ο-^ —o (S)-1-((S)-8- (4 ' - (aminomethyl)-5methoxybiphenyl3-ylsulfonyl)1-oxa-8- azaspiro[4.5]de can-3-ylamino)3- (3- (cyclopropylsulfonyl) phenoxy) propan-2-ol 230 XO WITH) Ο'^γ J ο=ω=ο 7 ΖΙ U'U / I o 0. ,W Ί\ (S)-1-((S)-8- (4 ' - (aminomethyl)-4ethoxybiphenyl3-ylsulfonyl)1-oxa-8- azaspiro[4.5]de can-3-ylamino)3- (3- (methoxymethylsulfonyl)phenoxy

- 35 041181

)propan-2-ol 232 °^t J Ο=ω=Ο zi /yu / t o 0. o' __ (5)-1-( (5)-8- (4 ' - (aminomethyl)-4ethoxybiphenyl- 3-ylsulfonyl)- 1-oxa-8- azaspiro[4.5]de can-3-ylamino)3- (3- (isopropylsulfonyl)phenoxy)propan-2-ol 234 _ He ? ⁿ CHA / ⁿ⁼ vj^ \ X j ι Ύ ^{0 0} ο (25)-1-(3-(1fluoroethylsulfonyl)phenoxy)-3- (Sh-8- (quinoline-6- ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3- ylamino)propan2-ol 240 ΗΝ - Χα OH Μ. ο Η 9 ^Η °S < VJ^ ^-Ν \ XJ Τ ϊ'° ο '- ^ζ Ο^ %% (5)-1-( (5)-8(4'-((tert-butylamino) methyl l) biphenyl-Zyl sulfonyl) -1-

- 36 041181

oxa-8azaspiro[4.5]de can-3-ylamino)3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol 241 HN^X OH o H ? ^H vJ^s \ Xj IT° (5)-1-(3-(1(hydroxymethyl)cyclopropylsulfonyl)phenoxy)3-( (5) —8— (4'— ((tertpentylamino) methyl) biphenyl-Zylsulfonyl) -1oxa-8azaspiro[4.5]de can-3- ylamino)propan2-ol 243 ο=ω=ο ZI ^τ about 0. °'Ή (5)-1-( (5)-8- (4’—(azetidine- 1- ylmethyl)biphenyl -3- ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3-ylamino)3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)p

- 37 041181

ropan-2-ol 244 HN^ Ha he Η. o H 9 ^H <χ| vj^'VX j T Ϊ ⁰ o o-^ (5)-1-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)3-( (5) —8— (4'— ((propylamino)methyl)biphenyl-Zylsulfonyl) -1oxa-8- azaspiro[4.5]de can-3- ylamino)propan2-ol 245 HN^ Oh? ^H O H 9 ^H o.Vl UV)Cr n° o '- ^/ oJ (5)-1-( (5)-8(4 '- ((butylamino)methyl)biphenyl-Zylsulfonyl)-1oxa-8azaspiro[4.5]decan-3-ylamino)3-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)propan-2-ol

- 38 041181

247 0" Ο=ω=ο 2 ζτο 0. (S) -1- (3-(1- (hydroxymethyl) cyclopropylsulfonyl) phenoxy)- 3-((S)-8-(4'- ( (2- methoxyethylamine o)methyl)biphenyl -3- ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3- ylamino)propan2-ol 296 -Λ Η ? ⁿ A H-h'Oo θ'° \=/ Q 1-ethyl-3-((5)- 3-((R)-2hydroxy-3-(3(methylsulfonyl)phenoxy)propyl amino)-1-oxa8- azaspiro[4.5]de can-8- ylsulfonyl)quinolin-4(1Н)-one 297 “Λ „ Η ^QH CH A Gu* CISfay V ° ^= ⁷ 0 3-((R)-3-((S)- 3-(3- (cyclopropylsulfonyl)phenoxy) -2- hydroxypropyl mino)-1-oxa-8azaspiro[4.5]de can-8-

- 39 041181

ylsulfonyl)-1- ethylquinoline- 4 (1Н) -one 300 OH n^ ⁿ .___. O H - \\ ><ν' \/ν ^Ν4 - ^Ζ ^ ^/Ο ν ^/ νθ'/“V/<\ XT TI ⁰ 0 'O' ¹ (5)-1-(3-(1- (hydroxymethyl) cyclopropylsulfonyl)phenoxy)3-(Sh-8(naphthalene-2- ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3- ylamino)propan2-ol 309 ο=ω=οz ZI )YU O 0.. b (S)-1-((N)-8(1Hpyrrolo[3,2-b]pyridin-6ylsulfonyl)-1oxa-8- azaspiro[4.5]de can-3-ylamino)3- (3- (cyclopropylsulfonyl) phenoxy) propan-2-ol 310 "Λ Η θ ^Η °4 HJ-Λ Xj ΥΎ° \ o ^x —'θ^ ⁴⁼⁷ o 1-ethyl-3-((R)3-((5)-2hydroxy-3-(3(methylsulfonyl)phenoxy)propyl amino)-1-oxa8-

- 40 041181

azaspiro[4.5]de can-8- ylsulfonyl)quinolin-4(1Н)-one 320 ο=ω=ο I ζ ° / ΖΤ Ο'UP Ο-\ (S)-1-((R)-8(1Hpyrrolo[3,2-L]pyridin-6ylsulfonyl)-1oxa-8azaspiro[4.5]decan-3-ylamino)3- (3- (methylsulfonyl)phenoxy)propan-2-ol 321 ο=ω=ο ζ ° / ζι ο Ο'__ (S)-1-((R)-8(1Hpyrrolo[3,2-L]pyridin-6ylsulfonyl)-1oxa-8azaspiro[4.5]decan-3-ylamino)3- (3- (isopropylsulfonyl)phenoxy)propan-2-ol 322 \ Ο I / ο( ΙΖ 4.0 ^χ ζ^ ο=ω=ο 3 1-ethyl-8-fluoro- 3-((R)-3-((S)2-hydroxy-3(3- (methylsulfonyl)phenoxy)propyl amino)-1-oxa-

- 41 041181

8- azaspiro[4.5]de can-8- ylsulfonyl)quinolin-4(1Н)-one 326 „(Ό% o t / O / IZ δ Ο=ω=ο υ ^τ 3-((R)-3-((S)- 3-(3- (cyclopropylsulfonyl)phenoxy) -2- hydroxypropyl mino)-1-oxa-8azaspiro[4.5]de can-8- ylsulfonyl)quinolin-4(1Н)-one 327 ΎΊ Η] jo Ο=ω=ο ΐ ΖΞΕ ) Ο / ΞΕ Ο Al' °'V 3-((R)-3-((S)- 3-(3- (cyclopropylsulfonyl)phenoxy) -2- hydroxypropyl mino)-1-oxa-8azaspiro[4.5]de can-8- ylsulfonyl)-8methylquinoline-4- ol 329 nJY Η ? ⁿ chL ^F A=( Ш χΥ 3|Ύ 'b 3-((R)-3-((S)- 3-(3- (cyclopropylsulfonyl)phenoxy) hydroxypropyl mino)-1-oxa-8- azaspiro[4.5]de can-8- ylsulfonyl)-7fluoroquinoline-4- ol 331 Ο=ω=Ο 3 ZI )Yu / =E ABOUT R. ABOUT __ 1-ethyl-8-fluoro3-( (Sch-3-((S)2-hydroxy-3-(3- (isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8- azaspiro[4.5]de can-8- ylsulfonyl)quinolin-4(1Н)-one

Some embodiments of this invention include any combination of one or more compounds and their pharmaceutically acceptable salts, solvates and hydrates selected from the following group, with the compound number in bold type immediately preceding the chemical name used in other parts of this disclosure :

Compound 5: (2S)-1 -(3-(2-hydroxyethylsulfonyl)phenoxy)-3 -(8-(naphthalen-2-ylsulfonyl)-1 oxa-8-azaspiro[4.5]decan-3-ylamino)propan- 2-ol;

Compound 88: (S)-1-(3-(2-Hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-ylamino )propan-2-ol;

Compound 123: 2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino) propoxy)phenylsulfonyl)acetamide;

Compound 136: (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan- 3-ylamino)propan-2-ol;

Compound 154: (S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H- 42 041181 pyrido[2,3-b] [1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;

Compound 161: (S)-1-((R)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;

Compound 163: (S)-1 -((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 169: (S)-1-((R)-8-(4'-(aminomethyl)-4-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 199: (S)-1 -((R)-8-(4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 210: (S)-1-((S)-8-(4'-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3 -(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;

Compound 211: (S)-1-((S)-8-(4'-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3 -(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 217: (S)-1 -((R)-8-(4'-(1-aminocyclopropyl)-6-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)- 3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 220: (S)-1 -((S)-8-(4'-(aminomethyl)-4-ethoxy-3'-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8 azaspiro[4.5]decan-3 -ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 225: (S)-1 -((S)-8-(4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 227: (S)-1 -((S)-8-(4'-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 229: (S)-1-((S)-8-(4'-(aminomethyl)-5-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3- (3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 230: (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(methoxymethylsulfonyl)phenoxy)propan-2-ol;

Compound 232: (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol;

Compound 234: (2S)-1-(3-(1-fluoroethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-ylamino )propan-2-ol;

Compound 240: (S)-1-((S)-8-(4'-((tert-butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino )-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 241: (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4'-((tert-pentylamino)methyl)biphenyl-3-ylsulfonyl)-1 -oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;

Compound 243: (S)-1 -((S)-8-(4'-(αzetudine-1 -ylmethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino) -3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 244: (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4'-((propylamino)methyl)biphenyl-3-ylsulfonyl)-1 -oxa-8-azaspiro [4.5]decan-3-ylamino)propan-2-ol;

Compound 245: (S)-1 -((S)-8-(4'-((butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 247: (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4'-((2methoxyethylamino)methyl)biphenyl-3-ylsulfonyl)-1 -oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;

Compound 296: 1 -ethyl-3-((S)-3-((R)-2-hydroxy-3 -(3 -(methylsulfonyl)phenoxy)propylamino)-1 oxa-8-azaspiro [4.5] decan-8 -ylsulfonyl)quinoline-4(1 H)-one;

Compound 297: 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1- ethylquinolin-4(1H)-one;

Compound 300: (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(naphthalen2-ylsulfonyl)-1-oxa-8-azaspiro [4.5] decan- 3-ylamino)propan-2-ol;

Compound 309: (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino) -3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;

Compound 310: 1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1oxa-8-azaspiro [4.5]decan-8- ylsulfonyl)quinoline-4(1 H)-one;

Compound 320: (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino) -3-(3-(methylsulfonyl)phenoxy)propan-2-ol;

Compound 321: (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino) -3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol;

Compound 322: 1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[ 4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;

Compound 326: 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinoline-4 (1H)-he;

Compound 327: 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8- methylquinolin-4-ol;

Compound 329: 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1 - 43 041181 oxa-8-azaspiro[4.5]decan-8-ylsulfonyl )-7-fluoroquinolin-4-ol and

Compound 331: 1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[ 4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one.

Some embodiments of this invention include any combination of one or more compounds and their pharmaceutically acceptable salts, solvates and hydrates selected from the following group, with the compound number in bold type immediately preceding the chemical name used in other parts of this disclosure :

In addition, the chemical classes of the invention and individual compounds, such as the compounds indicated in the above list and in Table A, including diastereoisomers and their enantiomers, cover all their pharmaceutically acceptable salts, solvates, hydrates and N-oxides.

Compounds of formula (Ia) according to the invention can be obtained according to appropriate published procedures in the literature, which are used by a person skilled in the art. Typical reagents and procedures for carrying out these reactions are given below in the working examples. Protection and deprotection can be performed using techniques well known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3rd edition, 1999 [Wiley]).

It is understood that this invention embraces each isomer, each diastereoisomer, each enantiomer and mixtures thereof of each compound and the general formulas are disclosed herein as if each were disclosed separately with a specific stereochemical designation for each chiral carbon atom. Individual isomers and enantiomers can be obtained by selective synthesis, for example, enantiomeric selective synthesis; or they may be prepared using separation techniques that are well known to those skilled in the art, such as HPLC (high performance liquid chromatography) (including normal phase, reversed phase, and chiral), recrystallization (i.e., e., diastereomeric mixtures) and similar methods.

Disorders and treatments

The compounds disclosed herein are useful in the treatment or prevention of a number of diseases, disorders, conditions and/or symptoms (collectively referred to herein as disorders). One of ordinary skill in the art will appreciate that when a disorder or a method of treatment or prevention is disclosed herein, such disclosure includes a secondary medical use (e.g., a compound for use in the treatment of a disorder, a use of a compound for the treatment of a disorder, and use of a compound in the manufacture of a medicament). agents for the treatment of the disorder).

In some embodiments, the compounds disclosed herein are used to treat or prevent a disorder. In some embodiments, the compounds disclosed herein are used to treat or prevent a subtype of a disorder. In some embodiments, the compounds disclosed herein are used to treat or prevent a symptom of a disorder.

Provided herein are methods for treating or preventing a beta-3 adrenergic receptor mediated disorder. In some embodiments, the compounds disclosed herein are used for the prevention of a beta-3 adrenergic receptor-mediated disorder. In some embodiments, the compounds disclosed herein are used to treat or prevent a beta-3 adrenergic receptor mediated disorder.

One aspect of the invention relates to methods for treating or preventing a beta-3 adrenergic receptor mediated disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention.

One aspect of the invention relates to methods for treating or preventing heart failure in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention.

One aspect of this invention relates to methods of treating a patient suffering from arterial hypotension or a patient who is on the verge of arterial hypotension, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention; pharmaceutical product according to the invention or pharmaceutical composition according to the invention. One aspect of the present invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a beta-3 adrenergic receptor mediated disorder in a patient.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of heart failure in

- 44 041181 patients.

One aspect of the present invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient suffering from arterial hypotension or a patient on the verge of hypotension.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient with normal blood pressure.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient suffering from arterial hypertension.

One aspect of this invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a patient following a myocardial infarction.

One aspect of this invention relates to the compounds of the invention; a pharmaceutical product of the invention or a pharmaceutical composition of the invention for use in a method of treating a human or animal body through therapy.

One aspect of this invention relates to the compounds of the invention; pharmaceutical products of the invention or pharmaceutical compositions of the invention for use in a method for treating or preventing a beta-3 adrenergic receptor mediated disorder in a patient.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is selected from the list consisting of: heart failure; decreased performance of the heart in heart failure; mortality, re-infarction and / or hospitalization due to heart failure; acute heart failure; acute decompensated heart failure; chronic heart failure; severe chronic heart failure; organ damage associated with heart failure (eg, kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; mortality from cardiovascular diseases due to myocardial infarction; mortality from cardiovascular disease in patients with left ventricular failure or left ventricular dysfunction; condition after myocardial infarction; left ventricular failure; left ventricular dysfunction; heart failure class II using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; heart failure class IV using the New York Heart Association (NYHA) classification system; LVEF <40% on radionuclide ventriculography and LVEF<35% on echocardiography or ventricular contrast angiography.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is a decrease in cardiac performance in heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is mortality, re-infarction, and/or hospitalization due to heart failure.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is acute heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is acute decompensated heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is chronic heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is severe chronic heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is an organ injury associated with heart failure (eg, kidney injury or kidney failure, heart valve problems, heart rhythm problems, and/or liver damage).

In some embodiments, the beta-3 adrenergic receptor mediated disorder is heart failure due to left ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is heart failure with a normal ejection fraction.

- 45 041181

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is cardiovascular death due to myocardial infarction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is accompanied by myocardial infarction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is left ventricular failure.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is left ventricular dysfunction.

Doctors can classify a patient's heart failure based on the severity of its symptoms. The table below describes the most commonly used classification system, the New York Heart Association (NYHA) functional classification. It places patients in one of four categories based on how limited they are in physical activity.

Class Patient symptoms I No restriction of physical activity. Ordinary physical activity does not cause excessive fatigue, heart palpitations, shortness of breath (difficulty breathing). II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity leads to fatigue, rapid heart rate, shortness of breath (difficulty breathing). III There was a limitation of physical activity. Comfortable at rest. Less than normal activity causes fatigue, heart palpitations, or shortness of breath. IV It is impossible to continue physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, the discomfort increases.

Accordingly, in some embodiments, the beta-3 adrenergic receptor-mediated disorder is class II heart failure using the New York Heart Association (NYHA) classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is class III heart failure using the New York Heart Association (NYHA) classification system.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is class IV heart failure using the New York Heart Association (NYHA) classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder is an LVEF <40% on radionuclide ventriculography.

In some embodiments, the beta-3 adrenergic receptor mediated disorder is <35% LVEF on echocardiography or ventricular contrast angiography.

Polymorphs and pseudopolymorphs

Polymorphism is the ability of a substance to exist in the form of two or more crystalline phases that have different arrangements and/or conformations of molecules in the crystal lattice. Polymorphs exhibit the same properties in the liquid or gaseous state, but they behave differently in the solid state.

In addition to single component polymorphs, drugs may also exist as salts and other multicomponent crystalline phases. For example, solvates and hydrates may contain the main API (active pharmacological ingredient) and solvent molecules or water molecules, respectively, as guest. Similarly, when the guest compound is a solid at room temperature, the resulting form is often referred to as a co-crystal. Salts, solvates, hydrates and co-crystals can also exhibit polymorphism. Crystalline phases that share the same major API, but differ from each other with respect to guest compounds, may be referred to as pseudopolymorphs of each other.

Solvates contain crystallization solvent molecules in a specific crystal lattice. Solvates in which the crystallization solvent is water are called hydrates. Because water is a constituent of the atmosphere, drug hydrates can form quite easily.

As an example, Stahly published a polymorphic screen of 245 compounds consisting of a wide variety of structural types, which showed that about 90% of them had multiple solid forms. Overall, approximately half of the compounds were polymorphic, often having one to three forms. About one third of the compounds formed hydrates and about one third formed solvates. Data from co-crystal screens of 64 compounds showed that 60% formed co-crystals other than hydrates or solvates. (G. P. Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026).

isotopes

This disclosure includes all isotopes of atoms found in the compounds provided herein. Isotopes include atoms having the same atomic number but different mass numbers. It is understood that some features of this(s) invention(s) include any combination of one or more atoms in the compounds provided herein, which are replaced by an atom having the same atomic number but a different mass number. One such example is the substitution of an atom that is the most naturally occurring isotope, such as 1H or ^12C found in one of the compounds provided herein, with another atom that is not the most naturally occurring isotope, such as ^2H or ³ H (replacing ¹ H), or ¹¹ C, ¹³ C or ¹⁴ C (replacing ¹² C). A compound in which such a substitution takes place is generally referred to as isotopically labeled. Isotopic labeling of the present compounds can be accomplished using any of a variety of different synthetic methods known to those skilled in the art and are credited with having an easy understanding of the synthetic methods and available reagents needed to perform such isotopic labeling. As a general example, but not limitation, isotopes of hydrogen include ² H (deuterium) and ³ H (tritium). The isotopes of carbon include ^P C, ¹³ C and ¹⁴ C. The isotopes of nitrogen include ¹³ N and ¹⁵ N. The isotopes of oxygen include ¹⁵ O, ¹⁷ O and ¹⁸ O. The isotope of fluorine includes ¹⁸ F. The isotope of sulfur includes includes ³⁵ S. The isotope of chlorine includes ³⁶ Cl. Isotopes of bromine include ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. The isotopes of iodine include ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ¹³¹ I. Compositions are also provided, for example, compositions obtained during synthesis, preformulation, and the like, and pharmaceutical compositions, for example, prepared for use in a mammal. for the treatment of one or more of the disorders described herein, containing one or more of these compounds, in which the natural distribution of isotopes in the composition is disturbed. Also provided herein are compositions and pharmaceutical compositions containing compounds of the invention as described herein, wherein the salt is enriched in one or more positions in an isotope other than the most naturally occurring isotope. To measure such isotopic disturbances or enrichments, readily available techniques are available, such as mass spectrometry, and for isotopes that are radioisotopes, additional techniques are available, such as radio detectors used in conjunction with HPLC or GC.

One of the challenges in drug development is improving absorption, distribution, metabolism, excretion and toxicity (ADMET) properties while maintaining the desired pharmacological profile. Structural changes to improve the properties of ADMET often change the pharmacology of the lead compound. Although the effects of deuterium substitution on ADMET properties are unpredictable, in some cases deuterium can improve the ADMET properties of a compound with minimal disturbance to its pharmacology. Two examples where deuterium has improved therapeutic formulations are: STR-347 and STR-354. STR-347 is a deuterated version of paroxetine with

- 47 041181 reduced predisposition to mechanical inactivation of CYP2D6, which is observed clinically with paroxetine. STR-354 is a deuterated version of a promising preclinical modulator (L-838417) of the gamma-aminobutyric acid (GABAA) receptor A that was not developed due to poor pharmacokinetic (PK) properties. In both cases, deuterium substitution resulted in improved ADMET profiles, offering the potential to improve safety, efficacy, and/or tolerability without significantly altering biochemical activity and selectivity compared to all-hydrogen compounds. Deuterium-substituted compounds of this invention are provided with improved ADMET profiles and substantially similar biochemical activity and selectivity compared to the corresponding all-hydrogen compounds.

Other useful properties

Another object of the present invention relates to the radiolabelled compounds of the present invention, which would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for the localization and quantification of beta-3 adrenergic receptors in tissue samples, including human, as well as to identify beta-3-adrenergic receptor ligands by inhibiting the binding of a radioactively labeled compound. Yet another object of the present invention is to develop novel beta-3 adrenergic receptor assays that contain such radiolabeled compounds.

This disclosure includes all isotopes of atoms occurring in the present compounds, intermediates, salts and crystalline forms thereof. Isotopes include atoms having the same atomic number but different mass numbers. One aspect of this invention includes any combination of one or more atoms in the present compounds, intermediates, salts and crystalline forms thereof, which are replaced by an atom having the same atomic number but a different mass number. One such example is the substitution of an atom that is the most naturally occurring isotope, such as 1H or ^12C , found in one of the compounds, intermediates, salts and crystal forms shown, with another atom that is not the most naturally occurring isotope, such as ^2H or ³ H (replacing 1H), or 11C, ¹³ C or ¹⁴ C (replacing ¹² C). A compound in which such a substitution takes place is generally referred to as an isotopically labeled compound. Isotopic labeling of the present compounds, intermediates, their salts and crystalline forms can be achieved using any of the many different synthetic methods known to those skilled in the art and an understanding of said synthetic methods and the available reagents necessary to carry out such a process is readily ascribed. introduction of isotopic labeling. As a general example, but not limitation, isotopes of hydrogen include ² H (deuterium) and ³ H (tritium). Isotopes of carbon include 11C, ^13C , and ^14C . Isotopes of nitrogen include ^13N and ^15N . Isotopes of oxygen include ^15O , ^17O , and ^18O . An isotope of fluorine includes ^18F . An isotope of sulfur includes ³⁵ S. The isotope of chlorine includes ³⁶ Cl. Isotopes of bromine include ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. The isotopes of iodine include ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ¹³¹ I. Another aspect of this invention includes compositions, such as those obtained from synthesis, preformulation, and the like, and pharmaceutical compositions, such as those obtained for use in a mammal for the treatment of one or more of the disorders described herein, containing one or more of these compounds, intermediates, salts and crystalline forms thereof, in which the natural distribution of isotopes in the composition is disturbed. Another aspect of the present invention includes compositions and pharmaceutical compositions containing compounds as described herein, wherein said compound is enriched in one or more positions in an isotope other than the most naturally occurring isotope. To measure such isotopic disturbances or enrichments, readily available techniques are available, such as mass spectrometry, and for isotopes that are radioisotopes, additional techniques are available, such as radio detectors used in conjunction with HPLC or GC.

Specific isotopically labeled compounds of this invention are useful for tissue distribution assays of a compound and/or substrate. In some embodiments of the invention, ³ H and/or ¹⁴ C radionuclide isotopes are applicable in these studies. In addition, substitution with heavier isotopes, such as deuterium (i.e., ² H), may confer certain therapeutic advantages as a result of higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. The isotopically labeled compounds of the invention can generally be prepared following procedures similar to those described in the Drawings and Examples below by replacing the non-isotopically labeled reagent with an isotopically labeled reagent. Other applicable synthesis methods are described below. In addition, it should be understood that all atoms present in the compounds of the invention may be the most frequently occurring isotope of such atoms, or a weaker radioisotope or a non-radioactive isotope.

Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the invention and are well known in the art. Exemplary synthesis methods for incorporating tritium activity levels into target molecules include, for example:

A. Catalytic reduction with gaseous tritium: This procedure usually produces products of high specific activity and requires the presence of halogenated or unsaturated precursors.

B. Reduction with sodium borohydride [ ³ H]: This procedure is relatively inexpensive and requires precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with lithium aluminum hydride [ ³ H]: This procedure offers products with near theoretical specific activity. It also requires that the precursors contain reducible functional groups such as aldehydes, ketones, lactones, esters, and the like.

D. Tritium gas impact labeling: This procedure involves impact precursors containing tritium gas exchangeable protons in the presence of a suitable catalyst.

E. N-methylation using methyl iodide [ ³ H]: This procedure is usually used to obtain O-methyl or N-methyl ( ³ H) products by treating the appropriate precursors with methyl iodide ( ³ H) with high specific activity. This method generally provides a higher specific activity, for example, about 70-90 Ci/mmol.

Synthetic methods for incorporating ¹²⁵ I activity levels into target molecules include:

A. Sandmeier Reaction and Similar Reactions: This procedure converts an arylamine or heteroarylamine to a diazonium salt, eg diazonium tetrafluoroborate salt, and then to a ¹²⁵ I labeled compound using Na ¹²⁵ I. The procedure presented was published by Zhu, GD. and collaborators at J. Org. Chem., 2002, 67, 943-948.

B. Ortho ¹²⁵ iodination of phenols: This procedure allows the insertion of ¹²⁵ I into the ortho position of the phenol, as reported by Collier, T. L. and collaborators at J. Labeled Compd. Radiopharm., 1999, 42, S264-S266.

C. Replacing aryl and heteroaryl bromide with ¹²⁵ I: This method is generally a two-step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate, using, for example, a reaction catalyzed by Pd (i.e. Pd(Ph ₃ P) ₄ ), or via aryl or heteroaryl lithium, in the presence of a trialkylthingalogenide or hexaalkyldithine [ eg (CH ₃ ) ₃ SnSn (CH ₃ ) ₃ ].

A radiolabeled compound of formula (Ia) beta-3 adrenergic receptor can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (ie, test compound) can be evaluated for its ability to reduce the binding of a radiolabeled compound of formula (Ia) to the beta-3 adrenergic receptor. Accordingly, the ability of a test compound to compete with the radiolabeled compound of formula (Ia) for binding to the beta-3 adrenergic receptor is directly correlated with its binding capacity.

Certain labeled compounds of the invention bind to specific beta-3 adrenergic receptors. In one embodiment, the IC ₅₀ of the labeled compound is less than about 500 μM, in another embodiment, the IC ₅₀ of the labeled compound is less than about 100 μM, in another embodiment, the IC ₅₀ of the labeled compound is less than about 10 μM, in yet another embodiment, the IC50 of the labeled compound is less than about 1 μM; and in yet another embodiment, the IC50 of the labeled compound is less than about 0.1 μM.

Compositions and dosage forms

Dosage forms may be prepared by any suitable method, generally by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both in the required proportions, and then, if necessary, shaping the resulting mixture into the desired shape.

Conventional excipients such as astringents, fillers, acceptable wetting agents, tablet lubricants and disintegrants can be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral preparations may be in the form of a dry powder which may be reconstituted with water or other suitable liquid carrier prior to use. Additional additives may be added to liquid preparations, such as suspending or emulsifying agents, non-aqueous carriers (including edible oils), preservatives, and flavoring and coloring agents. Parenteral dosage forms can be prepared by dissolving a compound provided herein in a suitable liquid carrier and sterilizing filtration of the solution prior to filling and sealing the appropriate vial or ampoule. These are just a few examples of the many suitable methods well known in the art for preparing dosage forms.

- 49 041181

The compound of this invention may be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. Suitable pharmaceutically acceptable carriers other than those mentioned herein are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th edition, 2000,

Lippincott Williams & Wilkins, (editors: Gennaro et al.).

While it is possible that, for use in prophylaxis or treatment, a compound as provided herein may, as an alternative use, be administered as a crude or pure chemical, it is preferable to present said compound or active ingredient in a pharmaceutical dosage form or composition further containing a pharmaceutical acceptable carrier.

Pharmaceutical dosage forms include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or in a form suitable for administration by inhalation, insufflation, or intravenous administration. in the form of a transdermal patch. Transdermal patches distribute the drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal drug degradation. Typically, transdermal patches contain an impervious backing, a single pressure-sensitive adhesive, and a release liner with a release backing. One of skill in the art will understand and appreciate methods suitable for making the desired effective transdermal patch based on need.

The compounds provided herein, together with a conventional excipient, carrier, or diluent, may thus be placed in the form of pharmaceutical dosage forms and unit dosage forms thereof, and in such form may be used as solids, e.g., tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their unit dosage forms may contain the usual ingredients in the usual proportions, with or without additional active compounds or chemical compound elements, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dose range to be used. .

For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, suspensions or liquids. The pharmaceutical composition is preferably in the form of a dosage unit containing a certain amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or suspension with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders, for example crystalline cellulose, cellulose derivatives, gum arabic, cornstarch or gelatin; with disintegrants, for example corn starch, potato starch or sodium carboxymethyl cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition in which, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.

The compounds provided herein, or a salt, solvate or hydrate thereof, can be used as active ingredients in pharmaceutical compositions, in particular as beta-3 adrenergic receptor modulators. The term active ingredient, defined in the context of a pharmaceutical composition, refers to the component of the pharmaceutical composition that provides the primary pharmacological effect, as opposed to the inactive ingredient, which is generally recognized as providing no pharmaceutical benefit.

The dosage when using the compounds provided herein can vary widely and, as is customary and known to the doctor or other clinician, must be adapted to individual conditions in each individual case. This depends, for example, on the nature and severity of the disease to be treated, on the condition of the patient, on the compound used, or whether the acute or chronic disease is being treated or whether prophylaxis is being carried out, or whether the active compounds are administered in addition to the compounds presented in this document. Typical dosages include, but are not limited to: about 0.001 to about 5000 mg, about 0.001 to about 2500 mg, about 0.001 to about 1000 mg, about 0.001 to about 500 mg, about 0.001 to about 250 mg , from about 0.001 to 100 mg, from about 0.001 to about 50 mg, and from about 0.001 to about 25 mg. Multiple doses may be administered throughout the day, especially when relatively large amounts are deemed necessary, such as 2, 3 or 4 doses. Depending on the patient and as deemed appropriate, the healthcare provider may be required to deviate up or down from the doses described herein.

- 50 041181

The amount of active ingredient or active salt or derivative thereof required for use in treatment will vary not only with the particular salt chosen, but also with the indication of the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the treating physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data from a system model, typically an animal model, to another, such as a human model. In some cases, these extrapolations may simply be based on the weight of the animal model compared to another, such as a mammal, preferably a human, however, more often these extrapolations are not simply based on weights, but rather include a variety of factors. Characteristic factors include the type, age, weight, sex, dietary and health status of the patient, disease severity, route of administration, pharmacological criteria such as potency, efficacy, pharmacokinetic and toxicological profiles of the particular compound used, whether a drug delivery system is being used, whether the treatment is an acute or chronic disease, or whether prophylaxis is carried out, or whether additional active compounds are administered in addition to the compounds provided herein, and also as part of a combination of active substances. The dosage regimen for the treatment of a disease state with the compounds and/or compositions provided herein is selected in accordance with the various factors noted above. Thus, the actual dosage regimen used may vary widely and therefore may deviate from the preferred dosage regimen, and one skilled in the art will recognize that dosage and dosage regimens outside of these typical ranges can be tested and, if necessary, can be used. in the ways proposed in this document.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more dose portions per day. The dose portion itself may be further subdivided, for example, into a number of separate conditionally distributed administrations. The daily dose may be divided, especially when relatively large amounts are administered, if deemed appropriate, into several administration portions, eg two, three or four. If necessary, depending on individual behavior, a deviation up or down from the indicated daily dose may be required.

The compounds provided herein can be administered in a wide variety of oral and parenteral dosage forms. Those skilled in the art will appreciate that dosage forms may contain, as the active ingredient, a compound as provided herein, or a pharmaceutically acceptable salt, hydrate, or solvate of a compound as provided herein.

For the preparation of pharmaceutical compositions from the compounds provided herein, the appropriate pharmaceutically acceptable carrier selected may be solid, liquid, or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with a carrier having the necessary binding power in suitable proportions and compacted to the desired shape and size.

Powders and tablets may contain the active compound in various percentages. A typical amount in a powder or tablet can be from 0.5% to about 90% of the active compound; however, one skilled in the art will know when amounts outside this range are needed. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term drug refers to the formulation of the active compound with an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without carriers, is surrounded by a carrier, which is thus associated with it. Similarly, the term includes cachets and lozenges for lozenges. Tablets, powders, capsules, pills, cachets and lozenges can be used in solid forms suitable for oral administration.

For the preparation of suppositories, a low-melting wax, for example a mixture of fatty acid glycerides or cocoa butter, is first melted, and the active ingredient is dispersed homogeneously in this melt, as with stirring. The molten homogeneous mixture is then poured into suitable sized molds, allowed to cool and thus solidify.

Dosage forms suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient

- 51 041181 dientu such suitable carriers as are known in the art.

Liquid form preparations include solutions, suspensions and emulsions, such as aqueous or aqueous propylene glycol solutions. For example, liquid preparations for parenteral administration may be formulated as solutions in aqueous polyethylene glycol. Injectable preparations, for example sterile injectable aqueous or oily suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in injectables.

The compounds provided herein may thus be formulated for parenteral administration (eg, by injection, eg, bolus injection or continuous drip) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusions, or multi-dose containers with an added preservative. Pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain adjuvants such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder obtained by aseptic isolation of a sterile solid or lyophilization from solution, for dilution prior to use with a suitable vehicle, eg, sterile, pyrogen-free water.

Aqueous dosage forms suitable for oral administration may be prepared by dissolving or suspending the active ingredient in water and adding the desired colorants, flavors, stabilizers and thickeners.

Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water with a viscous material such as natural or synthetic gums, gums, methylcellulose, sodium carboxymethylcellulose or other well known suspending agents.

Also included are solid form preparations which must be converted, shortly before use, to liquid preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis, the compounds provided herein may be formulated as ointments, creams, or lotions, or as a transdermal patch.

Ointments and creams, for example, may be formulated with an aqueous or oily base with the addition of suitable thickeners and/or gelling agents. Lotions may be formulated with an aqueous or oily base and typically also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or coloring agents.

Dosage forms suitable for topical oral administration include lozenges containing the active agent in a flavored base, typically sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base, for example in gelatin and glycerin, or in sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional methods, for example using a dropper, pipette or spray. Dosage forms may be presented in single dose or multi-dose form. In the latter case, this can be achieved by the patient injecting the appropriate predetermined volume of the solution or suspension using a dropper or pipette. In the case of a spray, this can be achieved, for example, by means of a spray pump for dosing irrigation.

Administration to the respiratory tract can also be achieved by an aerosol dosage form in which the active ingredient is provided in a pressurized package with a suitable propellant. When the compounds provided herein or pharmaceutical compositions containing them are administered as aerosols, such as nasal sprays or inhalation, this can be done, for example, using an injection, nebulizer, pump nebulizer, inhalation device, metered dose inhaler or powder inhaler . Pharmaceutical forms for the introduction of the compounds proposed herein in the form of an aerosol, can be obtained by methods well known to the person skilled in the art. To obtain them, for example, solutions or dispersions of the compounds proposed in this document, in water, mixtures in

- 52 041181 yes/alcohol or in suitable saline solutions can be used using conventional additives, such as benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, solubilizers, dispersants and others and, if necessary, conventional propellants include, for example , carbon dioxide, CFCs (chlorofluorocarbons) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; and so on. For convenience, the aerosol may also contain a surfactant such as lecithin. The dose of the drug can be controlled by means of a dosing valve.

In dosage forms intended for administration to the respiratory tract, including intranasal dosage forms, the specified connection, as a rule, has a small particle size, for example, on the order of 10 microns or less. This particle size can be obtained by means known in the art, for example, through micronization. If desired, dosage forms adapted to provide sustained release of the active ingredient can be used.

Alternatively, the active ingredients may be provided as a dry powder, eg a powder mixture of the compound in a suitable powder base, eg lactose, starch, starch derivatives eg hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP). For convenience, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example in capsules or boluses, such as gelatin, or in blister packs, from which the powder may be administered by inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. A unit dosage form may be a packaged preparation, a package containing individual quantities of a preparation, such as sachets, capsules, and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, cachet or lozenge, or it may be an appropriate amount of any of the above in packaged form.

Preferred compositions are tablets or capsules for oral administration and liquids for intravenous administration.

The compounds provided herein may optionally exist as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts derived from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Typical acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethylenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethic, lactic, maleic, malic, mandelic, methanesulfonic, mucin, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfide, tartaric, oxalic, ptoluenesulfonic, etc. Specific compounds provided herein that contain a carboxylic acid functional group may optionally exist as pharmaceutically acceptable salts containing non-toxic, pharmaceutically acceptable metal cations and cations derived from organic bases. Typical metals include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. In some embodiments, the pharmaceutically acceptable metal is sodium. Exemplary organic bases include, but are not limited to, benzathine (K1,N-dibenzylethane-1,2-diamine), chloroprocaine (2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine (2-(diethylamino)ethyl-4-aminobenzoate) and the like. Some pharmaceutically acceptable salts are listed in Berge, et. al., Journal of Pharmaceutical Sciences, 66:1-19 (1977).

Acid addition salts can be obtained as direct products of the synthesis of compounds. Alternatively, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt recovered by evaporation of the solvent or otherwise separating the salt and solvent. The compounds provided herein can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

The compounds provided herein can be converted to prodrugs. The term prodrugs refers to compounds that have been modified with specific chemical groups known in the art, and when administered to a patient, these groups undergo biotransformation to yield the parent compound. Thus, prodrugs can be considered as compounds provided herein containing one or more specialized non-toxic protecting groups used in a transient manner to alter or eliminate a property of the compound. In one general aspect, a prodrug approach is used to facilitate oral absorption. A detailed description is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems Vol. 14 from A.C.S. Symposium Series;

and in Bioreversible Carriers in Drug Design, eds. Edward B. Roche, American Pharmaceutical Association and

Pergamon Press, 1987

Some embodiments of the invention include a method for preparing a pharmaceutical composition for combination therapy, including mixing at least one compound in accordance with any of the compounds disclosed herein together with at least one known pharmaceutical agent and a pharmaceutically acceptable carrier.

It is noted that if beta-3 adrenergic receptor modulators are used as active ingredients in pharmaceutical compositions, they are intended for use not only in humans but also in non-human mammals. Recent advances in animal health require that there be a consensus when using active agents such as beta-3 adrenergic receptor modulators for the treatment of a beta-3 adrenergic receptor-associated disease or disorder in pets (e.g., cats, dogs, etc.). etc.), as well as in farm animals (for example, horses, cows, etc.). Those skilled in the art are readily credited with understanding the usefulness of such compounds in this formulation of the problem.

Other uses of the described receptors and methods will become apparent to those skilled in the art based on, inter alia, a review of this disclosure.

As will be appreciated, the steps of the methods of this invention need not be performed any particular number of times or in any particular sequence. Additional objects, advantages and new features of the present invention will become apparent to those skilled in the art upon examination of the following examples of the invention, which are intended to be illustrative and not restrictive.

Examples

Example 1 Preparation of Compounds of the Invention.

The compounds disclosed herein and their preparation are further illustrated by the following examples.

Further illustrated preparations for the compounds of this invention are shown in FIG. 1-24, where the symbols have the same definitions as used in this disclosure. The following examples are provided to further describe the invention, however, the present invention is not limited to the specific details of these examples. The compounds described above and below in this document are named according to AutoNom 2.2, CS ChemDraw Ultra Version 9.0.7, or ChemBioDraw Ultra 12.0.2.1076. In some cases, common names are used, and it is understood that these common names will be recognized by those skilled in the art.

Chemistry: Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker Avance III-400 equipped with a 5 mm BBFO probe. Chemical shifts are given in parts per million (ppm) using the residual solvent signal as a reference. NMR abbreviations are used as follows: s=singlet, d=doublet, dd=doublet of doublets, ddd=doublet of doublets, dddd=doublet of doublet of doublets, dt=doublet of triplets, t=triplet, q=quartet, m=multiplet, br. c=widened singlet, sextet=sextet.

Microwave radiation was carried out using the Initiator ⁺ ™ (Biotage ®). Thin layer chromatography (TLC) was performed on silica gel 60 F ₂₅₄ (Merck), preparative thin layer chromatography (preparative TLC) was performed on 1 mm PK6F 60 A silica gel plates (Whatman), and column chromatography was performed on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was carried out under reduced pressure on a Buchi rotary evaporator. Celite® 545 was used to filter the palladium.

Technical characteristics of LCMS (liquid chromatography-mass spectrometry): HPLC - Agilent 1200; pumps: G1312A; DAD:G1315B; sampler: G1367B; Mass spectrometer - Agilent G1956A; ionization source: ESI; Dry gas flow: 10 l/min; atomizer pressure: 40 psi (275.79 kPa); drying gas temperature: 350°C; capillary voltage: 2500 V) Software: Agilent Chemstation Rev.B.04.03.

Example 1.1. Preparation of benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decan-8carboxylate.

Stage A: Obtaining benzyl-4-allyl-4-hydroxypiperidine-1-carboxylate.

To a mixture of benzyl-4-oxo-piperidine-1-carboxylate (51 g, 218.6 mmol) in THF (36.44 ml) was added 3-bromoprop-1-ene (54.72 ml, 655.92 mmol) and saturated aqueous NH ₄ Cl (114 ml, 218.6 mmol). Zinc dust (31.59 g, 483.1 mmol) was then added in portions while keeping the internal reaction temperature below 40°C. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, it was quenched with H ₂ SO ₄ (10%, 225 ml). The reaction mixture was filtered through a pad of Celite® and washed with MTBE (1 L). The aqueous layer was extracted with MTBE (2x) and EtOAc (1x).

- 54 041181

The combined organic layers were washed with water and brine and then dried over MgSO ₄ , filtered and concentrated to give the title compound (62.39 g, yield

104%). This material was used in the next step without further purification. LCMS m/z=276.2 [M+H]+;

¹ H NMR (400 MHz, CDCl·,) δ ppm 1.55-1.63 (m, 5H), 2.24 (d, J=7.33 Hz, 2H), 3.25 (brs, 2H), 3.93 (brs, 2H) , 5.14 (s, 2H), 5.21 (td, J=9.54, 1.89 Hz, 1H), 5.79-5.93 (m, 1H), 7.33 (dd, J = 5.18, 3.41 Hz, 1H), 7.35-7.40 (m, 4H).

Step B: Preparation of benzyl 4-(2,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate.

A mixture of K ₃ Fe(CN) ₆ (62.64 g, 190.3 mmol), K ₂ CO ₃ (26.29 g, 190.3 mmol), quinuclidine (0.25 g, 2.25 mmol), K ₂ OsO ₂ (OH) ₄ (0.20 g, 0.53 mmol) was dissolved in H ₂ O (354.0 ml) and then stirred at room temperature for 20 min (Note: not all salts dissolved in water) . A solution of benzyl 4-allyl-4-hydroxypiperidine-1-carboxylate (14.72 g, 53.44 mmol) in t-BuOH (354 ml) was obtained, and then at room temperature it was added in portions to the aqueous salt solution through additional funnel. (Note: all salts went into solution as the benzyl 4-allyl-4hydroxypiperidine-1-carboxylate solution was added).

Then methanesulfonamide (5.08 g, 53.44 mmol) was added. The reaction mixture changed color from reddish to green and was stirred at room temperature for 5 hours. The reaction was quenched with Na ₂ SO ₃ (51.5 g). The organic layer was separated and concentrated. The residue was dissolved in EtOAc and extracted with water and brine, then dried over MgSO ₄ and filtered. The filtrate was concentrated to give the title compound (19 g, 115% yield) as an oil, which was used in the next step without further purification. LCMS m/z=310.4 [M+H]+;

¹ H NMR (400 MHz, CDC13) δ ppm 1.47 (dd, J=14.65, 2.27 Hz, 1H), 1.57 (s, 2H), 1.72 (dd, J=14.65, 11.12 Hz, 1H), 1 .81 (d, J=12.63 Hz, 1H), 1.88 (t, J=5.43 Hz, 1H), 3.12 (s, 2H), 3.16-3.23 (m, 1H), 3.25-3.37 (m, 1H), 3.48 (ddd, J=10.86, 6.95, 5.68 Hz, 1H), 3.65 (ddd, J=10, 80, 4.61, 3.54 Hz, 1H), 3.92 (brs, 2H), 4.14 (brs, 1H), 4.68 (brs, 1H), 5.14 (s, 2H), 7.29-7.40 (m, 5H).

Step C: Preparation of benzyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.

To a solution of benzyl 4-(2,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate (17.80 g, 57.55 mmol) in CH ₂ Cl ₂ (16 ml) and pyridine (8.90 ml) in N,N-dimethylpyridine4-amine (1.41 g, 11.51 mmol) and 4-methylbenzene-1-sulfonyl chloride (12.07 g, 63.30 mmol) were added under nitrogen at 0°C. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, it was quenched with water and extracted with DCM (dichloromethane) (5 times). The combined organic layers were washed with 1M aqueous HCl, water and brine, then dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (12.5 g, 75% yield) as a yellow oil. LCMS m/z=292.2 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.53-1.60 (m, 2H), 1.63-1.72 (m, 1H), 1.79 (ddd, J=13.52, 1.26, 1.14 Hz, 1H), 1.82-1.89 (m, 1H), 1.98 (dd, J=13.52, 6.44 Hz, 1H), 3.41 (brs, 2H), 3.67 (dd, J=12.51, 6.44 Hz, 2H), 3.74 (ddd, J=9.60, 2.53, 1.01 Hz, 1H), 3.90 (dd, J=9.60, 4.55 Hz, 1H), 4.39-4.48 (m, 1H), 5.11 (s, 2H), 7.267.39 (m, 5H).

Step D: Preparation of benzyl 3-azido-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.

Benzyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (10 g, 34.31 mmol) was dissolved in pyridine (22 ml) under nitrogen, then cooled to 0°C. Methansulfonyl chloride (8.76 ml, 113.2 mmol) was added. The reaction mixture was stirred at room temperature overnight. (Note: a precipitate has formed). After completion of the reaction, the mixture was diluted with EtOAc, then washed with H2O (40 ml), HCl (1N, 30 ml) and brine (30 ml). The aqueous layers were back extracted with EtOAc (2x). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give benzyl 3((methylsulfonyl)oxy)-1-oxa-8-azaspiro[4.5]decan-8-carboxylate as a brown oil which was used in the next step without additional cleaning. LCMS m/z=370.0 [M+H] ⁺ .

Benzyl 3-((methylsulfonyl)oxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate from the previous step was dissolved in DMF (dimethylformamide) (30 ml) under nitrogen atmosphere. Sodium azide (5.13 g, 78.91 mmol) was added. The reaction mixture was heated at 50° C. overnight. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc and washed with water and brine. The aqueous layer was back extracted with EtOAc (2x). The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (10.02 g, 92% yield). LCMS m/z=317.2 [M+H]+;

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.56-1.70 (m, 3H), 1.78-1.85 (m, 1H), 1.85-1.91 (m, 1H), 2.03 (dd, J=13.64 , 7.07 Hz, 1H), 3.29-3.41 (m, 2H), 3.72-3.83 (m, 2H), 3.85 (ddd, J=9.98, 3.16 , 1.01 Hz, 1H), 3.94-4.00 (m, 1H), 4.15-4.21 (m, 1H), 5.14 (s, 2H), 7.29-7, 40 (m, 5H).

Step E: Preparation of benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8carboxylate.

Acetic acid (16.59 ml, 290 .0 mmol) and zinc dust (10.84 g, 165.7

- 55 041181 mmol). The reaction mixture was heated at 70°C for 1 h After cooling the reaction mixture to room temperature, it was neutralized to pH 7 using NaHCO ₃ . The mixture was passed through a pad of Celite® and washed with EtOAc with IPA (isopropanol)/DCM (30%). The aqueous layer was back extracted with EtOAc (3x). (Note: product still remained in the aqueous layer which was then re-extracted with IPA/DCM (30%). The combined extracts were dried over MgSO ₄ and concentrated to give benzyl-3-amino-1-oxa-8-azaspiro[4.5]decane -8-carboxylate as a white sticky solid which was used in the next step without further purification LCMS m/z=291.2 [M+H]+.

Benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate from the previous step was dissolved in CH ₂ Cl ₂ (220 ml) followed by the addition of DIEA (diisopropylethylamine) (14.43 ml, 82.86 mmol) and (BOC) ₂ O (13.56 g, 62.15 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was removed and then purified by flash column chromatography to give the title compound (11.55 g, 71% yield) as a white solid. LCMS m/z=391.4 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.44 (s, 9H), 1.50-1.54 (m, 1H), 1.58-1.74 (m, 4H), 2.12 (dd, J=13.14, 8.08 Hz, 1H), 3.32-3.43 (m, 2H), 3.63 (dd, J=9.09, 5.56 Hz, 1H), 3.67-3.79 (m, 2H) , 3.99 (dd, J=8.97, 6.19 Hz, 1H), 4.21-4.43 (m, 1H), 4.67-4.70 (m, 1H), 5.11 (s, 2H), 7.28-7.39 (m, 5H).

Step F: Chiral HPLC resolution of benzyl 3-((tert-butoxycarbonyl)amino)-1oxa-8-azaspiro[4.5]decane-8-carboxylate enantiomers.

Racemic benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (11.55 g, 29.58 mmol) was separated to give the two enantiomers by conventional preparative chiral phase HPLC under the following conditions:

Column: Chiralcel OD, 5 cm x 50 cm ID, particle size 20 µm

Eluent: EtOH/Hex (10%) with TEA (triethylamide) (0.1%)

Solution for injection: 800 mg/6 ml per injection

gradient: isocratic

Flow rate: 60 ml/min

Detector: 250 nm

Retention time: 1st enantiomer 28.98 min, 2nd enantiomer 39.38 min

The 1st enantiomer (28.98 min on a Chiralcel OD column) and the 2nd enantiomer (39.38 min on a Chiralcel OD column) were verified by analytical normal phase preparative chiral HPLC under the following conditions:

Column: ChiralPak IC, 250x20 mm ID, particle size 5 µm

Eluent: EtOH/Hex (10%) with TEA (0.1%)

Solution for injection: 2 mg/ml per injection

gradient: isocratic

Flow rate: 1 ml/min

Detector: 250 nm

1st enantiomer retention time (28.97 min on Chiralcel OD) and % ee (enantiomeric excess): 31.13 min; e.i. 100%.

2nd enantiomer retention time (39.382 min on Chiralcel OD) and %ee: 28.14 min; e.i. 100%.

(S)-benzyl-3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1st enantiomer, 5.14 g, 45% yield, e.i. . 100%).

1H NMR (400 MHz, CD3OD) δ ppm 1.43 (s, 9H), 1.49-1.59 (m, 1H), 1.59-1.75 (m, 4H), 2.10 (dd, J=13.14, 8.08 Hz, 1H), 3.33-3.46 (m, 2H), 3.58 (dd, J=9.09, 5.56 Hz, 1H), 3.63-3.72 (m, 2H) , 3.99 (dd, J=9.09, 6.32 Hz, 1H), 4.11-4.20 (m, 1H), 5.11 (s, 2H), 6.86 (br.s , 1H), 7.26-7.39 (m, 5H).

(R)-benzyl-3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2nd enantiomer, 4.86 g, 42% yield, e.i. . 100%):

1H NMR (400 MHz, CD3OD) δ ppm 1.43 (s, 9H), 1.50-1.58 (m, 1H), 1.60-1.75 (m, 4H), 2.10 (dd, J=13.14, 8.08 Hz, 1H), 3.33-3.46 (m, 2H), 3.58 (dd, J=9.09, 5.56 Hz, 1H), 3.63-3.72 (m, 2H) , 3.99 (dd, J=9.09, 6.32 Hz, 1H), 4.10-4.20 (m, 1H), 5.11 (s, 2H), 6.86 (br.s , 1H), 7.24-7.40 (m, 5H).

Stereochemistry was established using Mosher's amide as shown in Example 1.2 and Example 1.3, respectively.

Example 1.2. Preparation of (S)-3,3,3-trifluoro-2-methoxy-N-((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)-2 -phenylpropanamide and (R)-3,3,3-trifluoro-2-methoxy-N-((S)-8-(naphthalen-2ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl) -2-phenylpropanamide.

Step A: Preparation of one enantiomer of tert-butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl) carbamate (from the 1st enantiomer).

1st enantiomer of benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8carboxylate (1.13 g, 2.89 mmol) from chiral HPLC Example 1.1 was dissolved in MeOH (10 ml). Palladium/C (30.72 mg, 0.289 mmol) and H ₂ were added from a balloon. The reaction mixture was stirred at room temperature overnight. The next day, the H ₂ atmosphere was removed from the balloon. reaction mixture

- 56 041181 was filtered through a pad of Celite®, washed with EtOAc and MeOH and concentrated to give the enantiomer of tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate (0.64 g, 86% yield) as a colorless gum , which was used in the next step without further purification. LCMS m/z=257.4

[M+ ^H]+ ;

1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9H), 1.39-1.42 (m, 2H), 1.46-1.59 (m, 4H), 1.95 (dd, J=12.63, 8.34 Hz, 1H), 2.70-2.82 (m, 2H), 3.17 (d, J=2.78 Hz, 1H), 3.40 (dd, J=8.59, 6.57 Hz , 1H), 3.84 (t, J=8.00 Hz, 1H), 3.93-4.10 (m, 1H), 6.99 (d, J=5.56 Hz, 1H).

The above obtained enantiomer of tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate (0.64 g, 2.49 mmol) was dissolved in CH ₂ Cl ₂ (12 ml). DIEA (1.00 ml, 5.77 mmol) was added, then the resulting mixture was cooled in an ice bath. Naphthalene-2-sulfonyl chloride (0.92 g, 4.04 mmol) was added to the cooled solution. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated and purified by silica gel column chromatography to give the title compound (1.12 g, 87% yield) as a white solid. LCMS m/z=447.4 [M+H]+;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.34 (s, 9H), 1.52 (dd, J=13.01, 6.44 Hz, 1H), 1.57-1.63 (m, 2H), 1.65-1.73 ( m, 2H), 1.89 (dd, J=12.88, 8.34 Hz, 1H), 2.62-2.70 (m, 2H), 3.27-3.35 (m, 3H) , 3.70 (dd, J=8.97, 6.44 Hz, 1H), 3.87-3.99 (m, 1H), 6.93-7.01 (m, 1H), 7.66 -7.78 (m, 3H), 8.08 (d, J=8.08 Hz, 1H), 8.17 (d, J=8.84 Hz, 1H), 8.21 (d, J= 7.83 Hz, 1H), 8.42 (d, J=1.52 Hz, 1H).

Step B: Preparation of one enantiomer of 8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine.

To a solution of tert-butyl (8-(naphtalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (1.12 g, 2.50 mmol) obtained in step A above , in CH ₂ Cl ₂ (20 ml) at room temperature was added 4 n. HCl (in dioxane, 6.25 ml, 25.01 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated to give the title compound (1.19 g, 125% yield) as a white solid, which was used in the next step without further purification. LCMS m/z=347.0 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.52-1.72 (m, 3H), 1.73-1.90 (m, 2H), 2.06 (dd, J=13.64, 8.08 Hz, 1H), 2.53- 2.70 (m, 2H), 3.33-3.44 (m, 2H), 3.58 (dd, J=9.60, 4.29 Hz, 1H), 3.69-3.82 ( m, 2H), 7.64-7.83 (m, 3H), 8.09 (d, J=8.08 Hz, 1H), 8.13-8.27 (m, 2H), 8.44 (d, J=1.52 Hz, 1H).

Step C: Preparation of (S)-3,3,3-trifluoro-2-methoxy-N-((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl )-2-phenylpropanamide.

To a solution of the above 8-(naphtalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (10 mg, 26.12 µmol) and DIEA (7.54 µl, 43.30 µmol ) in THF (1 ml) was added (R)-3,3,3-trifluoro-2methoxy-2-phenylpropanoyl chloride (7.92 mg, 31.34 µmol), then stirred for 1.5 h. The reaction was quenched with water, then extracted with DCM. The aqueous layer was again extracted with DCM (3x). The combined organics were dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to give the title compound (12 mg, 82% yield) as a white solid. The stereochemistry of the title compound was determined by NMR. LCMS m/z=563.4 [M+H]+;

1H NMR (400 MHz, CDC13) δ ppm 1.53-1.64 (m, 3H), 1.67-1.76 (m, 2H), 2.07 (dd, J=13.52, 7.45 Hz, 1H), 2.79 ( sq.d, J=5.68, 3.41 Hz, 2H), 3.39 (t, J=1.52 Hz, 3H), 3.49 (td, J=11.62, 8.59 Hz , 2H), 3.59 (dd, J=9.73, 3.41 Hz, 1H), 3.89 (dd, J=9.73, 5.43 Hz, 1H), 4.42-4, 51 (m, 1H), 6.81 (d, J=7.33 Hz, 1H), 7.36-7.43 (m, 3H), 7.46 (d, J=2.27 Hz, 2H ), 7.64 (q.d., J=7.71, 7.45 Hz, 2H), 7.75 (dd, J=8.59, 1.77 Hz, 1H), 7.93 (d, J=7.83 Hz, 1H), 7.98 (d, J=8.34 Hz, 2H), 8.33 (d, J=1.26 Hz, 1H).

Step D: Preparation of (R)-3,3,3-trifluoro-2-methoxy-N-((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl )-2-phenylpropanamide.

To a solution of the above 8-(naphtalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (10 mg, 26.12 µmol) and DIEA (6.82 µl, 39.17 µmol ) in THF (1 ml) was added (S)-3,3,3-trifluoro-2methoxy-2-phenylpropanoyl chloride (7.92 mg, 31.34 µmol). The reaction mixture was stirred at room temperature for 1.5 hours. It was quenched with water, then extracted with DCM. The aqueous layer was again extracted with DCM (3x). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography to give the title compound (12 mg, 82% yield) as a white solid. The stereochemistry of the title compound was determined by NMR. LCMS m/z=563.4 [M+H]+;

1H NMR (400 MHz, CDC13) δ ppm 1.64-1.80 (m, 4H), 1.82-1.92 (m, 1H), 2.13 (dd, J=13.52, 7.45 Hz, 1H), 2.78- 2.90 (m, 2H), 3.33 (d, J=1.26 Hz, 3H), 3.47-3.60 (m, 3H), 3.88 (dd, J=9.85, 5.56 Hz, 1H), 4.48 (d.sq., J=5.24, 3.81 Hz, 1H), 6.98 (d, J=7.33 Hz, 1H), 7.39 ( d, J=2.78 Hz, 3H), 7.42-7.48 (m, 2H), 7.64 (q.d., J=7.71, 7.45 Hz, 2H), 7.76 (dd, J=8.59, 1.77 Hz, 1H), 7.93 (d, J=8.08 Hz, 1H), 7.98 (d, J=8.34 Hz, 2H), 8 .34 (d, J=1.26 Hz, 1H).

Example 1.3. Preparation of (S)-3,3,3-trifluoro-2-methoxy-N-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)-2 -phenylpropanamide and (R)-3,3,3-trifluoro-2-methoxy-N-((R)-8-(naphthalene-2-57 041181 ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan- 3-yl)-2-phenylpropanamide.

Step A: Preparation of one enantiomer of tert-butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl) carbamate (from the 2nd enantiomer).

2nd enantiomer of benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-carboxylate (1.14 g, 2.92 mmol) from chiral HPLC Example 1.1 was dissolved in MeOH (10 ml). Palladium/C (31.07 mg, 0.29 mmol) and H ₂ from a balloon were added to the resulting solution. The reaction mixture was stirred at room temperature for 16 hours. The next day, the H ₂ atmosphere was removed from the balloon. The reaction mixture was filtered through a pad of Celite®, washed with EtOAc and MeOH and concentrated to give the enantiomer of tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate (peak 2, 735 mg, 98%) as a colorless gum, which was used in the next step without further purification. LCMS m/z=257.4 [M+H]+;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.34-1.45 (m, 11H), 1.52 (dd, J=6.69, 3.41 Hz, 4H), 1.96 (dd, J=12.63, 8.34 Hz, 1H), 2.51-2.59 (m, 2H), 2.71-2.84 (m, 2H), 3.41 (dd, J=8.59, 6.57 Hz, 1H), 3 .83 (dd, J=8.59, 6.82 Hz, 1H), 3.91-4.07 (m, 1H), 6.99 (brs, 1H).

The above resulting enantiomer of tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate was redissolved in CH ₂ Cl ₂ (12 ml) after addition of DIEA (1.02 ml, 5.84 mmol). The reaction mixture was cooled in an ice bath, then naphthalene-2-sulfonyl chloride (0.93 g, 4.09 mmol) was added. The resulting mixture was stirred at room temperature overnight then concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.07 g, 82% yield) as a white solid. LCMS m/z=447.4 [M+H]+;

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9H), 1.52 (dd, J=12.88, 6.32 Hz, 1H), 1.56-1.62 (m, 2H), 1.65-1.72 ( m, 2H), 1.89 (dd, J=12.88, 8.34 Hz, 1H), 2.60-2.71 (m, 2H), 3.27-3.35 (m, 3H) , 3.70 (dd, J=8.72, 6.44 Hz, 1H), 3.88-3.99 (m, 1H), 6.93-7.02 (m, 1H), 7.67 -7.78 (m, 3H), 8.08 (d, J=8.34 Hz, 1H), 8.17 (d, J=8.84 Hz, 1H), 8.21 (d, J= 8.08 Hz, 1H), 8.42 (d, J=1.26 Hz, 1H).

Step B: Preparation of one enantiomer of 8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine.

To a solution of tert-butyl (8-(naphtalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (1.07 g, 2.39 mmol) obtained in step A above HCl (4 N in dioxane, 5.97 mL, 23.89 mmol) was added to DCM at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, it was concentrated to give the title compound (934 mg, 102% yield) as a white solid, which was used in the next step without further purification. LCMS m/z=347.2 [M+H]+;

1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.72 (m, 3H), 1.80 (d, J=3.79 Hz, 2H), 2.01-2.12 (m, 1H), 2.542.73 (m, 6H) , 3.39 (d, J=15.41 Hz, 3H), 3.57 (d, J=5.05 Hz, 1H), 3.76 (d, J=8.84 Hz, 2H), 7 .66-7.80 (m, 3H), 8.09 (d, J=8.08 Hz, 1H), 8.17 (d, J=8.84 Hz, 1H), 8.21 (d, J=8.08 Hz, 1H), 8.44 (s, 1H).

Step C: Preparation of (S)-3,3,3-trifluoro-2-methoxy-N-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl )-2-phenylpropanamide.

To a solution of the above 8-(naphtalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (10 mg, 26.12 µmol) and DIEA (7.54 µl, 43.30 µmol ) in THF (1 ml) was added (R)-3,3,3-trifluoro-2methoxy-2-phenylpropanoyl chloride (7.92 mg, 31.34 µmol). The reaction mixture was stirred for 1.5 hours at room temperature. The reaction was then quenched with water and extracted with DCM. The aqueous layer was again extracted with DCM (3x). The combined organics were dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to give the title compound (11 mg, 75% yield) as a white solid. The stereochemistry of the title compound was determined by NMR. LCMS m/z=563.2 [M+H]+;

1H NMR (400 MHz, CDCl·,) δ ppm 1.65-1.80 (m, 4H), 1.82-1.92 (m, 1H), 2.13 (dd, J=13.64, 7.58 Hz, 1H), 2.79- 2.89 (m, 2H), 3.33 (d, J=1.52 Hz, 3H), 3.48-3.60 (m, 3H), 3.88 (dd, J=9.73, 5.43 Hz, 1H), 4.43-4.53 (m, 1H), 6.98 (d, J=7.33 Hz, 1H), 7.37-7.41 (m, 3H), 7.43-7.47 (m, 2H), 7.60-7.69 (m, 2H), 7.76 (dd, J=8.72, 1.89 Hz, 1H), 7.93 ( d, J=7.83 Hz, 1H), 7.98 (d, J=8.34 Hz, 2H), 8.34 (d, J=1.26 Hz, 1H).

Step D: Preparation of (R)-3,3,3-trifluoro-2-methoxy-N-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl )-2-phenylpropanamide.

To a solution of the above 8-(naphtalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (10 mg, 26.12 µmol) and DIEA (7.54 µl, 43.30 µmol ) in THF (1 ml) was added (S)-3,3,3-trifluoro-2methoxy-2-phenylpropanoyl chloride (7.92 mg, 31.34 µmol). The reaction mixture was stirred at room temperature for 1.5 h. It was then quenched with water and extracted with DCM. The aqueous layer was back extracted with DCM (3x). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography to give the title compound (12 mg, 82% yield) as a white solid. The stereochemistry of the title compound was determined by NMR. LCMS m/z=563.2 [M+H]+; 1H NMR (400 MHz, CDCl·,) δ ppm 1.54-1.66 (m, 2H), 1.67-1.79 (m, 3H), 2.06 (dd, J=13.52, 7.45 Hz, 1H), 2.73- 2.85 (m, 2H), 3.39 (d, J=1.52 Hz, 3H), 3.44-3.55 (m, 2H), 3.59 (dd, J=9.60, 3.54 Hz, 1H), 3.89 (dd, J=9.73, 5.43 Hz, 1H),

- 58 041181

4.41-4.52 (m, 1H), 6.81 (d, J=7.33 Hz, 1H), 7.37-7.44 (m, 3H), 7.45-7.53 ( m, 2H), 7.60-7.71 (m, 2H), 7.75 (dd,

J=8.59, 1.77 Hz, 1H), 7.93 (d, J=7.83 Hz, 1H), 7.97 (d, J=8.34 Hz, 2H), 8.33 ( s, 1H).

Example 1.4. Preparation of (R)-benzyl-3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decan-8carboxylate.

Stage A: Obtaining benzyl-4-allyl-4-hydroxypiperidine-1-carboxylate.

To an ice-cold mixture of benzyl 4-oxo-piperidine-1-carboxylate (900.00 g, 3.86 mol), 3-bromoprop-1-ene (1.17 kg, 9.65 mol) and NH ₄ Cl (3.30 L) in THF (750.00 ml) at 5-10° C., Zn (630.74 g, 9.65 mol) was added in portions. After the addition, the mixture was kept at 30°C for 3 hours. After consumption of benzyl-4-oxo-piperidine-1-carboxylate, the mixture was filtered. The filtrate was extracted with ethyl acetate (2 L x 3). The combined organic layer was washed with brine (1 L x 2), dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (1.02 kg, crude) as a yellow oil which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCI3) δ ppm 1.45-1.75 (m, 4H), 2.22 (d, J=4.0 Hz, 2H), 3.23 (brs, 1H), 3.92 (brs, 2H), 5 .05-5.25 (m, 4H), 5.75-5.95 (m, 1H), 7.25-7.45 (m, 5H).

Step B: Preparation of benzyl 4-(2,3-dihydroxypropyl)-4-hydroxypiperi]din-1-carboxylate.

To a solution of benzyl 4-allyl-4-hydroxypiperidine-1-carboxylate (1.16 kg, 4.21 mol) in THF (2.20 L), acetone (2.20 L) and H ₂ O (2.20 k) K ₂ OsO ₄ -2H ₂ O (7.76 g, 21.05 mmol) and NMO (1.04 kg, 8.84 mol, 933.08 ml) were added. The reaction mixture was then stirred at 30° C. for 12 hours. The mixture was diluted with saturated aqueous Na ₂ SO ₃ (5 L) and extracted with ethyl acetate (2 L x 2). The combined organics were washed with brine (2 L), dried over Na2SO4, filtered and concentrated to give the title compound as an off-white solid without further purification (1.10 kg, 83.14% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.40-1.60 (m, 6H), 3.00-3.30 (m, 4H), 3.65-3.86 (m, 3H), 4.52-4.62 (m, 2H ), 4.67-4.74 (m, 1H), 5.06 (s, 2H), 7.28-7.42 (m, 5H).

Step C: Preparation of benzyl 3-((methylsulfonyl)oxy)-1-oxa-8-azaspiro[4.5]decan-8carboxylate.

To a solution of benzyl 4-(2,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate (1.34 kg, 4.33 mol), DMAP (158.75 g, 1.30 mol) and pyridine (1.03 kg, 12.99 mol, 1.05 L) in DCM (5.36 L) was added MsCl (1.13 kg, 9.86 mol, 763.51 ml) at 0°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was then heated and stirred at 40°C for 12 hours. Additional MsCl (319.00 g, 2.78 mol, 215.54 ml) was then added to the mixture at 25°C and the resulting mixture was stirred at 40°C for 24 hours. The mixture was diluted with DCM (5 L), washed successively with 1N. HCl (4 L) and brine (4 L). The organic phase was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the title compound (1.55 kg) as a brown oil, which was used directly for the next step without further purification.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.75 (m, 6H), 1.96-2.20 (m, 2H), 3.12-3.41 (m, 5H), 3.50-3.67 (m, 2H ), 3.94-3.95 (m, 2H), 5.06 (s, 2H), 5.29 (s, 1H), 7.25-7.44 (m, 5H).

Step D: Preparation of benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.

NaN ₃ ( 61.00 g, 938.32 mmol, 32.97 ml) in H ₂ O (150.00 ml) and the resulting mixture was stirred at 70°C for 16 hours. PPh ₃ (425.99 g, 1 .62 mol, 2.00 eq.) at 70°C (caution: gas is formed). The mixture was stirred at 70°C for another 2 hours After cooling to 15°C, water (6 l) was added and the mixture was basified to pH=10 using Na ₂ CO ₃ . The mixture was extracted with ethyl acetate (3 L x 3) and the combined organic layers were washed with 1N HCl. HCl (3 L x 3). The combined aqueous phase was basified to pH=10 using NaOH, extracted with ethyl acetate (3 L x 3). The combined organics were washed with brine (3 L), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (153.00 g, 58.4% yield).

1H NMR (400 MHz, CDC13) δ ppm 1.37 (s, 1H), 1.42-1.85 (m, 5H), 2.05 (dd, J=12.8 Hz, 5.4 Hz, 1H), 3.253.45 (m, 2H ), 3.45-3.56 (m, 1H), 3.57-3.80 (m, 3H), 3.93 (dd, J=6.4 Hz, 5.7 Hz, 1H), 5 .11 (s, 2H), 7.24-7.42 (m, 5H).

Step E: Preparation of (R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.

Di-p-toluene- 6-tartaric acid (37 g, 95.5 mmol, 0.44 eq.) and the mixture was heated to 78°C. After stirring at this temperature for 5 hours, the mixture was slowly cooled to 25° C. and stirred at this temperature for 1 hour. The white solid was collected by filtration and the solid was washed with MeOH (500 ml). The filter cake was added to an aqueous solution of NaHCO3 (500 ml) and extracted with DCM (1 L x 2). The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (54 g) which was analyzed by supercritical fluid chromatography

- 59 041181 (SFC) (AD-3S_4_25_3ML, column: Chiralpak AD-3 100x4.6 mm ID, 3 µm; mobile phase: 25% isopropanol (0.05% DEA) in CO ₂ ; flow rate: 3 ml/min; wavelength: 220 nm) to have an e.i. 93%. The above material (42 g, 145 mmol, 1.0 eq.) was dissolved with MeOH (800 ml) followed by the addition of di-p-toluene-6-tartaric acid (27 g, 69 mmol, 0.96 eq.). The mixture was heated to 78°C. After stirring at this temperature for 5 hours, the mixture was slowly cooled to 25° C. and stirred at this temperature for 1 hour. The white solid was collected by filtration, washed with EtOH (500 ml). The precipitate was added to an aqueous solution of NaHCO ₃ (500 ml) and was extracted with DCM (1 l x 2). The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (36 g, 97.5% ee) as a colorless oil.

Step F: Preparation of (R)-benzyl-3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decan-8carboxylate.

TEA (25 g, 248 mmol, 2.0 eq.) and Boc ₂ O (30 g, 136 mmol, 1.1 eq.). The reaction mixture was stirred at 20° C. for 6 hours. The mixture was washed with cold aqueous HCl (1N, 200 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with petroleum ether to give the title compound (44 g, 91% yield) as a white solid. LCMS m/z=335.1 (M-tBu+H);

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.38 (s, 9H), 1.44-1.64 (m, 5H), 1.95-2.05 (m, 1H), 3, 39-3.36 (m, 2H), 3.53-3.55 (m, 3H), 3.89 (t, J=6.4 Hz, 1H), 4.01-4.10 (m, 1H), 5.06 (s, 2H), 7.10 (d, J=6.0 Hz, 1H), 7.38-7.32 (m, 5H).

SFC analysis: (AD-3S_5_40_3ML; column: Chiralpak AD-3 100x4.6 mm ID, 3 µm; mobile phase: 40% ethanol (0.05% DEA) in CO ₂ ; flow rate: 3 ml/min; wavelength : 220 nm) e.i. 100%.

Example 1.5. Preparation of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decan-8carboxylate.

Step A: Preparation of (S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.

Di-p-toluene- L-tartaric acid (40 g, 104 mmol, 0.62 eq.) and the mixture was heated to 78°C. After stirring at this temperature for 5 hours, the mixture was slowly cooled to 25° C. and stirred at this temperature for 1 hour. The white solid was collected by filtration and the solid was washed with MeOH (250 ml). The filter cake was added to an aqueous solution of NaHCO ₃ (300 ml) and extracted with DCM (500 ml x 2). The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a residue (45 g) which was analyzed by SFC (AD-3S 4 25 3ML; column: Chiralpak AD-3 100x4.6 mm ID, 3 μm ; mobile phase: 25% isopropanol (0.05% DEA) in CO ₂ ; flow rate: 3 ml/min, wavelength: 220 nm) to have an e.i. 95%. The above material (45 g, 150 mmol, 1.0 eq.) was dissolved in MeOH (1.2 L) followed by the addition of di-p-toluene-c-tartaric acid (28 g, 72 mmol, 0.96 eq.) and the mixture was heated to 78°C. After stirring at this temperature for 5 hours, the mixture was slowly cooled to 25° C. and stirred at this temperature for 1 hour. The white solid was collected by filtration, washed with EtOH (500 ml). The precipitate was added to an aqueous solution of NaHCO ₃ (300 ml) and was extracted with DCM (50 0 ml x 2). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (40 g, 97.5% ee) as a colorless oil.

Step B: Preparation of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decan-8carboxylate.

TEA (28 g, 276 mmol, 2.0 eq.) and Boc ₂ O (33 g, 152 mmol, 1.1 eq.). The reaction mixture was stirred at 20° C. for 6 hours. The mixture was washed with cold aqueous HCl. (1N, 200 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with petroleum ether to give the title compound (51 g, 131 mmol, 95% yield) as a white solid. LCMS m/z=335.1 (M-tBu+H);

1H NMR (400 MHz DMSO-d6) δ 1.38 (s, 9H), 1.48-1.62 (m, 5H), 1.96-2.07 (m, 1H), 3.19-3 .36 (m, 2H), 3.53-3.43 (m, 3H), 3.89 (t, J=6.4 Hz, 1H), 4.04-4.11 (m, 1H), 5.06 (s, 2H), 7.10-7.09 (d, J=6.0 Hz, 1H), 7.38-7.32 (m, 5H).

SFC analysis: (AD-3S_5_40_3ML; column: Chiralpak AD-3 100x4.6 mm ID, 3 µm; mobile phase: 40% ethanol (0.05% DEA) in CO ₂ ; flow rate: 3 ml/min; wavelength : 220 nm) e.i. 100%.

Example 1.6. Preparation of (S)-2-((3-((cyclopropylmethyl)sulfonyl)phenoxy)methyl)oxirane (method BB1).

Step A: Preparation of sodium 3-methoxybenzenesulfinate (method BB1A).

To a solution of sodium sulfite (3.56 g, 28.26 mmol) and sodium carbonate (3 g, 28.26 mmol) in H ₂ O (18.84 ml) was added 3-methoxybenzene-1-sulfonyl chloride (2 ml, 14 .13 mmol) and EtOH (9.42 ml). The reaction mixture was heated at 60°C for 3 hours. The mixture was concentrated and subjected to azeotropic distillation with

- 60 041181 toluene (2x) to give the title compound as a light yellow solid, which was used in the next step without further purification. LCMS m/z=170.8 [M-H] ⁺ ;

1H NMR (400 MHz, DMSO-d6) δ ppm 3.75 (s, 3H), 6.77 (d, J=1.01 Hz, 1H), 6.99-7.06 (m, 2H), 7.20 (t,

J=7.71 Hz, 1H).

Step B: Preparation of 1-((cyclopropylmethyl)sulfonyl)-3-methoxybenzene (method BB1B).

To a solution of sodium 3-methoxybenzenesulfinate (300 mg, 1.55 mmol) in DMF (6.0 ml) was added (bromomethyl)cyclopropane (0.63 g, 1.55 mmol). The reaction mixture was heated under microwave irradiation for 1.5 h at 120°C. It was then filtered through a pad of Celite®, washed with EtOAc and concentrated. The residue was purified by silica gel column chromatography to give the title compound (289 mg, 83% yield). LCMS m/z=227.0 [M+H] ⁺ ;

1H NMR (400 MHz, CDCI3) δ ppm 0.17 (kv, J=5.31 Hz, 2H), 0.59 (td, J=7.20, 5.05 Hz, 2H), 1.02 (tt, J=8.08, 4, 80 Hz, 1H), 3.03 (d, J=7.07 Hz, 2H), 3.88 (s, 3H), 7.18 (ddd, J=8.15, 2.59, 1.14 Hz, 1H), 7.44-7.50 (m, 2H), 7.53 (d.t., J=8.00, 1.39 Hz, 1H).

Step C: Preparation of 3-((cyclopropylmethyl)sulfonyl)phenol (method BB1C).

Boron tribromide (176 μl, 2 56 mmol) in DCM (2.6 ml). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was cooled to -20°C, then quenched with MeOH and neutralized with 7 N. NH3 to MeOH. The resulting mixture was filtered through a pad of Celite® to remove the NH ₄ Br salt; the organic layer was washed with water and brine, then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (229 mg, 72% yield). LCMS m/z=212.8 [M] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.12-0.24 (m, 2H), 0.52-0.65 (m, 2H), 0.95-1.07 (m, 1H), 3.05 (d, J=7.33 Hz, 2H), 6.12 (s, 1H), 7.15 (ddd, J=7.83, 2.40, 1.39 Hz, 1H), 7.44 (t, J=8.08 Hz , 1H), 7.47-7.52 (m, 2H).

Step D: Preparation of (S)-2-((3-((cyclopropylmethyl)sulfonyl)phenoxy)methyl)oxirane (Method BB1D).

To a 5 ml microwave tube was added 3-((cyclopropylmethyl)sulfonyl)phenol (100 mg, 0.47 mmol), potassium carbonate (195 mg, 1.41 mmol) and acetone (2 ml). The reaction mixture was stirred at room temperature for 10 minutes, then (S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (122 mg, 0.47 mmol) was added. The reaction mixture was heated at 70° C. overnight. After cooling to room temperature, the mixture was filtered through a pad of Celite®, washed with EtOAc and concentrated. The residue was purified by silica gel column chromatography to give the title compound (121 mg, 87% yield) as a colorless oil. LCMS m/z=269.0 [M+H] ⁺ .

Example 1.7. Preparation of (S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol (Method BB2)

Step A: Preparation of 3-((2-hydroxyethyl)thio)phenol.

A solution of 2-bromoethanol ( 17.35 g, 138.9 mmol) in DCM (75 ml) via an additional funnel. The reaction mixture was stirred at room temperature overnight.

After completion of the reaction, it was neutralized with an aqueous solution of HCl (0.5 N) to pH 6, then the organic layer was separated. The aqueous layer was again extracted with DCM. The combined organic layers were washed with brine, then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (21.65 g, 62% yield). LCMS m/z=171.2 [M+H] ⁺ ;

1H NMR (400 MHz, DMSO-d6) δ ppm 2.97 (t, J=6, 95 Hz, 2H), 3.51-3.58 (m, 2H), 4.91 (t, J=5.56 Hz, 1H), 6.57 (ddd , J=8.72, 1.39, 1.26 Hz, 1H), 6.70-6.75 (m, 2H), 7.09 (t, J=8.08 Hz, 1H), 9, 49 (s, 1H).

Step B: Preparation of 3-((2-hydroxyethyl)sulfonyl)phenol.

To a solution of 3-((2-hydroxyethyl)thio)phenol (21.65 g, 78.9 mmol) in MeOH (217.5 ml) and H ₂ O (54.38 ml) at 0 ° C was added peroxymonosulfate in parts potassium, Oxone® (72.95 g, 157.7 mmol). The reaction mixture was stirred at room temperature overnight. It was filtered through a pad of Celite®, washed with MeOH and concentrated. The residue was diluted in water, then brought to pH 8-9 using NaHCO ₃ . The aqueous solution was extracted with DCM. The combined organic layers were washed with water (1x) and brine (1x), then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (14.02 g, 88% yield) as a yellow solid. LCMS m/z=203.2 [M+H] ⁺ ;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.39 (t, J=6.44 Hz, 2H), 3.61-3.70 (m, 2H), 4.87 (t, J=5.43 Hz, 1H), 7.09 (ddd , J=8.15, 2.46, 1.01 Hz, 1H), 7.23 (d, J=2.27 Hz, 1H), 7.30 (dd, J=8.97, 1.39 Hz, 1H), 7.44 (t, J=7.96 Hz, 1H), 10.19 (s, 1H).

Step C: Preparation of (S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol

To a mixture of 3-((2-hydroxyethyl)sulfonyl)phenol (14.02 g, 45.76 mmol) and potassium carbonate (18.97 g,

- 61 041181

137.3 mmol) in acetone (91.51 ml) at room temperature under nitrogen was added (S)-oxiran-2ylmethyl-3-nitrobenzenesulfonate (11.86 g, 45.76 mmol). The reaction mixture was heated at 80° C. overnight. After the reaction mixture was cooled to room temperature, the mixture was filtered through a pad of Celite®, then washed with acetone, then concentrated. The residue was redissolved in EtOAc and washed with aqueous NaOH (1N), water and brine. The aqueous layer was back extracted with EtOAc (2x). The combined organic layers were washed with water and brine, then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (15.23 g, 85% yield). LCMS m/z=259.2 ^[M+H] +;

¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.74 (dd, J=5.05, 2.53 Hz, 1H), 2.86 (t, J=4.29 Hz, 1H), 3.33-3.38 (m, 1H), 3 .46 (t, J=6.44 Hz, 2H), 3.63-3.70 (m, 2H), 3.94 (dd, J=11.37, 6.57 Hz, 1H), 4, 46 (dd, J=11.37, 2.53 Hz, 1H), 4.87 (t, J=5.56 Hz, 1H), 7.32 (d.t, J=8.27, 1, 29 Hz, 1H), 7.42 (d, J=2.27 Hz, 1H), 7.46-7.49 (m, 1H), 7.56 (t, J=7.96 Hz, 1H) .

Example 1.8. Preparation of (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (method BB3).

Step A: Preparation of 3-(methylsulfonyl)phenol (method BB3A).

_A solution _of boron tribromide (2, 63 ml, 27.72 mmol). The reaction changed color from pale yellow to red. The reaction mixture was slowly warmed to room temperature overnight. After completion of the reaction, the mixture was cooled to -20°C, then quenched Meon, and then diluted with CH ₂ Cl ₂ . The reaction mixture was neutralized with NaHCO ₃ by slowly adding NaHCO ₃ to a saturated aqueous solution followed by solid NaHCO ₃ . The organic layer was separated and the aqueous layer was again extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.46 g, 103% yield) as a white solid. LCMS m/z=173.2 [M+H]+;

1H NMR (400 MHz, CDCI3) δ ppm 3.09 (s, 3H), 7.15 (ddd, J=7.83, 2.53, 1.52 Hz, 1H), 7.41-7.53 (m, 3H).

Step B: Preparation of (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane.

To a solution of 3-(methylsulfonyl)phenol (2.46 g, 14.29 mmol) in acetone (70 ml) was added potassium carbonate (3.95 g, 28.57 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then (S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (3.70 g, 14.29 mmol) was added. The reaction mixture was heated at 70° C. overnight under nitrogen. After cooling to room temperature, the mixture was filtered through a pad of celite®, washed with acetone and concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.03 g, 93% yield) as a colorless oil. LCMS m/z=229.4 [M+H]+;

1H NMR (400 MHz, CDC13) δ ppm 2.79 (dd, J=4.80, 2.78 Hz, 1H), 2.94 (t, J=4 Hz, 1H), 3.06 (s, 3H), 3.333.42 (m, 1H ), 3.99 (dd, J=11.12, 6.06 Hz, 1H), 4.37 (dd, J=11.12, 2.78 Hz, 1H), 7.22 (dd, J= 8.21, 2.65, 1.01 Hz, 1H), 7.46-7.52 (m, 2H), 7.54-7.58 (m, 1H).

Example 1.9. Preparation of (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane (method BB4).

Step A: Preparation of 3-(cyclopropylthio)phenol.

To a stirred suspension of potassium tert-butoxide (8.00 g, 71.33 mmol) in DMSO (70 ml) under nitrogen at 0°C was added 3-mercaptophenol (5 g, 39.63 mmol); the reaction mixture was stirred at room temperature for 30 minutes. Bromocyclopropane (5.72 ml, 71.33 mmol) was then added to the reaction mixture.

The reaction mixture was heated at 90° C. overnight. After completion of the reaction, the mixture was diluted with EtOAc. The organic layer was washed with water, saturated aqueous NH ₄ Cl (2x) and brine. The aqueous layer was back extracted with EtOAc (1x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (6.19 g, 85% yield). LCMS m/z=167.2 ^[M+H]+ ;

1H NMR (400 MHz, CDC13) δ ppm 0.68-0.74 (m, 2H), 1.05-1.12 (m, 2H), 2.13-2.22 (m, 1H), 4.75 (s, 1H), 6, 60 (d.t, J=8.08, 1.26 Hz, 1H), 6.89 (t, J=2.27 Hz, 1H), 6.93 (ddd, J=7.83, 1, 64, 0.88 Hz, 1H), 7.15 (t, J=7.96 Hz, 1H).

Step B: Preparation of (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane.

Water (71 ml) was added to a round bottom flask containing Al2O3 (56 g). To this mixture was added a solution of 3-(cyclopropylthio)phenol (6.19 g, 33.60 mmol) in CC14 (170 mL) followed by potassium peroxymonosulfate (Oxone®) (31.09 g, 67.21 mmol).

The reaction mixture was heated at 40°C for 8 h; then the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through a pad of Celite® and washed with CH2C12. The organic layer was washed with water and brine, then dried over Na ₂ SO ₄ , filtered and concentrated to give 3-(cyclopropylsulfonyl)phenol (7.07 g, 106% yield) as a solid. This material was used in the next step without further purification.

- 62 041181 ki. LCMS m/z=199.2 [M+H]+;

1H NMR (400 MHz, CDC13) δ ppm 1.02-1.10 (m, 2H), 1.33-1.39 (m, 2H), 2.49 (tt, J=8.05, 4.83 Hz, 1H), 6.18 ( brs, 1H), 7.13 (d.t., J=6.51, 2.56 Hz, 1H), 7.40-7.48 (m, 3H).

To a solution of 3-(cyclopropylsulfonyl)phenol in acetone (170.0 ml) was added potassium carbonate (9.29 g, 67.21 mmol) and (S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (8.71 g, 33.60 mmol).

The reaction mixture was heated at 70° C. overnight under nitrogen. After completion of the reaction, the mixture was filtered through a pad of Celite®, washed with acetone and concentrated. The residue was purified by silica gel column chromatography to give the title compound (7.63 g, 89% yield) as a light yellow oil. LCMS m/z=255.2 [M+H]+;

1H NMR (400 MHz, CDCI3) δ ppm 1.01-1.08 (m, 2H), 1.33-1.39 (m, 2H), 2.47 (tt, J=7.99, 4.89 Hz, 1H), 2.79 ( dd, J=4.80, 2.53 Hz, 1H), 2.93 (t, J=4.29 Hz, 1H), 3.35-3.41 (m, 1H), 3.99 (dd , J=11.12, 5.81 Hz, 1H), 4.36 (dd, J=11.12, 2.78 Hz, 1H), 7.20 (dd, J=8.02, 2.59 , 1.26 Hz, 1H), 7.44 (t, J=2.27 Hz, 1H), 7.47 (t, J=7.71 Hz, 1H), 7.50-7.54 (m , 1H).

Example 1.10. Preparation of (S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide (method BB5).

Step A: Preparation of 2-((3-hydroxyphenyl)thio)acetamide (method BB5A).

To a solution of sodium hydroxide (4.82 g, 123.6 mmol) in MeOH (120 ml) at 0°C was added a solution of 3-mercaptophenol (10.51 ml, 103.0 mmol) in MeOH (20 ml). The reaction mixture was warmed to room temperature, then stirred for 30 minutes. A solution of 2-bromoacetamide (31.28 g, 226.6 mmol) in MeOH (100 ml) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through a pad of Celite®, then washed with MeOH. The filtrate was concentrated, then the residue was redissolved in water and extracted with IPA/DCM (10%, 2x). The combined organic layers were washed with water and brine, then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with DCM/Hex (2:1 ratio) to give the title compound (17.19 g, 96% yield) as a light brown solid. LCMS m/z=184.2 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 3.59 (s, 2H), 6.64 (ddd, J=8.15, 2.34, 0.88 Hz, 1H), 6.80-6.86 (m, 2H), 7.11 ( t, J=7.83 Hz, 1H).

Step B: Preparation of 2-((3-hydroxyphenyl)sulfonyl)acetamide (method BB5B).

To a solution of 2-((3-hydroxyphenyl)thio)acetamide (18.04 g, 98.46 mmol) in MeOH (272 ml) and H ₂ O (68 ml) at 0°C was added in portions a solution of potassium peroxymonosulfate (Oxone ®) (91.09 g, 196.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite®, washed with MeOH and then concentrated. The residue was dissolved in water and neutralized with saturated aqueous NaHCO ₃ to pH 8. (Note: The aqueous layer changed color to light pink.) The aqueous layer was extracted with IPA/DCM (10%). The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to give the title compound (15.11 g, 71% yield) as a white solid. LCMS m/z=216.0 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 4.10 (s, 2H), 7.11 (ddd, J=7.83, 2.53, 1.26 Hz, 1H), 7.33 (t, J=2.02 Hz, 1H), 7 .39 (t, J=1.52 Hz, 1H), 7.42 (t, J=7.58 Hz, 1H).

Step C: Preparation of (S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide.

To a solution of 2-((3-hydroxyphenyl)sulfonyl)acetamide (24.35 g, 70.2 mmol) in acetone (351 ml) was added potassium carbonate (19.39 g, 140.3 mmol) and (S)-oxirane -2-ylmethyl 3-nitrobenzenesulfonate (28.5 g, 104.4 mmol). The reaction mixture was heated at 80° C. for 23 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of celite®, washed with acetone and then concentrated. The residue was purified by silica gel column chromatography to give the title compound (13.9 g, 73% yield) as a light yellow solid. LCMS m/z=272.0 [M+H]+;

1H NMR (400 MHz, CDCl·,) δ ppm 2.78 (dd, J=4.80, 2.78 Hz, 1H), 2.94 (t, J=4.04 Hz, 1H), 3.38 (dddd, J=6.13, 3, 85, 2.91, 2.78 Hz, 1H), 3.96-4.04 (m, 3H), 4.36 (dd, J=11.12, 2.78 Hz, 1H), 5.61 (brs, 1H), 6.72 (brs, 1H), 7.24-7.29 (m, 1H), 7.47 (t, J=1.77 Hz, 1H), 7, 52 (t, J=7.83 Hz, 1H), 7.54 (d.t, J=7.83, 1.52 Hz, 1H).

Example 1.11. Preparation of (S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl) methanol (method BB6).

Step A: Preparation of 3-((3-Chloropropyl)thio)phenol.

Triethylamine (9.94 ml _, 71.33 _mmol ). 1-bromo-3-chloropropane (6.74 g, 42.80 mmol) was added dropwise to the resulting suspension at 0°C. The reaction mixture was stirred at room temperature for 1 hour. DCM (100 ml) and water (60 ml) were added to the mixture. The organic layer was separated and the aqueous layer was extracted with DCM (2x). The organic extracts were combined and washed with water (2x), brine, dried over Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a thick yellowish liquid without further purification.

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Step B: Preparation of 3-((3-chloropropyl)sulfonyl)phenol. The crude 3-((3-chloropropyl)thio)phenol from step A above was dissolved in dioxane and water (4:1, 100 ml). To this solution was added Oxone® (65.78 g, 107.0 mmol) in portions. The white suspension was stirred at room temperature for 1 hour. The white solid was filtered off and washed with EtOAc (50 ml). The filtrate was concentrated under reduced pressure to remove organic solvents. The resulting aqueous solution was extracted with EtOAc (3x75 ml). The combined organic extracts were washed with saturated aqueous NaHCO ₃ , brine, dried over Na 2 SO ₄ and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (7.77 g, 89.7% yield). LCMS m/z=235.2 [M+H]+;

¹ H NMR (400 M Hz, CDCI3) δ ppm 2.18-2.25 (m, 2H), 3.27-3.31 (m, 2H), 3.61 (t, J=6.20 Hz, 2H), 7.147.19 (m, 1H) , 7.43-7.47 (m, 3H).

Step C: Preparation of 3-(cyclopropylsulfonyl)phenol.

Potassium bis(trimethylsilyl)amide (1.0 M in MTBE, 46.87 ml, 46.87 mmol) resulting in a thick suspension. The reaction mixture was vigorously stirred for 30 min, then warmed to room temperature overnight. The mixture was quenched with 2N. HCl (50 ml) and the aqueous layer was extracted with 5% MeOH/EtOAc (3x). The combined organic extract was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.6 g, 85.2% yield) as a light yellow solid. LCMS m/z=199.4 [M+H]+;

¹ H NMR (400 M Hz, CDC1 ₃ ) δ ppm 1.03-1.09 (m, 2H), 1.33-1.38 (m, 2H), 2.45-2.52 (m, 1H), 6.44 (s, 1H), 7, 10-7.15 (m, 1H), 7.40-7.46 (m, 3H).

Step D: Preparation of ethyl 1-((3-((ethoxycarbonyl)oxy)phenyl)sulfonyl)cyclopropanecarboxylate.

To a solution of 3-(cyclopropylsulfonyl)phenol (3.6 g, 18.16 mmol) in THF (100 ml) at -78° C. was added n-butyllithium (18.75 ml, 46.87 mmol) dropwise. The reaction mixture was stirred for 30 minutes at the same temperature. Then, at -78° C., ethyl chloroformate (5.27 ml, 55.39 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and continued stirring at room temperature for 2 hours. After completion of the reaction, the mixture was quenched with saturated aqueous NH4C1. The aqueous layer was extracted with EtOAc (3x). The organic extracts were combined and washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the title compound (6.4 g, 87.7% yield) without further purification. LCMS m/z=343.2 [M+H] ⁺ .

Step E: Preparation of 3-((1-(Hydroxymethyl)cyclopropyl)sulfonyl)phenol (method BB6E).

A 2.0 M solution of lithium aluminum hydride (23 .43 ml, 46.87 mmol). After stirring at 0°C for 10 min, the reaction mixture was warmed to room temperature, after which it was stirred for another 3 h. NaOH at 0°C to obtain a thick suspension. EtOAc (150 ml) was added to the suspension and the reaction mixture was stirred for 1 hour at room temperature. The EtOAc layer was decanted from the suspension. Added 6 n. HCl (100 ml) and the mixture was stirred for 1 h to obtain a transparent layer. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.74 g, 76.9% yield) as a light yellow solid. LCMS m/z=229.4 [M+H]+;

1H NMR (400 M Hz, CDC13) δ ppm 1.04-1.07 (m, 2H), 1.58-1.61 (m, 2H), 3.67 (s, 2H), 7.12-7.15 (m, 1H), 7. 34 (d.t, J=1.41, 7.70 Hz, 1H), 7.37 (d, J=7.76 Hz, 1H), 7.38-7.40 (m, 1H), 9 .18 (s, 1H).

Step F: Preparation of (S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol.

(S )-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (2.50 g, 9.638 mmol). The reaction mixture was heated at 75° C. overnight. The reaction mixture was cooled to room temperature. The solid was separated by filtration and washed with acetone (2x10 ml). The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.55 g, 90.5% yield) as a yellowish liquid. LCMS m/z=285.0 [M+H]+;

1H NMR (400 M Hz, CDC13) δ ppm 1.05-1.08 (m, 2H), 1.62-1.66 (m, 2H), 2.64-2.74 (m, 1H), 2.78 (dd, J=2.69 , 4.94 Hz, 1H), 2.94 (dd, J=4.19, 4.79 Hz, 1H), 3.35-3.39 (m, 1H), 3.66 (br.s, 2H), 3.98 (dd, J=6.08, 11.60 Hz, 1H), 4.37 (dd, J=2.76, 11.05 Hz, 1H), 7.21-7.25 (m, 1H), 7.44-7.45(m, 1H), 7.48-7.51 (m, 2H).

Example 1.12. Preparation of (S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol (method BB7).

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Step A: Preparation of ethyl 2,2-difluoro-2-((3-methoxyphenyl)thio)acetate.

To a suspension of sodium hydride (0.28 g, 6.99 mmol) in THF at 0°C was added 3-methoxybenzenethiol (0.7 g, 4.99 mmol) in THF (2 ml) and stirred at room temperature for 30 min. The reaction mixture was again cooled to 0° C. and a solution of ethyl 2-bromo-2,2-difluoroacetate (0.70 ml, 5.49 mmol) in THF (0.5 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h and quenched with ice. The aqueous layer was separated and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.26 g, 82% yield). LCMS m/z=263.2 [M+H]+;

¹ H NMR (400 M Hz, CDCI3) δ ppm 1.27 (t, J=7.15 Hz, 3H), 3.81 (s, 3H), 4.26 (q, J=7.15 Hz, 2H), 6.987.01 (m, 1H), 7.14-7.15 (m, 1H), 7.18-7.20 (m, 1H), 7.29 (q, J=7.86 Hz, 1H).

Step B: Preparation of ethyl 2,2-difluoro-2-((3-methoxyphenyl)sulfonyl)acetate.

3-chlorobenzoperoxic acid ( 3.36 g, 14.98 mmol). The reaction mixture was stirred at room temperature overnight.

The mixture was filtered through a pad of Celite®, then washed with DCM. NaHCO ₃ was added to the filtrate, then stirred for 30 minutes. The mixture was filtered through a pad of celite®. The filtrate was washed once with saturated aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.01 g, 69% yield). LCMS m/z=295.2 [M+H] ⁺ .

Step C: Preparation of 2,2-difluoro-2-((3-methoxyphenyl)sulfonyl)ethanol.

To a solution of ethyl 2,2-difluoro-2-((3-methoxyphenyl)sulfonyl)acetate (261 mg, 0.887 mmol) was added lithium aluminum hydride (2.0 M, 0.375 ml, 0.750 mmol) at 0°C. After stirring at 0°C for 10 min and at room temperature for 3 h, the reaction mixture was quenched at 0°C with 1N. NaOH. 10% MeOH in DCM was added to the suspension and stirred for 30 minutes at room temperature. The mixture was filtered and washed with 10% MeOH in DCM (3x). The aqueous layer was extracted with 10% MeOH in DCM (3x). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel-silica gel column chromatography to give the title compound (0.201 g, 89% yield). LCMS m/z=253.0 ^[M+H]+ ;

¹ H NMR (400 M Hz, CDCl·,) δ ppm 3.89 (s, 3H), 4.29 (t, J=12.70 Hz, 2H), 7.29-7.32 (m, 1H), 7.46-7.47 (m, 1H) , 7.54 (t, J=7.88 Hz, 1H), 7.59 (m, 1H).

Step D: Preparation of 3-((1,1-difluoro-2-hydroxyethyl)sulfonyl)phenol.

To a solution of 2,2-difluoro-2-((3-methoxyphenyl)sulfonyl)ethanol (0.201 g, 0.668 mmol) in DCM (2 mL) at -78°C under N mmol). The reaction mixture was stirred at -78°C for 1 h, then warmed to room temperature and stirred for 1 h. After the reaction was complete, the mixture was cooled to -20°C, then quenched iPrOH. The mixture was neutralized with aqueous NaHCO ₃ to pH 7, then extracted with 20% iPrOH in DCM. The combined organic extracts were washed once with brine, separated, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the title compound without further purification. LCMS m/z=239.2 [M+H]+;

¹ H NMR (400 M Hz, CDC13) δ ppm 4.29 (t, J=12.72 Hz, 2H), 7.24-7.27 (m, 1H), 7.45-7.46 (m, 1H), 7.49 (t, J= 7.84 Hz, 1H), 7.53-7.56 (m, 1H).

Step E: Preparation of (S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol.

To a mixture of 3-((1,1-difluoro-2-hydroxyethyl)sulfonyl)phenol (0.132 g, 0.555 mmol) and potassium carbonate (0.207 g, 1.501 mmol) in acetone (15 ml) was added (S)-oxirane-2 -ylmethyl-3-nitrobenzenesulfonate (0.214 g, 0.826 mmol). The reaction mixture was heated at 75° C. overnight. The mixture was cooled to room temperature, filtered and washed with acetone (2x5 ml). The filtrate was concentrated and the residue was purified by silica gel column chromatography to give the title compound (0.205 g, 69% yield). LCMS m/z=295.4 [M+H]+;

¹ H NMR (400 M Hz, CDC13) δ ppm 2.47 (t, J=7.33 Hz, 1H), 2.79 (dd, J=2.18, 4.79 Hz, 1H), 2.95 (t, J=4.04 Hz, 1H ), 3.36-3.40 (m, 1H), 4.00 (dd, J=11.24, 5.94 Hz, 1H), 4.22-4.33 (m, 2H), 4, 38 (dd, J=11.12, 2.78 Hz, 1H), 7.31-7.39 (m, 1H), 7.47-7.52 (m, 1H), 7.55 (t, J=7.96 Hz, 1H), 7.58-7.64 (m, 1H).

Example 1.13: Preparation of quinoline-6-sulfonyl chloride.

Step A: Preparation of methyl 3-(quinolin-6-ylsulfonyl)propanoate.

To a 5 ml microwave tube was added 6-bromoquinoline (200 mg, 0.96 mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (0.84 g, 4.81 mmol), and copper (I) iodide (0. 92 g, 4.81 mmol), followed by the addition of DMSO (2 ml). The reaction mixture was degassed (2x) with nitrogen, then heated at 110° C. overnight. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc. The resulting mixture was filtered through a plug of silica gel, washed with EtOAc, and then

- 65 041181 concentrated. The residue was purified by silica gel column chromatography to give the title compound (95 mg, 33% yield) as a yellow oil. LCMS m/z=280.2 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 2.77 (t, J=7.20 Hz, 2H), 3.55 (s, 3H), 3.65 (t, J=7.20 Hz, 2H), 7.72 (dd, J=8 .46, 4.42 Hz, 1H), 8.17-8.22 (m, 1H), 8.24-8.29 (m, 1H), 8.61 (dd, J=8.46, 1 .14 Hz, 1H), 8.64 (d, J=2.02

Hz, 1H), 9.07 (dd, J=4.29, 1.77 Hz, 1H).

Step B: Preparation of quinoline-6-sulfonyl chloride.

To a solution of methyl 3-(quinolin-6-ylsulfonyl)propanoate (425 mg, 1.52 mmol) in THF (15 ml) was added sodium methoxide (0.35 μl, 1.52 mmol) at room temperature. The reaction mixture was stirred for 30 minutes then concentrated to give methylquinoline-6-sulfonate as a yellow solid. LCMS m/z=266.0 [M+H] ⁺ .

The methylquinoline-6-sulfonate obtained above was dissolved at 0° C. in CH ₂ Cl ₂ (15.00 ml). NCS (0.20 g, 1.52 mmol) was then added. The reaction mixture was stirred for 2 hours. The reaction was quenched with brine, then allowed to warm to room temperature. The organic layer was separated and the aqueous layer was washed with DCM. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (199 mg, 57% yield) as a beige solid. LCMS m/z=228.2 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 7.78 (dd, J=8.59, 4.29 Hz, 1H), 8.35 (d, J=1.52 Hz, 2H), 8.69 (dd, J=8.59, 1, 52 Hz, 1H), 8.86 (s, 1H), 9.14 (dd, J=4.29, 1.77 Hz, 1H).

Example 1.14. Preparation of tert-butyl 6-(chlorosulfonyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

Step A: Preparation of 6-(benzylthio)-1H-pyrrolo[3,2-b]pyridine.

To a mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine (1.970 g, 10 mmol), phenylmethanethiol (1.291 ml, 11.00 mmol), DIEA (3.484 ml, 20.00 mmol) and Pd ₂ ( dba) ₃ (0.458 g, 0.500 mmol) in dioxane (10 mL) was added (9,9dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.579 g, 1.000 mmol). The reaction mixture was heated to 150° C. for 2 h under microwave irradiation. After the reaction mixture was cooled to room temperature, it was dissolved in EtOAc. The mixture was washed with NaHCO ₃ (3x) and brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.31 g, 96.1% yield) as an orange solid. LCMS m/z=241.2 [M+H]+;

1H NMR (400 MHz, CD3OD) δ 4.05 (s, 2H), 6.55 (d, J=4.04 Hz, 1H), 7.10-7.16 (m, 2H), 7.16 -7.25 (m, 3H) 7.56 (d, J=3.28 Hz, 1H), 7.73 (d, J=1.01 Hz, 1H), 8.17 (d, J=1 .77 Hz, 1H).

Step B: Preparation of tert-butyl 6-(benzylthio)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.

To a solution of 6-(benzylthio)-1H-pyrrole[3,2-b]pyridine (2.304 g, 9.587 mmol) and pyridine (1.551 ml, 19.17 mmol) in THF ( ₂₀ ml) was added 2.511 g, 11.50 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with water (3x) and brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.59 g, 79.4% yield) as a yellow solid. LCMS m/z=341.4 [M+H]+;

1H NMR (400 MHz, CDCI3) δ ppm 1.65 (s, 9H), 4.10 (s, 2H), 6.73 (d, J=3.28 Hz, 1H), 7.14-7.33 (m, 5H), 7.79 (d, J=3.79 Hz, 1H), 8.34 (broad s, 1H), 8.45 (d, J=2.02 Hz, 1H).

Step C: Preparation of tert-butyl 6-(chlorosulfonyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (method BB8C).

NCS (3.039 g , 22.76 mmol). The reaction mixture was stirred for 5 hours. The mixture was concentrated. The residue was dissolved in DCM and washed with aqueous NaHCO ₃ solution. The aqueous layer was extracted with DCM (2x). The combined organics were dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.540 g, 22.5% yield) as a yellow solid. LCMS m/z=317.2 [M+H]+;

1H NMR (400 MHz, CDCI3) δ ppm 1.72 (s, 9H), 6.94 (d, J=3.03 Hz, 1H), 8.16 (d, J=3.54 Hz, 1H), 9.02 (br s, 1H ), 9.16 (d, J=2.27 Hz, 1H).

Example 1.15. Preparation of 1-methyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine-7-sulfonyl chloride (method BB9).

Step A: Preparation of 7-(benzylthio)-1-methyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine

From 7-bromo-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, the title compound was obtained in an analogous manner to that described in Example 1.14, step A. LCMS m/ z=272.8 [M+H] ⁺ .

Step B: Preparation of 1-methyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine-7-sulfonyl chloride

From 7-(benzylthio)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, the title compound was obtained in a manner analogous to that described in Example 1.14, step C. LCMS m/z=249.2 [M+H]+; ¹ H NMR (400 M Hz, CDCl·,) δ ppm 3.00 (s, 3H), 3.39-3.42 (m, 2H), 4.54-4.57 (m, 2H), 7.24 (d, J=2.27 Hz, 1H) , 8.22 (d, J=2.02 Hz, 1H).

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Example 1.16: Preparation of 3-methyl-3H-imidazo[4,5-b]pyridine-6-sulfonyl chloride (method BB10).

Step A: Preparation of 5-(benzylthio)-N ² -methylpyridine-2,3-diamine.

From 5-bromo-M ² -methylpyridine-2,3-diamine, the title compound was obtained in a manner analogous to that described in Example 1.14, Step A. LCMS m/z=246.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.80 (d, J=4.55 Hz, 3H), 3.91 (s, 2H), 4.72 (s, 2H), 5.79 (q, J=4.55 Hz, 1H), 6.72 (d, J=2.27 Hz, 1H), 7.17-7.22 (m, 3H), 7.24-7.29 (m, 2H), 7.31 (d, J= 2.27Hz, 1H)

Step B: Preparation of 6-(benzylthio)-3-methyl-3H-imidazo[4,5-b]pyridine.

To a solution of 5-(benzylthio)-N ² -methylpyridine-2,3-diamine (0.195 g, 0.795 mmol) in THF (5 ml) was added trimethoxymethane (4 ml, 36.56 mol) followed by a few drops of TFA (trifluoroacetic acids). The reaction mixture was stirred overnight. The mixture was diluted with EtOAc, washed with water (3x) and brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (1:1 EtOAc/hexane) to give the title compound (1.74 g, 87.5% yield) as a tan solid. LCMS m/z=256.4 [M+H]+; 1H NMR (400 M Hz, CDC13) δ ppm 3.91 (s, 3H), 4.06 (s, 2H), 7.14-7.26 (m, 5H), 8.03 (d, J=2.02 Hz, 1H), 8.08 (s, 1H), 8.35 (d, 1H).

Step C: Preparation of 3-methyl-3H-imidazo[4,5-b]pyridine-6-sulfonyl chloride.

From 6-(benzylthio)-3-methyl-3H-imidazo[4,5-b]pyridine, the title compound was obtained in a manner analogous to that described in Example 1.14, step C. LCMS m/z=232.2 [M+H ]+; 1H NMR (400 MHz, CDCl·,) δ ppm 4.02 (s, 3H), 8.29 (s, 1H), 8.71 (d, J=2.02 Hz, 1H), 9.10 (d, J=2.02 Hz, 1H).

Example 1.17. Preparation of 1-(2-methoxyethyl)-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine-7-sulfonyl chloride (method BB11).

Step A: Preparation of 7-bromo-1-(2-methoxyethyl)-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine.

To a solution of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (0.430 g, 2 mmol) in DMF was added sodium hydride (0.120 g, 3.000 mmol). The reaction mixture was stirred for 20 minutes. 1 Bromo-2-methoxyethane (0.207 ml, 2.200 mmol) was added. The reaction mixture was heated to 60° C. for 2 hours. The mixture was concentrated. The residue was dissolved in EtOAc, washed with water (3x) and brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.451 g, 82.6% yield) as a white solid. LCMS m/z=273.0 [M+H]+;

1H NMR (400 M Hz, CDC13) δ ppm 3.36 (s, 3H), 3.39-3.47 (m, 4H), 3.58 (t, J=5.43 Hz, 2H), 4.35 (t, J=4.80 Hz , 2H), 6.97 (d, J=2.02 Hz, 1H), 7.55 (d, J=2.27 Hz, 1H).

Step B: Preparation of 7-(benzylthio)-1-(2-methoxyethyl)-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine.

From 7-bromo-1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, the title compound was prepared in a manner analogous to that described in Example 1.14, Step A LCMS m/z=317.0 ^[M+H]+ ;

1H NMR (400 M Hz, CDC13) δ ppm 3.29 (t, J=5.31 Hz, 2H), 3.32 (s, 3H), 3.37-3.45 (m, 4H), 3.96 (s, 2H), 4.35 (t, J=4.55 Hz, 2H), 6.70 (d, J=2.02 Hz, 1H), 7.15-7.32 (m, 5H), 7.53 (d, J= 2.02 Hz, 1H).

Step C: Preparation of 1-(2-methoxyethyl)-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine-7-sulfonyl chloride.

From 7-(benzylthio)-1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, the title compound was obtained in a manner analogous to that described in Example 1.14, stage C. LCMS m/z=292.8 ^[M+H]+ ;

1H NMR (400 M Hz, CDC13) δ ppm 3.36 (s, 3H), 3.52-3.56 (m, 4H), 3.63 (t, J=5.05 Hz, 2H), 4.46-4.50 (m, 2H) , 7.34 (d, J=2.27 Hz, 1H), 8.17 (d, J=2.02 Hz, 1H).

Example 1.18. Preparation of 7-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (method BB12)

To chlorosulfuric acid (10.71 g, 91.9 mmol, 30 eq.) at 0°C under N ₂ was added 7fluoroquinolin-4-ol (500 mg, 3.06 mmol, 1.0 eq.). The resulting solution was stirred at 90° C. for 16 hours. After cooling to room temperature, the reaction mixture was added dropwise onto ice. The precipitate formed was filtered off and the filter cake was washed with CH ₃ CN/H ₂ O (2:1), the filtrate was lyophilized to give the title compound (550 mg, 65% yield) as a white solid. LCMS m/z=261.9 [M+H]+;

1H NMR (400 MHz, DMSO-d6): δ ppm 6.90 (brs, 1H), 7.59 (t.d., J=8.9, 2.4 Hz, 1H), 7.78 (dd, J=9.8, 2.5 Hz, 1H), 8.41 (dd, J=9.3, 6.0 Hz, 1H), 8.99 (s, 1H).

Example 1.19. Preparation of 4-hydroxy-7-methylquinoline-3-sulfonyl chloride (method BB13).

To chlorosulfuric acid (10.98 g, 94.2 mmol) at 0° C. under N2 was added 7-methylquinolin-4ol (500 mg, 3.14 mmol). The resulting solution was stirred at 80° C. for 16 hours. After cooling to room temperature, the reaction mixture was added dropwise onto ice. The precipitate formed was filtered off and the filter cake was washed with CH3CN/H2O (3:1), the filtrate was lyophilized to give the title compound (250 mg, 17% yield) as a yellow solid, further purification failing to improve purity. LCMS m/z=258.0 [M+H]+;

1H NMR (400 MHz, DMSO-d6): δ ppm 2.57 (s, 3H), 7.64 (d, J=8.3 Hz, 1H), 7.82 (broad s, 1H), 8.26 (d,

- 67 041181

J=8.4 Hz, 1H), 9.07-9.15 (m, 1H).

Example 1.20. Obtaining 1H-indole-3-sulfonyl chloride (method BB14)

Stage A: Obtaining 1H-indole-sulfonic acid

A solution of 1H-indole (2.0 g, 17.07 mmol) and sulfur trioxide-pyridine complex (2.72 g, 17.07 mmol) in pyridine (10 mL) was refluxed with stirring for 2 h and then cooled to room temperature. The reaction mixture was diluted with water (20 ml) and washed with diethyl ether (2x20 ml). The aqueous phase was concentrated to give the title compound, which was used in the next step without further purification.

Step B: Preparation of 1H-indole-3-sulfonyl chloride

The pyridinium salt of 1H-indole-sulfonic acid from the previous step was dissolved in 40 ml of a 1:1 mixture of sulfolane (20 ml)-MeCN (20 ml). The solution was cooled to 0° C. and phosphoryl trichloride (6 ml, 64.57 mmol) was added dropwise with stirring. The reaction mixture was heated to 70°C for 2 h and then cooled to 0°C. Cold water (10 ml) was added dropwise to the reaction mixture. The precipitate was filtered off, washed with water and dried under reduced pressure to give the title compound (1.7 g, 40% yield) as a brown solid. LCMS m/z=216.0 ^[M+H] +;

1H NMR (400 MHz, acetone-d ₆ ) δ ppm 7.38-7.46 (m, 2H), 7.69 (dd, J=6.57, 2.78 Hz, 1H), 7.95 (dd, J=6.57, 2.78 Hz, 1H), 8.38 (s, 1H), 11.77 (br s, 1H).

Example 1.21. Preparation of 3-((3-methoxyphenyl)sulfonyl)cyclobutanol

To a solution of 1-methoxy-3-(methylsulfonyl)benzene (200 mg, 1.074 mmol) in THF (10 ml) at 0°C was added n-butyl lithium (2.5 M in hexane, 0.86 ml, 2. 15 mmol), which led to the formation of a yellowish suspension and continued stirring for 1 h at 0°C. Then 2-(chloromethyl)oxirane (99.37 mg, 1.07 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature overnight and quenched with saturated aqueous NH ₄ Cl. The aqueous layer was extracted with EtOAc (3x). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.248 g, 86% yield) as a thick liquid. LCMS m/z=243.0 [M+H]+;

1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.40-2.52 (m, 2H), 2.56-2.67 (m, 2H), 3.36 (quin, J = 8.21 Hz, 1H), 3.87 (s, 3H) , 4.20 (quin, J=7.70 Hz, 1H), 7.17 (d.t., J=7.14, 2.37 Hz, 1H), 7.34-7.40 (m, 1H ), 7.40-7.51 (m, 2H).

Example 1.22. Preparation of 2-((3-fluoro-5-methoxyphenyl)thio)ethanol

A mixture of 1-bromo-3-fluoro-5-methoxybenzene (0.5 g, 2.44 mmol), 2-mercaptoethanol (0.210 g, 2.683 mmol), DIEA (0.94 ml, 5.37 mmol), Pd ₂ (dba) ₃ (0.22 g, 0.24 mmol) and (9,9-dimethyl-9H-xanthene-4,5diyl)bis(diphenylphosphine) (0.14 g, 0.24 mmol) in DMF (2 ml) was heated to 110°C during the night. After cooling to room temperature, the mixture was diluted with EtOAc and water. The mixture was filtered through a pad of celite. The aqueous layer was extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated to give the title compound without further purification.

Example 1.23. Preparation of 7-(benzylthio)-1,8-dimethyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine

Step A: Preparation of ethyl 2-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)acetate

DBU was added dropwise to a solution of 5-bromo-2-chloro-4-methyl-3-nitropyridine (5.00 g, 19.9 mmol) in ethyl 2-hydroxyacetate (12.42 g, 119 mmol) at room temperature. (9.08 g, 59.7 mmol). The color of the reaction mixture changed from yellow to reddish brown. The mixture was stirred at 100°C for 8 hours and then cooled to room temperature. After that, the reaction mixture was quenched with 30 ml of water and was extracted with ethyl acetate (2x20 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (2.0 g, 29% yield, 91% purity) as a yellow solid.

Step B: Preparation of 7-bromo-8-methyl-2H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a solution of ethyl 2-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)acetate (2.00 g, 5.70 mmol, 1.0 eq. 91% purity) in EtOH ( 4 ml) and AcOH (10 ml) zinc powder (2.05 g, 31.4 mmol) was added at room temperature. The reaction mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, the solution was concentrated in vacuo. MeOH (20 mL) was added to the residue and the pH was adjusted to 9 with ammonia. The mixture was filtered and the filtrate concentrated in vacuo to give the title compound (1.40 g, crude) as a brown solid which was used in the next step without further cleaning.

Step C: Preparation of 7-bromo-8-methyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine

To a solution of 7-bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.40 g crude, 5.76 mmol, 1.0 eq. .) in THF (5 ml) at 0° C. under N2 was added BH3-THF (23 ml, 1 M solution in THF, 23 mmol, 4.0 eq.). The mixture was then heated to 80° C. for 6 hours. After cooling to room temperature, the reaction was quenched by adding 3 ml of H ₂ O and 3 ml of MeOH. The mixture was concentrated in vacuo and purified by silica gel column chromatography to give the title co

- 68 041181 compounds (800 mg, 54% yield, 89% purity) as a white solid.

Step D: Preparation of 7-bromo-1,8-dimethyl-2,3-dihydro-2H-iirido[2,3-b][1,4]oxazine.

To a solution of 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (800 mg, 3.11 mmol, 89% purity) in DMF (6 mL) under N2 was added NaH (167.60 mg, 60% purity, 4.19 mmol) and then stirred at 0°C for 1 hour. To the above solution at 0°C was added iodomethane (13.00 g, 91.4 mmol) and then stirred at 20° C. for another 1 hour. The reaction mixture was quenched by adding saturated aqueous NH ₄ C1 (4 ml), diluted with H ₂ O (4 ml) and extracted with ethyl acetate (3x8 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (690 mg, 65% yield, 80% purity) as a white oil.

Step E: Preparation of 7-(benzylthio)-1,8-dimethyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine

Phenylmethanethiol (1.46 g, 11.7 mmol, 3.0 eq.), 7bromo-1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b] was added to the microwave tube under N2 atmosphere. [1,4]oxazine (950 mg, 3.91 mmol), dioxane (6.00 ml), Pd(dppf)C1 ₂ -CH ₂ C1 ₂ (1.43 g, 1.96 mmol, 0.50 eq ), tri-tert-butylphosphine (791 mg, 3.91 mmol, 1.0 eq.) and DIEA (2.02 g, 15.6 mmol, 4.0 eq.). The sealed tube was heated at 150° C. for 6 hours under microwave irradiation. After cooling, the mixture was diluted with H ₂ O (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (base condition) to give the title compound (500 mg, 44% yield) as a brown oil. LCMS m/z=287.4 [M+H]+;

1H NMR (CDCl ₃ , 400 MHz): δ ppm 2.17 (s, 3H), 2.62 (s, 3H), 3.03-3.11 (m, 2H), 3.89 (s, 2H), 4.31-4.38 (m, 2H), 7.06-7.15(m, 2H), 7.18-7.26(m, 3H), 7.94(s, 1H).

Example 1.24. Preparation of (R)-7-(benzylthio)-1,3-dimethyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine.

Step A: Preparation of (R)-methyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)propanoate

To a solution of 5-bromo-2-chloro-3-nitropyridine (8.00 g, 33.7 mmol, 1.0 eq.), methyl (2R)-2-hydroxypropanoate (10.52 g, 101 mmol, 3.0 eq. .) in MeCN (250 ml) was added K2CO3 (18.63 g, 135 mmol, 4.0 eq.). The reaction mixture was stirred at 75° C. for 15 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (4.84 g, 47% yield) as a yellow oil.

Step B: Preparation of (R)-7-bromo-3-methyl-2H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

Fe powder (4.39 g, 78.7 mmol) and then the mixture was heated to 80° C. for 1 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (10 g) without further purification.

Step C: Preparation of (R)-7-bromo-1,3-dimethyl-2H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.

To a solution of (R)-7-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (4.81 g crude, 19.8 mmol) in acetone (80 ml) MeI (3.98 g, 28.0 mmol) and K2CO3 (2.74 g, 19.8 mmol) were added. The mixture was stirred at 50-70° C. for 15 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (1.24 g, 24% yield, 88% purity) as a white solid. LCMS m/z=256.9 [M+H]+.

Step D: Preparation of (R)-7-bromo-1,3-dimethyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine

To a solution of (R)-7-bromo-1,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (400 mg, 1.37 mmol, purity 88%) in THF (40 ml) BH3-THF (15.6 ml, 1 M solution in THF, 15.6 mmol) was added dropwise at 0° C. under N2. The mixture was then stirred at 25°C for 15 hours. The reaction mixture was quenched by adding MeOH (4 ml) at 0°C and then 1M HCl was added to bring to pH<7. Thereafter, the mixture was heated at reflux for 1 hour. After cooling, 1 M NaOH aqueous solution was added to bring to pH>7. The reaction mixture was diluted with H2O (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (269 mg, 71% yield) as a yellow solid. LCMS (ESI): m/z=242.9 [M+H] ⁺ .

Step E: Preparation of (R)-7-(benzylthio)-1,3-dimethyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine

From (R)-7-bromo-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, the title compound was prepared in a manner analogous to that described in Example 1.23, step E. LCMS m/z=287.1 ^[M+H]+ ;

1H NMR (CDC13, 400 MHz): δ ppm 1.42 (d, J=6.4 Hz, 3H), 2.73 (s, 3H), 2.98 (dd, J=11.5, 8.4 Hz, 1H), 3.16 (dd , J=11.6, 2.6 Hz, 1H), 3.97 (s, 2H), 4.48 (dqd, J=8.5, 6.3, 2.6 Hz, 1H), 6, 66 (d, J=2.0 Hz, 1H), 7.18-7.32 (m, 5H), 7.57 (d, J=2.0 Hz, 1H).

Example 1.25. Preparation of (3S)-7-benzylsulfanyl-1,3-dimethyl-2,3-dihydropyrido[2,3-b][1,4]oxa

- 69 041181 zine.

Step A: Preparation of methyl (2S)-2-[(5-bromo-3-nitro-2-pyridyl)oxy]propanoate

K ₂ CO ₃ (18.63 g, 135 mmol). The mixture was stirred at 75° C. for 15 hours. After cooling, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (6.10 g, 59% yield) as a yellow oil.

Step B: Preparation of (3S)-7-bromo-3-methyl-2H-pyrido[2,3-b][1,4]oxazin-2-one

Fe powder (4.58 g, 82.0 mmol) and then the mixture was heated to 80°C for 1 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified with basic resin to give the title compound (3.58 g, 90% yield) without further purification.

Step C: Preparation of (3S)-7-bromo-3-methyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazine

To a solution of (3S)-7-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (2.20 g, 9.05 mmol) in THF (100 ml ) at 0°C was added BH3-THF (90.5 ml, 1 M solution in THF, 90.5 mmol). The reaction mixture was then stirred at 25° C. for 15 hours. The reaction mixture was quenched by adding MeOH (4.0 ml) at 0° C. and then HCl (1 M, 2.0 ml) was added to bring to pH<7. The mixture was refluxed for 1 hour and then cooled to room temperature. NaOH (IM aqueous solution, 4.0 ml) was added to give pH>7. The aqueous phase was extracted with DCM (3x100 ml). The combined organic phase was washed with brine (2x30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (679 mg, 33% yield) as a white solid.

Step D: Preparation of (3S)-7-bromo-1,3-dimethyl-2,3-dihydropyrido[2,3-b][1,4]oxazine

To a solution of (3S)-7-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (100 mg, 411 µmol) in DMFA (20 ml) at 0° C under N ₂ was added NaH (104 mg, 2.59 mmol, 60% pure). The mixture was stirred at 25° C. for 15 hours before cooling with ice water. The mixture was then extracted with ethyl acetate (3x20 ml). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (80 mg, 80% yield) as a white solid.

Step E: Preparation of (3S)-7-benzylsulfanyl-1,3-dimethyl-2,3-dihydropyrido[2,3-b][1,4]oxazine

From (3S)-7-bromo-1,3-dimethyl-2,3-dihydropyrido[2,3-b][1,4]oxazine, the title compound was obtained in a manner analogous to that described in Example 1.23, step E. LCMS m/z=287.1 [M+H]+;

¹ H NMR (CDCl·,, 400 MHz): δ ppm 1.41 (d, J=6.4 Hz, 3H), 2.72 (s, 3H), 2.97 (dd, J=11.5, 8.4 Hz, 1H), 3.15 (dd , J=11.5, 2.5 Hz, 1H), 3.96 (s, 2H), 4.43-4.53 (m, 1H), 6.64 (d, J=1.9 Hz, 1H), 7.16-7.30 (m, 5H), 7.55 (d, J=2.0 Hz, 1H).

Example 1.26. Preparation of 7-benzylsulfanyl-1,3,3-trimethyl-2H-pyrido[2,3-b][1,4]oxazine

Step A: Preparation of 2-bromo-N-(5-bromo-2-hydroxypyridin-3-yl)-2-methylpropanamide

To a solution of 3-amino-5-bromopyridin-2-ol (4.00 g, 21.2 mmol, 1.0 eq.) in THF (40 ml) at 0 5 mmol) and 2-bromo-2-methylpropanoyl bromide (5.35 g, 23.3 mmol). The reaction mixture was stirred at 17° C. for 2 hours. The mixture was diluted with H ₂ O (60 ml) and extracted with ethyl acetate (2x30 ml). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (6.30 g, crude) as a white solid without further purification. LCMS: m/z=336.9 [M+H] ⁺ .

Step B: Preparation of 7-bromo-3,3-dimethyl-2H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

K ₂ CO ₃ (6, 50 g, 47.0 mmol). The mixture was stirred at 70° C. for 8 hours under N ₂ atmosphere. After cooling, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give the title compound (2.70 g, 67% yield) as a yellow solid.

Step C: Preparation of 7-bromo-3,3-dimethyl-1,2-dihydropyrido[2,3-b][1,4]oxazine.

To a solution of 7-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (2.70 g, 10.5 mmol) in THF (20 ml) BH3-THF (31.5 ml, 1 M solution in THF, 31.5 mmol) was added at 0° C. under N2 atmosphere. The reaction mixture was stirred at 80° C. for 4 hours. After cooling, the reaction mixture was quenched by adding H ₂ O (3 ml) and MeOH (3 ml). The mixture was concentrated in vacuo to give the title compound (2.80 g, crude) as a yellow solid. LCMS m/z=243.0 [M+H] ⁺ .

Step D: Preparation of 7-bromo-1,3,3-trimethyl-2H-pyrido[2,3-b][1,4]oxazine

To a solution of 7-bromo-3,3-dimethyl-1,2-dihydropyrido[2,3-b][1,4]oxazine (2.80 g, 11.5 mmol) in DMF

- 70 041181 (30 ml) NaH (691 mg, 17.3 mmol, 60% purity) was added at 0° C. over 30 minutes under N2 atmosphere. Iodomethane (2.45 g, 17.3 mmol) was then added at 0°C. The reaction mixture was stirred at 15° C. for 1 h. The mixture was quenched by adding saturated aqueous NH ₄ Cl (20 ml) and then extracted with ethyl acetate (2x20 ml). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (150 mg) as a white solid.

Step E: Preparation of 7-benzylsulfanyl-1,3,3-trimethyl-2H-pyrido[2,3-b][1,4]oxazine

From 7-bromo-1,3,3-trimethyl-2H-pyrido[2,3-b][1,4]oxazine, the title compound was obtained in a manner analogous to that described in Example 1.23, step E. LCMS m/z= 301.1 [M+H]+;

¹ H NMR (CDCl3, 400 MHz): δ ppm 1.38 (s, 6H), 2.75 (s, 3H), 2.91-2.98 (m, 2H), 3.96 (s, 2H), 6.65 (d, J=2, 0 Hz, 1H), 7.16-7.32 (m, 5H), 7.59 (d, J=2.0 Hz, 1H).

Example 1.27. Preparation of 7-benzylsulfanyl-1-methylspiro[2H-pyrido[2,3-b][1,4]oxazine-3,1'cyclopropane]

Step A: Preparation of methyl 1-[(5-bromo-3-nitro-2-pyridyl)oxy]cyclopropanecarboxylate

To a mixture of methyl 1-hydroxycyclopropanecarboxylate (3.00 g, 25.82 mmol) in THF (100 ml) NaH (1.55 g, 38.7 mmol, 60% purity) was added in portions at 0°C under N2. The mixture was stirred at 0° C. for 30 minutes, then 5-bromo-2-chloro-3-nitropyridine (6.13 g, 25.8 mmol) in THF (20 ml) was added dropwise. The mixture was stirred at 0° C. for 1.5 hours. The solution was quenched with water (50 ml) and then extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (2x200 ml), dried over Na2SO4, filtered and then concentrated in vacuo. The residue was purified by chromatography to give the title compound (5.35 g, 65% yield) as a red solid. LCMS m/z=316.9 [M+H] ⁺ .

Step B: Preparation of 7-bromospiro[2H-pyrido[2,3-b][1,4]oxazin-3,1'-cyclopropan]-2-one

Zinc powder (2 .10 g, 32.1 mmol). The reaction mixture was then stirred at 100° C. for 1 hour. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2.20 g) as a yellow solid without further purification. LCMS m/z=255.0 [M+H] ⁺ .

Step C: Preparation of 7-bromospiro[1,2-dihydropyrido[2,3-b][1,4]oxazine-3,1'-cyclopropane]

To a solution of 7-bromospiro[1H-pyrido[2,3-b][1,4]oxazin-3,1'-cyclopropan]-2-one (3.00 g, 10.2 mmol) in THF (20 ml ) at 0° C. under N2 atmosphere, borane; tetrahydrofuran (40.9 ml, 1 M solution in THF, 40.9 mmol) was added. The reaction mixture was then stirred at 80° C. for 3 hours. After cooling to 20° C., methanol (10 ml) was added and the resulting solution was concentrated in vacuo. The residue was diluted in ethyl acetate (15 ml) and washed with saturated aqueous NaHCO ₃ (2x20 ml), water (2x20 ml), brine (2x20 ml). The organic layer was then concentrated in vacuo to give the title compound (1.50 g, 28% yield) as a yellow oil. LCMS m/z=240.9 [M+H] ⁺ .

Step D: Preparation of 7-bromo-1-methylspiro[2H-pyrido[2,3-b][1,4]oxazine-3,1'-cyclopropane]

To a solution of 7-bromospiro[1,2-dihydropyrido[2,3-b][1,4]oxazine-3,1'-cyclopropane] (1.00 g, 1.91 mmol, 46% purity, 1, 0 eq.) in DMF (25 ml) at 0° C. was added NaH (60 mg, 2.48 mmol, 60% purity, 0.78 eq.), after stirring for 5 minutes, iodomethane (542 mg, 3 .82 mmol, 2.0 eq.). The reaction mixture was stirred at 0° C. for 1.5 h and then quenched with water (30 ml) and brine (30 ml). The reaction solution was extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with water (2x50 ml) and brine (2x50 ml) and then concentrated in vacuo. The residue was purified by chromatography to give the title compound (400 mg, 66% yield) as a yellow oil. LCMS m/z=255.0 [M+H]+;

1H NMR (300 MHz, CDCl·,): δ ppm 0.71-0.79 (m, 2H), 1.13-1.22 (m, 2H), 2.91 (s, 3H), 3.22 (s, 2H), 6.97 (d, J=2.1 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H).

Step E: Preparation of 7-benzylsulfanyl-1-methylspiro[2H-pyrido[2,3-b][1,4]oxazine-3,1'cyclopropane]

From 7-bromo-1-methylspiro[2H-pyrido[2,3-b][1,4]oxazine-3,1'-cyclopropane] the title compound was obtained in a manner analogous to that described in Example 1.23, Step E (for excluding acidic HPLC conditions). LCMS m/z=299.1 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 0.72-0.82 (m, 2H), 0.91-1.00 (m, 2H), 2.79 (s, 3H), 3.20 (s, 2H), 4.13 (s, 2H), 6.93 (d, J=1.8 Hz, 1H), 7.19-7.30 (m, 5H), 7.31 (d, J=2.0 Hz, 1H).

Example 1.28. Preparation of (S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclobutyl)methanol

Step A: Preparation of ethyl 1-((3-methoxyphenyl)thio)cyclobutanecarboxylate.

To a solution of 3-methoxybenzenethiol (0.88 mL, 7.13 mmol) in EtOH (20 mL) was added potassium hydroxide powder (0.44 g, 7.85 mmol) followed by ethyl 1-bromocyclobutanecarboxylate (1.63 g , 7.85 mmol). The reaction mixture was refluxed for 3 h and then refluxed.

- 71 041181 got along to room temperature. The solid was separated by filtration and washed with EtOH (20 ml). The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (50 ml) and washed with saturated aqueous NaHCO ₃ (50 ml). The aqueous layer was back extracted with DCM (50 ml). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the title compound (1.7 g, 90% yield) without further purification. LCMS m/z=267.4 [M+H]+;

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.21 (t, J=7.07 Hz, 3H), 1.86-1.97 (m, 1H), 2.14-2.32 (m, 3H), 2.66-2.75 ( m, 2H), 3.79 (s, 3H), 4.16 (q, J=7.07 Hz, 2H), 6.82 (dd, J=8.34, 2.53 Hz, 1H), 6.91-6.98 (m, 2H), 7.20 (t, J=8.08 Hz, 1H).

Step B: Preparation of ethyl 1-((3-methoxyphenyl)sulfonyl)cyclobutanecarboxylate

To a solution of ethyl 1-((3-methoxyphenyl)thio)cyclobutanecarboxylate (0.60 g, 2.25 mmol) in dioxane/H ₂ O (20 ml/5 ml, 4:1) was added several portions of Oxone® (4 .15 g, 6.76 mmol). The white suspension was stirred at room temperature for 3 hours. The white solid was separated by filtration and washed with dioxane (20 ml). The filtrate was concentrated and the resulting aqueous solution was extracted with DCM (3x40 ml). The combined organic extracts were washed with saturated aqueous NaHCO3, brine and dried over Na2SO4 then filtered. The filtrate was concentrated to give the title compound (0.6 g, 88% yield) as a solid without further purification. LCMS m/z=299.4 [M+H]+;

¹ H NMR (400 MHz, CDCl·,) δ ppm 1.17 (t, J=7.07 Hz, 3H), 1.88-2.05 (m, 1H), 2.05-2.19 (m, 1H), 2.55-2.66 ( m, 2H), 2.98 (ddd, J=13.89, 9.98, 7.71 Hz, 2H), 3.86 (s, 3H), 4.12 (kv, J=7.07 Hz , 2H), 7.18 (ddd, J=6.95, 2.53, 2.40 Hz, 1H), 7.33 (t, J=1.01 Hz, 1H), 7.39-7, 47 (m, 2H).

Step C: Preparation of (1-((3-methoxyphenyl)sulfonyl)cyclobutyl)methanol.

To a solution of ethyl 1-((3-methoxyphenyl)sulfonyl)cyclobutanecarboxylate (0.6 g, 1.99 mmol) in THF at 0°C was added lithium aluminum hydride (2.0 M, 1.13 ml, 2.25 mmol). After stirring at 0° C. for 10 minutes and at room temperature for 2 hours, the reaction was quenched with 1N HCl. NaOH at 0°C. MeOH/DCM (10%) was added to the suspension and stirred for 30 minutes at room temperature. The suspension was filtered and washed with MeOH/DCM (10%, 3x). The aqueous layer was extracted with MeOH/DCM (3x). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the title compound (0.55 g, 92% yield) without further purification. LCMS m/z=257.2 [M+H]+;

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.94-2.10(m, 4H), 2.65-2.80(m, 2H), 3.49(s, 1H), 3.83(s, 2H), 3.88(s, 3H), 7.21 (d.t, J=7.52, 1.17 Hz, 1H), 7.38 (t, J=2.27 Hz, 1H), 7.42-7.55 (m , 2H).

Step D: Preparation of 3-((1-(hydroxymethyl)cyclobutyl)sulfonyl)phenol

To a solution of (1-((3-methoxyphenyl)sulfonyl)cyclobutyl)methanol (0.55 g, 2.08 mmol) in CH ₂ Cl ₂ (2 ml) at -78° C., a solution of boron tribromide was added slowly under N ₂ atmosphere (0.43 ml, 4.51 mmol). The reaction mixture was stirred at -78°C for 5 h, then stirred at room temperature for 2 h. The reaction mixture was cooled to -20°C and quenched using 'PrOH. The mixture was neutralized with an aqueous solution of NaHCO ₃ to pH 7. The resulting mixture was extracted with 'PrOH/DCM (20%). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and filtered, then concentrated to give the title compound (0.49 g, 84% yield) without further purification. LCMS m/z=243.0 [M+H] ⁺ .

Step E: Preparation of (S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclobutyl)methanol.

(S)- oxiran-2-ylmethyl-3-nitrobenzenesulfonate (0.30 g, 1.16 mmol). The reaction mixture was heated at 70° C. overnight. After cooling to room temperature, the solid material was filtered through a pad of Celite® and washed with acetone (2x5 ml). The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.30 g, 84% yield). LCMS m/z=299.4 [M+H]+;

¹ H NMR (400 MHz, CDCl·,) δ ppm 1.91-2.09 (m, 4H), 2.67-2.76 (m, 2H), 2.78 (dd, J=4.80, 2.53 Hz, 1H), 2.87 ( t, J=6.32 Hz, 1H), 2.93 (d, J=4.04 Hz, 1H), 3.30-3.40 (m, 1H), 3.83 (d, J=6 .32 Hz, 2H), 3.98 (dd, J=11.12, 6.06 Hz, 1H), 4.37 (dd, J=11.24, 2.65 Hz, 1H), 7.22 -7.26 (m, 1H), 7.41 (t, J=1.26 Hz, 1H), 7.45-7.53 (m, 2H).

Example 1.29. Preparation of (S)-2-methyl-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)propan-1-ol

Step A: Preparation of ethyl 2-((3-hydroxyphenyl)thio)-2-methylpropanoate

To a solution of 3-mercaptophenol (1.0 g, 7.93 mmol) in MeOH (20 ml) was added dropwise 1.0 N hydrochloric acid over 30 min at -5°C. sodium hydroxide (8.72 ml, 8.72 mmol). The reaction mixture was stirred at 5° C. for 1 hour. A solution of ethyl 2-bromo-2-methylpropanoate (1.70 g, 8.72 mmol) in MeOH (5 ml) was added at -5° C. over 15 minutes. The reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated. The residue was treated with 25 ml of water and 100 ml of TBME. After extraction and phase separation, the organic phase was washed with 50 ml of saturated NaHCO3 and 50 ml of brine. The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound

- 72 041181 (1.47 g, 77% yield). LCMS m/z=241.2 [M+H]+;

1H NMR (400 MHz, CDC13) δ ppm 1.23 (t, J=7.07 Hz, 3H), 1.51 (s, 6H), 4.13 (kv, J=7.24 Hz, 2H), 6.85 (ddd, J=8 .08, 2.53, 1.01 Hz, 1H), 6.98 (t, J=2.53 Hz, 1H), 7.03 (d.t, J=7.64, 1.36 Hz, 1H), 7.18 (t, J=7.83 Hz,

1H).

Step B: Preparation of ethyl 2-((3-hydroxyphenyl)sulfonyl)-2-methylpropanoate

To a solution of ethyl 2-((3-hydroxyphenyl)thio)-2-methylpropanoate (500 mg, 2.08 mmol) in dioxane/water (4:1, 30 mL) was added Oxone® (3.84 g, 6.24 mmol). The white suspension was stirred at room temperature for 3-4 hours. The white solid was filtered off and washed with dioxane (20 ml) and the filtrate was concentrated. The resulting aqueous solution was extracted with DCM (3x40 ml). The combined organic extracts were washed with saturated aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.54 g, 91% yield). LCMS m/z=273.4 [M+H]+;

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.17 (t, J=7.07 Hz, 3H), 1.64 (s, 6H), 4.13 (kv, J=7.16 Hz, 2H), 6.77 (s, 1H), 7.16-7.20 (m, 1H), 7.36-7.47 (m, 3H).

Step C: Preparation of 3-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)phenol

To a solution of ethyl 2-((3-hydroxyphenyl)sulfonyl)-2-methylpropanoate (500 mg, 1.84 mmol) in THF (30 ml) at 0°C was added lithium aluminum hydride (2.0 M in THF, 1.10 ml , 2.20 mmol). After stirring at 0° C. for 10 min and at room temperature for 3 h, the reaction was quenched with water and aqueous HCl (6.0 M) at 0° C., then warmed to room temperature. 'PrOH/DCM (20%) was added to the resulting mixture, followed by stirring for 30 minutes at room temperature. The aqueous layer was extracted with 'PrOH/DCM (20%, 3x). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated to give the title compound (411 mg, 97% yield) without further purification. LCMS m/z=231.0 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.29 (s, 6H), 3.65 (s, 2H), 7.12 (ddd, J=8.15, 2.46, 1.01 Hz, 1H), 7.26 (t, J= 2.27 Hz, 1H), 7.29-7.34 (m, 1H), 7.43 (t, J=7.96 Hz, 1H).

Step D: Preparation of (S)-2-methyl-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)propan-1-ol

To a mixture of 3-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)phenol (411 mg, 1.79 mmol) and potassium carbonate (0.76 g, 5.51 mmol) in acetone (30 ml) (S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (0.52 g, 2.02 mmol) was added. The reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled to room temperature. The solid was filtered off and washed with acetone (2x10 ml). The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.50 g, 95% yield) as a thick liquid. LCMS m/z=287.0 ^[M+H]+ ;

1H NMR (400 MHz, CDCl·,) δ ppm 1.31 (s, 6H), 2.78 (dd, J=4.80, 2.78 Hz, 1H), 2.87-2.97 (m, 2H), 3.343.40 (m, 1H) , 3.74 (d, J=4.29 Hz, 2H), 3.98 (dd, J=11.24, 5.94 Hz, 1H), 4.36 (dd, J=11.12, 2 .78 Hz, 1H), 7.227.26 (m, 1H), 7.41 (t, J=1.01 Hz, 1H), 7.45-7.51 (m, 2H).

Example 1.30. Preparation of (R)-8-((1-methyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro [4.5]decane-3-amine.

Step A: Preparation of (R)-tert-butyl-1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate.

The title compound was prepared in a manner analogous to that described in Method B, Step A.

Step B: Preparation of (R)-tert-butyl (8-((1-methyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazin-7yl)sulfonyl)-1- oxa-8-azaspiro[4.5]decan-3-yl)carbamate.

From 1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonyl chloride and (R)-tert-butyl-1oxa-8-azaspiro[4.5]decan- 3-ylcarbamate, the title compound was obtained in a manner analogous to that described in Method B, Step B. LCMS m/z=469.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.42 (s, 9H), 1.59-1.83 (m, 5H), 2.05 (dd, J=13.14, 8.08 Hz, 1H), 2.732.84 (m, 2H) , 2.98 (s, 3H), 3.33-3.42 (m, 5H), 3.51 (dd, J=9.09, 5.56 Hz, 1H), 3.85-3.93 (m, 1H), 4.05-4.15 (m, 1H), 4.51 (t, J=4.55 Hz, 1H), 7.13 (d, J=2.02 Hz, 1H) , 7.75 (d, J=2.02 Hz, 1H).

Step C: Preparation of (R)-8-((1-methyl-2,3-dihydro-2H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1oxa-8- azaspiro[4.5]decane-3-amine

To a solution of (R)-tert-butyl (8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]oxazin-7 -yl)sulfonyl)1-oxa -8-azaspiro[4.5]decan-3-yl)carbamate (189.0 mg, 0.40 mmol) in CH ₂ Cl ₂ (10 mL) was added HCl (1.01 mL, 4.03 mmol) in dioxane. The reaction mixture was stirred at room temperature overnight. The next day, white precipitation was observed. The reaction was quenched with water, then neutralized with saturated aqueous NaHCO ₃ . The resulting solution was extracted with 'PrOH/DCM (20%, 2x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (149 mg, 92% yield) as an off-white solid. LCMS m/z=369.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.50 (dd, J=13.01, 6.19 Hz, 1H), 1.60-1.78 (m, 2H), 1.78-1.86 (m, 2H),

- 73 041181

2.07 (dd, J=12.88, 7.58 Hz, 1H), 2.74-2.87 (m, 2H), 2.97 (s, 3H), 3.33-3.46 ( m, 6H), 3.50-3.57 (m, 1H), 3.86 (dd,

J=8.84, 5.81 Hz, 1H), 4.51 (t, J=4.55 Hz, 2H), 7.13 (d, J=2.02 Hz, 1H), 7.75 ( e, J=2.27 Hz, 1H).

Example 1.31. Preparation of (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine

Step A: Preparation of (R)-tert-butyl-1-oxa-8-azacniro[4.5]decan-3-ylcarbamate.

The title compound was prepared in a manner analogous to that described in Method B, Step A.

Step B: Preparation of (R)-tert-butyl (8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)carbamate

From quinolin-6-sulfonyl chloride and (R)-tert-butyl-1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate, the title compound was obtained in a manner analogous to that described in Method B, Step B, LCMS m/z =448.4 [M+H] ⁺ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.40 (s, 9H), 11.59 (dd, J=13.14, 6.06 Hz, 1H), 1.66-1.74 (m, 2H), 1.75-1.83 ( m, 2H), 1.97-2.05 (m, 1H), 2.77-2.89 (m, 2H), 3.41-3.51 (m, 3H), 3.84 (dd, J=9.22, 6.19 Hz, 1H), 4.014.12(m, 1H), 7.69(dd, J=8.34, 4.29 Hz, 1H), 8.07(dd, J = 8.84, 2.02 Hz, 1H), 8.23 (d, J=8.84 Hz, 1H), 8.48 (d, J=2.02 Hz, 1H), 8.58 (d , J=7.58 Hz, 1H), 9.03 (dd, J=4.29, 1.77 Hz, 1H).

Step C: Preparation of (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine

To a solution of (R)-tert-butyl (8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (398 mg, 0.89 mmol) in DCM (12 ml) TFA (0.68 ml, 8.89 mmol) was added at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and then neutralized with saturated aqueous NaHCO ₃ to pH 7. The resulting solution was extracted with iPrOH/DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ and filtered, then concentrated to give the title compound, which was used in the next step without purification (350 mg, 106% yield). LCMS m/z=348.2 [M+H] ⁺ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.58 (dd, J=13.64, 5.31 Hz, 1H), 1.61-1.70 (m, 1H), 1.76 (d.t, J=17.43, 14.15 Hz, 1H), 1.85 (dd, J=7.45, 4.42 Hz, 2H), 2.13 (dd, J=13.52, 7.96 Hz, 1H), 2.76-2 .90 (m, 2H), 3.45-3.56 (m, 3H), 3.63-3.71 (m, 1H), 3.85 (dd, J=9.73, 5.68 Hz , 1H), 7.70 (dd, J=8.34, 4.29 Hz, 1H), 8.07 (dd, J=8.97, 2.15 Hz, 1H), 8.23 (d, J=8.84 Hz, 1H), 8.48 (d, J=2.02 Hz, 1H), 8.58 (d, J=8.59 Hz, 1H), 9.04 (dd, J= 4.29, 1.77 Hz, 1H).

Example 1.32. Preparation of Other Intermediates of the Invention

The following chemicals were obtained using similar methods as described in the examples above, from the corresponding intermediate(s) obtained using commercial sources or synthesized according to the method described in the literature receipt. The relevant particular method(s) is(are) presented in the following table:

No. of structural element Chemical structure chemical name Method for obtaining NIA LCMS data [M+1]

- 74 041181

Cl I am yar And (5)-2-( (3- (propylsul foni l) phenoxy)methyl) oxirane BB1 257.4 C2 0”0 O\°4 (5)-2-( (3- ((cyclopropylmethyl) sulfonyl)phenoxy) methyl)oxirane BB1 269.0 NW Ο-ω^% o \ (5)-2-( (3- (isopropylsulf o no l) phenoxy)methyl) oxirane BB1 257.6 C4 Ooo ^„/CL^/sk^CFs and (5)-2-((3- ((3,3,3trifluoropropyl)sulfonyl)phenoxy) methyl)oxirane BB1 311.4 C5 And (5)-2-( (3- (isobutylsulfo Nile) phenoxy)methyl) oxirane BB1 271.2 C6 And (5)-2-( (3- (isopentylsulf o no l) phenoxy)methyl) oxirane BB1 285.2 C7 ^N ^40S^^r>HV 2-((3hydroxyphenyl)sulfonyl)aceto BB1A BB1B ВВ1С 198.0

- 75 041181

nitrile C8 ^>0 O° ^H 3- ((cyclobutyl meth silt) sulfonyl)phenol BB1A BB1B ВВ1С 227.2 C9 ABOUT 3-((4,4,4trifluorobutyl)sulfonyl)phenol BB1A BB1B ВВ1С 269.0 CIO Ο °χθ And (5)-2-( (3- (ethylsulfonyl)phenoxy)methyl)oxirane BB1 243.2 Cll Със ^ ° ⁿ and 3- ((cyclohexylme til) sulfonyl)phenol BB1A BB1B ВВ1С 255.4 C12 s : O\°4‘ (2S)-2-((3- (((2,2-difluorocyclopropyl) methyl) sulfonyl) phenoxy) methyl) oxirane BB1 305.2 C13 D. u (5)-2-( (3- (cyclobutylsul fonil) phenoxy)methyl) oxirane BB1 269, 2 C14 o ^χ ω ъ 3- (cyclopentylsul phonyl) phenol BB1A BB1B ВВ1С 227.2

- 76 041181

C15 0 0 О τ 3- (benzylsulfoni k) phenol BB1A BB1B ВВ1С 249.0 C16 V °ν ^Ν ^ ί> ^ΟΗ _Ύ '— tert-butyl-3- ((3- hydroxyphenyl)sulfonyl)azeti din-1- carboxylate BB1A BB1B ВВ1С 332.6 [M+18] + C17 Ο ο AV° \____ 1 ^Η 0 0—on tert-butyl-(2- ((3- hydroxyphenyl) sulfonyl) ethyl) carbamate BB1A BB1B ВВ1С 302.4 C18 ο And (5)-2-((3iodophenoxy)methyl) oxirane BB1D 277.0 C19 V ο \ of (25)-2-( (3- (second- butylsulfonyl) phenoxy) methyl) oxirane BB1 271.2 C20 Ρ° \ ο 0. 0° (5)-2-( (3- ((fluoromethyl)sulfonyl)phenoxy) methyl)oxirane vvz No data See NMR Below C21 \ <ο WC i ο \ Ο0 (5)-2-( (3- ((methylsulfonyl) methyl)phenoxy) methyl)oxirane BB1 No data See NMR Below C22 Ρ° 0.0 ^ο ο I (5)-2-methyl-2- ( (3-(oxirane-2- ylmethoxy)phenyl Described as an example 287.0

- 77 041181

) sulfonyl) propa n-1-ol e 1.29 C23 ooo (S)-(1- ( (3(oxiran-2ylmethoxy)phenyl ) sulfonyl)cyclobutyl)methanol Described in example e 1.28 299.4 C24 O o O!9 Λ (5}-2-methyl-2- ( (3-(oxiran-2ylmethoxy)phenyl ) sulfonyl)propa namide BB5A ВВ5В BB1D 300.2 C25 o 49 ^z ^OH and {5}-3-((3- (oxiran-2ylmethoxy)phenyl ) sulfonyl) propa n-1-ol BB1 273.2 C26 ' And {5}-2-((3- ((methoxymethyl)sulfonyl)phenoxy)methyl)oxira n BB5 276.0 [M+18] C27 Oh oo o^ /θ^^,ε-~ζ and (S)-2-((3-((3methoxypropyl)sulfonyl)phenoxy) methyl)oxirane BB5 287.0 C28 Рх 49 /^/ ^νη 2 V ° (S)-3-((3- (oxiran-2ylmethoxy)phenyl ) BB1 286, 2

- 78 041181

sulfonyl) propa namid C29 ς οΧζ °~ω U O \ (5)-ethyl-2methyl-2-((3- (oxiran-2ylmethoxy)phenyl) sulfonyl) propa noat BB5A ВВ5В BB1D 329.4 SZO I am 39 UD U^on (5)-3-((3- (oxiran-2ylmethoxy)phenyl ) sulfonyl)cyclobutanol VVZA BB1D 285.2 C31 ft /H_ oh oh 1Н-pyrrole[3,2- b] pyridine-6sul fonyl chloride BB9 217.2 C32 i f (5)-2-((3-bromo2-fluorophenoxy)methyl)oxirane BB1D 245.2 SPZ pho \o 0.° (25)-2-((3-((1fluoroethyl)sulfonyl) phenoxy)methyl) oxirane BB6A ВВ6В BB6E BB1D 260.8 C34 ooo V F (5)-2-((3-fluoro5-(oxiran-2ylmethoxy)phenyl ) sulfonyl)ethano l ВВ5В VVZA BB1D 277.2

- 79 041181

C35 2.3 0 ΙΖ^Ζ 1Η- benzo[d]imidazo l-5- sul phonyl chloride BB9 217.0 C36 -Ί \0 -ηΗζ Ο \_ ο 1,8-dimethyl- 2,3-dihydro-1Нpyrido[2,3- b][1,4]oxazine- 7- sul phonyl chloride ВВ8С 263.2 C37 ο \ \ ωζ Ο__-Ζ-— 1,6-dimethyl- 2,3-dihydro-1Hpyrido[2,3- b][1,4]oxazine- 7- sul phonyl chloride BB9 263.0 C38 /-^- E X 1ω Ο\_ο 1-ethyl-2,3dihydro-ΙΗpyrido[2,3- b][1,4]oxazine- 7- sul phonyl chloride BB9 263.2 C39 ί ;ω cr\_ ο 5-oxo-b,7dihydro-5Hpyrrole[3,4- b] pyridine-3sul fonyl chloride BB9 233.2 C40 ο Λζ CO ο ο 2-OXO-2,3dihydro-ΙΗimidazo[4,5- b] pyridine-6sul fonyl chloride BB9 234.0 C41 ° _w ° ” ^; 'TO N— 5, 6,7,8- tetrahydroquinol in-3- BB9 232.2

- 80 041181

sul phonyl chloride C42 1 ^ckS w ⁿ t NO (5)-1,3dimethyl-2,3-dihydro-1Н- pyrido[2,3b][1,4]oxazine7- sul phonyl chloride ВВ8С 263.0 C43 Ο _χ O ^crS 0X7 NO 3,4-dihydro-2Hpyrano[2,3- b] pyridine-6sul fonyl chloride BB9 234.0 C44 Ο _χ O ^? N°) ^N^T 2,3-dihydro[1,4]dioxin[2, 3-b]pyridine-7sulfonyl chloride BB9 236.0 C45 °x/° N N 1 4-methyl-3,4dihydro-2Нpyrido[3,2— b][1,4]oxazine7- sul phonyl chloride BB9 249.2 C46 O _W O | -¾ 1,3,3-trimethyl- 2,3-dihydro-1Hpyrido[2,3- b][1,4]oxazine- 7- sul phonyl chloride ВВ8С 277.2 C47 (VO./ o _o u γ ^Ν^Χ tert-butyl-7(chlorosulfonyl)-2,3-dihydro1H-pyrido[2,3-b][1,4]oxazine- BB9 335.4

- 81 041181

1-carboxylate C48 (D°1 “'''αχ NO^* (^)-1,3dimethyl-2,3-dihydro-1Hpyrido[2,3-b][1,4]oxazine7- sul phonyl chloride ВВ8С 263.2 C49 About F'CI ^N Y 1Н-pyrrole[2,3— b] pyridine-3sul fonyl chloride BB9 217.2 C50 ^ci y 1 >o ^N H 2-OXO-2,3dihydro-1Hpyrrole[2,3- b] pyridine-5sul fonyl chloride BB9 233.2 C51 about P ωί. € 1Н-pyrazole[4,3— b] pyridine-6sul fonyl chloride BB9 218.0 C52 °< o'° 8-fluoro-4- hydroxyquinoline -3- sul phonyl chloride BB12 261.9 C53 4-hydroxy-8methylquinoline-3sulfonyl chloride BB13 258.0

- 82 041181

C54 HE l 3- (ethylsulfonyl)phenol BB1A BB1B ВВ1С 187.0 C55 helluu “sh N tert-butyl-6(chlorosulfonyl)-1H-pyrrole[3,2b]pyridine-1carboxylate ВВ8С 317.0 C56 C °'b 1- ethoxynaphthalene- 2- sul phonyl chloride BB9 270.8 C57 pyrrole[1,2a]pyrimidine-3sulfonyl chloride BB9 216.8 C58 /I he °' ^C1 4- hydroxyquinoline -3- sul phonyl chloride A: stage E 244.2 C59 °h ° 1 1'-methyl-1', 2'dihydrospiro [cyclopropane- 13'- pyrido[2,3— b][1,4]oxazine] -7'- sul phonyl chloride ВВ8С 275.2 C60 ίΧΧ ,ρ ^^it ^Cl 4-hydroxy-6methylquinoline-3sulfonyl chloride BB13 258.1 C61 ο^° 6-fluoro-4- hydroxyquinoline -3- sul phonyl chloride BB12 262.0 C62 HE °' 3- (cyclobutylsul phonyl) phenol BB1A BB1B ВВ1С 213.0 C63 Λ Οχ ο^° 1-methyl-4-oxo- 1.4- dihydroquinoline- 3- sul phonyl chloride A: stage D, E 258.2

(S)-2-((3-((fluoromethyl)sulfonyl)phenoxy)methyl)oxirane (building block no. C20): 1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.74 (dd, J=5.05, 2.78 Hz, 1H), 2.86 (dd, J=5, 05, 4.29 Hz, 1H), 3.36 (dddd, J=6, 66, 4.39, 2.53, 2.34 Hz, 1H), 3.96 (dd, J=11.37, 6.57 Hz, 1H), 4.48 (dd, J=11.37, 2.53 Hz, 1H), 5.75 (d, J=45.73 Hz, 2H), 7.41-7.46 (m, 2H), 7.53 (ddd, J=7.71, 1 .26, 1.14 Hz, 1H), 7, 64 (t, J=7.58 Hz, 1H).

(S)-2-((3-((methylsulfonyl)methyl)phenoxy)methyl)oxirane (building block no. C21): 1H NMR (400 MHz, CDCl3) δ ppm 2.75-2.79 (m, 4H), 2.92 (dd, J=4.8, 4.28 Hz, 1H), 3.36 (dddd, J=5.78, 4.20, 2 .91, 2.78 Hz, 1H), 3.96 (dd, J=11.12, 5.81 Hz, 1H), 4.22 (s, 2H), 4.29 (dd, J=11, 12, 2.78 Hz, 1H), 6.95-6.99 (m, 1H), 6.997.03 (m, 2H), 7.33 (t, J=8.08 Hz, 1H).

Example 1.33. Preparation of 1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8- ylsulfonyl)quinolin-4(1H)-one (compound 310) as mesylic acid salt (Method A)

Step A: Preparation of (R)-benzyl-3-(((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)1-oxa-8-azaspiro[4.5]decan-8- carboxylate

Solution of (8)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (11.26 g, 49.32 mmol) and (K)-benzyl-3amino-1-oxa-8-azaspiro[4.5]decane -8-carboxylate (28.64 g, 98.63 mmol) in EtOH (978 ml) was sparged

- 83 041181 nitrogen for 1 h. The reaction mixture was heated at 70°C for 2 days. After cooling to room temperature, the solvent was removed under vacuum. The residue was dissolved in EtOAc (500 ml) and was extracted with saturated aqueous NaHCO ₃ . The EtOAc layer was separated. The aqueous layer was washed with EtOAc (1x). The combined organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (22.17 g, 87% yield). LCMS m/z=519.4 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.48-1.58 (m, 1H), 1.58-1.77 (m, 4H), 2.12 (dd, J=12.88, 7.58 Hz, 1H), 2.71- 2.82 (m, 2H), 3.11 (s, 3H), 3.34-3.44 (m, 2H), 3.45-3.52 (m, 1H), 3.61-3, 70 (m, 3H), 3.96-4.14 (m, 4H), 5.11 (s, 2H), 7.26-7.33 (m, 2H), 7.34-7.37 ( m, 4H), 7.48-7.51 (m, 1H), 7.51-7.57 (m, 2H).

Step B: Preparation of (R)-benzyl-3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[ 4.5]decane-8-carboxylate.

To a solution of (R)-benzyl-3 -(((S)-2-hydroxy-3 -(3 -(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8azaspiro[4.5]decane-8-carboxylate (23 .20 g, 44.73 mmol) in CH ₂ Cl ₂ (300 ml) was added DIEA (23.37 ml, 134.2 mmol) and (BOC) ₂ O (29.29 g, 134.2 mmol). The reaction mixture was stirred under nitrogen at room temperature overnight. After completion of the reaction, the mixture was washed with saturated aqueous NH4Cl, water and then brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (25.21 g, 91% yield). LCMS m/z=619.6 [M+H]+;

L NMR (400 MHz, CD3OD) δ ppm 1.46 (s, 9H), 1.48-1.57 (m, 1H), 1.60-1.74 (m, 3H), 1.89 (dd, J=12.76, 8.21 Hz, 1H), 2.11 (dd, J=12.76, 8.46 Hz, 1H), 3.11 (s, 3H), 3.22-3.29 (m, 1H), 3.34 -3.46 (m, 2H), 3.56 (dd, J=14.53, 4.42 Hz, 1H), 3.60-3.71 (m, 2H), 3.89-3.97 (m, 1H), 3.99-4.11 (m, 3H), 4.13-4.23 (m, 1H), 4.48-4.61 (m, 1H), 5.11 (s , 2H), 7.25-7.38 (m, 6H), 7.50 (t, J=1.26 Hz, 1H), 7.51-7.59 (m, 2H).

Step C: Preparation of tert-butyl-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1oxa-8-azaspiro[4.5]decan-3-yl)carbamate.

To a solution of (R)-benzyl-3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5] decane-8-carboxylate (20.8 g, 33.62 mmol) in MeOH (336.2 ml) under H2 atmosphere, palladium/C (3.59 g, 3.36 mmol) was added from a balloon. The reaction mixture was stirred at room temperature. After completion of the reaction, the mixture was filtered through a pad of celite®, then washed with MeOH. The filtrate was concentrated to give the title compound (15.43 g, 88% yield) as a white foam. LCMS m/z=485.4 [M+H]+;

L NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (s, 9H), 1.41 (d, J=6, 82 Hz, 2H), 1.49-1.58 (m, 2H), 1.66 (dd, J=12.38, 8.59 Hz, 1H), 2.01 (dd, J=12.38, 8.34 Hz, 1H), 2.52-2.58 (m, 1H), 2.71-2.84 (m , 2H), 3.01-3.13 (m, 1H), 3.21 (s, 3H), 3.42 (dd, J=14.27, 4.17 Hz, 1H), 3.75- 3.89 (m, 2H), 3.92-4.11 (m, 3H), 4.44 (brs, 1H), 5.25 (d, J=3.79 Hz, 1H), 7 .27 (dd, J=8.21, 1.64 Hz, 1H), 7.41 (t, J=2.02 Hz, 1H), 7.49 (d, J=7.83 Hz, 1H) , 7.57 (t, J=7.96 Hz, 1H).

Step D: Preparation of 1-ethylquinolin-4(1H)-one

To a solution of quinolin-4-ol (25 g, 172.2 mmol) in DMF (100 ml) was added potassium carbonate (47.61 g, 344.5 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Bromoethane (17.87 ml, 241.1 mmol) was added. The reaction mixture was heated to 80° C. overnight. After completion of the reaction and cooling to room temperature, the mixture was filtered through a pad of celite and washed with DCM. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (13.65 g, 46% yield) as a yellow solid. LCMS m/z=174.2 [M+H]+;

L NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.34 (t, J=7.07 Hz, 3H), 4.28 (q, J=7.16 Hz, 2H), 6.05 (d, J=7.58 Hz, 1H), 7. 37 (ddd, J=7.96, 4.93, 3.03 Hz, 1H), 7.69-7.76 (m, 2H), 7.99 (d, J=7.58 Hz, 1H) , 8.19 (d, J=7.83 Hz, 1H).

Step E: Preparation of 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride

Freshly distilled chlorosulfuric acid (9.21 mL, 138.6 mmol) was added dropwise under N2 to a 3-neck round bottom flask containing 1-ethylquinolin-4(1H)-one (4 g, 23.09 mmol) until isolation bubbles did not slow down (Note: a lot of smoke and gas evolved.) The resulting clear brown solution was stirred at room temperature for 30 minutes and then heated at 100° C. under N2 overnight. The reaction mixture was cooled to room temperature. The mixture was slowly poured into crushed ice in a 500 ml beaker with vigorous stirring. The precipitate was filtered off and washed with cold water to give the title compound (3.86 g, 54% yield) as a beige solid. LCMS m/z=271.8 [M] ⁺ ;

L NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.46 (t, J=7.07 Hz, 3H), 4.76 (kv, J=7.07 Hz, 2H), 7.79 (t, J=7.58 Hz, 1H), 8. 08 (dd, J=15.66, 1.52 Hz, 1H), 8.22 (d, J=8.84 Hz, 1H), 8.43 (dd, J=8.34, 1.52 Hz , 1H), 9.26 (s, 1H).

Step F: Preparation of tert-butyl ((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1oxa-8-azaspiro[4.5]decan-3-yl ) ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate.

To a solution of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (15.51 g, 32.01 mmol) in CH ₂ Cl ₂ (160 ml) was added DIEA (12.94 ml,

- 84 041181

74.18 mmol) and 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride (85.4% 12.07 g, 37.94 mmol). The reaction mixture was stirred at room temperature for 4 h, then quenched with water and washed with 10% IPA/DCM. The aqueous layer was back extracted with IPA/DCM (10%). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (21.2 g, 82% yield) as a white foam. LCMS m/z=720.6 [M+H]+;

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 1.37-1.42 (m, 3H), 1.47-1.57 (m, 1H), 1.58-1.76 (m, 4H), 2, 98-3.17 (m, 3H), 3.19 (s, 3H), 3.35 (d, J=4.04 Hz, 1H), 3.41 (dd, J=14.27, 3, 92 Hz, 1H), 3.77 (t, J=8.21 Hz, 1H), 3.84 (d, J=7.07 Hz, 1H), 3.89-4.06 (m, 4H) , 4.45 (q, J=7.07 Hz, 3H), 5.22 (d, J=5.05 Hz, 1H), 7.25 (ddd, J=6.82, 1.52, 1 .26 Hz, 1H), 7.39 (d, J=2.53 Hz, 1H), 7.44-7.49 (m, 1H), 7.50-7.58 (m, 2H), 7 .86 (d, J=1.26 Hz, 2H), 8.26 (d, J=7.58 Hz, 1H), 8.61 (s, 1H).

Step G: Preparation of 1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decane -8-ylsulfonyl)quinolin-4(1H)-one (compound 310) as mesylic acid salt

A solution of tert-butyl ((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)(( S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate (17.42 g, 24.19 mmol) in acetone (78.81 ml) was prepared in a 500 ml round bottom flask collected with a condenser and a septum at the exit of the needle to obtain a clear light yellow solution. The resulting solution was heated to 60°C. Methansulfonic acid (2.02 ml, 31.45 mmol) was added dropwise to the reaction solution with vigorous stirring. After 1 hour of stirring, a white precipitate formed; a seed crystal of the mesylate salt of the title compound (15 mg) was added to the reaction mixture. After the addition of the seed crystal, more precipitate formed over 20 minutes. The mixer has stopped. The precipitated cake was broken with a spatula and more acetone (84 ml) was added. Heating was continued overnight with stirring. The heating was turned off the next day. The reaction mixture was stirred at room temperature overnight. The next day, the reaction mixture was reheated to 60°C with stirring for 1 h, then the precipitate was collected, still hot, by vacuum filtration. The cake was washed with acetone (3x100 ml) at room temperature and dried in a heated vacuum oven at 50° C. to give the title compound (15.24 g, 88% yield) as a white solid. LCMS m/z=620.4 [M+H]+;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (t, J=7.07 Hz, 3H), 1.51-1.61 (m, 1H), 1.62-1.71 (m, 1H), 1.711.82 (m, 3H) , 2.20 (dd, J=13.26, 8.21 Hz, 1H), 2.30 (s, 3H), 2.94-3.05 (m, 1H), 3.06-3.20 (m, 3H), 3.21 (s, 3H), 3.30-3.43 (m, 1H), 3.76-3.85 (m, 1H), 3.90-3.99 (m , 2H), 4.07 (d, J=5.05 Hz, 2H), 4.10-4.19 (m, 1H), 4.46 (q, J=7.07 Hz, 2H), 5 .91 (broad s, 1H), 7.30 (ddd, J=8.15, 2.46, 0.76 Hz, 1H), 7.44 (t, J=2.27 Hz, 1H), 7.50-7.56 (m, 2H), 7.59 (t, J=7.96 Hz, 1H), 7.82-7.91 (m, 2H), 8.25 (dd, J= 7.83, 1.26 Hz, 1H), 8.63 (s, 1H), 8.76 (broad s, 2H).

¹³ C NMR (400 MHz, DMSO-d6) δ ppm 14.30, 35.68, 36.35, 42.54, 43.10, 43.21, 43.35, 48.09, 50.44, 58.11, 67.65, 70.45, 71, 00, 78.90, 112.31, 117.02, 117.43, 118.81, 120.05, 125.12, 126.17, 127.71, 130.58, 133.31, 138.91, 142.03, 147.53, 158.91, 171.53.

Example 1.34. Preparation of (S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amino)propane -2-ol (Compound 88) (Method B)

Step A: Preparation of (R)-tert-butyl-1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate

To a solution of (R)-benzyl-3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-carboxylate (39.8 g, 101.9 mmol) in MeOH (254, 8 ml) under H ₂ atmosphere, palladium/C (10.85 g, 10.19 mmol) was added from a balloon at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through a pad of Celite®, washed with MeOH and concentrated. The residue was triturated with EtOAc/Hex (10%) to give the title compound (21.02 g, 80% yield) as a yellow gum. LCMS m/z=257.4 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.37 (s, 9H), 1.41 (t, J=5, 68 Hz, 2H), 1.52 (dd, J=6.69, 3.41 Hz, 3H), 1.96 (dd , J=12.63, 8.34 Hz, 1H), 2.52-2.58 (m, 2H), 2.72-2.84 (m, 2H), 3.41 (dd, J=8 .59, 6.57 Hz, 1H), 3.83 (dd, J=8.59, 6.82 Hz, 1H), 3.92-4.08 (m, 1H), 6.99 (br. s, 1H).

Step B: Preparation of (R)-tert-butyl (8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)carbamate

To a solution of (R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate (21.02 g, 82.00 mmol) in CH ₂ Cl ₂ (370 ml) at 0° C. under atmospheric nitrogen was added DIEA (14.28 ml, 82.00 mmol) followed by the addition of a solution of quinoline-3-sulfonyl chloride (20.54 g, 90.20 mmol) in CH ₂ Cl ₂ via an additional funnel. The reaction mixture was slowly warmed to room temperature overnight. After completion of the reaction, the mixture was washed with water and then with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with hexane to give the title compound (42.31 g, 112% yield) as a light yellow solid. LCMS m/z=448.4 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.34 (s, 9H), 1.53 (dd, J=13.01, 6.44 Hz, 1H), 1.62 (t, J=4.29 Hz, 2H), 1.71 (t , J=4.55 Hz, 2H), 1.91 (dd, J=12.88, 8.34 Hz, 1H), 2.65-2.83 (m, 2H), 3.31-3, 39 (m, 2H), 3.72 (dd, J=8.84, 6.57 Hz, 1H), 3.87-4.01 (m, 1H), 6.99 (d, J=5, 81 Hz, 1H), 7.81 (ddd, J=8.15, 7.01, 1.01 Hz, 1H), 8.00

- 85 041181 (ddd, J=8.46, 6.95, 1.52 Hz, 1H), 8.17 (d, J=8.34 Hz, 1H), 8.29 (d, J=7, 58 Hz, 1H), 8.92 (d, J=l.77 Hz, 1H), 9.13 (d, J=2.27 Hz, 1H).

Step C: Preparation of (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine

To a solution of (R)-tert-butyl (8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (42.52 g, 95.01 mmol) in CH ₂ Cl ₂ (237.5 ml) at 0° C. slowly added TFA (79 ml, 1.032 mol). The reaction mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the mixture was concentrated. The reddish brown oil residue was triturated with MTBE to give the title compound (30.34 g, 92% yield) as a light brown solid. LCMS m/z=348.2 [M+H]+;

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (dd, J=13.01, 5.68 Hz, 1H), 1.53-1.67 (m, 2H), 1.70-1.84 (m, 2H), 1.94 ( dd, J=13.01, 7.71 Hz, 1H), 2.65-2.80 (m, 2H), 3.16-3.45 (m, 3H), 3.53 (d.sq., J=7.71, 5.68 Hz, 1H), 3.69 (dd, J=9.09, 6.06 Hz, 1H), 7.81 (td, J=7.58, 1.01 Hz , 1H), 8.00 (td, J=8.46, 6.95, 1.52 Hz, 1H), 8.18 (d, J=8.59 Hz, 1H), 8.28 (d, J=1.01 Hz, 1H), 8.93 (d, J=2.02 Hz, 1H), 9.13 (d, J=2.27 Hz, 1H).

Step D: Preparation of (S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- amino)propan-2-ol (Compound 88) (BD Method)

A solution of (S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol (15.23 g, 38.91 mmol) and (R)-8(quinolin-3-ylsulfonyl)-1- oxa-8-azaspiro[4.5]decan-3-amine (27.04 g, 77.82 mmol) in EtOH (160 ml) was heated at 70° C. for 24 h. After completion of the reaction, the mixture was concentrated. The residue was purified by preparative HPLC. The fractions were combined and neutralized with saturated aqueous NaHCO ₃ . The volatile phase was evaporated and then the aqueous layer was extracted with IPA/CH ₂ Cl ₂ (10%). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (9.70 g, 41% yield) as a white solid. LCMS m/z=606.4 [M+H]+;

1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (dd, J=12.63 5.31 Hz, 1H), 1.60 (t, J=5.68 Hz, 2H), 1.65-1.81 (m, 2H), 1, 88 (dd, J=12.25, 7.20 Hz, 1H), 2.53-2.61 (m, 2H), 2.68-2.79 (m, 2H), 3.32-3, 40 (m, 3H), 3.44 (t, J=6.44 Hz, 2H), 3.62-3.73 (m, 3H), 3.78-3.86 (m, 1H), 3 .89-3.95 (m, 1H), 3.98-4.04 (m, 1H), 4.86 (t, J=5.56 Hz, 1H), 5.02 (brs, 1H ), 7.25 (ddd, J=8.21, 2.53, 0.88 Hz, 1H), 7.36 (t, J=2.53 Hz, 1H), 7.43 (dd, J= 8.34, 1.77 Hz, 1H), 7.52 (t, J=7.96 Hz, 1H), 7.81 (ddd, J=8.15, 7.01, 1.01 Hz, 1H ), 8.00 (ddd, J=8.46, 6.95, 1.52 Hz, 1H), 8.18 (d, J=8.34 Hz, 1H), 8.29 (dd, J= 8.46, 0.88 Hz, 1H), 8.92 (d, J=1.77 Hz, 1H), 9.13 (d, J=2.27 Hz, 1H).

Example 1.35. Preparation of (2S)-1-(4-(methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 334) (Method C).

Step A: Preparation of tert-butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)carbamate.

Benzene-3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (4.1 g, 10.50 mmol) was dissolved in MeOH (15 ml). Made palladium/C (0.11 g, 1.05 mmol) and hydrogen (gas) from two cylinders. The reaction mixture was vigorously stirred at room temperature for 2 hours. After this time, the reaction was complete. The reaction mixture was filtered through a celite plug. The solvent was completely removed. The resulting viscous oil was redissolved in CH ₂ Cl ₂ (30 ml). DIEA (2.74 ml, 15.75 mmol) was added followed by naphthalene-2-sulfonyl chloride (2.62 g, 11.55 mmol) (slightly exothermic reaction and gas bubbling took place). The reaction mixture was stirred at room temperature for half an hour. After this time, the reaction was complete. The solvent was removed and the residue was purified by silica gel column chromatography to give the title compound (4.5 g, 95.0% yield) as a white solid. LCMS m/z=447.6 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9H), 1.48-1.56 (m, 1H), 1.56-1.63 (m, 2H), 1.64-1.74 (m, 2H), 1. 85-1.94 (m, 1H), 2.59-2.72 (m, 2H), 3.25-3.33 (m, 3H), 3.67-3.75 (m, 1H), 3.88-3.99 (m, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.67-7.79 (m, 3H), 8.08 (d, J= 8.0 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.42 (d, J=1, 4 Hz, 1H).

Step B: Preparation of tert-butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-oxiran-2-ylmethyl)carbamate

tert-Butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (2.0 g, 4.48 mmol) was dissolved in DMF (6 ml, solution remained slightly cloudy). Sodium hydride (0.32 g, 13.44 mmol) was added at room temperature (gas bubbles were observed). The reaction mixture was stirred at room temperature for half an hour. Then (S)-2-(chloromethyl)oxirane (2.07 g, 22.39 mmol) was added to the stirred solution. The reaction mixture was stirred at room temperature for one hour. After this time, it was analyzed by TLC that the reaction was about 50% complete. The reaction mixture was heated in an oil bath to 40° C. and stirred at this temperature for 2 hours. After this time, the starting material was consumed. The reaction mixture was cooled and diluted with EtOAc (20 ml). The reaction mixture was poured into a separating funnel with H ₂ O (30 ml) and was extracted with EtOAc. The combined organic layer was dried, concentrated and the residue was purified by silica gel column chromatography to give the title compound (1.47 g, 2.63 mmol, 58.8% yield) as a white foamy solid.

- 86 041181 substances. LCMS m/z=503.6 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.37 (s, 9H), 1.50-1.81 (m, 5H), 1.88-1.99 (m, 1H), 2.41-2.48 (m, 1H), 2. 57-2.75 (m, 3H), 2.92-3.00 (m, 1H), 3.23-3.43 (m, 3H), 3.43-3.50 (m, 1H), 3.52-3.59 (m, 1H), 3.63-3.73 (m, 1H), 4.35-4.51 (m, 1H), 7.66-7.79 (m, 3H ), 8.09 (d, J=7.9 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.43 (s, 1H).

Step C: Preparation of (2S)-1-(4-(methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa8-azaspiro[4.5]decan-3-ylamino)propan-2- ol (compound 334) tert-Butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-oxiran-2-ylmethyl)carbamate (10 mg , 19.90 µmol), 4-(methylsulfonyl)phenol (4.11 mg, 23.87 µmol) and potassium carbonate (8.25 mg, 59.69 µmol) were dissolved/suspended in DMF (0.2 ml). The reaction mixture was heated to 100° C. overnight. The mixture was filtered through a Celite® plug. The filtrate was concentrated and purified by preparative LCMS to give tert-butyl-((S)-2-hydroxy-3-(4(methylsulfonyl)phenoxy)propyl)(8-(naphthalen-2-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl)carbamate. After lyophilization, the material was dissolved in ACN (acetonitrile) (1.5 ml). Added 4 n. HCl in dioxane (100 μl, 0.400 mmol) and the reaction was left until complete cleavage of the Boc group. The solvents were completely removed and the resulting material was dissolved in ACN (0.2 ml) and H ₂ O (0.5 ml), frozen and lyophilized again to give the HCl salt of the title compound. Due to the presence of an impurity observed in LCMS after the lyophilization step, the material was again purified by preparative LCMS to give the title compound (3.3 mg, 23.8% yield) as a white solid (TFA salt). LCMS m/z=575.4 [M+H] ⁺ .

Example 1.36. Preparation of (2S)-1-(3-(ethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 15)

Step A: Preparation of tert-butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-oxiran-2-ylmethyl)carbamate.

tert-Butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (1.5 g, 3.36 mmol)) was dissolved in anhydrous DMF (12 ml ) under N2 to give a clear, colorless solution. Sodium hydride (0.61 g, 15.12 mmol) was added. The greyish suspension was stirred at room temperature for 30 minutes followed by the addition of (S)-2-(chloromethyl)oxirane (1.32 ml, 16.80 mmol). The reaction mixture was stirred at room temperature under N ₂ for 2 hours. The reaction was quenched with water, then poured into saturated aqueous NaHCO ₃ (25 ml). The resulting mixture was extracted with EtOAc (3x). The combined organic layer was washed with water and brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to the title compound (323 mg, 22% yield). LCMS m/z=503.4 ^[M+H]+ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.44 (s, 9H), 1.56-1.69 (m, 1H), 1.69-1.88 (m, 4H), 1.97-2.05 (m, 1H), 2. 50 (d.t., J=4.80, 2.40 Hz, 1H), 2.72-2.77 (m, 1H), 2.77-2.88 (m, 2H), 2.98- 3.07 (m, 1H), 3.32-3.38 (m, 2H), 3.38-3.50 (m, 2H), 3.56 (dd, J=14.78, 1.89 Hz, 1H), 3.70-3.81 (m, 1H), 4.49 (brs, 1H), 7.63-7.73 (m, 2H), 7.77 (dd, J= 8.59, 1.77 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.08 (d, J=8.34 Hz, 2H), 8.37 (d, J=1.26 Hz, 1H).

Step B: Preparation of (2S)-1-(3-(ethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)propan-2- ola (compound 15)

tert-Butyl (8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-oxiran-2ylmethyl)carbamate solution (15mg, 29.84µmol) in DMF (0.2 ml) was added to a 5 ml scintillation vial containing 3-(ethylsulfonyl)phenol (10.28 mg, 59.69 μmol) and K2CO3 (12.37 mg, 89.53 μmol). The reaction mixture was heated at 70° C. overnight. After completion of the reaction, the mixture was filtered through a pad of celite®, then concentrated. The residue was purified by mass directed preparative HPLC to give tert-butyl ((S)-2-hydroxy-3-(3-(ethylsulfonyl)phenoxy)propyl)(8-(naphthalen-2ylsulfonyl)-1-oxa-8-azaspiro [4.5]decan-3-yl)carbamate. LCMS m/z=689.4 [M+H] ⁺ . To a solution of tert-butyl ((S)-2-hydroxy-3-(3-(ethylsulfonyl)phenoxy)propyl)(8-(naphthalen-2-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate in ACN (2 ml) was added 4N. HCl (in dioxane, 75 ml, 0.30 mmol). The reaction mixture was gently shaken for 2 h at room temperature and concentrated. The residue was purified by mass-oriented preparative HPLC to give the title compound (8.1 mg, 39% yield) as a white solid. LCMS m/z=589.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.20 (t, J=8.00 Hz, 3H), 1.67 (dd, J=10.86, 4.29 Hz, 1H), 1.75-1.96 (m, 4H), 2 .28 (ddd, J=13.58, 8.02, 2.40 Hz, 1H), 2.73-2.90 (m, 2H), 3.06-3.29 (m, 4H), 3 .49 (t, J=12.63 Hz, 2H), 3.79-3.88 (m, 1H), 3.92-4.03 (m, 2H), 4.04-4.13 (m , 2H), 4.18-4.27 (m, 1H), 7.29 (ddd, J=8.08, 2.53, 1.26 Hz, 1H), 7.44 (t, J=4 .00 Hz, 1H), 7.48-7.52 (m, 1H), 7.55 (t, J=8.00 Hz, 1H), 7.68 (sq.d, J=8.25, 8.08 Hz, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.08 (d, J=8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Example 1.37. Preparation of (2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 1) (Method D) (S)-2-((3-(Methylsulfonyl)phenoxy)methyl)oxirane (20 mg, 87.62 µmol) and 8-(naphtalen-2ylsulfonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-amine (33.39 mg, 96.38 µmol, derived from benzyl-3-87 041181 ((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-carboxylate using a method similar to that described in example 1.2, steps A and B) was dissolved in EtOH (2.5 ml). The reaction mixture was heated at 60° C. overnight. After completion of the reaction and cooling to room temperature, the mixture was concentrated and purified by bulk direct preparative HPLC to give the title compound (7 mg, 12% yield). LCMS m/z=575.4 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.31-1.38 (m, 1H), 1.61-1.72 (m, 1H), 1.77-1.96 (m, 4H), 2.29 (dd, J=13.77 , 8.21 Hz, 1H), 2.74-2.91 (m, 2H), 3.10 (s, 3H), 3.44-3.55 (m, 4H), 3.79-3, 87 (m, 1H), 3.93-4.03 (m, 2H), 4.09 (d, J=4.80 Hz, 2H), 4.20-4.29 (m, 1H), 7 .26-7.33 (m, 1H), 7.49 (s, 1H), 7.55 (d, J=5.05 Hz, 2H), 7.62-7.74 (m, 2H), 7.77 (d, J=8.59 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d, J=8.59 Hz, 2H), 8. 38 (s, 1H).

Example 1.38. Preparation of (S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro1H-pyrido[2,3-b][1,4]oxazine -7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 154) (Method E)

Step A: Preparation of (R)-benzyl-3-((tert-butoxycarbonyl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5 ]decane-8-carboxylate.

Solution of (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane (7.63 g, 30.00 mmol) and (R)benzyl-3-amino-1-oxa-8-azaspiro[4.5] decane-8-carboxylate (17.42 g, 60.01 mmol) in EtOH (150 ml) was heated at 70° C. overnight. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column chromatography to give (R)-benzyl 3-(((S)-3-(3(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane -8-carboxylate (6.34 g, 61% yield). LCMS m/z=545.6 [M+H]+;

¹ H NMR (400 MHz, CDCI3) δ ppm 1.00-1.09 (m, 2H), 1.32-1.39 (m, 2H), 1.46-1.58 (m, 1H), 1.60-1.74 (m, 2H ), 1.79 (dd, J=13.14, 5.81 Hz, 2H), 2.10-2.17 (m, 1H), 2.48 (tt, J=7.96, 4.93 Hz, 1H), 2.92-3.09 (m, 2H), 3.35 (kv, J=10.78 Hz, 2H), 3.61-3.70 (m, 1H), 3.70 -3.81(m, 2H), 3.84-3.92(m, 1H), 4.01-4.14(m, 3H), 4.21-4.31(m, 1H), 5 .13 (s, 2H), 7.17 (ddd, J=7.89, 2.46, 1.26 Hz, 1H), 7.28-7.39 (m, 5H), 7.40-7 .55 (m, 3H).

To a solution of (R)-benzyl 3-(((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1oxa-8-azaspiro[4.5]decan-8-carboxylate (6.34 g, 11.63 mmol) in CH ₂ Cl ₂ (150.0 ml) was added DIEA (3.7 ml, 21.2 mmol) and (BOC) ₂ O (4.4 g, 20.2 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (5.81 g). LCMS m/z=645.4 [M+H]+;

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.00-1.08 (m, 2H), 1.31-1.39 (m, 2H), 1.50 (s, 10H), 1.63-1.76 (m, 3H), 1, 82 (dd, J=13.01, 8.21 Hz, 1H), 2.09 (dd, J=12.88, 8.59 Hz, 1H), 2.41-2.52 (m, 1H) , 3.27-3.54 (m, 4H), 3.663.79 (m, 2H), 3.80-3.90 (m, 1H), 3.92-4.07 (m, 3H), 4 .11-4.20 (m, 1H), 4.57-4.69 (m, 1H), 5.14 (s, 2H), 7.16 (ddd, J=8.02, 2.59, 1.26 Hz, 1H), 7.29-7.40 (m, 5H), 7.42 (t, J=2.27 Hz, 1H), 7.45-7.54 (m, 2H).

Step B: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (R)-benzyl-3-((tert-butoxycarbonyl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decan-8 -carboxylate (5.80 g, 9.00 mmol) in MeOH (45 ml) under nitrogen atmosphere was added palladium/C (0.96 g, 0.90 mmol). The reaction mixture was stirred at room temperature overnight under H2 from balloons. After completion of the reaction, the mixture was filtered through a pad of Celite® and washed with MeOH. The filtrate was concentrated to give the title compound (4.6 g, 100% yield) as a white foam LCMS m/z=511.6 [M+H]+;

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.00-1.09 (m, 2H), 1.32-1.38 (m, 2H), 1.50 (s, 9H), 1.56-1.80 (m, 6H), 2, 13 (dd, J=12.88, 8.84 Hz, 1H), 2.46 (tt, J=7.96, 4.80 Hz, 1H), 2.71-2.81 (m, 2H) , 2.93-3.07 (m, 2H), 3.38-3.56 (m, 2H), 3.76-3.87 (m, 1H), 3.93-4.07 (m, 3H), 4.12-4.20 (m, 1H), 4.59-4.71 (m, 1H), 7.16 (ddd, J=7.83, 2.53, 1.52 Hz, 1H), 7.42 (t, J=1.52 Hz, 1H), 7.45-7.55 (m, 2H).

Step C: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2hydroxypropyl)((R)-8-((1-methyl-2,3-dihydro-2H-pyrido[2, 3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate.

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (1.96 g , 3.84 mmol) in CH ₂ Cl ₂ (19.18 ml) was added DIEA (0.80 ml, 4.60 mmol) and 1-methyl-2,3-dihydro-1H-pyrido[2,3-b ][1,4]oxazine-7-sulfonyl chloride (1.10 g, 4.41 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated. The residue was then purified by silica gel column chromatography to give the title compound (2.5 g, 90% yield). LCMS m/z=723.6 [M+H] ⁺ .

Step D: Preparation of (S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1Hpyrido[2,3-b][1, 4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 154).

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)carbamate (2.5 g, 3.46 mmol) in DCM (19 mL) TFA was added (7 ml, 91.41 mmol). reaction mixture

- 88 041181 stirred at room temperature for 1 hour the Mixture was concentrated. The remainder was diluted with water. The mixture was neutralized with saturated aqueous NaHCO ₃ , then extracted with IPA/DCM (10%). The organic layer was washed with water and brine, then dried over Na ₂ SO ₄ and filtered.

The filtrate was concentrated to give the title compound (2.1 g, 88% yield) as a foam. LCMS m/z=623.4 [M+H]+;

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.07 (m, 2H), 1.09-1.13 (m, 2H), 1.47 (dd, J=12.76, 5.43 Hz, 1H), 1.56- 1.61 (m, 2H), 1.67 (dd, J=10.61, 4.29 Hz, 1H), 1.72-1.80 (m, 1H), 1.89 (dd, J= 12.76, 7.45 Hz, 1H), 2.53-2.68 (m, 4H), 2.87 (dd, J=12.63, 3.03 Hz, 1H), 2.91 (s , 3H), 3.23 (dd, J=10.74, 5.94 Hz, 2H), 3.33-3.43 (m, 4H), 3.75 (dd, J=8.59, 5 .81 Hz, 1H), 3.80-3.88 (m, 1H), 3.91-3.98 (m, 1H), 4.02-4.07 (m, 1H), 4.45 ( t, J=4.8 Hz, 2H), 4.96-5.06 (m, 1H), 7.02 (d, J=2.27 Hz, 1H), 7.28 (dd, J=7 .83, 2.02 Hz, 1H), 7.35 (t, J=1.77 Hz, 1H), 7.43 (d, J=8.34 Hz, 1H), 7.55 (t, J = 7.96 Hz, 1H), 7.71 (d, J=2.02 Hz, 1H).

¹³ C NMR (400 MHz, CD3OD) δ ppm 6.51, 25.39, 33.55, 35.28, 36.97, 38.42, 41.06, 44.42, 44.81, 48.12, 50.51, 59.71, 66, 69 67.80 68.45 71.71 80.99 114.62 117.44 121.12 121.26 129.23 131.54 132.03 135.13 143.44, 154.96, 160.46.

Example 1.39. Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1- ethylquinolin-4(1H)-one (compound 297).

Step A: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinoline- 3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)carbamate.

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (294 mg, 0 .58 mmol) in CH ₂ Cl ₂ (5 ml) was added DIEA (0.22 ml, 1.26 mmol) followed by the addition of 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride (0.27 g, 0.98 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated.

The residue was purified by silica gel column chromatography to give the title compound. LCMS m/z=746.4 [M+H] ⁺ .

Step B: Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl) -1-ethylquinolin-4(1H)-one (compound 297).

tert-Butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-ethyl-4-oxo1,4-dihydroquinolin-3-yl)sulfonyl) -1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (from the previous step) was stirred in TFA/DCM (14%, 5 ml) at room temperature overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The combined fractions were neutralized with aqueous NaHCO ₃ then the MeCN was removed under pressure. The aqueous layer was extracted with IPA/DCM (10%, 2x150 ml). The combined organic layer was washed with brine, then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in ACN (14 ml) then HCl (4N in dioxane, 2.3 eq.) was added. The solution was stirred at room temperature for 1 h followed by the addition of water (21 ml). The mixture was then lyophilized to give the title compound (356 mg, 86% yield). LCMS m/z=646.4 [M+H]+;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00-1.08 (m, 2H), 1.08-1.15 (m, 2H), 1.38 (t, J=7.07 Hz, 3H), 1.511.60 (m, 1H) , 1.62-1.70 (m, 1H), 1.72-1.84 (m, 3H), 2.20 (dd, J=13.39, 8.08 Hz, 1H), 2.87 (tt, J=7.80, 4.83 Hz, 1H), 2.93-3.04 (m, 1H), 3.05-3.22 (m, 3H), 3.29-3.42 (m, 2H), 3.78-3.87 (m, 1H), 3.87-3.99 (m, 2H), 4.07 (d, J=5.05 Hz, 2H), 4, 14-4.23 (m, 1H), 4.46 (q, J=7.07 Hz, 2H), 7.31 (dd, J=8.08, 1.77 Hz, 1H), 7.38 (t, J=1.77 Hz, 1H), 7.48 (d, J=7.83 Hz, 1H), 7.53 (ddd, J=7.96, 6.32, 1.64 Hz, 1H), 7.58 (t, J=7.96 Hz, 1H), 7.82-7.92 (m, 2H), 8.24 (d, J=1.26 Hz, 1H), 8, 63 (s, 1H), 8.96 (brs, 1H), 9.09 (brs, 1H).

Example 1.40. Preparation of 2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl) acetamide (compound 123). (Method E2)

Step A: Preparation of (R)-benzyl 3-(((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2hydroxypropyl)amino)-1-oxa-8-azaspiro[ 4.5]decane-8-carboxylate.

A solution of (S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide (14.75 g, 54.38 mmol) and (R)benzyl-3-amino-1-oxa-8- azaspiro[4.5]decane-8-carboxylate (62.5 g, 98.8 mmol) in EtOH (550 ml) was heated at 70° C. for 40 h. After completion of the reaction and cooling to room temperature, the mixture was concentrated. The residue was used in the next step without purification. LCMS m/z=562.4 [M+H] ⁺ .

Step B: Preparation of (R)-benzyl-3-(((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2hydroxypropyl)(tert-butoxycarbonyl)amino)-1- oxa-8-azaspiro[4.5]decane-8-carboxylate (R)-benzyl 3-((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)amino )-1-oxa8-azaspiro[4.5]decane-8-carboxylate from the previous step was dissolved in CH ₂ Cl ₂ (550 ml), then cooled to 0°C. DIEA (37.89 ml, 217.5 mmol) and (BOC) ₂ O (71.21 g, 326.3 mmol) were added. The reaction mixture was stirred at room temperature. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (22.1 g, 61% yield) as a yellow foam. LCMS m/z=662.6 [M+H]+;

1H NMR (400 MHz, CDCI3) δ ppm 1.50 (s, 10H), 1.64-1.85 (m, 4H), 2.09 (dd, J=13.14, 8.84 Hz, 1H), 3.29-

- 89 041181

3.55 (m, 4H), 3.68-3.87 (m, 3H), 3.92-4.01 (m, 4H), 4.02-4.08 (m, 1H), 4, 11-4.19 (m, 1H), 4.61-4.71 (m, 1H), 5.13 (s, 2H), 5.58-5.93 (m, 1H), 6.62- 6.73 (m, 1H), 7.21 (ddd, J=7.83, 2.53, 1.52 Hz, 1H), 7.30-7.39 (m, 5H), 7.43 ( T,

J=1.77 Hz, 1H), 7.48-7.58 (m, 2H).

Step C: Preparation of tert-butyl ((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decane -3-yl) carbamate

To a solution of (R)-benzyl-3-(((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)(tert-butoxycarbonyl)amino)-1- oxa-8-azaspiro[4.5]decane-8-carboxylate (22.1 g, 32.40 mmol) in MeOH (324 ml) under N ₂ was added palladium/C (3.45 g, 3.24 mmol). The reaction mixture was stirred overnight under H ₂ from balloons. The mixture was passed through a pad of Celite® and washed with MeOH. The filtrate was concentrated to give the title compound (17.6 g, 103% yield) as a white foam, which was used in the next step without purification. LCMS m/z=528.6 ^[M + ^H]+ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.50 (s, 9H), 1.54-1.69 (m, 2H), 1.71-1.83 (m, 3H), 2.10 (dd, J=13.01, 8.97 Hz, 1H), 2.72-2.88 (m, 2H), 3.00 (dddd, J=17.27, 8.56, 8.40, 4.17 Hz, 2H), 3.38- 3.56 (m, 2H), 3.66-3.85 (m, 1H), 3.92-4.09 (m, 5H), 4.10-4.18 (m, 1H), 4. 58-4.73 (m, 1H), 6.19-6.51 (m, 1H), 6.75 (brs, 1H), 7.22 (dd, J=7.58, 2.53 Hz, 1H), 7.44 (t, J=1.77 Hz, 1H), 7.48-7.58 (m, 2H).

Step D: Preparation of tert-butyl ((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2hydroxypropyl)((R)-8-(quinolin-3-ylsulfonyl)-1 -oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of tert-butyl ((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)1-oxa-8-azaspiro[4.5]decan 3-yl)carbamate (15.93 g, 30.20 mmol) in CH ₂ Cl ₂ (151 ml) under nitrogen at room temperature DIEA (7.89 ml, 45.29 mmol) and quinoline-3sulfonyl chloride were added in portions (8.25 g, 36.23 mmol). The reaction mixture was stirred for 1 hour. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (18.89 g, 87% yield) as a light yellow foam. LCMS m/z=719.4 [M+H]+;

1H NMR (400 MHz, CDC13) δ ppm 1.47 (s, 9H), 1.56-1.73 (m, 1H), 1.75-1.84 (m, 2H), 1.85-1.94 (m, 2H), 2. 05 (dd, J=13.14, 8.84 Hz, 1H), 2.75-2.90 (m, 2H), 3.30-3.42 (m, 1H), 3.42-3, 49 (m, 1H), 3.56-3.76 (m, 3H),

3.77-3.84 (m, 1H), 3.88-3.96 (m, 1H), 3.97-4.04 (m, 3H), 4.07-4.15 (m, 1H ), 4.58 (quin, J=7.52 Hz, 1H), 5.81 (br.s, 1H), 6.75 (br.s, 1H), 7.18 (ddd, J=7, 83, 2.65, 1.39 Hz, 1H), 7.39 (t, J=2.27 Hz, 1H), 7.47-7.57 (m,

2H), 7.71 (ddd, J=8.15, 7.01, 1.26 Hz, 1H), 7.91 (ddd, J=8.53, 7.01, 1.39 Hz, 1H) , 7.99 (d, J=8.34 Hz, 1H), 8.22 (d, J=8.34 Hz, 1H), 8.65 (d, J=1.77 Hz, 1H), 9 .20 (d, J=2.27 Hz, 1H).

Step E: Preparation of 2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)propoxy )phenylsulfonyl)acetamide (compound 123) tert-Butyl ((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-(quinoline3- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate from the previous step (18.89 g, 26.28 mmol) was dissolved in dioxane (100 ml) to give a clear yellow solution at 0°C . With vigorous stirring, slowly add 4N. HCl (in dioxane, 35 ml, 140 mmol). Formed a yellow piece; the reaction flask was removed from the ice bath; then it was sonicated to break the piece, after which stirring was continued at room temperature. A white solid was formed and collected to give the title compound (16.18 g, 87% yield). LCMS m/z=619.4 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.57-1.74 (m, 2H), 1.74-1.86 (m, 3H), 2.16 (dd, J=13.39, 8.08 Hz, 1H), 2.68- 2.82 (m, 2H), 2.90-3.01 (m, 1H), 3.04-3.15 (m, 1H), 3.3-3.45 (m, 2H), 3. 72-3.80 (m, 1H), 3.82-3.93 (m, 2H), 4.04 (d, J=4.80 Hz, 2H), 4.14-4.22 (m, 1H), 4.25 (s, 2H), 4.71 (br s, 2H), 7.26-7.33 (m, 2H), 7.39 (t, J=1.77 Hz, 1H ), 7.46 (d, J=8.08 Hz, 1H), 7.55 (t, J=7.96 Hz, 1H), 7.60 (br.s, 1H), 7.81 (td , J=7.58, 1.01 Hz, 1H), 8.01 (ddd, J=8.46, 6.95, 1.52 Hz, 1H), 8.18 (d, J=8.59 Hz, 1H), 8.29 (d, J=7.58 Hz, 1H), 8.94 (d, J=1.77 Hz, 1H), 9.00 (brs, 1H), 9, 11-9.21 (m, 2H).

¹³ C NMR (400 MHz, CD3OD) δ ppm 35.09, 37.00, 41.12, 44.33, 44.76, 50.34, 59.77, 62.50, 66.61, 68.35, 71.57, 80.99, 115, 36, 122.02, 122.29, 128.33, 129.58, 130.06, 130.84, 131.61, 131.82, 134.46, 139.42, 141.86, 148.02, 149.86, 160.26, 166.00.

Example 1.41. Preparation of (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-(3 -(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 163) (Method F)

Step A: Preparation of (S)-benzyl-3-(((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)amino)-1-oxa-8 -azaspiro[4.5]decane-8-carboxylate.

(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol (380mg, 1.34mmol) and (S)benzyl-3-amino-1-oxa-8- azaspiro[4.5]decane-8-carboxylate (0.70 g, 2.41 mmol) was dissolved in EtOH (10 mL).

The reaction mixture was heated at 80° C. overnight. After cooling to room temperature, the mixture was concentrated to give the title compound, which was used directly in the next step without further purification. LCMS m/z=57 5.6 [M+H] ⁺ .

- 90 041181

Step B: Preparation of (S)-benzyl-3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-((1(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)amino)-1 -oxa-8-azaspiro[4.5]decane-8carboxylate.

To a solution of (S)-benzyl-3-(((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro [4.5]decane-8-carboxylate in CH ₂ Cl ₂ (20 mL) DIEA (1.397 mL, 8.019 mmol) and (BOC) ₂ O (1.167 g, 5.346 mmol) were added at room temperature. After completion of the reaction monitored by TLC, the reaction was quenched with water. The aqueous layer was extracted with CH ₂ Cl ₂ (3x). The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (720 mg, 72.1% yield). LCMS m/z=675.2 [M+H]+;

¹ H NMR (400 MHz, CDC13) δ ppm 1.04-1.08 (m, 2H), 1.44-1.47 (m, 1H), 1.49 (s, 9H), 1.61-1.64 (m, 2H), 1, 65-1.73 (m, 4H), 1.77-1.84 (m, 1H), 2.08 (dd, J=8.85, 12.87 Hz, 1H), 3.30-3, 40 (m, 2H), 3.44-3.51(t, J=4.20 Hz, 1H), 3.66 (s, 2H), 3.68-3.75 (m, 2H), 3 .81 (dd, J=5.63, 9.65 Hz, 1H), 3.91-4.06 (m, 3H), 4.09-4.15 (m, 1H), 4.62 (t , J=6.98 Hz, 1H), 5.12 (s, 2H), 7.18-7.21 (m, 1H), 7.28-7.36 (m, 5H), 7.41- 7.42 (m, 1H), 7.46-7.52 (m, 2H).

Step C: Preparation of tert-butyl ((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5 ]decan-3-yl)carbamate

Palladium/C (0.142 g, 1.336 mmol) was withdrawn into a 50 ml baffled round bottom flask, the vessel was evacuated and filled with argon. MeOH (20 ml) was added thereto, followed by (S)benzyl-3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy) propyl)amino)-1-oxa-8-azaspiro[4.5]decan-8-carboxylate (720 mg, 0.963 mmol) in MeOH (5 ml). The reaction mixture was stirred at room temperature for 2 minutes, washed with hydrogen and stirred at room temperature under a balloon of hydrogen for 5 hours. The mixture was filtered through a pad of celite and washed with MeOH. The filtrate was concentrated to give the title compound (620 mg, 85.1% yield) as a white solid and used in the next step without further purification. LCMS m/z=541.4 [M+H]+;

¹ H NMR (400 M Hz, CD3OD) δ ppm 1.07-1.11 (m, 2H), 1.47 (s, 9H), 1.47-1.52 (m, 2H), 1.53-1.64 (m, 1H), 1, 65-1.75 (m, 1H), 1.75-1.85 (m, 2H), 2.06-2.15 (m, 2H), 2.80-2.91 (m, 2H), 2.95-3.08 (m, 2H), 3.25-3.36 (m, 1H), 3.57 (dd, J=5.22, 15.09 Hz, 1H), 3.73 ( s, 2H), 3.83 (dd, J=7.55, 9.29 Hz, 1H), 3.94-4.05 (m, 2H), 4.05-4.11 (m, 1H) , 4.14-4.20 (m, 1H), 4.52 (quin, J=7.58 Hz, 1H), 7.29 (ddd, J=7.89, 2.59, 1.39 Hz , 1H), 7.45-7.56 (m, 3H).

Step D: Preparation of tert-butyl ((S)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)((S)-2-hydroxy- 3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate.

To a solution of tert-butyl ((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl) ((S)-1-oxa-8-azaspiro[4.5]decane -3-yl)carbamate (380 mg, 0.703 mmol) in CH ₂ Cl ₂ (3.0 ml) was added DIEA (0.122 ml, 0.703 mmol) followed by the addition at 0° C. of 5-bromo-2ethoxybenzene-1-sulfonyl chloride ( 0.211 g, 0.703 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography to give the title compound (0.521 g, 86% yield) as a white solid. LCMS m/z=803.4 [M+H]+;

1H NMR (400 M Hz, CDCl·,) δ ppm 1.05-1.08 (m, 2H), 1.45 (t, J=7.00 Hz, 3H), 1.49 (s, 9H), 1.58-1.65 (m, 3H) , 1.71-1.86 (m, 5H), 2.07 (dd, J=8.62, 12.93 Hz, 1H), 3.04-3.14 (m, 2H), 3.46 (d, J=3.72 Hz, 2H), 3.53-3.58 (m, 2H), 3.66 (s, 2H), 3.77 (dd, J=6.03, 9.48 Hz, 1H), 3.91 (dd, J=6.90, 9.48 Hz, 1H), 3.96-4.04 (m, 2H), 4.094.15 (m, 3H), 4.55 -4.62 (m, 1H), 6.86 (d, J=8.84 Hz, 1H), 7.18 (d.t, J=2.31, 7.17 Hz, 1H), 7. 40-7.41 (m, 1H), 7.46-7.52 (m, 2H), 7.56 (dd, J=2.54, 8.80 Hz, 1H), 8.00 (d, J=2.52 Hz, 1H).

Step E: Preparation of tert-butyl ((S)-8-((4'-(((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1'biphenyl]-3-yl)sulfonyl)- 1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl ((S)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-2-hydroxy-3- (3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (0.521 g, 0.604 mmol) in EtOH/H ₂ O (4.5 mL, 2:1 ratio) added potassium carbonate (97.14 mg, 0.703 mmol), Pd(dppf) ₂ complex with DCM (0.578 g, 0.703 mmol) and (4-(((tert-butoxycarbonyl) amino) methyl) phenyl) boronic acid (0.176 g, 0.703 mmol). The reaction mixture was heated to 80°C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with water (3x) and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (440 mg, 61.5% yield) as a white solid. LCMS m/z=930.6 [M+H] ⁺ .

Step F: Preparation of (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3 -(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 163)

- 91 041181 tert-Butyl ((S)-8-((4'-(((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)- 1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (380 mg, 0.409 mmol) was dissolved in MeOH (1.0 ml) followed by the addition of HCl (4N in dioxane, 1.5 ml, 6.128 mmol) at room temperature. The reaction mixture was stirred at room temperature until the Boc groups were cleaved (~30 min). The mixture was concentrated and the residue was purified by preparative HPLC. The combined fractions were concentrated and the residue was dissolved in water and neutralized with saturated aqueous NaHCO ₃ (pH~8). The aqueous layer was extracted with 5% MeOH/CH ₂ Cl ₂ (3x). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in MeOH (1.0 ml) and HCl (4N in dioxane, 1.532 ml, 6.128 mmol) was added. The solution was aged for 1 hour, then concentrated, then lyophilized to give the title compound (263 mg, 80.2% yield) as a white solid. LCMS m/z=730.6 [M+H]+;

¹ H NMR (400 M Hz, CD3OD) δ ppm 1.07-1.10 (m, 2H), 1.48 (t, J=7.00 Hz, 3H), 1.49-1.51 (m, 2H), 1.611.68 (m, 1H) , 1.79-1.92 (m, 4H), 2.36 (dd, J=8.09, 13.75 Hz, 1H), 3.08-3.21 (m, 3H), 3.32 -3.36 (m, 1H), 3.533.61 (m, 2H), 3.72 (s, 2H), 3.94 (dd, J=4.05, 9.71 Hz, 1H), 4, 01-4.08 (m, 1H), 4.08-4.14 (m, 3H), 4.16 (s, 2H), 4.26 (kv, J=7.00 Hz, 2H), 4 .24-4.31 (m, 1H), 7.30 (d, J=8.72 Hz, 1H), 7.28-7.32 (m, 1H), 7.47-7.52 (m , 3H), 7.55 (d, J=7.20 Hz, 2H), 7.69 (d, J=8.24 Hz, 2H), 7.87 (dd, J=2.32, 8, 71 Hz, 1H), 8.08 (d, J=2.36 Hz, 1H).

Example 1.42. Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxy propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1 -ethyl-8-fluoroquinolin-4(1H)-one (compound 333). (Method G)

Step A: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2hydroxypropyl)((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1 -oxa-8-azaspiro[4.5]decan-3-yl) carbamate

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (50 mg, 97 .92 µmol) in CH ₂ Cl ₂ (3.26 ml) under nitrogen were added DIEA (34.11 µl, 0.20 mmol) and 8-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (28.18 mg, 0 .11 mmol). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was then concentrated and purified by silica gel column chromatography to give the title compound (76 mg, 95% yield) as a white solid. LCMS m/z=736.4 ^[M+H]+ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.01-1.09 (m, 2H), 1.18-1.23 (m, 2H), 1.32-1.36 (m, 1H), 1.45 (s, 9H), 1, 57-1.65 (m, 1H), 1.69-1.76 (m, 1H), 1.79 (t, J=5.94 Hz, 2H), 1.86 (dd, J=12, 63, 8.08 Hz, 1H), 2.07 (dd, J=12.63, 8.59 Hz, 1H), 2.66 (tt, J=7.83, 4.80 Hz, 1H), 3.21-3.28 (m, 3H), 3.42-3.56 (m, 3H), 3.85-3.92 (m, 1H), 3.94-4.08 (m, 3H ), 4.11-4.19 (m, 1H), 4.52 (dd, J=13.89, 7.07 Hz, 1H), 7.27 (ddd, J=8.15, 2.59 , 1.14 Hz, 1H), 7.42 (t, J=2.27 Hz, 1H), 7.43-7.53 (m, 3H), 7.60 (ddd, J=10.80, 7.89, 1.26 Hz, 1H), 8.08 (d, J=8.34 Hz, 1H), 8.47 (s, 1H).

Step B: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-ethyl-8-fluoro-4-oxo-1, 4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan3-yl)carbamate

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((8fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa -8-azaspiro[4.5]decan-3-yl)carbamate (76 mg, 0.10 mmol) in DMF (1.5 mL) DIEA (44.98 μL, 0.258 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. Bromoethane (43.3 µl, 0.77 mmol) was then added. The reaction mixture was heated under microwave irradiation at 110° C. for 4 hours. The mixture was purified by semi-preparative HPLC to give the title compound (44 mg, 56% yield) as a white solid. LCMS m/z=764.4 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.01-1.08 (m, 2H), 1.17-1.23 (m, 2H), 1.45 (s, 9H), 1.52 (t, J=6.57 Hz, 3H) , 1.61 (ddd, J=13.39, 9.73, 3.92 Hz, 1H), 1.73 (ddd, J=13.52, 4.04, 3.92 Hz, 1H), 1 .79 (t, J=5.81 Hz, 2H), 1.86 (dd, J=12.76, 8.21 Hz, 1H), 2.07 (dd, J=12.63, 8.59 Hz, 1H), 2.66 (tt, J=7.86, 4.77 Hz, 1H), 3.20-3.30 (m, 3H), 3.41-3.57 (m, 3H) , 3.83-3.91 (m, 1H), 3.94-4.08 (m, 3H), 4.11-4.21 (m, 1H), 4.45-4.61 (m, 3H), 7.27 (ddd, J=8.08, 2.53, 1.01 Hz, 1H), 7.42 (t, J=2.53 Hz, 1H), 7.43-7.47 (m, 1H), 7.49-7.55 (m, 2H), 7.65 (ddd, J=14.91, 8.08, 1.52 Hz, 1H), 8.22 (dd, J = 8.08, 1.01 Hz, 1H), 8.56 (s, 1H).

Step C: Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl) -1-ethyl-8-fluoroquinolin-4(1Н)-one (compound 333)

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1ethyl-8-fluoro-4-oxo-1,4-dihydroquinoline- 3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (33 mg, 44.85 µmol) in THF (2 ml) HCl (2 N in dioxane, 1 ml) was added , 2.0 mmol). The reaction mixture was stirred at room temperature overnight. DCM (2 ml) was added to improve solubility and an additional 2N was added. HCl (in dioxane, 0.5 ml). After completion of the reaction, the mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (26.3 mg, 87% yield), which was then converted to its HCl salt. LCMS m/z=664.6 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.02-1.10 (m, 2H), 1.19-1.25 (m, 2H), 1.52 (t, J=6.57 Hz, 3H), 1.591.70 (m, 1H) , 1.77-1.91 (m, 4H), 2.35 (dd, J=13.64, 8.08 Hz, 1H), 2.67 (tt, J=7.96, 4.80 Hz , 1H), 3.17-3.30 (m, 4H), 3.52-3.65 (m, 2H), 3.90-3.97 (m, 1H), 3.98-4.06 (m, 1H), 4.06-4.15 (m, 3H), 4.21-4.30 (m, 1H), 4.55 (q.d., J=7.07, 3.03 Hz , 2H), 7.30 (ddd, J=7.89, 2.59, 1.39 Hz, 1H), 7.45 (t, J=2.27 Hz, 1H), 7.49-7, 59 (m, 3H), 7.67 (ddd, J=14.91, 8.08, 1.52 Hz, 1H), 8.22 (dd, J=8.46, 1.14 Hz, 1H) , 8.58 (s, 1H).

¹³ C NMR (400 MHz, CD3OD) δ ppm 6.42, 33.52, 35.72, 37.66, 41.14, 44.25, 44.68, 50.39, 59.86, 66.71, 68.37, 71.62, 81, 65, 114.53, 119.17, 119.33, 120.17, 121.10, 121.38, 122.44, 122.48, 126.61, 126.68, 130.19, 130.57, 130.71, 132.02, 143.59, 145.09, 152.63, 155.12, 160.48, 174.52, 174.55.

Example 1.43. Preparation of (S)-1-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5] decan-3-ylamino)propan-2-ol (compound 130)

Step A: Preparation of tert-butyl ((S)-3-(3-((1,1-difluoro-2-hydroxyethyl)sulfonyl)phenoxy)-2hydroxypropyl)((R)-8-(quinolin-3-ylsulfonyl) -1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate.

(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol (20mg, 67.96µmol) and (R)-8(quinolin-3-ylsulfonyl) -1-oxa-8-azaspiro[4.5]decan-3-amine (37.78 mg, 0.109 mmol) was dissolved in EtOH (0.5 ml). The reaction mixture was heated at 75° C. overnight. The mixture was concentrated and the residue was purified by flash chromatography to give the title compound as a white solid.

Step B: Preparation of (S)-1-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3ylsulfonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-ylamino)propan-2-ol (compound 130).

Tert-butyl ((S)-3-(3-((1,1-difluoro-2-hydroxyethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-8(quinolin-3-ylsulfonyl)-1- oxa-8-azaspiro[4.5]decan-3-yl) carbamate was dissolved in HCl (4 N in dioxane, 0.34 mL, 1.36 mmol) and aged for 2 h. The mixture was concentrated to give the title compound (25.5 mg, 50.5% yield) as a white solid. LCMS m/z=642.4 ^[M+H]+ ;

1H NMR (400 M Hz, CD3OD) δ ppm 1.68-1.75 (m, 1H), 1.83-1.99 (m, 4H), 2.34 (dd, J=7.24, 13.45 Hz, 1H), 2.89- 3.00 (m, 2H), 3.13-3.18 (m, 1H), 3.25-3.33 (m, 1H), 3.57-3.60 (m, 2H), 3. 61-3.68 (m, 5H), 3.72-3.75 (m, 2H), 3.86-3.91 (m, 1H), 3.99-4.05 (m, 2H), 4.09-4.12 (m, 1H), 4.14 (t, J=13.97 Hz, 2H), 4.24-4.29 (m, 1H), 7.427.45 (m, 1H) , 7.51 (brs, 1H), 7.59 (d, J=7.76 Hz, 1H), 7.63 (t, J=7.76 Hz, 1H), 7.94 (t, J=7.50 Hz, 1H), 8.16 (t, J=7.54 Hz, 1H), 8.27 (d, J=8.52 Hz, 1H), 8.35 (d, J= 8.20 Hz, 1H), 9.21 (brs, 1H), 9.36 (brs, 1H).

Example 1.44. Preparation of (S)-1-(3-(methylsulfonyl)phenoxy)-3-((R)-8-(naphtalen-2-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2 -ol (compound 3) (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (8 mg, 35.05 µmol) and (R)-8-(naphthalen-2ylsulfonyl)-1-oxa- 8-azaspiro[4.5]decan-3-amine (24.28 mg, 70.09 µmol) was dissolved in EtOH (1.5 ml). The reaction mixture was heated at 60° C. overnight. After completion of the reaction and cooling to room temperature, the mixture was concentrated and purified by bulk direct preparative HPLC to give the title compound (15.1 mg, 62% yield). LCMS m/z=575.4 ^[M+H]+ ;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.60-1.71 (m, 1H), 1.76-1.95 (m, 4H), 2.29 (dd, J=13.77, 8.21 Hz, 1H), 2.73- 2.91 (m, 2H), 3.10 (s, 3H), 3.11-3.16 (m, 1H), 3.25 (dd, J=12.88, 3.03 Hz, 1H) , 3.43-3.55 (m, 2H), 3.80-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.13 (m, 2H), 4.17-4.27 (m, 1H), 7.25-7.33 (m, 1H), 7.49 (d, J=1.52 Hz, 1H), 7.55 (d , J=5.56 Hz, 2H), 7.68 (q.d., J=8.25, 8.08 Hz, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.06-8.12 (m, 2H), 8.38 (d, J=1.26 Hz, 1H).

Example 1.45. Preparation of (S)-1-(3-(methylsulfonyl)phenoxy)-3-((S)-8-(naphtalen-2-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2 -ola (compound 4).

(S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (50mg, 0.22mmol) and (S)-8-(naphthalen-2ylsulfonyl)-1-oxa-8-azaspiro[4.5] decan-3-amine hydrochloride (0.17 g, 0.44 mmol) was dissolved in EtOH (3 ml) followed by the addition of DIEA (83.94 μl, 0.482 mmol). The reaction mixture was heated at 60° C. overnight. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and then purified by mass direct preparative HPLC. The resulting TFA salt was lyophilized and redissolved in MeOH. The solution was passed through an SCX cartridge and washed with 2N NH3 in MeOH. The filtrate was added with HCl (4 N in dioxane, 400 (j, L) and concentrated to give the title compound (27 mg, 20% yield) as a white solid. LCMS m/z=575.4 [M+ H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.61-1.71 (m, 1H), 1.76-1.96 (m, 4H), 2.29 (dd, J=13.64, 8.34 Hz, 1H), 2.73- 2.89 (m, 2H), 3.05-3.15 (m, 4H), 3.27 (dd, J=12.88, 3.03 Hz, 1H), 3.44-3.56 ( m, 2H), 3.78-3.86 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.13 (m, 2H), 4.18-4, 26 (m, 1H), 7.25-7.32 (m, 1H), 7.49 (d, J=1.52 Hz, 1H), 7.54-7.58 (m, 2H), 7 .63-7.74 (m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8, 05-8.12 (m, 2H), 8.38 (d, J=1.52 Hz, 1H).

Example 1.46. Preparation of (2S)-1-(8-(4'-((methylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl) phenoxy)propan-2-ol (compound 78). (Method H)

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Step A: Preparation of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8azaspiro[4.5]decan-3-yl) carbamate.

From (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane and benzyl-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, the title compound was prepared in a manner analogous to that described. method A, steps A, B and C.

Step B: Preparation of tert-butyl (8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-2-hydroxy-3-(3-(methylsulfonyl) phenoxy) propyl) carbamate

To a solution of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (243 mg, 0.50 mmol ) in THF (7 mL) under nitrogen was added DIEA (0.18 mL, 1.00 mmol) and 3-bromobenzene-1-sulfonyl chloride (0.17 g, 0.65 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (313 mg, 89% yield) as a white foam. LCMS m/z=705.3 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.44 (s, 9H), 1.57-1.67 (m, 1H), 1.71-1.79 (m, 1H), 1.79-1.87 (m, 2H), 1. 98-2.05 (m, 1H), 2.77 (ddd, J=15.03, 11.87, 11.75 Hz, 2H), 3.11 (s, 3H), 3.21-3, 27 (m, 1H), 3.34-3.41 (m, 3H), 3.53 (dd, J=14.65, 4.55 Hz, 1H), 3.80-3.90 (m, 1H), 3.93-4.10 (m, 3H), 4.11-4.18 (m, 1H), 4.43-4.51 (m, 1H), 7.28 (d.t., J=5.87, 3.00 Hz, 1H), 7.48 (d, J=1.52 Hz, 1H), 7.51-7.58 (m, 3H), 7.75 (d, J = 7.83 Hz, 1H), 7.84 (d, J=8.08 Hz, 1H), 7.90 (t, J=1.77 Hz, 1H).

Step C: Preparation of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4'(hydroxymethyl)-[1,1'-biphenyl]-3- yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl) carbamate

To a 20 ml microwave tube containing a magnetic stir bar was added Pd(dppf) ₂ , DCM (0.54 g, 0.65 mmol), and (4-(hydroxymethyl)phenyl)boronic acid (59.34 mg, 0.39 mmol). Then a solution of tert-butyl (8-((3-bromophenyl)sulfonyl)-1oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-( methylsulfonyl)phenoxy)propyl)carbamate (229 mg, 0.33 mmol) and sodium carbonate solution (0.358 ml, 0.716 mmol). The resulting mixture was heated at 90° C. overnight. After completion of the reaction, the mixture was diluted in EtOAc, then washed with water and brine. The organic layer was dried over Mg ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (209 mg, 87% yield). LCMS m/z=731.5 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.43 (s, 9H), 1.56-1.69 (m, 1H), 1.70-1.79 (m, 1H), 1.79-1.89 (m, 2H), 1. 95-2.10 (m, 2H), 2.74-2.85 (m, 2H), 3.09 (s, 3H), 3.16-3.27 (m, 1H), 3.35- 3.44 (m, 2H), 3.46-3.55 (m, 1H), 3.70-4.07 (m, 4H), 4.09-4.18 (m, 1H), 4. 42-4.51 (m, 1H), 4.67 (s, 2H), 7.21-7.31 (m, 1H), 7.45-7.54 (m, 5H), 7.63- 7.72 (m, 3H), 7.72-7.77 (m, 1H), 7.92-8.00 (m, 3H).

Step D: Preparation of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4'((methylamino)methyl)-[1,1'-biphenyl] 3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl) carbamate.

To a solution of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl )sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (10 mg, 13.68 µmol) in dioxane (1 ml) was added methanesulfonyl chloride (9.53 µl, 123.15 µmol). The reaction mixture was stirred at room temperature overnight. The next day, methanamine (637.4 μg, 20.52 μmol) was added and the reaction mixture was stirred overnight. After completion of the reaction, the mixture was quenched with water and purified by mass-oriented preparative HPLC. The isolated fractions were lyophilized to give the title compound as a white solid. LCMS m/z=744.4 [M+H] ⁺ .

Step E: Preparation of (2S)-1-(8-(4'-((methylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-(3- (methylsulfonyl)phenoxy)propan-2-ol (compound 78).

TFA salt tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4'-((methylamino)methyl)-[1,1'-biphenyl] -3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl) carbamate was dissolved in ACN (2 ml) and HCl (4 N in dioxane, 51.31 μl, 0.21 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then concentrated and purified by preparative HPLC to give the title compound (4.8 mg, 46% yield). LCMS m/z=644.4 ^[M+H]+ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.68 (m, 1H), 1.79-1.97 (m, 4H), 2.31 (ddd, J=13.77, 8.21, 2.02 Hz, 1H), 2.69- 2.85 (m, 5H), 3.11 (s, 3H), 3.12-3.19 (m, 1H), 3.25-3.29 (m, 1H), 3.42-3, 55 (m, 2H), 3.83-3.93 (m, 1H), 3.95-4.07 (m, 2H), 4.07-4.15 (m, 2H), 4.21- 4.30 (m, 3H,) 7.26-7.33 (m, 1H), 7.49 (t, J=1.25 Hz, 1H), 7.56 (d, J=5.05 Hz , 2H), 7.62 (d, J=8.34 Hz, 2H), 7.74 (t, J=8.34 Hz, 1H), 7.76-7.83 (m, 3H), 7 .94-8.01 (m, 2H).

Example 1.47. Preparation of (S)-1-((R)-8-(2H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-( 3-(methylsulfonyl)phenoxy)propan-2-ol (compound 320)

Step A: Preparation of tert-butyl ((R)-8-((2H-pyrrole[3,2-b]pyridin-6-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)( (S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl) carbamate (30 mg, 61.91 µmol) in CH ₂ Cl ₂ (5 ml) was added DIEA (12.94 µl,

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74.29 µmol) and 1H-pyrrole[3,2-b]pyridine-6-sulfonyl chloride (16.09 mg, 74.29 µmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (14 mg, 34% yield). LCMS m/z=665.4 [M+H]+.

Step B: Preparation of (S)-1-((R)-8-(2H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino )-3-(3-(methylsulfonyl)phenoxy)propan-2-ol (compound 320)

tert-Butyl ((R)-8-((1H-pyrrole[3,2-b]pyridin-6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)- 2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate (14mg, 21.1μmol) was dissolved in DCM (3mL) followed by HCl (4N in dioxane, 0.2mL). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was concentrated to give a white solid which was then triturated with MeCN to give the title compound (11.2 mg, 28% yield) as a solid. LCMS m/z=565.4 [M+H]+;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56-1.87 (m, 5H), 2.15 (dd, J=13.64, 8.08 Hz, 1H), 2.57-2.73 (m, 2H), 2.89- 3.01 (m, 1H), 3.07-3.15 (m, 1H), 3.21 (s, 3H), 3.25-3.37 (m, 2H), 3.64-3, 98 (m, 4H), 4.06 (d, J=5.05 Hz, 2H), 4.13-4.20 (m, 1H), 6.78 (brs, 1H), 7.29 (ddd, J=8.08, 2.53, 1.01 Hz, 1H), 7.43 (d, J=1.77 Hz, 1H), 7.48-7.54 (m, 1H), 7.58 (t, J=7.96 Hz, 1H), 8.06 (d, J=2.27 Hz, 1H), 8.20 (br s, 1H), 8.68 (s, 1H ), 8.95 (brs, 1H), 9.08 (brs, 1H), 12.05 (brs, 1H).

Example 1.48. Preparation of (S)-1-((R)-8-(2H-pyrrole[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-( 3-(isopropylsulfonyl)phenoxy)propan-2-ol (Compound 321) (Method E3)

Step A: Preparation of tert-butyl ((R)-8-((2H-pyrrole[3,2-b]pyridin-6-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)( (S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate

From (S)-2-((3-(isopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate and tert-butyl- 6-(chlorosulfonyl)-1H-pyrrole[3,2-B]pyridine-1-carboxylic acid prepared the title compound in a manner analogous to that described in Method E, Steps A, B, and C. LCMS m/z=793.6 [M+N] ⁺ .

Step B: Preparation of (S)-1-((R)-8-(2H-pyrrole[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)- 3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol (compound 321)

From tert-butyl ((R)-8-((1H-pyrrolo[3,2-b]pyridin-6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S) -2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate gave the title compound in a manner analogous to that described in Method G, Step C. LCMS m/z=593.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.24 (d, J=6.82 Hz, 6H), 1.65-1.78 (m, 1H), 1.83-1.99 (m, 4H), 2.36 (dd, J= 13.64, 7.83 Hz, 1H), 2.83-2.99 (m, 2H), 3.16 (dd, J=12.63, 9.85 Hz, 1H), 3.27 (d , J=3.03 Hz, 1H), 3.323.37 (m, 1H), 3.55-3.64 (m, 2H), 3.64-3.76 (m, 1H), 3.86- 3.95 (m, 1H), 3.99-4.07 (m, 2H), 4.07-4.15 (m, 2H), 4.23-4.32 (m, 1H), 7. 04 (d, J=3.23 Hz, 1H), 7.33 (dd, J=8.34, 1.77 Hz, 1H), 7.42 (t, J=1.52 Hz, 1H), 7.48 (d, J=7.83 Hz, 1H), 7.57 (t, J=7.96 Hz, 1H), 8.42 (d, J=3.28 Hz, 1H), 8. 86 (s, 1H), 9.05 (d, J=1.26 Hz, 1H).

Example 1.49. Preparation of 1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5] decan-8-ylsulfonyl)quinolin-4(1Н)-one (compound 322)

Step A: Preparation of tert-butyl ((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl) ((S)- 2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

From tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (40, 0 mg, 82.54 d mol) and 8-fluoro-4-hydroxyquinoline-3-sulfonyl chloride gave the title compound in a manner analogous to that described in Method G, step A. LCMS m/z=7106 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.45 (s, 9H), 1.61 (ddd, J=13.39, 5.18, 4.93 Hz, 1H), 1.69-1.77 (m, 1H), 1.80 ( t, J=8 Hz, 2H), 1.86 (dd, J=12.63, 8.08 Hz, 1H), 2.08 (dd, J=12.76, 8.46 Hz, 1H), 3.09 (s, 3H), 3.223.29 (m, 3H), 3.42-3.56 (m, 4H), 3.85-3.92 (m, 1H), 3.96-4, 08 (m, 3H), 4.12-4.19 (m, 1H), 4.47-4.57 (m, 1H), 7.28 (d.t., J=7.39, 2.24 Hz, 1H), 7.43-7.55 (m, 4H), 7.61 (ddd, J=10.80, 8.02, 1.14 Hz, 1H), 8.08 (d, J= 8.34 Hz, 1H), 8.47 (s, 1H).

Step B: Preparation of 1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro [4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (compound 322).

To a solution of tert-butyl ((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)- 2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate (48 mg, 67.62 µmol) in DMF (2 ml) was added iodoethane (81.13 µl, 1.01 mmol) and DIEA (0. 18 ml, 1.01 mmol). The reaction mixture was heated at 120° C. for 2.5 hours. After completion of the reaction, the mixture was diluted in EtOAc, then washed with water (2x) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl ((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8- azaspiro[4.5]decan-3yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate. LCMS m/z=738.6 [M+H] ⁺ .

tert-Butyl ((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3 -yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate from the previous step was dissolved in EtOAc (2 ml) followed by the addition of HCl (4N in dioxane, 0.4 ml). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was concentrated and the residue was purified by HPLC to give the FTA salt of the title compound. The TFA salt was lyophilized then neutralized. The resulting material was dissolved in EtOAc (2 ml) and treated with HCl (4N in dioxane, 0.1 ml). The mixture was concentrated to give the HCl salt of the title compound (36.2 mg, 75% yield) as a white solid. LCMS m/z=638.6 [M+H]+;

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (t, J=6.69 Hz, 3H), 1.52-1.61 (m, 1H), 1.62-1.71 (m, 1H), 1.721.83 (m, 3H) , 2.20 (dd, J=13.26, 7.96 Hz, 1H), 2.94-3.05 (m, 1H), 3.06-3.20 (m, 3H), 3.22 (s, 3H), 3.33-3.43 (m, 2H), 3.77-3.86 (m, 1H), 3.87-3.99 (m, 2H), 4.07 (d , J=5.05 Hz, 2H), 4.13-4.22 (m, 1H), 4.44-4.54 (m, 1H), 5.91 (d, J=4.80 Hz, 1H), 7.30 (dd, J=8.08, 1.77 Hz, 1H), 7.44 (t, J=2.02 Hz, 1H), 7.49-7.56 (m, 2H ), 7.59 (t, J=7.96 Hz, 1H), 7.76 (ddd, J=15.03, 7.96, 1.52 Hz, 1H), 8.11 (d, J= 7.83 Hz, 1H), 8.56(s, 1H), 8.91(brs, 1H), 8.98(brs, 1H).

Example 1.50. Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinoline-4 (1Н)-one (compound 326) as HCl salt.

Step A: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa -8-azaspiro[4.5]decan-3-yl)carbamate

From tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate and 4-hydroxyquinoline-3 -sulfonyl chloride gave the title compound in a manner analogous to that described in Method G, Step A. LCMS m/z=718.6 ^[M+H]+ ;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.00-1.09 (m, 2H), 1.18-1.23 (m, 2H), 1.45 (s, 9H), 1.56-1.66 (m, 1H), 1, 68-1.76 (m, 1H), 1.80 (t, J=6.82 Hz, 2H), 1.86 (dd, J=12.88, 8.34 Hz, 1H), 2.07 (dd, J=12.76, 8.46 Hz, 1H), 2.62-2.71 (m, 1H), 3.20-3.28 (m, 3H), 3.38-3.57 (m, 4H), 3.84-3.92 (m, 1H), 3.95-4.06 (m, 3H), 4.11-4.19 (m, 1H), 4.44-4 .56 (m, 1H), 7.26 (d.t., J=8.08, 1.26 Hz, 1H), 7.39-7.46 (m, 2H), 7.47-7.54 (m, 2H), 7.62 (d, J=7.83 Hz, 1H), 7.76-7.82 (m, 1H), 8.29 (dd, J=8.08, 1.01 Hz, 1H), 8.51 (s, 1H).

Step B: Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl) quinolin-4(1H)-one (compound 326) as HCl salt.

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((4hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro [4.5]Decan-3-yl)carbamate (17 mg, 23.68 µmol) in THF/DCM (1:1 ratio, 4 mL) HCl (4N in dioxane, 1 mL, 1.0 mmol) was added. The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was concentrated and the residue was purified by preparative HPLC to give the TFA salt of the title compound. The TFA salt was lyophilized and converted to the HCl salt of the title compound (12.1 mg, 78.1% yield). LCMS m/z=618.4 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.02-1.10 (m, 2H), 1.19-1.25 (m, 2H), 1.31-1.34 (m, 1H), 1.56-1.72 (m, 1H ), 1.77-1.91 (m, 4H), 2.33-2.39 (m, 1H), 2.62-2.71 (m, 1H), 3.14-3.29 (m , 3H), 3.50-3.63 (m, 2H), 3.90-3.97 (m, 1H), 3.98-4.06 (m, 1H), 4.07-4.15 (m, 3H), 4.22-4.29 (m, 1H), 7.30 (ddd, J=7.89, 2.59, 1.39 Hz, 1H), 7.45 (t, J =2.27 Hz, 1H), 7.49-7.59 (m, 3H), 7.63 (d, J=8.08 Hz, 1H), 7.80 (ddd, J=8.40, 7.01, 1.52 Hz, 1H), 8.29 (dd, J=8.08, 1.01 Hz, 1H), 8.53 (s, 1H).

Example 1.51. Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8- methylquinolin-4-ol (Compound 327)

Step A: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2hydroxypropyl)((R)-8-((4-hydroxy-8-methylquinolin-3-yl)sulfonyl)-1 -oxa-8-azaspiro[4.5]decan-3yl)carbamate

From tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate and 4-hydroxy-8 -methylquinoline-3-sulfonyl chloride gave the title compound in a manner analogous to that described in Method G, Step A. LCMS m/z=732.6 [M+H]+;

¹ H NMR (400 MHz, CDC13) δ ppm 1.01-1.10 (m, 2H), 1.30-1.37 (m, 2H), 1.47 (s, 9H), 1.66 (dd, J=11.24, 4.17 Hz, 1H), 1.75-1.92 (m, 5H), 2.04 (dd, J=13.01, 8.72 Hz, 1H), 2.47 (tt, J=7.93, 4.71 Hz, 1H), 2.63(s, 3H), 2.65-2.78(m, 2H), 3.36(brs, 1H), 3.43-3.55(m , 3H), 3.73-3.86 (m, 2H), 3.92-4.03 (m, 2H), 4.09-4.18 (m, 1H), 4.51-4.64 (m, 1H), 6.48 (d, J=7.33 Hz, 1H), 7.14 (d.t, J=6.88, 2.49 Hz, 1H), 7.38 (d, J=1.52Hz, 1H), 7.467.51(m, 2H), 7.82(d, J=1.26Hz, 1H), 7.86(d, J=7.58Hz, 1H) , 8.63 (d, J=1.77 Hz, 1H), 9.63 (brs, 1H).

Step B: Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl) -8-methylquinolin-4-ol (Compound 327).

From tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl) ((R)-8-((4-hydroxy8-methylquinolin-3-yl)sulfonyl)-1-oxa- 8-azaspiro[4.5]decan-3-yl)carbamate gave the title compound in a manner analogous to that described in Method G, Step C. LCMS m/z=632.6 [M+H]+;

- 96 041181 ¹ H NMR (400 MHz, CD3OD) δ ppm 1.02-1.10 (m, 2H), 1.18-1.25 (m, 2H), 1.64-1.75 (m, 1H), 1.80-1.98 (m,

4H), 2.33 (dd, J=13.77, 7.96 Hz, 1H), 2.67 (tt, J=7.96, 4.80 Hz, 1H), 2.71-2.87 (m, 5H), 3.15 (dd, J=12.76, 9.73

Hz, 1H), 3.24-3.30 (m, 1H), 3.49-3.61 (m, 2H), 3.82-3.91 (m, 1H), 3.96-4, 04 (m, 2H), 4.06-4.14 (m, 2H), 4.214.29 (m, 1H), 6.99 (d, J=7.07 Hz, 1H), 7.29 (ddd , J=8.02, 2.46, 1.39 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.48-7.59 (m, 2H), 8, 09 (d, J=1.01 Hz, 1H), 8.55 (d, J=6.82 Hz, 1H), 8.61 (d, J=1.52 Hz, 1H).

Example 1.52. Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-7- fluoroquinolin-4-ol (compound 329)

Step A: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((7-fluoro-4-hydroxyquinolin-3-yl)sulfonyl) -1-oxa-8-azaspiro[4.5]decan-3yl)carbamate.

From tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate and 7-fluoro-4 -hydroxyquinoline-3-sulfonyl chloride gave the title compound in a manner analogous to that described in Method G, Step A. LCMS m/z=736.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.00-1.09 (m, 2H), 1.17-1.24 (m, 2H), 1.45 (s, 9H), 1.56-1.66 (m, 1H), 1, 69-1.81 (m, 3H), 1.86 (dd, J=12.76, 8.21 Hz, 1H), 2.07 (dd, J=12.88, 8.59 Hz, 1H) , 2.67 (tt, J=7.96, 4.80 Hz, 1H), 3.21-3.29 (m, 3H), 3.39-3.50 (m, 2H), 3.53 (dd, J=14.53, 4.67 Hz, 1H), 3.85-3.91 (m, 1H), 3.95-4.08 (m, 3H), 4.11-4.20 (m, 1H), 4.45-4.58 (m, 1H), 7.24-7.35 (m, 3H), 7.40-7.47 (m, 2H), 7.51 (t , J=7.96 Hz, 1H), 8.33 (dd, J=9.09, 6.06 Hz, 1H), 8.51 (s, 1H).

Step B: Preparation of 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl) -7-fluoroquinolin-4-ol (compound 329)

From tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((7-fluoro-4hydroxyquinolin-3-yl)sulfonyl)-1-oxa- 8-azaspiro[4.5]decan-3-yl)carbamate gave the title compound in a manner analogous to that described in Method E, Step D. LCMS m/z=636.6 ^[M+H]+ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.03-1.11 (m, 2H), 1.18-1.26 (m, 2H), 1.59-1.71 (m, 1H), 1.76-1.90 (m, 4H ), 2.35 (dd, J=13.89, 8.34 Hz, 1H), 2.67 (tt, J=7.96, 4.80 Hz, 1H), 3.16-3.30 ( m, 3H), 3.51-3.62 (m, 2H), 3.643.70 (m, 1H), 3.72-3.76 (m, 1H), 3.91-3.97 (m, 1H), 3.98-4.06 (m, 1H), 4.06-4.15 (m, 3H), 4.26 (td, J=4.80, 3.03 Hz, 1H), 7 .25-7.36 (m, 3H), 7.46 (t, J=2.27 Hz, 1H), 7.50-7.59 (m, 2H), 8.33 (dd, J=9 .09, 5.81 Hz, 1H), 8.53 (s, 1H).

Example 1.53. Preparation of 1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5] decan-8-ylsulfonyl)quinolin-4(1Н)-one (compound 331)

Step A: Preparation of tert-butyl ((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl) ((S)- 2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate

From (S)-2-((3-(isopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl-3-amino-1-oxa-8azaspiro[4.5]decan-8-carboxylate and 8-fluoro-4- hydroxyquinoline-3-sulfonyl chloride, the title compound was obtained in a manner analogous to that described in Method E, steps A, B and C. LCMS m/z=738.6 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.23 (d, J=6.82 Hz, 6H), 1.45 (s, 9H), 1.61 (ddd, J=13.64, 9.85, 4.04 Hz, 1H), 1 .73 (ddd, J=13.52, 4.04, 3.92 Hz, 1H), 1.79 (t, J=5.81 Hz, 2H), 1.86 (dd, J=12.76 , 8.21 Hz, 1H), 2.07 (dd, J=12.76, 8.46 Hz, 1H), 3.20-3.29 (m, 4H), 3.42-3.57 ( m, 3H), 3.85-3.91 (m, 1H), 3.95-4.02 (m, 2H), 4.024.07 (m, 1H), 4.11-4.19 (m, 1H), 4.52 (dd, J=15.66, 8.34 Hz, 1H), 7.29 (dd, J=8.34, 2.53, 1.01 Hz, 1H), 7.39 (t, J=2.53 Hz, 1H), 7.40-7.44 (m, 1H), 7.44-7.49 (m, 1H), 7.53 (t, J=7.96 Hz, 1H), 7.60 (ddd, J=10.86, 8.08, 1.26 Hz, 1H), 8.08 (d, J=8.08 Hz, 1H), 8.48 (s , 1H).

Step B: Preparation of tert-butyl ((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decane -3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate.

From tert-butyl ((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-2-hydroxy -3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate and ethyl iodide gave the title compound in a manner analogous to that described in Method G, Step B. LCMS m/z=766.6 [M+H] ⁺ .

Step C: Preparation of 1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro [4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (compound 331)

From tert-butyl ((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3- yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate gave the title compound in a manner analogous to that described in Method E, Step D. LCMS m/z=666.6 [M +H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.25 (d, J=7.07 Hz, 6H), 1.52 (t, J=6.57 Hz, 3H), 1.60-1.69 (m, 1H), 1.77-1 .90 (m, 4H), 2.35 (dd, J=13.77, 8.21 Hz, 1H), 3.16-3.29 (m, 4H), 3.53-3.69 (m , 3H), 3.91-3.97 (m, 1H), 3.99-4.15 (m, 4H), 4.26 (dddd, J=9.60, 4.99, 4.86, 3.28 Hz, 1H), 4.55 (q.d., J=7.12, 2.91 Hz, 2H), 7.33 (ddd, J=8.15, 2.59, 0.88 Hz , 1H), 7.43 (t, J=2.53 Hz, 1H), 7.47-7.51 (m, 1H), 7.53 (d.t, J=8.02, 3.95 Hz, 1H), 7.58 (t,

- 97 041181

J=7.96 Hz, 1H), 7.67 (ddd, J=14.91, 7.83, 1.52 Hz, 1H), 8.22 (d, J=8.08 Hz, 1H), 8.58 (s, 1H).

Example 1.54. Preparation of 1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8- ylsulfonyl)quinoline-4(1H)-one (compound 332).

Step A: Preparation of tert-butyl ((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)((R)1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From (S)-2-((3-(isopropylsulfonyl)phenoxy)methyl)oxirane and (R)-benzyl-3-amino-1-oxa-8azaspiro[4.5]decane-8-carboxylate, the title compound was prepared by the method as described in method A, steps A, B and C.

Step B: Preparation of 1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decane -8-ylsulfonyl)quinolin-4(1Н)-one (compound 332)

From tert-butyl ((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate and 1- ethyl 4-oxo-1,4-dihydroquinolin-3-sulfonyl chloride gave tert-butyl ((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa -8-azaspiro[4.5]-decan-3yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate in a manner analogous to that described in method A, step F.

From tert-butyl ((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)(( S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate gave the title compound in a manner analogous to that described in Method G, Step C. LCMS m/z=648.6 [M+H]+ ;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.25 (d, J=6, 82 Hz, 6H), 1.52 (t, J=7.20 Hz, 3H), 1.60-1.70 (m, 1H), 1.77-1 .90 (m, 4H), 2.35 (dd, J=13.77, 8.21 Hz, 1H), 3.14-3.30 (m, 4H), 3.52-3.64 (m , 2H), 3.90-3.96 (m, 1H), 3.97-4.05 (m, 1H), 4.05-4.14 (m, 3H), 4.19-4.30 (m, 1H), 4.48 (kv, J=7.07 Hz, 2H), 7.33 (ddd, J=8.27, 2.59, 1.01 Hz, 1H), 7.43 ( t, J=2.27 Hz, 1H), 7.49 (d.t, J=8.00, 1.26 Hz, 1H), 7.54-7.61 (m, 2H), 7.85 -7.92 (m, 2H), 8.38 (d, J=7.83 Hz, 1H), 8.68 (s, 1H).

Example 1.55. Preparation of (S)-1-((R)-8-(4'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl) )phenoxy)propan-2-ol (compound 189)

Step A: Preparation of tert-butyl ((R)-8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-3-(3-(cyclopropylsulfonyl) phenoxy)-2-hydroxypropyl)carbamate

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (81 mg, 0 .16 mmol) in CH2Cl2 (5 ml) under nitrogen atmosphere were added DIEA (69.07 μl, 0.40 mmol) and 3-bromobenzene-1-sulfonyl chloride (48.64 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (88 mg, 76% yield) as a colorless oil. LCMS m/z=729.6 [M] ⁺ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.03-1.09 (m, 2H), 1.19-1.26 (m, 2H), 1.44 (s, 9H), 1.57-1.68 (m, 1H), 1, 71-1.89 (m, 4H), 2.00-2.07 (m, 1H), 2.61-2.85 (m, 3H), 3.18-3.28 (m, 1H), 3.33-3.40 (m, 2H), 3.53 (dd, J=14.65, 4.55 Hz, 1H), 3.79-3.88 (m, 1H), 3.91- 4.19 (m, 5H), 4.44-4.53 (m, 1H), 7.27 (ddd, J=7.89, 2.59, 1.14 Hz, 1H), 7.43 ( t, J=2.27 Hz, 1H), 7.47-7.57 (m, 3H), 7.75 (ddd, J=7.83, 1.77, 1.01 Hz, 1H), 7 .84 (ddd, J=7.89, 1.96, 1.01 Hz, 1H), 7.90 (t, J=1.77 Hz, 1H).

Step B: Preparation of (S)-1-((R)-8-(4'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-(3 -(cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 189).

tert-Butyl solution -2-hydroxypropyl)carbamate (32 mg, 43.85 µmol), Pd (dpp f) ₂ , DCM (5.41 mg, 6.6 µmol), sodium carbonate (48.24 µl, 96.48 µmol) and (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (13.21 mg, 52.62 µmol) in dioxane (4 ml) was degassed using N ₂ for 10 min, then heated at 100° C during the night. After completion of the reaction and cooling to room temperature, solid Na ₂ SO ₄ was added. The mixture was stirred for 2 h and filtered through a pad of Celite® and Na ₂ SO ₄ . The filtrate was washed with DCM/MeOH (5%) and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl ((R)-8-((4'-(((tert-butoxycarbonyl)amino)methyl)-[1,1'-biphenyl]-3-yl)sulfonyl)- 1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate.

LCMS m/z=857.8 [M+H] ⁺ .

To a solution of tert-butyl ((R)-8-((4'-((((tert-butoxycarbonyl)amino)methyl)-[1,1'-biphenyl]-3yl)sulfonyl)-1-oxa-8-azaspiro [4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate from previous step in MeCN (4.0 mL) HCl (4N in dioxane, 0.3 ml). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was concentrated. The residue was purified by preparative HPLC. Collected fractions were added with HCl (4N in dioxane, 200 μl) and lyophilized to give the title compound (24 mg, 74% yield) as a solid. LCMS m/z=656.6 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.03-1.10 (m, 2H), 1.19-1.25 (m, 2H), 1.61-1.74 (m, 1H), 1.79-1.94 (m, 4H ), 2.33 (dd, J=13.77, 8.21 Hz, 1H), 2.63-2.71 (m, 1H), 2.71-2.84 (m, 2H), 3, 16 (dd, J=12.38, 9.35 Hz, 1H),

- 98 041181

3.45-3.56 (m, 2H), 3.56-3.77 (m, 2H), 3.86-3.92 (m, 1H), 3.96-4.04 (m, 2H ), 4.10 (dd, J=5.18, 2.91 Hz, 2H), 4.20 (s, 2H), 4.22-4.29 (m, 1H), 7.29 (ddd, J=7.89, 2.59, 1.39 Hz, 1H), 7.45 (t, J=2.27 Hz, 1H), 7.50-7.63 (m, 4H),

7.70-7.83 (m, 4H), 7.95-8.00 (m, 2H).

Example 1.56. Preparation of (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-(2 -fluoro-3-(methylsulfonyl)phenoxy)propan-2-ol (compound 209) (Method I)

Step A: Preparation of (S)-benzyl-3-(((S)-3-(3-bromo-2-fluorophenoxy)-2-hydroxypropyl)(tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5] decane-8-carboxylate

A solution of (S)-benzyl-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.65 g, 2.23 mmol) and (S)2-((3-bromo-2 -fluorophenoxy)methyl)oxirane (0.28 g, 1.12 mmol) in EtOH (15 mL) was heated at 70° C. overnight under nitrogen. After completion of the reaction, the mixture was concentrated to give (S)benzyl-3-(((S)-3-(3-bromo-2-fluorophenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane -8-carboxylate (0.55 g, 92% yield) as a yellow oil without further purification.

LCMS m/z=537.2 [M] ⁺ .

To a solution of (S)-benzyl 3-(((S)-3-(3-bromo-2-fluorophenoxy)-2-hydroxypropyl)amino)-1-oxa-8azaspiro[4.5]decan-8-carboxylate from the previous step (0.55 g, 1.02 mmol) in CH ₂ Cl ₂ (15 ml) was added (BOC) ₂ O (0.49 g, 2.23 mmol) and DIEA (0.20 ml, 1.12 mmol) . The reaction mixture was stirred at room temperature overnight under nitrogen. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (565 mg, 79% yield) as a clear gum. LCMS m/z=637.4 [M] ⁺ ;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.42-1.54 (m, 11H), 1.59-1.68 (m, 1H), 1.69-1.77 (m, 2H), 2.02-2.14 (m, 2H ), 3.40 (brs, 2H), 3.56 (dd, J=14.53, 4.67 Hz, 1H), 3.59-3.70 (m, 2H), 3.83 ( dd, J=8.84, 7.33 Hz, 1H), 3.93-4.11 (m, 3H), 4.12-4.21 (m, 1H), 4.46-4.58 ( m, 1H), 5.11 (s, 2H), 7.03 (td, J=8.21, 1.64 Hz, 1H), 7.09 (td, J=7.45, 1.64 Hz , 1H), 7.16 (ddd, J=7.89, 6.00, 1.52 Hz, 1H), 7.26-7.40 (m, 5H).

Step B: Preparation of (S)-benzyl 3-((tert-butoxycarbonyl)((S)-3-(2-fluoro-3(methylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro [4.5]decane-8-carboxylate.

(S)-benzyl 3-(((S)-3-(3bromo-2-fluorophenoxy)-2-hydroxypropyl)(tert-butoxycarbonyl)amino)-1-oxa-8 was added to a 5 ml microwave tube under N2 atmosphere. -azaspiro[4.5]decane-8-carboxylate (150 mg, 0.24 mmol), sodium methanesulfinate (108.06 mg, 0.71 mmol), copper (I) trifluoromethanesulfonate-benzene complex (26.06 mg, 70.56 µmol ) and N ₁ ,N ₂ -dimethylethane-1,2-diamine (12.45 mg, 141.22 μmol) followed by the addition of DMSO (4 ml). The reaction mixture was heated at 110°C for 4 h under microwave irradiation. The mixture was diluted in EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (96 mg, 64% yield) as a colorless oil. LCMS m/z=637.8 [M+H] ⁺ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.46 (s, 9H), 1.47-1.55 (m, 1H), 1.61-1.70 (m, 1H), 1.70-1.78 (m, 2H), 2, 04-2.15 (m, 2H), 3.23 (s, 3H), 3.34-3.46 (m, 2H), 3.58 (dd, J=14.65, 4.55 Hz, 1H), 3.61-3.71 (m, 2H), 3.84 (dd, J=8.84, 7.33 Hz, 1H), 3.97 (dd, J=8.97, 7, 71 Hz, 1H), 4.06-4.16 (m, 2H), 4.16-4.23 (m, 1H), 4.51-4.58 (m, 1H), 5.11 (s , 2H), 7.27-7.38 (m, 6H), 7.43-7.53 (m, 2H).

Step C: Preparation of tert-butyl ((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3- yl) carbamate

To a solution of (S)-benzyl 3-((tert-butoxycarbonyl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5] decane-8-carboxylate (96 mg, 0.15 mmol) in MeOH (10 ml) under N ₂ was added palladium/C (16.05 mg, 15.08 μmol) followed by the addition of H ₂ from a balloon. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through a pad of celite®, washed with MeOH and concentrated to give the title compound (76 mg, 100% yield) as a white foam, which was used in the next step without further purification. LCMS m/z=503.4 [M+H] ⁺ .

Step D: Preparation of tert-butyl ((S)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)((S)-3-(2 -fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate

To a solution of tert-butyl ((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl) ((S)-1-oxa8-azaspiro[4.5]decan-3-yl)carbamate and DIEA (65.85 μl, 0.38 mmol) in CH ₂ Cl ₂ (10 ml) under nitrogen atmosphere was added 5-bromo-2-ethoxybenzene-1-sulfonyl chloride (70.78 mg, 0.23 mmol).

The reaction mixture was stirred at room temperature for 6 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (55 mg, 48% yield) as a white foam. LCMS m/z=767.4 [M+2H] ⁺ ;

1H NMR (400 MHz, CDCl·,) δ ppm 1.42-1.52 (m, 12H), 1.60-1.89 (m, 6H), 2.04-2.12 (m, 1H), 3.03-3.16 (m, 2H ), 3.21 (s, 3H), 3.44-3.52 (m, 2H), 3.59 (dd, J=13.01, 4.42 Hz, 2H), 3.78 (dd, J=9.60, 6.57 Hz, 1H), 3.92 (dd, J=9.47, 7.45 Hz, 1H), 3.98-4.05 (m, 1H), 4.05 -4.19 (m, 4H), 4.48-4.67 (m, 1H), 6.87 (d, J=8.59 Hz, 1H), 7.217.32 (m, 2H), 7, 56 (dd, J=11.87, 9.35 Hz, 2H), 8.01 (d, J=2.53 Hz, 1H).

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Step E: Preparation of (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3 -(2-fluoro-3-(methylsulfonyl)phenoxy)propan-2-ol (compound 209) as HCl double salt.

A mixture of tert-butyl ((S)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)3-(2-fluoro -3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate (55mg, 71.83dmol), (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (27.05mg, 108µmol), sodium carbonate, Pd(dppf) ₂ , DCM (11.82 mg, 14.34 μmol) in dioxane (5 ml) was degassed using N 2 for 5 min. The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, solid Na ₂ SO ₄ was added. The mixture was stirred at room temperature for 2 hours. The mixture was filtered through a pad of Celite® and Na2SO4, washed with DCM and then concentrated. The residue was purified by silica gel column chromatography to give tert-butyl ((S)-8-((4'-(((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1'-biphenyl]-3-yl )sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate. LCMS m/z=892.6 [M+H]+.

tert-Butyl ((S)-8-((4'-(((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1-oxa -8-azaspiro[4.5]decan-3-yl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate from the previous step was dissolved in DCM (5 ml). Then HCl (4 N in dioxane, 180 μl) was added. The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was the concentration. The residue was purified by preparative HPLC. The combined fractions were added with HCl (4N in dioxane, 200 μl) and lyophilized to give the title compound (27.5 mg, 50% yield) as a white foam. LCMS m/z=692.4 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.49 (t, J=7.07 Hz, 3H), 1.60-1.70 (m, 1H), 1.78-1.93 (m, 4H), 2.37 (dd, J= 13.64, 8.34 Hz, 1H), 3.07-3.22 (m, 4H), 3.24 (s, 3H), 3.51-3.63 (m, 2H), 3.94 (dd, J=10.11, 4.04 Hz, 1H), 4.01-4.09 (m, 1H), 4.09-4.33 (m, 8H), 7.30 (d, J = 8.59 Hz, 1H), 7.35 (td, J=8.08, 1.52 Hz, 1H), 7.47-7.58 (m, 4H), 7.70 (d, J= 8.34 Hz, 2H), 7.88 (dd, J=8.59, 2.53 Hz, 1H), 8.08 (d, J=2.53 Hz, 1H).

Example 1.57. Preparation of (2S)-1-(8-(chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol (compound 28) (Method J)

Step A: Preparation of (2S)-1-(1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol.

From (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane and benzyl-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, the title compound was prepared in a manner analogous to that described. in method A, stage A and C. LCMS m/z=385.2 [M+H] ⁺ .

Step B: Preparation of (2S)-1-(8-(chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3(3-(methylsulfonyl)phenoxy)propan-2 -ola (compound 28).

To a solution of (2S)-1-(1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan2-ol (10 mg, 26.01 µmol) and DIEA (9.060 µl, 52.02 µmol) in dioxane (0.4 ml) was added chroman-6sulfonyl chloride (7.26 mg, 31.21 µmol). The reaction mixture was stirred overnight at room temperature for 16 hours. The reaction was quenched with water, then purified by mass-oriented preparative HPLC. The collected fractions were lyophilized to give the title compound (9.1 mg, 50% yield). LCMS m/z=581.2 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.66 (td, J=10.99, 4.17 Hz, 1H), 1.76-1.90 (m, 4H), 1.99-2.06 (m, 2H), 2.31 ( ddd, J=13.83, 8.27, 2.40 Hz, 1H), 2.63-2.78 (m, 2H), 2.85 (t, J=6.44 Hz, 2H), 3 .11 (s, 3H), 3.13-3.20 (m, 1H), 3.25-3.42 (m, 3H), 3.89 (td, J=8.59, 5.81 Hz , 1H), 3.96-4.08 (m, 2H), 4.11 (dd, J=4.93, 1.64 Hz, 2H), 4.214.30 (m, 3H), 6.90 ( d, J=8.34 Hz, 1H), 7.26-7.34 (m, 1H), 7.43-7.48 (m, 2H), 7.50 (t, J=1.26 Hz , 1H), 7.56 (d, J=5.05 Hz, 2H).

Example 1.58. Preparation of (3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8azaspiro[4.5]decan-8-yl)(4-methyl-3,4-dihydro -2H-benzo[b][1,4]oxazin-7-yl)methanone (compound 64) (Method K)

Step A: Preparation of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl) (8-(4methyl-3,4-dihydro-2H-benzo[b][1,4 ]oxazine-7-carbonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate.

tert-Butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl) carbamate solution (15 mg, 30.95 µmol) 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7carboxylic acid (7.18 mg, 37.14 µmol), HATU (14.12 mg, 37.14 µmol ) and triethylamine in DMF (1 M, 61.91 μl, 61.91 μmol) were added to a 5 ml scintillation vial followed by DMF (1 ml). The reaction mixture was heated at 70° C. for 16 hours. The reaction mixture was filtered and purified by direct mass preparative HPLC. The collected fractions were lyophilized to give the title compound. LCMS m/z=660.6 [M+H] ⁺ .

Step B: Preparation of (3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8azaspiro[4.5]decan-8-yl)(4-methyl-3, 4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanone (compound 64) as HCl salt.

To a solution of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl) (8-(4-methyl-3,4dihydro-2H-benzo[b][1,4]oxazine -7-carbonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl) carbamate in ACN (3 ml)

- 100 041181 added HCl (4 N in dioxane, 100 μπ). The reaction mixture was stirred for 4 hours. The mixture was concentrated. The residue was triturated with hexane to give the title compound (11 mg, yield

60%). LCMS m/z=560.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.61 (t, J=10.36 Hz, 1H), 1.69-1.86 (m, 3H), 1.91 (d.t, J=13.58, 5.72 Hz, 1H) , 2.40 (ddd, J=13.64, 8.21, 2.15 Hz, 1H), 2.92 (s, 3H), 3.12 (s, 3H), 3.19 (d.t , J=12.82, 9.25 Hz, 1H), 3.32-3.38 (m, 2H), 3.40-3.53 (m, 2H), 3.95-4.20 (m , 6H), 4.22-4.33 (m, 3H), 6.70 (d, J=8.34 Hz, 1H), 6.78 (d, J=2.02 Hz, 1H), 6 .91 (dd, J=8.34, 2.02 Hz, 1H), 7.32 (td, J=3.73, 1.89 Hz, 1H), 7.52 (t, J=1.26 Hz, 1H), 7.57 (d, J=5.31 Hz, 2H).

Example 1.59. Preparation of (2S)-1-(3-(fluoromethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)1-oxa-8-azaspiro [4.5]decan-3-ylamino)propan-2-ol ( connection 86)

To a solution of 8-(naphtalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (14.07 mg, 40.61 µmol) dissolved in EtOH (0.6 ml) was added (S)-2-((3-((fluoromethyl)sulfonyl)phenoxy)methyl)oxirane (5 mg, 20.30 µmol) previously dissolved in EtOH (0.3 ml). The reaction mixture was stirred at 90° C. overnight. The next day, the solvent was removed and the residue was purified by preparative LC/MS to give the title compound (6.2 mg, 8.7 µmol, 42.8% yield) as a solid. LCMS m/z=593.4 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.55-1.65 (m, 1H), 1.66-1.85 (m, 4H), 2.07-2.19 (m, 1H), 2.58-2.75 (m, 2H ), 2.86-3.02 (m, 1H), 3.03-3.16 (m, 1H), 3.27-3.43 (m, 3H), 3.65-3.74 (m , 1H), 3.80-3.94 (m, 2H), 4.014.07 (m, 2H), 4.07-4.16 (m, 1H), 5.66 (s, 1H), 5, 78 (s, 1H), 7.35-7.44 (m, 2H), 7.54 (d, J=7.96 Hz, 1H), 7.64 (t, J=7.98 Hz, 1H ), 7.67-7.80 (m, 3H), 8.09 (d, J=8.04 Hz, 1H), 8.18 (d, J=8.72 Hz, 1H), 8.21 (d, J=7.92 Hz, 1H), 8.44 (s, 1H), 8.73 (br s, 2H).

Example 1.60. Preparation of (S)-1-((R)-8-(4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3 -(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 199).

Step A: Preparation of tert-butyl ((R)-8-((3-bromo-4-methoxyphenyl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)((S)-2-hydroxy- 3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate.

From tert-butyl ((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan- 3-yl)carbamate and 3-bromo-4-methoxybenzene-1-sulfonyl chloride gave the title compound in a manner analogous to that described in Method F, Step D. LCMS m/z=789.4/791.4 [M+H] ⁺ .

Step B: Preparation of tert-butyl ((R)-8-((4'-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-6methoxy-[1,1'-biphenyl]-3-yl)sulfonyl) -1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

From tert-butyl ((R)-8-((3-bromo-4-methoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2hydroxy-3-( 3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate and (4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid prepared the title compound in a manner analogous to that described in Method F, step E. LCMS m/z=942.6 [M+H] ⁺ .

Step C: Preparation of (S)-1-((R)-8-(4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-ylamino) -3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan2-ol (compound 199)

From tert-butyl ((R)-8-((4'-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-6-methoxy-[1,1'-biphenyl]3-yl)sulfonyl)-1 -oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate gave the title compound in a manner similar to that described in method F, step F. LCMS m/z=742.8 [M+H]+;

1H NMR (400 M Hz, CD3OD) δ ppm 1.07-1.10(m, 2H), 1.33-1.37(m, 2H), 1.40-1.44(m, 2H), 1.48-1.51(q, J = 3.77 Hz, 2H), 1.63-1.70 (m, 1H), 1.81-1.91 (m, 4H), 2.33 (dd, J=8.13, 13.55 Hz, 1H), 2.69-2.80 (m, 2H), 3.16 (dd, J=9.75, 13.00 Hz, 1H), 3.28 (d, J=2.96 Hz , 1H), 3.39-3.46 (m, 2H), 3.72 (s, 2H), 3.90 (s, 3H), 3.93 (d, J=3.52 Hz, 1H) , 3.99-4.07 (m, 2H), 4.09-4.14 (m, 2H), 4.25-4.30 (m, 1H), 7.30 (m, 1H), 7 .31 (d, J=8.64 Hz, 1H), 7.47-7.60 (m, 7H), 7.63 (d, J=2.32 Hz, 1H), 7.78 (dd, J=2.52, 9.00 Hz, 1H).

Example 1.61. Preparation of (S)-1-((R)-8-(4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)- 3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 165) (Method L)

Step A: Preparation of tert-butyl ((R)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)((S)-2-hydroxy- 3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate.

From (S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol, (R)-benzyl-3-amino1-oxa-8-azaspiro[4.5]decan-8-carboxylate and 5-bromo-2-ethoxybenzene-1-sulfonyl chloride gave the title compound in a manner analogous to that described in Method F, Steps A, B, C and D.

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Step B: Preparation of tert-butyl ((R)-8-((4-ethoxy-4'-formyl-[1,1'-biphenyl]-3-yl)sulfonyl)-1oxa-8-azaspiro[4.5]decane -3-yl) ((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl ((R)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-2-hydroxy-3 - (3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (25 mg, 31.10 µmol) in EtOH (0.6 ml)/H ₂ O (0.300 ml) added potassium carbonate (9.457 mg , 68.43 µmol), Pd(dppf) ₂ , DCM (255.9 µg, 0.311 µmol) and (4-formylphenyl)boronic acid (6.529 mg, 43.54 µmol). The reaction mixture was degassed for 5 min before heating to 80°C for 1 h. The mixture was diluted with EtOAc, washed with water (3x) and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography to give the title compound (21 mg, 78.2% yield) as a white solid. LCMS m/z=829.6 [M+H]+;

¹ H NMR (400 M Hz, CDCl ₃ ) δ ppm 1.03-1.09(m, 2H), 1.48(s, 9H), 1.52(spt, 3H), 1.59-1.63(m, 2H), 1.631.69(m, 2H), 1.71-1.79 (m, 2H), 1.81-1.91 (m, 2H), 2.08 (dd, J=13.01, 8.72 Hz, 1H), 3 .05-3.18 (m, 2H), 3.353.45 (m, 1H), 3.45-3.51 (m, 1H), 3.57-3.65 (m, 2H), 3.66 (s, 2H), 3.77-3.85 (m, 1H), 3.88-3.94 (m, 1H), 3.99 (t, J=5.18 Hz, 2H), 4, 09-4.17 (m, 1H), 4.22 (q, J=6.99 Hz, 2H), 4.56-4.65 (m, 1H), 7.08 (d, J=8, 84 Hz, 1H), 7.157.19 (m, 1H), 7.39-7.42 (m, 1H), 7.45-7.52 (m, 2H), 7.73 (d, J=8 .34 Hz, 2H), 7.76 (dd, J=8.59, 2.53 Hz, 1H), 7.95 (d, J=8.34 Hz, 2H), 8.20 (d, J \u003d 2.53 Hz, 1H), 10.05 (s, 1H)

Step C: Preparation of tert-butyl ((R)-8-((4-ethoxy-4'-((isopropylamino)methyl)-[1,1'-biphenyl]-3yl)sulfonyl)-1-oxa-8- azaspiro[4.5]decan-3-yl) ((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl ((R)-8-((4-ethoxy-4'-formyl-[1,1'-biphenyl]-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3 -yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (21 mg, 24.32 µmol, 78.2%) in dichloroethane ( 1 ml) added acetic acid (8.894 µl, 0.156 mmol), isopropylamine (12.73 µl, 0.156 mmol) and stirred for 30 min. Sodium triacetoxyborohydride (13.18 mg, 62.21 µmol) was added in one portion and stirred for 2 h at room temperature and at 60° C. overnight. The reaction was quenched with water and extracted with DCM (x3). The combined organic layer was washed with brine, filtered, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography using EtOAc to give the title compound (18.28 mg, 67% yield) as a white solid. LCMS m/z=872.8 [M+H]+;

1H NMR (400 M Hz, CDCl,) δ ppm 1.03-1.08 (m, 2H), 1.14 (d, J=6.32 Hz, 6H), 1.20-1.36 (m, 2H) 1.47 (s, 9H), 1.49 (t, J=6.82 Hz, 3H), 1.57-1.62 (m, 2H), 1.62-1.67 (m, 1H), 1.71-1.77 ( m, 1H), 1.78-1.89 (m, 2H), 2.07 (dd, J=12.88, 8.84 Hz, 1H), 2.86-2.94 (m, 1H) , 3.04-3.16 (m, 2H), 3.35-3.44 (m, 1H), 3.45-3.51 (m, 1H), 3.543.65 (m, 2H), 3 .66 (s, 2H), 3.83 (s, 2H), 3.87-3.92 (m, 1H), 3.95-4.04 (m, 2H), 4.09-4.23 (m, 1H), 4.16-4.22 (m, 2H), 4.54-4.65 (m, 1H), 7.03 (d, J=8.59 Hz, 1H), 7, 16 (d.t., J=7.01, 2.43 Hz, 1H), 7.38-7.42 (m, 3H), 7.44-7.54 (m, 4H), 7.68 ( dd, J=8.59, 2.53 Hz, 1H), 8.11 (d, J=2.27 Hz, 1H).

Step D: Preparation of (S)-1-((R)-8-(4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)1-oxa-8-azaspiro[4.5]decan-3 -ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 165).

To a solution of tert-butyl ((R)-8-((4-ethoxy-4'-((isopropylamino)methyl)-[1,1'-biphenyl]-3yl)sulfonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (18.28 mg, 20.84 µmol) in MeOH (1 ml) at room temperature was added HCl in dioxane (0.156 ml, 0.622 mmol). The reaction mixture was allowed to stand at room temperature until the Boc group was cleaved. The solvent was then removed and the residue was lyophilized to give the title compound (12 mg, 67% yield) as a white solid. LCMS m/z=772.6 [M+H]+;

1H NMR (400 M Hz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.41 (d, J=6.57 Hz, 6H), 1.49 (t, J=6, 95 Hz, 3H),

1.49-1.52 (m, 2H), 1.60-1.70 (m, 1H), 1.76-1.93 (m, 3H), 2.37 (dd, J=13.77 , 8.21 Hz, 1H), 3.06-3.23 (m, 3H),

3.24-3.27 (m, 1H), 3.43-3.50 (m, 1H), 3.52-3.56 (m, 1H), 3.56-3.63 (m, 2H ), 3.64-3.69 (m, 1H), 3.72 (s, 2H),

3.73-3.75 (m, 1H), 3.94-3.98 (m, 1H), 4.01-4.07 (m, 1H), 4.08-4.15 (m, 2H ), 4.23-4.31 (m, 3H), 4.25 (s, 2H),

7.26-7.32 (m, 2H), 7.46-7.51 (m, 1H), 7.51-7.57 (m, 2H), 7.59 (d, J=8.34 Hz, 2H), 7.72 (d, J=8.34 Hz, 2H), 7.88 (dd, J=8.72, 2.40 Hz, 1H), 8.09 (d, J=2 .53 Hz, 1H).

Example 1.62. Preparation of (S)-1-((R)-8-(1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7ylsulfonyl)-1-oxa-8-azaspiro[ 4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 222).

Step A: Preparation of tert-butyl ((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5 ]decan-3-yl)carbamate

From (S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol and (R)-benzyl-3-amino1-oxa-8-azaspiro[4.5]decan-8-carboxylate prepared the title compound in a manner analogous to that described in Method F, Steps A, B, C.

- 102 041181

Step B: Preparation of tert-butyl ((R)-8-((5-bromo-6-chloropyridin-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl) ((S)- 2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate.

To a solution of tert-butyl ((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decane -3-yl)carbamate (200 mg, 0.370 mmol) in CH ₂ Cl ₂ (3.0 mL) was added DIEA (0.155 mL, 0.888 mmol) followed by 5-bromo-6-chloropyridine-3sulfonyl chloride (0.129 g, 0.444 mmol) at 0°С. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (230 mg, 73.7% yield) as a white solid. LCMS m/z=796.4 [M+H]+.

Step C: Preparation of tert-butyl ((R)-8-((1,4-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7yl)sulfonyl)-1-oxa-8 -azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a mixture of tert-butyl ((R)-8-((5-bromo-6-chloropyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-2- hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (25 mg, 31.44 µmol), potassium carbonate (13.04 mg, 94.32 µmol) in DMF (0 .8 ml) was added K1, ^K2 -dimethylethane1,2-diamine (3.326 mg, 37.73 µmol) in a microwave ampoule. The reaction mixture was heated at 160°C for 15 min under microwave irradiation. The mixture was filtered and washed with MeOH. The filtrate was concentrated and purified by silica gel column chromatography to give the title compound (21 mg, 83.0% yield) as a white solid. LCMS m/z=766.6 [M+H] ⁺ .

Step D: Preparation of (S)-1-((R)-8-(1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7ylsulfonyl)-1-oxa-8 -azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 222)

To a solution of tert-butyl ((R)-8-((1,4-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7yl)sulfonyl)-1-oxa-8-azaspiro [4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (21 mg, 26.10 µmol, 83, 0%) dissolved in MeOH (0.2 ml), HCl in dioxane (0.118 ml, 0.472 mmol) was added at room temperature. The reaction mixture was allowed to stand at room temperature until the Boc group was cleaved (~30 min). The mixture was concentrated and the residue was lyophilized to give the title compound (19 mg, 25.49 µmol, 81.1% yield) as a white solid. LCMS m/z=666.4 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.09-1.13 (m, 2H), 1.50-1.54 (m, 2H), 1.66-1.75 (m, 1H), 1.84-1.99 (m, 4H ), 2.39 (dd, J=13.64, 8.34 Hz, 1H), 2.84-2.92 (m, 1H), 2.91-2.98 (m, 1H), 3, 04 (s, 3H), 3.20 (dd, J=12.76, 9.47 Hz, 1H), 3.34-3.37 (m, 1H), 3.36 (s, 3H), 3 .45-3.49 (m, 2H), 3.49-3.57 (m, 2H), 3.74 (s, 2H), 3.85 (t, J=5.18 Hz, 2H), 3.92-3.99 (m, 1H), 4.02-4.12 (m, 2H), 4.11-4.19 (m, 2H), 4.26-4.34 (m, 1H ), 6.82 (d, J=1.52 Hz, 1H), 7.32 (ddd, J=7.83, 2.53, 1.52 Hz, 1H), 7.48-7.51 ( m, 1H), 7.51-7.54 (m, 1H), 7.56 (d, J=7.83 Hz, 1H), 7.60 (d, J=1.77 Hz, 1H).

Example 1.63. Preparation of (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3-(3 -(cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 160) (Method M)

Step A: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane and (S)-benzyl-3-amino-1-oxa-8azaspiro[4.5]decane-8-carboxylate, the title compound was prepared by the method as described in method A, steps A, B and C.

Step B: Preparation of tert-butyl ((S)-8-((5-Bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)((S)-3-(3 -(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8azaspiro [4.5]decan-3-yl) carbamate (177 mg, 0 .35 mmol) in DCM (15 ml) was added DIEA (0.17 ml, 0.98 mmol) and 5-bromo-2-ethoxybenzene-1-sulfonyl chloride (0.14 g, 0.45 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (233 mg, 87% yield) as a colorless glass. LCMS m/z=773.6 [M] ⁺ ;

1E NMR (400 MHz, CD3OD) δ ppm 1.03-1.10 (m, 2H), 1.19-1.25 (m, 2H), 1.43-1.47 (m, 12H), 1.50-1.63 (m, 1H ), 1.71 (ddd, J=13.39, 3.92, 3.66 Hz, 1H), 1.81 (t, J=4.55 Hz, 2H), 1.99-2.13 ( m, 2H), 2.62-2.71 (m, 1H), 3.06-3.22 (m, 2H), 3.24-3.29 (m, 1H), 3.36-3, 50 (m, 2H), 3.55 (dd, J=14.65, 4.80 Hz, 1H), 3.80 (dd, J=8.84, 7.33 Hz, 1H), 3.92 (t, J=8.21 Hz, 1H), 3.98-4.03 (m, 1H), 4.04-4.10 (m, 1H), 4.11-4.22 (m, 3H ), 4.49 (t, J=7.71 Hz, 1H), 7.12 (d, J=9.09 Hz, 1H), 7.28 (ddd, J=8.02, 2.59, 1.26 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.47 (d.t, J=8.0, 1.39 Hz, 1H), 7.52 ( t, J=8.08 Hz, 1H), 7.69 (dd, J=8.84, 2.53 Hz, 1H), 7.90 (d, J=2.53 Hz, 1H).

Step C: Preparation of tert-butyl ((S)-8-((4'-(((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1'biphenyl]-3-yl)sulfonyl)- 1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate

- 103 041181

Solution tert-butyl ((S)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3yl)((S)-3-(3-(cyclopropylsulfonyl )phenoxy)-2-hydroxypropyl)carbamate (233 mg, 0.30 mmol), Pd(dppf) ₂ , DCM (24.77 mg, 30.11 µmol), sodium carbonate (0.33 ml, 0.66 mmol ) and (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (90.73 mg, 0.36 mmol) in dioxane (12 mL) were degassed with N2 for 10 min. The reaction mixture was heated at 100° C. for 18 hours. After cooling to room temperature, the mixture was diluted with IPA/DCM (20%) and washed with water. The aqueous layer was back extracted with IPA/DCM (20%, 2x). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (126 mg, 47% yield). LCMS m/z=900.8 [M+H]+.

Step D: Preparation of (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8azaspiro[4.5]decan-3-ylamino)-3 -(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 160)

To a solution of tert-butyl ((S)-8-((4'-((((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1'-biphenyl]-3yl)sulfonyl)-1-oxa -8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2hydroxypropyl)carbamate (126 mg, 0.16 mmol) in ACN (4 mL) HCl ( 4 N in dioxane, 0.3 ml, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated. The residue was purified by preparative HPLC to give the TFA salt of the title compound. The TFA salt was converted to the HCl salt of the title compound (68.7 mg, 30% yield). LCMS m/z=700.4 [M+H]+;

¹ H NMR (400 MHz, CD3OD) δ ppm 1.03-1.10 (m, 2H), 1.19-1.25 (m, 2H), 1.49 (t, J=6, 95 Hz, 3H), 1.601.70 (m, 1H) , 1.77-1.85 (m, 1H), 1.85-1.94 (m, 3H), 2.37 (dd, J=13.64, 8.34 Hz, 1H), 2.68 (tt, J=7.96, 4.80 Hz, 1H), 3.06-3.23 (m, 3H), 3.32-3.37 (m, 1H), 3.51-3.64 (m, 2H), 3.91-3.97 (m, 1H), 4.00-4.08 (m, 1H), 4.09-4.15 (m, 3H), 4.17 (s , 2H), 4.22-4.33 (m, 3H), 7.27-7.33 (m, 2H), 7.46 (t, J=2.27 Hz, 1H), 7.50- 7.59 (m, 4H), 7.667.73 (m, 2H), 7.88 (dd, J=8.72, 2.40 Hz, 1H), 8.08 (d, J=2.53 Hz , 1H).

Example 1.64. Preparation of (S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(3-methyl-3Nimidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8 -azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 279). (Method N)

Step A: Preparation of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2hydroxypropyl)((R)-8-((3-methyl-3H-imidazo[4,5-b]pyridine- 6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate.

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (20 mg, 39 .17 µmol) in THF (4 mL) was added DIEA (13.64 µL, 78.33 µmol) followed by 3-methyl-3H-imidazo[4,5-b]pyridine-6-sulfonyl chloride (10.89 mg , 47.00 µmol). The reaction mixture was stirred for 2 hours. The mixture was diluted with EtOAc, washed with water (3x) and brine and concentrated. The residue was purified by silica gel column chromatography to give a white solid. LCMS m/z=706.4 [M+H]+;

1H NMR (400 M Hz, CD3OD) δ ppm 1.02-1.08 (m, 2H), 1.18-1.24 (m, 2H), 1.43 (s, 9H), 1.60-1.68 (m, 1H), 1, 73-1.88 (m, 4H), 1.99-2.04 (m, 1H), 2.71-2.82 (m, 2H), 3.20 (m, 1H), 3.38- 3.44 (m, 2H), 3.48-3.52 (m, 2H),

3.76-3.80 (m, 1H), 3.89-3.92 (m, 1H), 3.95-3.97 (m, 1H), 3.99 (s, 3H), 4, 01-4.04 (m, 1H), 4.09-4.14 (m, 1H),

4.42-4.50 (m, 1H), 7.23-7.26 (m, 1H), 7.40-7.41 (m, 1H), 7.47 (d.t., J=7 .96, 1.49 Hz, 1H), 7.52 (t, J=7.88 Hz,

1H), 8.40 (d, J=1.96 Hz, 1H), 8.55 (s, 1H), 8.80 (d, J=1.96 Hz, 1H).

Step B: Preparation of (S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(3-methyl-3H-imidazo[4,5b]pyridin-6-ylsulfonyl)-1- oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 279) as HCl double salt.

To a solution of tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((3methyl-3H-imidazo[4,5-b]pyridine-6- yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl) carbamate (13 mg, 18.42 µmol) in EtOAc (10 mL) HCl (671.5 µg, 18.42 µmol) was added . The reaction mixture was stirred for 3 hours. The mixture was concentrated to give the title compound as a white solid. LCMS m/z=606.6 [M+H]+;

1H NMR (400 M Hz, CD3OD) δ ppm 1.03-1.09 (m, 2H), 1.19-1.24 (m, 2H), 1.65-1.73 (m, 1H), 1.79-1.86 (m, 1H ), 1.88-1.98 (m, 1H), 2.32 (dd, J=7.39, 12.94 Hz, 1H), 2.63-2.69 (m, 1H), 2, 70-2.82 (m, 2H), 3.16 (d, J=8.53 Hz, 1H), 3.25-3.29 (m, 1H), 3.32-3.37 (m, 1H), 3.50-3.59 (m, 3H), 3.64-3.69 (m, 1H), 3.83-3.90 (m, 1H), 4.00 (d, J= 6.64 Hz, 2H), 4.04 (s, 3H), 4.09 (dd, J=3.42, 4.95 Hz, 2H), 4.20-4.26 (m, 1H), 7.27-7.30 (m, 1H), 7.44 (dd, J=1.67, 2.39 Hz, 1H), 7.51 (d.t, J=1.56, 7.81 Hz, 1H), 7.55 (t, J=7.82 Hz, 1H), 8.48 (d, J=1.88 Hz, 1H), 8.85 (s, 1H), 8.88 ( e, J=1.92 Hz, 1H).

Example 1.65. Preparation of 1-ethyl-3-((S)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8- ylsulfonyl)quinoline-4(1H)-one (compound 338)

Step A: Preparation of (S)-benzyl 3-(((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)1-oxa-8-azaspiro [4.5]decan-8-carboxylate

Solution of (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (0.10 g, 0.44 mmol) and (S)-benzyl-3amino-1-oxa-8-azaspiro[4.5]decane -8-carboxylate (0.25 g, 0.88 mmol) in EtOH (8.76 ml) was heated at 70°C for 1 day. After cooling to room temperature, the mixture was concentrated to give the title compound, which was used in the next step without further purification. LCMS m/z=519.4 [M+H]+.

Step B: Preparation of (S)-benzyl-3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[ 4.5]decane-8-carboxylate

To a solution of (S)-benzyl-3 -(((S)-2-hydroxy-3 -(3 -(methylsulfonyl)phenoxy)propyl)amino)-1 -oxa-8 azaspiro[4.5]decan-8-carboxylate ( from the previous step) in DCM (8 ml) was added DIEA (0.23 ml, 1.31 mmol) and (Boc) ₂ O (0.29 g, 1.31 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was extracted with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to give the title compound (174.0 mg, 64.2%). LCMS m/z=619.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.47 (s, 9H), 1.48-1.54 (m, 1H), 1.59-1.68 (m, 1H), 1.69-1.77 (m, 2H), 2. 04-2.15 (m, 2H), 3.11 (s, 3H), 3.40 (broad s, 2H), 3.57 (dd, J=14.65, 4.80 Hz, 1H) , 3.65 (t, J=13.01 Hz, 2H), 3.84 (dd, J=8.97, 7.20 Hz, 1H), 3.93-4.12 (m, 4H), 4.16 (ddd, J=7.26, 4.80, 4.61 Hz, 1H), 4.47-4.59 (m, 1H), 5.11 (s, 2H), 7.27- 7.34 (m, 2H), 7.34-7.37 (m, 4H), 7.48-7.58 (m, 3H).

Step C: Preparation of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1oxa-8-azaspiro[4.5]decan-3-yl)carbamate (S )-benzyl-3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decan-8- the carboxylate (162 mg, 0.26 mmol) was dissolved in MeOH (8 ml) under N2 followed by the addition of Pd/C (30 mg, 28.12 µmol). The reaction mixture was placed under H ₂ from a balloon and stirred at room temperature overnight. The mixture was filtered through a pad of Celite® and washed with MeOH, then concentrated to give the title compound (120 mg, 88.1%) as a yellow solid. This material was used in the next step without further purification. LCMS m/z=485.4 [M+H]+;

1H NMR (400 MHz, CDC13) δ ppm 1.50 (s, 9H), 1.53-1.68 (m, 1H), 1.69-1.77 (m, 3H), 1.80 (t, J=5.31 Hz, 1H) , 2.04-2.19 (m, 1H), 2.31 (s, 1H), 2.38-2.56 (m, 3H), 2.79 (dd, J=11.12, 5, 81 Hz, 1H), 2.95-3.04 (m, 1H), 3.06 (s, 3H), 3.49 (d, J=2.53 Hz, 2H), 3.80 (ddd, J=9.54, 6.25, 3.16 Hz, 1H), 3.89-4.02 (m, 2H), 4.02-4.08 (m, 1H), 4.12 (t, J=3.54 Hz, 1H), 4.56-4.69 (m, 1H), 7.20 (ddd, J=8.08, 2.53, 1.01 Hz, 1H), 7.43 -7.52 (m, 2H), 7.53-7.58 (m, 1H).

Step D: Preparation of tert-butyl ((S)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1oxa-8-azaspiro[4.5]decan-3-yl ) ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl ((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (120 mg, 0.25 mmol) in CH ₂ Cl ₂ (2 ml) at room temperature was added DIEA (86.26 μl, 0.50 mmol), then added 1-ethyl-4-oxo-1,4-dihydroquinoline-3sulfonyl chloride (0 .10 g, 0.37 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to give the title compound (92 mg, 51.6%) as a yellow gum. LCMS m/z=720.6 ^[M+H]+ ;

1H NMR (400 MHz, CD3OD) δ ppm 1.45 (s, 9H), 1.52 (t, J=7.20 Hz, 3H), 1.56-1.63 (m, 1H), 1.72 (d.t, J=13, 58, 4.33 Hz, 1H), 1.83 (t, J=5.81 Hz, 2H), 1.98-2.10 (m, 2H), 3.08 (s, 3H), 3, 20-3.29 (m, 3H), 3.39-3.57 (m, 3H), 3.78 (dd, J=8.84, 7.07 Hz, 1H), 3.91 (t, J=8.21Hz, 1H), 3.97-4.09(m, 2H), 4.10-4.18(m, 1H), 4.48(q, J=7.16Hz, 3H ), 7.27 (d.t., J=7.39, 2.24 Hz, 1H), 7.45-7.52 (m, 3H), 7.56 (ddd, J=8.15, 4 .99, 3.03 Hz, 1H), 7.857.89 (m, 2H), 8.39 (d, J=7.83 Hz, 1H), 8.66 (s, 1H).

Step E: Preparation of 1-ethyl-3-((S)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decane -8-ylsulfonyl)quinolin-4(1H)-one (compound 338) tert-Butyl ((S)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)- 1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate (92 mg, 0.13 mmol) was stirred in TFA /DCM (1:3, 2 ml) at room temperature. After completion of the reaction, the solvent was removed. The residue was purified by preparative HPLC. The resulting material was dissolved in water and neutralized with saturated NaHCO ₃ then was extracted with IPA/DCM (10%, 2x100 ml). The organic layer was washed with saturated brine, dried over Na2SO4, filtered and concentrated. The free base was dissolved in acetone and HCl (4N, 0.2 ml) was added. The resulting solution was stirred for 2 hours then concentrated to give the title compound (63.5 mg, 75.1%). LCMS m/z=620.4 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (t, J=7.07 Hz, 3H), 1.51-1.62 (m, 1H), 1.62-1.71 (m, 1H), 1.721.86 (m, 3H) , 2.18 (dd, J=13.01, 8.46 Hz, 1H), 2.90-3.01 (m, 1H), 3.05-3.20 (m, 3H), 3.21 (s, 3H), 3.35-3.42 (m, 2H), 3.77-3.83 (m, 1H), 3.87-4.00 (m, 2H), 4.07 (d , J=5.05 Hz, 2H), 4.12-4.22(m, 1H), 4.46(kv, J=6.82 Hz, 2H), 5.91(brs, 1H) , 7.30 (dd, J=7.71, 2.15 Hz, 1H), 7.44 (t, J=1.77 Hz, 1H), 7.49-7.56 (m, 2H), 7.57 (t, J=7.83 Hz, 1H), 7.82-7.90 (m, 2H), 8.24 (d, J=1.26 Hz, 1H), 8.63 (s , 1H), 8.85 (br.s, 1H), 9.02 (br.s, 1H).

Example 1.66. Preparation of 1-ethyl-3-((S)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8- ylsulfonyl)quinoline-4(1Н)-one (compound 296)

- 105 041181

Step A: Preparation of (R)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane

To a solution of 3-(methylsulfonyl)phenol (1.34 g, 6.98 mmol) in acetone (34.87 ml) was added potassium carbonate (1.93 g, 13.95 mmol). The reaction mixture was stirred at room temperature for 10 min followed by the addition of (R)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (1.90 g, 6.98 mmol).

The reaction mixture was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite® and washed with acetone, then concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.43 g, 88.0% yield) as a colorless oil, then solidified after standing at room temperature.

¹ H NMR (400 MHz, CDCl·,) δ ppm 2.79 (dd, J=4.93, 2.65 Hz, 1H), 2.94 (t, J=4.04 Hz, 1H), 3.06 (s, 3H), 3.35-3 .41 (m, 1H), 4.00 (dd, J=10.99, 5.94 Hz, 1H), 4.37 (dd, J=11.12, 2.78 Hz, 1H), 7, 22 (ddd, J=8.08, 2.53, 1.01 Hz, 1H), 7.48 (t, J=2.27 Hz, 1H), 7.50 (d, J=8.08 Hz , 1H), 7.54-7.58 (m, 1H).

Step B: Preparation of (S)-benzyl-3-(((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)1-oxa-8-azaspiro[4.5]decan-8- carboxylate.

Solution of (R)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (100 mg, 0.44 mmol) and (S)-benzyl-3amino-1-oxa-8-azaspiro[4.5]decan-8 -carboxylate (0.25 g, 0.88 mmol) in EtOH (8.8 ml) was heated at 70° C. overnight. After cooling to room temperature, the mixture was concentrated. The residue was redissolved in DCM and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound, which was used directly in the next step. LCMS m/z=519.6 [M+H]+.

Step C: Preparation of (S)-benzyl-3-((tert-butoxycarbonyl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[ 4.5]decane-8-carboxylate.

To a solution of (S)-benzyl-3-(((R)-2-hydroxy-3-(3 -(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8 azaspiro[4.5]decan-8-carboxylate ( 326 mg, 0.63 mmol) in DCM (8.8 ml) at room temperature were added DIEA (0.15 ml, 0.88 mmol) and (Boc) 2 O (0.19 g, 0.88 mmol). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (176 mg, 64.9%) as a white foam. LCMS m/z=619.6 [M+H]+;

1H NMR (400 MHz, MeOD) δ ppm 1.40-1.52 (m, 11H), 1.59-1.74 (m, 3H), 1.80 (dd, J=12.88, 8.08 Hz, 1H), 2.06 ( dd, J=12.76, 8.46 Hz, 1H), 3.03 (s, 3H), 3.17-3.29 (m, 1H), 3.33-3.42 (m, 2H) , 3.50 (dd, J=14.65, 3.79 Hz, 1H), 3.59-3.69 (m, 2H), 3.89-4.00 (m, 4H), 4.49 -4.60 (m, 1H), 5.07 (s, 2H), 7.18 (ddd, J=6.69, 2.65, 2.53 Hz, 1H), 7.25-7.35 (m, 5H), 7.42 (t, J=1.77 Hz, 1H), 7.46-7.51 (m, 2H).

Step D: Preparation of tert-butyl ((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1oxa-8-azaspiro[4.5]decan-3-yl)carbamate.

To a solution of (S)-benzyl-3-((tert-butoxycarbonyl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5] decane-8-carboxylate (176 mg, 0.28 mmol) in MeOH (10 ml) was added palladium/C (30.27 mg, 28.44 µmol). The reaction mixture was placed under H ₂ from a balloon and stirred at room temperature overnight. The mixture was filtered through a pad of celite® and washed with MeOH. The filtrate was concentrated to give the title compound (137 mg, 68.9%) as a yellow foam. This material will be used in the next step without further purification. LCMS m/z=485.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.47 (s, 9H), 1.52-1.81 (m, 4H), 1.86 (dd, J=12.63, 8.34 Hz, 1H), 2.062.16 (m, 1H) , 2.26 (s, 1H), 2.38-2.56 (m, 1H), 2.73-2.81 (m, 1H), 2.91-3.03 (m, 1H), 3 .12 (s, 3H), 3.23-3.29 (m, 1H), 3.56 (ddd, J=14.53, 4.55, 1.89 Hz, 1H), 3.89-3 .97 (m, 1H), 3.98-4.11 (m, 3H), 4.15-4.22 (m, 1H), 4.55 (d.sq., J=7.71, 7, 54 Hz, 1H), 7.27-7.33 (m, 1H), 7.49-7.52 (m, 1H), 7.52-7.59 (m, 2H).

Step E: Preparation of tert-butyl ((S)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1oxa-8-azaspiro[4.5]decan-3-yl ) ((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl ((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8azaspiro[4.5]decan-3-yl)carbamate (73 mg, 0.15 mmol) in CH ₂ Cl ₂ (2 ml) was added DIEA (89.21 μl, 0.51 mmol) and 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride (82.27 mg , 0.18 mmol). The reaction mixture was stirred at room temperature overnight. The next day additional tert-butyl ((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl) was added carbamate (23 mg, 0.05 mmol) and DIEA (30 µl, 0.17 mmol). The reaction mixture was stirred for another 5 h, then concentrated. The residue was purified by silica gel column chromatography to give the title compound (67 mg, 61.8%) as a clear glass. LCMS m/z=720.6 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.45 (s, 9H), 1.52 (t, J=7.20 Hz, 3H), 1.57-1.66 (m, 1H), 1.69-1.77 (m, 1H) , 1.77-1.82 (m, 2H), 1.85 (dd, J=12.76, 8.21 Hz, 1H), 2.07 (dd, J=12.88, 8.59 Hz , 1H), 3.08 (s, 3H), 3.20-3.30 (m, 3H), 3.41-3.49 (m, 2H), 3.50-3.56 (m, 1H ), 3.88 (dd, J=7.58, 1.77 Hz, 1H), 3.95-4.02 (m, 2H), 4.03-4.08 (m, 1H), 4, 12-4.19 (m, 1H), 4.44-4.56 (m, 3H), 7.27 (ddd, J=7.64, 2.08, 1.89 Hz, 1H), 7, 45-7.52 (m, 3H), 7.53-7.58

- 106 041181 (m, 1H), 7.85-7.91 (m, 2H), 8.39 (d.t., J=7.89, 0.85 Hz, 1H), 8.65 (s, 1H).

Step F: Preparation of 1-ethyl-3-((S)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decane -8-ylsulfonyl)quinolin-4(1Н)-one (compound 296)

To a solution of tert-butyl ((S)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)( (R)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate (67mg, 93.07µmol) in CH2C12 (1.50mL) TFA (0.5mL) was added. The resulting solution was stirred at ambient temperature for 2 hours then concentrated. The residue was purified by preparative HPLC to give the title compound as the TFA salt, which was then converted to the HCl salt (53.5 mg, 87.6%) as a solid. LCMS m/z=620.4 [M+H]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (t, J=7.07 Hz, 3H), 1.52-1.61 (m, 1H) 1.62-1.70 (m, 1H), 1.711.82 (m, 3H), 2.20 (dd, J=12.88, 7.83 Hz, 1H), 2.94-3.05 (m, 1H), 3.05-3.20 (m, 4H), 3.21 ( s, 3H), 3.26-3.42 (m, 1H), 3.78-3.86 (m, 1H), 3.88-3.99 (m, 2H), 4.07 (d, J=5.05Hz, 2H), 4.12-4.21(m, 1H), 4.46(q, J=7.24Hz, 2H), 5.90(d, J=4.80 Hz, 1H), 7.30 (dd, J=8.08, 1.77 Hz, 1H), 7.44 (t, J=1.52 Hz, 1H), 7.49-7.56 (m , 2H), 7.59 (t, J=7.83 Hz, 1H), 7.82-7.91 (m, 2H), 8.24 (dd, J=7.33, 1.26 Hz, 1H), 8.63 (s, 1H), 8.88 (broad s, 2H).

Example 1.67. Preparation of 1-ethyl-3-((R)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy) propylamino)-1-oxa-8-azaspiro[4.5]decan-8- ylsulfonyl)quinoline-4(1H)-one (compound 337)

Step A: Preparation of (R)-benzyl-3-(((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decan-8 -carboxylate.

Solution of (R)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (100 mg, 0.44 mmol) and (R)-benzyl-3amino-1-oxa-8-azaspiro[4.5]decan-8 -carboxylate (0.25 g, 0.88 mmol) in EtOH (8.8 ml) was heated at 70° C. overnight. After cooling to room temperature, the mixture was concentrated. Ethyl acetate was added to the residue, then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound, which was used in the next step without purification. LCMS m/z=519.6 [M+H] ⁺ .

Step B: Preparation of (R)-benzyl-3-((tert-butoxycarbonyl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[ 4.5]decane-8-carboxylate.

To a solution of (R)-benzyl-3 -(((S)-2-hydroxy-3 -(3 -(methylsulfonyl)phenoxy)propyl)amino)-1 -oxa-8 azaspiro[4.5]decan-8-carboxylate ( 176 mg, 0.34 mmol) in DCM (8.8 ml) at room temperature was added DIEA (0.15 ml, 0.88 mmol) and (Boc) ₂ O (0.19 g, 0.88 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, then washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to give the title compound (166 mg, 61.2%) as a white foamy solid. LCMS m/z=619.6 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.46 (s, 9H), 1.48-1.54 (m, 1H), 1.61-1.69 (m, 1H), 1.70-1.77 (m, 2H), 2. 06-2.14 (m, 2H), 3.11 (s, 3H), 3.34-3.46 (m, 2H), 3.54-3.70 (m, 3H), 3.84 ( dd, J=8.84, 7.07 Hz, 1H), 3.94-4.11 (m, 3H), 4.13-4.20 (m, 1H), 4.48-4.57 ( m, 2H), 5.11 (s, 2H), 7.27-7.37 (m, 6H), 7.50 (t, J=1.26 Hz, 1H), 7.527.58 (m, 2H ).

Step C: Preparation of tert-butyl ((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (R)-benzyl-3-((tert-butoxycarbonyl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5] decane-8-carboxylate (187 mg, 0.30 mmol) in MeOH (10 mL) palladium/C (32.16 mg, 30.22 µmol) was added under nitrogen. The reaction mixture was placed under H ₂ from a balloon and stirred at room temperature overnight. The mixture was filtered through a pad of Celite®, then washed with MeOH. The filtrate was concentrated to give the title compound (137 mg, 93.5%) as a white foam. This material was used in the next step without further purification. LCMS m/z=485.4 [M+H]+;

1H NMR (400 MHz, CD3OD) δ ppm 1.47 (s, 9H), 1.49-1.84 (m, 4H), 2.08 (t, J=7.96 Hz, 2H), 2.37-2.66 (m, 2H) , 2.67-2.78 (m, 1H), 2.87-3.00 (m, 1H), 3.12 (s, 3H), 3.25-3.34 (m, 1H), 3 .57 (ddd, J=14.65, 4.80, 1.52 Hz, 1H), 3.78-3.85 (m, 1H), 3.95 (ddd, J=8.78, 7, 64, 5.56 Hz, 1H), 3.99-4.06 (m, 1H), 4.06-4.11 (m, 1H), 4.13-4.21 (m, 1H), 4 .46-4.57 (m, 1H), 7.30 (d.t, J=7.01, 2.43 Hz, 1H), 7.50 (t, J=2.02 Hz, 1H), 7.52-7.58 (m, 2H).

Step D: Preparation of tert-butyl ((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1oxa-8-azaspiro[4.5]decan-3-yl )((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl ((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8azaspiro[4.5]decan-3-yl) carbamate (137 mg, 0.28 mmol) in CH ₂ Cl ₂ (3 ml) was added DIEA (0.17 ml, 0.96 mmol) and 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride (0.13 g , 0.28 mmol). The reaction mixture was stirred at room temperature overnight, then quenched with water and extracted with IPA/DCM (10%, 2x100 ml). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ then filtered. The filtrate was concentrated and purified by silica gel column chromatography to give the title compound as a white foamy solid (116 mg, 57.0%). LCMS m/z=720.6 [M+H]+;

1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.37 (m, 13H), 1.45-1.54 (m, 1H), 1.56-1.64 (m, 1H), 1.67-1.73

- 107 041181 (m, 2H), 1.92-1.98 (m, 1H), 3.04-3.22 (m, 7H), 3.33-3.44 (m, 2H), 3, 63 (t, J=7.96 Hz, 1H), 3.79 (t, J=8.21 Hz,

1H), 3.90-4.01 (m, 3H), 4.34-4.50 (m, 3H), 5.20 (d, J=4.55 Hz, 1H), 7.25 (dd , J=8.08, 2.27 Hz, 1H), 7.39 (s, 1H),

7.44-7.49 (m, 1H), 7.50-7.57 (m, 2H), 7.82-7.90 (m, 2H), 8.26 (d, J=8.59 Hz, 1H), 8.61 (s, 1H).

Step E: Preparation of 1-ethyl-3-((R)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decane -8-ylsulfonyl)quinolin-4(1H)-one (compound 337).

A solution of tert-butyl ((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8azaspiro[4.5]decan-3-yl)(( R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate (116 mg, 0.16 mmol) in TFA (0.5 ml, 6.529 mmol) and CH ₂ Cl ₂ (1.50 ml ) was stirred at room temperature for 2 h, then concentrated. The residue was purified by preparative HPLC to give the title compound (74.3 mg, 70.3%). LCMS m/z=620.4 [M+H]+;

¹ H NMR (400 MHz, D ₂ O) δ ppm 1.54 (t, J=7.20 Hz, 3H), 1.66-1.76 (m, 1H), 1.78-1.93 (m, 4H), 2.39 (dd, J= 13.39, 7.58 Hz, 1H), 3.08-3.20 (m, 1H), 3.20-3.24 (m, 1H), 3.24 (s, 3H), 3.25 -3.33 (m, 2H), 3.40-3.49 (m, 2H), 3.87-4.02 (m, 2H), 4.09-4.15 (m, 1H), 4 .16-4.25(m, 2H), 4.27-4.33(m, 1H), 4.52(q, J=7.24Hz, 2H), 7.37(d.t, J = 8.08, 1.26 Hz, 1H), 7.51 (s, 1H), 7.54-7.64 (m, 2H), 7.67 (t, J=7.33 Hz, 1H) , 7.91-8.01 (m, 2H), 8.36 (d, J=8.08 Hz, 1H), 8.77 (s, 1H).

Example 1.68. Preparation of Additional Compounds of the Invention

The following compounds were obtained using methods similar to those described in the examples above, from the appropriate intermediate(s) obtained(s) using commercial sources, or synthesized(s) as described above, or in in line with the literature. The specific method(s) used(s) to prepare the compounds and LCMS [M+H]+ for each compound are given below:

The following NMR data refer to the selected compounds above:

Compound 2: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.37 (s, 9H), 1.47-1.81 (m, 5H), 1.84-2.01 (m, 1H), 2.42-2.48 (m, 1H), 2. 57-2.76 (m, 3H), 2.92-3.01 (m, 1H), 3.27-3.39 (m, 3H), 3.43-3.50 (m, 1H), 3.51-3.59 (m, 1H), 3.63-3.74 (m, 1H), 4.32-4.54 (m, 1H), 7.66-7.80 (m, 3H ), 8.08 (d, J=7.9 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.43 (s, 1H).

Compound 6: 1H NMR (400 MHz, CD3OD) δ ppm 0.98 (t, J=7.33 Hz, 3H), 1.59-1.72 (m, 3H), 1.76-1.95 (m, 4H), 2.28 (dd, J= 12.63, 7.33 Hz, 1H), 2.71-2.89 (m, 2H), 3.06-3.19 (m, 3H), 3.26 (t, J=9.98 Hz , 1H), 3.423.55 (m, 2H), 3.79-3.89 (m, 1H), 3.92-4.02 (m, 2H), 4.03-4.12 (m, 2H ), 4.23 (d, J=4.80 Hz, 1H), 7.29 (d, J=7.83 Hz, 1H), 7.44 (s, 1H), 7.48-7.60 (m, 2H), 7.62-7.74 (m, 2H), 7.77 (d, J=8.59 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H) , 8.08 (d, J=6.57 Hz, 2H), 8.37 (s, 1H).

Compound 7: 1H NMR (400 MHz, CD3OD) δ ppm 0.09-0.17 (m, 2H), 0.46-0.55 (m, 2H), 0.86-0.99 (m, 1H), 1.60-1.71 (m, 1H ), 1.75-1.94 (m, 4H), 2.28 (dd, J=13.77, 7.96 Hz, 1H), 2.73-2.90 (m, 2H), 3, 06-3.18 (m, 3H), 3.22-3.30 (m, 1H), 3.49 (t, J=11.49 Hz, 2H), 3.78-3.88 (m, 1H), 3.92-4.03 (m, 2H), 4.08 (d, J=4.29 Hz, 2H), 4.22 (dd, J=8.46, 3.41 Hz, 1H ), 7.30 (t, J=3.16 Hz, 1H), 7.46 (s, 1H), 7.51-7.57 (m, 2H), 7.61-7.74 (m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.08 (d, J=7.33 Hz, 2H), 8.38 (s, 1H).

Compound 8: 1H NMR (400 MHz, CD3OD) δ ppm 1.23 (d, J=6.57 Hz, 6H), 1.66 (m, 1H), 1.75-1.95 (m, 4H), 2.28 (dd, J=12.76, 7.71 Hz, 1H), 2.72-2.90 (m, 2H), 3.05-3.18 (m, 1H), 3.21-3.29 (m, 1H), 3.34 (m, 1H), 3.48 (t, J=12.38 Hz, 2H), 3.78-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4, 08 (d, J=4.80 Hz, 2H), 4.23 (dd, J=8.97, 3.66 Hz, 1H), 7.30 (d, J=7.58 Hz, 1H), 7.40 (s, 1H), 7.45-7.50 (m, 1H), 7.56 (t, J=7.96 Hz, 1H), 7.61-7.73 (m, 2H) , 7.77 (d, J=8.59 Hz, 1H), 8.00 (d, J=8.08 Hz, 1H), 8.07 (d, J=8.34 Hz, 2H), 8 .37 (s, 1H).

Compound 9: 1H NMR (400 MHz, CD3OD) δ ppm 1.67 (td, J=10.74, 4.17 Hz, 1H), 1.76-1.92 (m, 4H), 2.28 (ddd, J=13.58, 8.15, 2 .53 Hz, 1H), 2.49-2.64 (m, 2H), 2.73-2.90 (m, 2H), 3.12 (dt, J=12.82, 9.51 Hz, 1H), 3.22-3.30 (m, 1H), 3.42-3.54 (m, 4H), 3.80-3.88 (m, 1H), 3.92-4.03 ( m, 2H), 4.10 (d, J=4.80 Hz, 2H), 4.19-4.27 (m, 1H), 7.33 (ddd, J=7.39, 2.34, 2.15 Hz, 1H), 7.50 (d, J=2.02 Hz, 1H), 7.53-7.62 (m, 2H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.00 (d, J=7.83 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H ), 8.38 (d, J=1.52 Hz, 1H).

Compound 11: 1H NMR (400 MHz, CD3OD) δ ppm 0.86 (dd, J=6.57, 1.01 Hz, 6H), 1.46-1.55 (m, 2H), 1.56-1.70 (m, 2H), 1.76- 1.92 (m, 4H), 2.28 (ddd, J=13.64, 8.08, 2.53 Hz, 1H), 2.73-2.89 (m, 2H), 3.07- 3.15 (m, 1H), 3.15-3.22 (m, 2H), 3.25 (dt, J=12.82, 2.81 Hz, 1H), 3.49 (t, J= 12.76 Hz, 2H), 3.80-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.12 (m, 2H), 4.19 -4.27 (m, 1H), 7.29 (ddd, J=8.08, 2.53, 1.26 Hz, 1H), 7.42-7.48 (m, 1H), 7.54 (ddd, J=15.28, 7.83, 7.71 Hz, 2H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.59, 1.77 Hz , 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H ).

Compound 12: 1H NMR (400 MHz, CD3OD) δ ppm 1.59-1.70 (m, 1H), 1.71-1.93 (m, 4H), 2.14-2.32 (m, 1H), 2.32-2.53 (m, 1H ), 2.73-2.88 (m, 2H), 2.88-3.03 (m, 1H), 3.08-3.26 (m, 1H), 3.33-3.42 (m , 1H), 3.43-3.55 (m, 2H), 3.75-3.85 (m, 1H), 3.87-4.04 (m, 2H), 7.14-7.57 (m, 4H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (s, 1H).

Compound 13: 1H NMR (400 MHz, CD3OD) δ ppm 1.61-1.74 (m, 1H), 1.74-1.95 (m, 8H), 1.96-2.06 (m, 2H), 2.29 (dd, J=13.64 , 8.08 Hz, 1H), 2.56-2.68 (m, 1H), 2.74-2.89 (m, 2H), 3.07-3.18 (m, 1H), 3, 25 (dd, J=12.88, 3.03 Hz, 1H), 3.43-3.54 (m, 2H), 3.79-3.88 (m, 1H), 3.93-4, 02 (m, 2H), 4.08 (dd, J=4.93, 2.40 Hz, 2H), 4.18-4.27 (m, 1H), 7.29 (dd, J=8, 08, 2.53, 1.01 Hz, 1H), 7.42 (t, J=2.52 Hz, 1H), 7.47-7.51 (m, 1H), 7.54 (t, J = 8.08 Hz, 1H), 7.68 (q.d., J=7.96, 7.71 Hz, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H) , 8.01 (d, J=8.08 Hz, 1H), 8.08

- 108 041181 (d, J=8.84 Hz, 2H), 8.38 (d, J=1.26 Hz, 1H).

Compound 14: 1H NMR (400 MHz, CD3OD) δ ppm 1.68 (td, J=10.99, 4.17 Hz, 1H), 1.76-1.95 (m, 6H), 2.23-2.38 (m, 3H), 2.74- 2.89 (m, 2H), 3.07-3.17 (m, 1H), 3.21-3.30 (m, 2H), 3.49 (t, J=12.88 Hz, 2H) , 3.79-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.12 (m, 2H), 4.19-4.27 (m, 1H), 7.32 (ddd, J=8.08, 2.53, 1.26 Hz, 1H), 7.46 (t, J=2.27 Hz, 1H), 7.56 (dt, J =15, 66, 7.83 Hz, 2H), 7.68 (q.d., J=8.25, 8.08 Hz, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 16: 1H NMR (400 MHz, CD3OD) δ ppm 1.08(kv, J=12.29Hz, 2H), 1.14-1.31(m, 3H), 1.571.72(m, 4H), 1.75-1.93(m, 7H) , 2.29 (ddd, J=13.77, 7.96, 2.02 Hz, 1H), 2.73-2.90 (m, 2H), 3.09 (dd, J=5.94, 1.89 Hz, 2H), 3.14 (t, J=9.22 Hz, 1H), 3.22-3.30 (m, 1H), 3.42-3.57 (m, 2H), 3.78-3.88 (m, 1H), 3.93-4.02 (m, 2H), 4.04-4.12 (m, 2H), 4.18-4.27 (m, 1H ), 7.29 (ddd, J=7.89, 2.59, 1.39 Hz, 1H), 7.45 (t, J=2.27 Hz, 1H), 7.497.53 (m, 1H) , 7.55 (t, J=7.56 Hz, 1H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d, J=8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 17: 1H NMR (400 MHz, CD3OD) δ ppm 1.16 (dddd, J=11.81, 7.83, 7.64, 3.79 Hz, 1H), 1.521.70 (m, 2H), 1.77-1.95 (m, 5H), 2.28 (ddd, J=13.64, 8.21, 2.40 Hz, 1H), 2.73-2.89 (m, 2H), 3.12 (dt, J=12.82, 9 .51 Hz, 1H), 3.21-3.29 (m, 1H), 3.33-3.43 (m, 2H), 3.49 (t, J=12.63 Hz, 2H), 3 .79-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.13 (m, 2H), 4.19-4.27 (m, 1H) , 7.32 (dt, J=7.33, 2.27 Hz, 1H), 7.47 (d, J=2.02 Hz, 1H), 7.52-7.60 (m, 2H), 7.68 (qd, J=8.25, 8.08 Hz, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J= 8.08 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.26 Hz, 1H).

Compound 18: 1H NMR (400 MHz, CD3OD) δ ppm 1.68 (td, J=10.99, 4.17 Hz, 1H), 1.76-2.08 (m, 6H), 2.11-2.22 (m, 2H), 2.29 ( ddd, J=13.77, 8.08, 2.15 Hz, 1H), 2.40-2.53 (m, 2H), 2.73-2.89 (m, 2H), 3.06- 3.17 (m, 1H), 3.26 (ddd, J=12.82, 9.66, 3.03 Hz, 1H), 3.44-3.56 (m, 2H), 3.79- 3.88 (m, 1H), 3.92-4.03 (m, 3H), 4.03-4.11 (m, 2H), 4.17-4.27 (m, 1H), 7. 28 (dd, J=6.57, 1.77 Hz, 1H), 7.40 (t, J=2.77 Hz, 1H), 7.47 (dd, J=7.71, 1.26, 1.14 Hz, 1H), 7.54 (t, J=7.96 Hz, 1H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.72, 1 .89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 19: 1H NMR (400 MHz, CD3OD) δ ppm 1.56-1.76 (m, 5H), 1.76-1.92 (m, 6H), 1.92-2.03 (m, 2H), 2.28 (ddd, J=13.58 , 8.15, 2.27 Hz, 1H), 2.74-2.89 (m, 2H), 3.07-3.17 (m, 1H), 3.22-3.29 (m, 1H ), 3.43-3.56 (m, 2H), 3.67 (d.sq., J=8.65, 7.14 Hz, 1H), 3.80-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.12 (m, 2H), 4.22 (sextet, J=3.79 Hz, 1H) 7.29 (ddd, J=8 .02, 2.59, 1.01 Hz, 1H), 7.44 (t, J=2.53 Hz, 1H), 7.53 (ddd, J=16.42, 8.08, 7.83 Hz, 2H), 7.63-7.74 (m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=7.83 Hz , 1H), 8.08 (d, J=8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 20: 1H NMR (400 MHz, CD3OD) δ ppm 1.66 (dd, J=10.86, 4.29 Hz, 1H), 1.75-1.92 (m, 4H), 2.28 (dd, J=13.83, 8.15, 1 .77 Hz, 1H), 2.74-2.89 (m, 2H), 3.02-3.12 (m, 1H), 3.22 (ddd, J=12.69, 9.54, 3 .03 Hz, 1H), 3.45-3.56 (m, 2H), 3.82 (td, J=8.97, 3.03 Hz, 1H), 3.90-4.02 (m, 4H), 4.17 (td, J=9.09, 5.56 Hz, 1H), 4.48 (d, J=1.26 Hz, 2H), 7.09-7.15 (m, 3H ), 7.24 (t, J=7.45 Hz, 3H), 7.27-7.33 (m, 2H), 7.45 (t, J=8.08 Hz, 1H), 7.637.74 (m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.09 (d, J= 8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 21: 1H NMR (400 MHz, CD3OD) δ ppm 1.68 (td, J=10.74, 3.92 Hz, 1H), 1.75-1.92 (m, 4H), 2.24-2.34 (m, 1H), 2.73- 2.88 (m, 2H), 3.06-3.16 (m, 1H), 3.21-3.29 (m, 1H), 3.44-3.56 (m, 2H), 3. 84 (dd, J=8.21, 6.19 Hz, 1H) 3.93-4.03 (m, 2H), 4.09 (d, J=5.05 Hz, 2H), 4.23 ( dd, J=8.72, 3.92 Hz, 1H), 4.37 (d, J=7.58 Hz, 4H), 4.53 (q, J=7.24 Hz, 1H), 7, 37 (d, J=7.07 Hz, 1H), 7.49 (s, 1H), 7.59 (dt, J=15.16, 7.58 Hz, 2H), 7.64-7.74 (m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d, J= 8.84 Hz, 2H), 8.38 (s, 1H).

Compound 22: 1H NMR (400 MHz, CD3OD) δ ppm 1.68 (td, J=11.12, 4.29 Hz, 1H), 1.76-1.93 (m, 4H), 2.25-2.33 (m, 1H), 2.73- 2.87 (m, 2H), 3.08-3.17 (m, 1H), 3.22-3.28 (m, 1H), 3.35-3.43 (m, 3H), 3. 46-3.53 (m, 3H), 3.58 (td, J=6.76, 1.64 Hz, 2H), 3.79-3.88 (m, 1H), 3.94-4, 02 (m, 2H), 4.10 (d, J=5.05 Hz, 2H), 4.19-4.27 (m, 1H), 7.37 (d, J=9.35 Hz, 1H ), 7.52 (d, J=1.77 Hz, 1H), 7.58-7.64 (m, 2H), 7.64-7.74 (m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.09 (d, J=9.09 Hz, 2H), 8.38 ( e, J=1.01 Hz, 1H).

Compound 23: 1H NMR (400 MHz, CD3OD) δ ppm 1.67 (td, J=10.74, 4.17 Hz, 1H), 1.76-1.92 (m, 4H), 2.28 (dd, J=13.89, 8.34 Hz, 1H), 2.72-2.89 (m, 2H), 3.05-3.14 (m, 4H), 3.28 (dd, J=12.76, 3.16 Hz, 1H), 3.433 .55 (m, 2H), 3.77-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.08 (dd, J=4.93, 1.64 Hz , 2H), 4.23 (dddd, J=9.60, 4.99, 4.86, 3.03 Hz, 1H), 7.28 (dd, J=6.57, 2.78 Hz, 1H ), 7.49 (d, J=1.52 Hz, 1H), 7.52-7.58 (m, 2H), 7.62-7.73 (m, 2H), 7.77 (dd, J=8.59, 2.02 Hz, 1H), 8.00 (d, J=8.08 Hz, 1H), 8.08 (d, J=9.09 Hz, 2H), 8.37 ( e, J=1.26 Hz, 1H).

Compound 24: 1H NMR (400 MHz, CD3OD) δ ppm 1.68 (td, J=10.86, 4.29 Hz, 1H), 1.76-1.95 (m, 4H), 2.28 (ddd, J=13.71, 8.15, 2 .40 Hz, 1H), 2.74-2.90 (m, 2H), 3.12 (dt, J=12.63, 9.60 Hz, 1H), 3.26 (ddd, J=12, 88, 9.98, 3.16 Hz, 1H), 3.49 (t, J=12.51 Hz, 2H), 3.79-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.08 (d, J=5.05 Hz, 2H), 4.19-4.26 (m, 1H), 4.66-4.75 (m, 1H), 4, 76-4.89 (m, 4H), 7.32 (ddd, J=8.08, 2.65, 1.14 Hz, 1H), 7.46 (t, J=2.27 Hz, 1H) , 7.51 (dt, J=8, 1.26 Hz, 1H), 7.56 (t, J=2.83 Hz, 1H), 7.68 (sq.d, J=8.25, 8 .08 Hz, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J = 8.59 Hz, 2H), 8.38 (d, J=1.26 Hz, 1H).

Compound 25: 1H NMR (400 MHz, CD3OD) δ ppm 0.97 (t, J=7.45 Hz, 3H), 1.22 (d, J=6.82 Hz, 3H), 1.35-1.48 (m, 1H), 1.67 (td , J=10.86, 3.79 Hz, 1H), 1.76-1.98 (m, 5H), 2.22-2.33 (m, 1H), 2.72-2.89 (m , 2H), 3.12 (ddd, J=12.51, 9.60, 9.47 Hz, 2H), 3.22-3.29 (m, 1H), 3.49 (t, J=12 .76 Hz, 1H), 3.78-3.89 (m, 1H), 3.92-4.02 (m, 2H), 4.08 (d, J=4.29 Hz, 2H), 4 .18-4.27 (m, 1H), 7.30 (dd, J=8.21, 1.64 Hz, 1H), 7.41 (s, 1H), 7.47 (d, J=8 .21 Hz

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1H), 7.55 (t, J=7.96 Hz, 1H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.59, 1.52 Hz, 1H ), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d,

J=8.84 Hz, 2H), 8.37 (s, 1H).

Compound 26: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.20 (t, J=7.33 Hz, 3H), 1.68 (dt, J=10.99, 4.42 Hz, 1H), 1.75-1.97 (m, 4H), 2 .28 (dd, J=13.77, 8.21 Hz, 1H), 2.73-2.89 (m, 2H), 3.06-3.15 (m, 1H), 3.20 (kv , J=7.33 Hz, 2H), 3.24-3.29 (m, 2H), 3.34-3.37 (m, 1H), 3.44-3.56 (m, 2H), 3.79-3.85 (m, 1H), 3.92-4.02 (m, 2H), 4.08 (dd, J=5.05, 1.52 Hz, 2H), 4.18- 4.26 (m, 1H), 7.30 (ddd, J=8.08, 2.53, 1.01 Hz, 1H), 7.44 (t, J=J=2.27 Hz, 1H) , 7.50 (dt, J=8.21, 1.39 Hz, 1H), 7.55 (t, J=8.08 Hz, 1H), 7.64-7.74 (m, 2H), 7.78 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d, J=8.84 Hz, 2H ), 8.38 (d, J=1.52 Hz, 1H).

Compound 27: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.20 (t, J=7.45 Hz, 3H), 1.68 (td, J=10.99, 4.17 Hz, 1H), 1.75-1.97 (m, 4H), 2 .29 (dd, J=13.64, 8.08 Hz, 1H), 2.81 (d.sq., J=14.43, 11.27 Hz, 2H), 3.07-3.16 (m , 1H), 3.16-3.28 (m, 3H), 3.44-3.54 (m, 2H), 3.56-3.77 (m, 1H), 3.80-3.88 (m, 1H), 3.91-4.02 (m, 2H), 4.08 (dd, J=5.18, 1.64 Hz, 2H), 4.17-4.26 (m, 1H ), 7.30 (ddd, J=8.08, 2.65, 1.14 Hz, 1H), 7.44 (t, J=2.53 Hz, 1H), 7.50 (dt, J= 8.08, 1.39 Hz, 1H), 7.56 (t, J=7.83 Hz, 1H), 7.63-7.74 (m, 2H), 7.77 (dd, J=8 .72, 1.89 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.06-8.11 (m, 2H), 8.38 (d, J=1, 52 Hz, 1H).

Compound 29: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.60-1.69 (m, 1H), 1.77-1.91 (m, 8H), 2.31 (ddd, J=13.71, 8.27, 2.27 Hz, 1H), 2.63-2.77 (m, 2H), 2.85 (br s, 4H), 3.11 (s, 3H), 3.12-3.19 (m, 1H), 3.25- 3.30 (m, 1H), 3.33-3.44 (m, 2H), 3.88 (td, J=8.72, 3.03 Hz, 1H), 3.95-4.07 ( m, 2H), 4.07-4.17 (m, 2H), 4.25 (td, J=9.22, 3.41 Hz, 1H), 7.25-7.33 (m, 2H) , 7.42-7.46 (m, 2H), 7.51 (t, J=1.77 Hz, 1H), 7.53-7.60 (m, 2H).

Compound 30: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.59-1.71 (m, 1H), 1.77-1.91 (m, 4H), 2.33 (ddd, J=7.83, 6.06 2.27 Hz, 1H), 3 .01-3.20 (m, 6H), 3.28 (dd, J=9.22, 3.16 Hz, 1H), 3.67 (t, J=13.52 Hz, 2H), 3, 89 (td, J=8.08, 6.06 Hz, 1H), 3.96-4.15 (m, 4H), 4.25 (dt, J=9.09, 3.79 Hz, 1H) , 7.30 (td, J=4.67, 2.53 Hz, 1H), 7.50 (d, J=1.26 Hz, 1H), 7.53-7.59 (m, 2H), 7.77 (d, J=7.33 Hz, 1H), 8.04 (d, J=7.58 Hz, 1H).

Compound 31: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.68 (td, J=12.63, 4.80 Hz, 1H), 1.79-1.98 (m, 5H), 2.26-2.37 (m, 1H), 2.66- 2.83 (m, 2H), 3.09-3.20 (m, 4H), 3.27 (bds, 1H), 3.40-3.52 (m, 2H), 3.89 ( td, J=8.65, 2.40 Hz, 1H), 3.97-4.08 (m, 2H), 4.08-4.15 (m, 2H), 4.25 (brs, 1H), 7.26-7.35 (m, 1H), 7.50 (s, 1H), 7.57 (d, J=5.05 Hz, 2H), 7.61 (t, J=7 .83 Hz, 1H), 7.67-7.74 (m, 2H), 7.77 (t, J=1.77 Hz, 1H).

Compound 32: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.65 (td, J=10.74, 3.92 Hz, 1H), 1.76-1.90 (m, 4H), 2.30 (ddd, J=13.52, 8.21, 2 .27 Hz, 1H), 2.66-2.83 (m, 2H), 2.92 (s, 3H), 3.11 (s, 3H), 3.12-3.20 (m, 1H) , 3.253.30 (m, 1H), 3.34-3.40 (m, 2H), 3.90 (td, J=9.22, 3.79 Hz, 1H), 3.96-4.08 (m, 2H), 4.08-4.15 (m, 2H), 4.26 (dt, J=9.35, 3.28 Hz, 1H), 4.32 (t, J=4.55 Hz, 2H), 6.84 (d, J=8.34 Hz, 1H), 6.96 (d, J=2.27 Hz, 1H), 6.97-7.01 (m, 1H), 7.27-7.34 (m, 1H), 7.50 (t, J=1.26 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H).

Compound 33: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.60-1.71 (m, 1H), 1.75-1.92 (m, 4H), 2.29 (dd, J=13.77, 8.21 Hz, 1H), 2.74- 2.89 (m, 2H), 3.10 (s, 3H), 3.15 (d, J=9.85 Hz, 1H), 3.25 (dd, J=12.76, 3.16 Hz , 1H), 3.42-3.56 (m, 2H), 3.79-3.88 (m, 1H), 3.93-4.01 (m, 2H), 4.04-4.13 (m, 2H), 4.18-4.26 (m, 1H), 7.24-7.31 (m, 1H), 7.49 (d, J=1.52 Hz, 1H), 7, 51-7.58 (m, 2H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 34: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.61-1.71 (m, 1H), 1.78-1.96 (m, 4H), 2.29 (dd, J=13.77, 8.21 Hz, 1H), 2.81 ( qt, J=12.25, 3.03 Hz, 2H), 3.05-3.15 (m, 1H), 3.24-3.27 (m, 1H), 3.34-3.37 ( m, 1H), 3.40 (t, J=6.32 Hz, 2H), 3.45-3.55 (m, 2H), 3.85 (t, J=6.19 Hz, 3H), 3.93-4.03 (m, 2H), 4.09 (dd, J=4.93, 2.40 Hz, 2H), 4.18-4.26 (m, 1H), 7.29 ( ddd, J=6.25, 2.97, 2.65 Hz, 1H), 7.47 (t, J=1.26 Hz, 1H), 7.51-7.57 (m, 2H), 7 .62-7.74 (m, 2H), 7.78 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8, 09 (d, J=8.84 Hz, 2H), 8.38 (s, 1H).

Compound 36: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.50 (t, J=7.33 Hz, 3H), 1.68 (dd, J=11.24, 4.17 Hz, 1H), 1.77-1.95 (m, 4H), 2 .31 (ddd, J=7.96, 6.32, 5.94 Hz, 1H), 2.69-2.86 (m, 2H), 3.08-3.19 (m, 4H), 3 .23-3.29 (m, 1H), 3.40-3.53 (m, 2H), 3.87 (td, J=8.46, 5.94 Hz, 1H), 3.95-4 .06 (m, 2H), 4.10 (dd, J=4.93, 2.40 Hz, 2H), 4.24 (q, J=7.33 Hz, 3H), 7.30 (td, J=4.61, 2.65 Hz, 1H), 7.50 (d, J=1.52 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.587.63 ( m, 2H), 7.83-7.94 (m, 3H), 8.14 (s, 1H).

Compound 37: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.68 (td, J=10.99, 4.17 Hz, 1H), 1.78-1.95 (m, 4H), 2.31 (ddd, J=13.77, 8.21, 1 .77 Hz, 1H), 2.70-2.87 (m, 2H), 3.08-3.19 (m, 4H), 3.27 (ddd, J=9.98, 3.03, 2 .91 Hz, 1H), 3.40-3.53 (m, 2H), 3.87 (td, J=8.46, 5.94 Hz, 1H), 3.94-4.05 (m, 2H), 4.10 (dd, J=5.05, 2.27 Hz, 2H), 4.204.29 (m, 1H), 7.25-7.33 (m, 1H), 7.50 (d , J=1.52 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.61 (d, J=5.31 Hz, 2H), 7.867, 94 (m, 2H ), 8.07 (s, 2H).

Compound 38: ¹ H NMR (400 MHz, CD3OD) δ ppm 0.94 (t, J=7.33 Hz, 3H), 1.68 (td, J=10.99, 4.17 Hz, 1H), 1.78-1.97 (m, 6H), 2 .31 (ddd, J=13.77, 8.21, 1.77 Hz, 1H), 2.70-2.86 (m, 2H), 3.08-3.18 (m, 4H), 3 .24-3.29 (m, 1H), 3.38-3.53 (m, 2H), 3.87 (td, J=8.46, 5.94 Hz, 1H), 3.94-4 .06 (m, 2H), 4.08-4.12 (m, 2H), 4.15 (t, J=6.95 Hz, 2H), 4.24 (dt, J=9.09, 3 .54 Hz, 1H), 7.25-7.33 (m, 1H), 7.50 (t, J=1.52 Hz, 1H), 7.56 (d, J=5.31 Hz, 2H ), 7.59-7.62 (m, 2H), 7.84-7.93 (m, 3H), 8.14 (s, 1H).

Compound 39: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.05-1.11 (m, 2H), 1.11-1.18 (m, 2H), 1.68 (td, J=10.99, 4.42 Hz, 1H), 1.77- 1.96 (m, 4H), 2.31 (dd, J=13.52, 7.96 Hz, 1H), 2.69-2.86 (m, 2H), 3.08-3.19 ( m, 4H), 3.24-3.29 (m, 2H), 3.39-3.52 (m, 2H), 3.66-3.76 (m, 1H), 3.83-3, 92 (m, 1H), 3.94-4.05 (m, 2H), 4.10 (dd, J=4.80, 2.53 Hz, 2H), 4.19-4.27 (m, 1H), 4.54 (brs, 1H), 7.26-7.36 (m, 1H), 7.50 (d, J=1.52 Hz, 1H), 7.56 (d, J = 5.05 Hz, 2H), 7.58-7.63 (m, 2H), 7.84-7.94 (m, 3H), 8.18 (s, 1H).

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Compound 40: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.68 (td, J=10.86, 4.04 Hz, 1H), 1.78-1.95 (m, 4H),

2.31 (ddd, J=13.77, 8.21, 1.77 Hz, 1H), 2.70-2.85 (m, 2H), 3.09-3.18 (m, 4H), 3.24-3.29 (m, 1H), 3.46 (t, J=12.76

Hz, 2H), 3.87 (td, J=8.72, 3.03 Hz, 1H), 3.95 (s, 3H), 3.97-4.05 (m, 2H), 4.06 -4.14 (m, 2H), 4.24 (dt, J=9.09,

3.54 Hz, 1H), 7.26-7.33 (m, 1H), 7.50 (d, J=1.52 Hz, 1H), 7.56 (d, J=5.31 Hz, 2H), 7.58-7.62 (m, 2H), 7.82-7.91 (m, 3H), 8.09 (s, 1H).

Compound 41: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.69 (td, J=11.12, 4.04 Hz, 1H), 1.77-1.97 (m, 4H), 2.32 (ddd, J=13.71, 8.27, 2 .27 Hz, 1H), 2.78 (q.d, J=11.94, 2.91 Hz, 2H), 3.09-3.19 (m, 4H), 3.25-3.29 ( m, 1H), 3.43-3.55 (m, 2H), 3.88 (td, J=8.59, 5.81 Hz, 1H), 3.96-4.06 (m, 2H) , 4.10 (dd, J=4.93, 2.40 Hz, 2H), 4.19 (s, 2H), 4.22-4.29 (m, 1H), 7.26-7.34 (m, 1H), 7.49 (t, J=1.26 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.60 (d, J=8.34 Hz , 2H), 7.69-7.82 (m, 4H), 7.93-8.01 (m, 2H).

Compound 42: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.69 (td, J=11.24, 4.42 Hz, 1H), 1.79-1.98 (m, 4H), 2.32 (ddd, J=13.77, 8.21, 1 .77 Hz, 1H), 2.70-2.85 (m, 2H), 3.09-3.19 (m, 4H), 3.24-3.29 (m, 1H), 3.44- 3.56 (m, 2H), 3.87 (td, J=8.46, 5.94 Hz, 1H), 3.95-4.05 (m, 2H), 4.10 (dd, J= 4.93, 2.40 Hz, 2H), 4.19-4.28 (m, 1H), 7.267.33 (m, 1H), 7.50 (d, J=1.52 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.75 (t, J=7.96 Hz, 1H), 7.81-7.89 (m, 3H), 7.988.06 (m , 4H).

Compound 44: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.63-1.74 (m, 1H), 1.80-1.99 (m, 4H), 2.33 (ddd, J=7.26, 5.46, 1.77 Hz, 5H), 2.70-2.85 (m, 4H), 3.08-3.20 (m, 2H), 3.24-3.30 (m, 2H), 3.50-3.61 (m, 1H ), 3.823.91 (m, 1H), 3.96-4.06 (m, 2H), 4.06-4.15 (m, 2H), 4.19-4.28 (m, 1H), 7.26-7.33 (m, 1H), 7.49 (t, J=1.01 Hz, 1H), 7.56 (d, J=5.31 Hz, 2H), 7.86 (t , J=7.83 Hz, 1H), 7.99 (dt, J=8.08, 1.26, 1.01 Hz, 1H), 8.04 (d, J=5.81 Hz, 1H) , 8.12 (s, 1H), 8.19 (d, J=7.83 Hz, 1H), 8.22 (t, J=1.64 Hz, 1H), 8.69 (d, J= 6.06 Hz, 1H).

Compound 45: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.62-1.73 (m, 1H), 1.78-1.97 (m, 4H), 2.31 (ddd, J=13.77, 8.21, 2.02 Hz, 1H), 2.73-2.89 (m, 2H), 3.11 (s, 3H), 3.12-3.18 (m, 1H), 3.24-3.29 (m, 1H), 3. 42-3.58 (m, 2H), 3.83-3.90 (m, 1H), 3.95-4.05 (m, 2H), 4.06-4.13 (m, 2H), 4.19-4.27 (m, 1H), 7.25-7.33 (m, 1H), 7.46-7.51 (m, 2H), 7.54-7.58 (m, 2H ), 7.76 (t, J=7.83 Hz, 1H), 7.87 (dt, J=7.83, 1.39 Hz, 1H), 7.96-8.04 (m, 2H) , 8.27 (dt, J=7.83, 1.39 Hz, 1H), 8.39 (t, J=1.64 Hz, 1H), 8.70 (dt, J=4.86, 1 .36 Hz, 1H).

Compound 46: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.61-1.72 (m, 1H), 1.79-1.96 (m, 4H), 2.33 (ddd, J=13.89, 8.34, 2.02 Hz, 1H), 2.69-2.84 (m, 2H), 3.09-3.20 (m, 4H), 3.24-3.30 (m, 1H), 3.44-3.60 (m, 2H ), 3.843.94 (m, 1H), 3.98-4.08 (m, 2H), 4.11 (dd, J=4.93, 2.40 Hz, 2H), 4.21-4, 29 (m, 1H), 7.25-7.34 (m, 1H), 7.50 (t, J=1.26 Hz, 1H), 7.57 (d, J=5.05 Hz, 2H ), 7.68 (dd, J=8.08, 4.80 Hz, 1H), 8.21 (dd, J=8.21, 1.89 Hz, 1H), 8.85 (broad s, 1H), 8.94 (brs, 1H).

Compound 47: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.59-1.70 (m, 1H), 1.77-1.94 (m, 4H), 2.30 (ddd, J=13.77, 8.21, 2.27 Hz, 1H), 2.66-2.81 (m, 2H), 3.11 (s, 3H), 3.16 (t, J=9.47 Hz, 1H), 3.28 (dd, J=9.47, 3.16 Hz, 1H), 3.43 (t, J=12.63 Hz, 2H), 3.88 (td, J=8.72, 5.94 Hz, 1H), 3.95-4, 06 (m, 2H), 4.10 (dd, J=4.93, 1.89 Hz, 2H), 4.25 (dt, J=9.09, 3.54 Hz, 1H), 7.25 -7.34 (m, 1H), 7.50 (t, J=1.26 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.59-7.64 ( m, 2H), 7.65-7.71 (m, 1H), 7.74-7.81 (m, 2H).

Compound 48: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.58-1.70 (m, 1H), 1.77-1.94 (m, 4H), 2.31 (ddd, J=13.83, 8.27, 2.15 Hz, 1H), 2.45 (s, 3H), 2.67-2.79 (m, 2H), 3.11 (s, 3H), 3.16 (t, J=9.47 Hz, 1H), 3.25 -3.30 (m, 1H), 3.42 (t, J=12.76 Hz, 2H), 3.88 (td, J=8.59, 6.06 Hz, 1H), 3.94- 4.07 (m, 2H), 4.11 (dd, J=4.93, 2.15 Hz, 2H), 4.25 (dt, J=9.22, 3.41 Hz, 1H), 7 .26-7.34 (m, 1H), 7.45-7.52 (m, 3H), 7.53-7.63 (m, 4H).

Compound 49: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.59-1.71 (m, 1H), 1.78-1.94 (m, 4H), 2.31 (ddd, J=13.83, 8.27, 2.15 Hz, 1H), 2.68-2.84 (m, 2H), 3.11 (s, 3H), 3.16 (t, J=9.47 Hz, 1H), 3.25-3.30 (m, 1H) , 3.43 (t, J=13.01 Hz, 2H), 3.84-3.93 (m, 4H), 3.96-4.07 (m, 2H), 4.11 (dd, J =4.93, 2.15 Hz, 2H), 4.21-4.29(m, 1H), 7.217.36(m, 4H), 7.49-7.60(m, 4H).

Compound 50: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.62-1.71 (m, 1H), 1.78-1.96 (m, 4H), 2.32 (ddd, J=13.83, 8.27, 1.89 Hz, 1H), 2.67-2.82 (m, 2H), 3.11 (s, 3H), 3.16 (t, J=9.22 Hz, 1H), 3.24-3.30 (m, 1H) , 3.443.58 (m, 2H), 3.84-3.92 (m, 1H), 3.96-4.07 (m, 2H), 4.11 (dd, J=4.93, 2, 40 Hz, 2H), 4.25 (dt, J=8.84, 3.54 Hz, 1H), 7.27-7.33 (m, 1H), 7.50 (t, J=1.77 Hz, 1H), 7.54-7.61 (m, 2H), 7.85 (t, J=7.96 Hz, 1H), 7.98-8.04 (m, 2H), 8.06 (d, J=7.83 Hz, 1H).

Compound 51: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.65-1.76 (m, 1H), 1.82-2.00 (m, 4H), 2.34 (ddd, J=13.64, 8.21, 2.15 Hz, 1H), 2.81-2.97 (m, 2H), 3.11 (s, 3H), 3.17 (t, J=9.60 Hz, 1H), 3.26-3.30 (m, 1H) , 3.47 (t, J=12.63 Hz, 2H), 3.91 (td, J=9.16, 3.92 Hz, 1H), 3.98-4.14 (m, 4H), 4.25 (dt, J=9.22, 3.41 Hz, 1H), 7.27-7.33 (m, 1H), 7.37-7.52 (m, 5H), 7.54- 7.56 (m, 2H), 7.56 (s, 1H), 7.65-7.72 (m, 2H).

Compound 52: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.62-1.72 (m, 1H), 1.82-1.94 (m, 4H), 2.31-2.41 (m, 4H), 2.63 (s, 3H), 2. 87-3.03 (m, 2H), 3.12 (s, 3H), 3.18 (ddd, J=12.38, 9.35, 9.09 Hz, 1H), 3.32-3, 37 (m, 1H), 3.41-3.52 (m, 2H), 3.91-3.99 (m, 1H), 4.00-4.17 (m, 4H), 4.23- 4.32 (m, 1H), 7.26-7.36 (m, 1H), 7.51 (t, J=1.26 Hz, 1H), 7.54-7.60 (m, 2H) .

Compound 53: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.61-1.71 (m, 1H), 1.78-1.95 (m, 4H), 2.32 (ddd, J=13.83, 8.27, 2.15 Hz, 1H), 2.66-2.81 (m, 2H), 3.11 (s, 3H), 3.17 (t, J=9.60 Hz, 1H), 3.26-3.30 (m, 1H) , 3.41 (t, J=12.76 Hz, 2H), 3.89 (td, J=8.34, 5.81 Hz, 1H), 3.97-4.08 (m, 2H), 4.11 (dd, J=4.93, 2.40 Hz, 2H), 4.20-4.31 (m, 1H), 4.70 (s, 2H), 7.13 (d, J= 8.59 Hz, 1H), 7.27-7.33 (m, 2H), 7.37 (dd, J=8.46, 2.15 Hz, 1H), 7.50 (t, J=1 .26 Hz, 1H), 7.53-7.60 (m, 2H).

- 111 041181

Compound 54: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.58-1.71 (m, 1H), 1.77-1.95 (m, 4H), 2.32 (ddd,

J=13.77, 8.34, 2.15 Hz, 1H), 2.69-2.84 (m, 2H), 3.11 (s, 3H), 3.17 (t, J=9, 35 Hz, 1H), 3.25-3.30 (m, 1H), 3.393.53 (m, 2H), 3.89 (td, J=8.46, 5.94 Hz, 1H), 3, 96-4.08 (m, 2H), 4.11 (dd, J=4.93, 2.15 Hz, 2H), 4.25 (dt, J=9.09,

3.28 Hz, 1H), 7.26-7.34 (m, 1H), 7.40-7.48 (m, 1H), 7.49-7.54 (m, 2H), 7.57 (d, J=5.05 Hz, 2H), 7.59-7.69 (m,

2H).

Compound 55: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.60-1.72 (m, 1H), 1.79-1.95 (m, 4H), 2.32 (ddd, J=13.77, 8.34, 2.15 Hz, 1H), 2.69-2.85 (m, 2H), 3.12 (s, 3H), 3.17 (t, J=9.47 Hz, 1H), 3.26-3.30 (m, 1H) , 3.433.54 (m, 2H), 3.89 (td, J=8.46, 5.94 Hz, 1H), 3.96-4.07 (m, 2H), 4.11 (dd, J =5.05, 2.27 Hz, 2H), 4.26 (dt, J=9.09, 3.54 Hz, 1H), 7.25-7.34 (m, 1H), 7.50 ( t, J=1.26 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.81 (t, J=7.71 Hz, 1H), 8.05 (dddd, J=11.05, 7.96, 1.33, 1.14 Hz, 2H), 8.15 (t, J=1.52 Hz, 1H).

Compound 63: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.71 (td, J=11.24, 4.17 Hz, 1H), 1.80-2.00 (m, 4H), 2.34 (ddd, J=13.39, 7.96, 1 .64 Hz, 1H), 2.70-2.89 (m, 2H), 3.07-3.20 (m, 4H), 3.24-3.29 (m, 1H), 3.50- 3.61 (m, 2H), 3.83-3.93 (m, 1H), 3.98-4.08 (m, 2H), 4.11 (dd, J=4.93, 1.89 Hz, 2H), 4.26 (brs, 1H), 7.23-7.37 (m, 1H), 7.50 (d, J=1.26 Hz, 1H), 7.53-7 .60 (m, 2H), 7.87 (t, J=7.83 Hz, 1H), 7.98 (d, J=8.08 Hz, 1H), 8.14 (d, J=7, 83 Hz, 1H), 8.18-8.28 (m, 2H), 8.92 (brs, 1H), 8.98 (d, J=8.34 Hz, 1H), 9.29 ( br.s, 1H).

Compound 106: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.30 (s, 6H), 1.56 (dd, J=13.01, 5.18 Hz, 1H), 1.72 (dd, J=7.58, 4.04 Hz, 2H), 1 .81-1.89 (m, 2H), 2.00 (dd, J=13.14, 7.33 Hz, 1H), 2.67-2.75 (m, 1H), 2.76-2 .88 (m, 3H), 3.40 (dd, J=7.07, 5.56 Hz, 1H), 3.52 (dd, J=9.22, 4.93 Hz, 1H), 3, 56-3.65 (m, 2H), 3.73 (s, 2H), 3.82 (dd, J=9.22, 5.68 Hz, 1H), 3.97-4.04 (m, 3H), 5.30 (s, 2H), 7.16-7.23 (m, 1H), 7.34-7.38 (m, 1H), 7.43-7.52 (m, 2H) , 7.66-7.73 (m, 1H), 7.90 (ddd, J=8.53, 7.01, 1.39 Hz, 1H), 7.96 (d, J=8.08 Hz , 1H), 8.20 (d, J=8.59 Hz, 1H), 8.60 (d, J=1.77 Hz, 1H), 9.17 (d, J=2.27 Hz, 1H ).

Compound 107: ¹ H NMR (400 MHz, CDCl,) δ ppm 1.56 (dd, J=13.01, 5.18 Hz, 1H), 1.69-1.76 (m, 2H), 1.81-1.89 (m, 2H), 1.94- 2.07 (m, 6H), 2.64-2.76 (m, 3H), 2.76-2.87 (m, 3H), 3.35-3.44 (m, 1H), 3. 52 (dd, J=9.09, 4.80 Hz, 1H), 3.57-3.65 (m, 2H), 3.78-3.86 (m, 3H), 3.96-4, 04 (m, 3H), 7.15-7.22 (m, 1H), 7.34-7.39 (m, 1H), 7.43-7.51 (m, 2H), 7.65- 7.73 (m, 1H), 7.90 (ddd, J=8.53, 7.01, 1.39 Hz, 1H), 7.96 (d, J=8.34 Hz, 1H), 8 .21 (d, J=8.34 Hz, 1H), 8.60 (d, J=1.77 Hz, 1H), 9.17 (d, J=2.27 Hz, 1H).

Compound 108: Ή NMR (400 MHz, CD3OD) δ ppm 1.29 (s, 6H), 1.31-1.37 (m, 1H), 1.55-1.64 (m, 2H), 1.68-1.76 (m, 2H), 1. 76-1.81 (m, 2H), 1.90 (dd, J=12.88, 7.58 Hz, 1H), 2.61-2.69 (m, 2H), 2.70-2, 78 (m, 2H), 2.82-2.96 (m, 2H), 3.33-3.43 (m, 1H), 3.60-3.70 (m, 2H), 3.75- 3.83 (m, 1H), 3.99 (br s, 4H), 4.55 (s, 1H), 7.25 (ddd, J=8.08, 2.53, 1.26 Hz, 1H), 7.34-7.38 (m, 1H), 7.40-7.45 (m, 1H), 7.45-7.51 (m, 1H), 7.74-7.82 ( m, 1H), 7.98 (ddd, J=8.53, 7.01, 1.39 Hz, 1H), 8.17 (d, J=9.60 Hz, 2H), 8.82 (d , J=2.27 Hz, 1H), 9.12 (d, J=2.27 Hz, 1H).

Compound 109: Ή NMR (400 MHz, CD3OD) δ ppm 1.28 (s, 6H), 1.61-1.71 (m, 1H), 1.77-1.95 (m, 4H), 2.30 (dd, J=13.77, 7.96 Hz, 1H), 2.75-2.90 (m, 2H), 3.14 (dd, J=12.63, 9.60 Hz, 1H), 3.22-3.29 (m, 1H) , 3.463.58 (m, 2H), 3.65 (s, 2H), 3.81-3.90 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4 .12 (m, 2H), 4.20-4.28 (m, 1H), 7.27-7.33 (m, 1H), 7.38-7.42 (m, 1H), 7.44 -7.50 (m, 1H), 7.54 (t, J=7.96 Hz, 1H), 7.74 (dd, J=8.34, 4.29 Hz, 1H), 8.09 ( dd, J=8.84, 2.02 Hz, 1H), 8.25 (d, J=9.09 Hz, 1H), 8.51 (d, J=2.02 Hz, 1H), 8, 64 (d, J=7.33 Hz, 1H), 9.07 (broad s, 1H).

Compound 110: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.61-1.71 (m, 1H), 1.77-1.91 (m, 4H), 1.92-2.02 (m, 2H), 2.05-2.15 (m, 2H ), 2.30 (dd, J=13.77, 7.96 Hz, 1H), 2.60-2.74 (m, 2H), 2.76-2.91 (m, 2H), 3, 14 (dd, J=12.76, 9.73 Hz, 1H), 3.23-3.29 (m, 1H), 3.46-3.60 (m, 2H), 3.71 (s, 2H), 3.82-3.90 (m, 1H), 3.94-4.02 (m, 2H), 4.03-4.11 (m, 2H), 4.19-4.28 ( m, 1H), 7.23-7.31 (m, 1H), 7.39-7.43 (m, 1H), 7.45-7.49 (m, 1H), 7.50-7, 56 (m, 1H), 7.74 (dd, J=8.34, 4.29 Hz, 1H), 8.10 (dd, J=8.84, 2.02 Hz, 1H), 8.25 (d, J=8.84 Hz, 1H), 8.52 (d, J=1.77 Hz, 1H), 8.65 (d, J=7.58 Hz, 1H), 9.07 (dd , J=4.29, 1.26 Hz, 1H).

Compound 120: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.62-1.73 (m, 1H), 1.81-1.97 (m, 4H), 2.32 (dd, J=13.64, 8.08 Hz, 1H), 2.38 ( s, 3H), 2.73-2.88 (m, 2H), 3.14 (dd, J=12.76, 9.47 Hz, 1H), 3.41 (t, J=6.19 Hz , 2H), 3.45-3.55 (m, 2H), 3.82-3.90 (m, 3H), 3.96-4.06 (m, 2H), 4.07-4.15 (m, 2H), 4.21-4.30 (m, 1H), 7.27-7.34 (m, 1H), 7.47-7.50 (m, 1H), 7.52-7 .61 (m, 3H), 7.78-7.83 (m, 1H), 7.83-7.88 (m, 1H), 7.90-7.96 (m, 2H), 8.04 (d, J=7.07 Hz, 1H), 8.54 (d, J=4.29 Hz, 1H).

Compound 125: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.69 (dd, J=11.12, 4.29 Hz, 1H), 1.79-1.95 (m, 4H), 2.29 (dd, J=13.64, 8.34 Hz, 1H), 2.73-2.89 (m, 2H), 3.09 (dd, J=12.63, 9.60 Hz, 1H), 3.26 (dd, J=12.76, 2, 91 Hz, 1H), 3.40 (t, J=6.19 Hz, 2H), 3.45-3.56 (m, 2H), 3.84 (t, J=6.32 Hz, 3H) , 3.92-3.99 (m, 1H), 3.99-4.04 (m, 1H), 4.06-4.12 (m, 2H), 4.18-4.26 (m, 1H), 7.26-7.33 (m, 1H), 7.45-7.49 (m, 1H), 7.51-7.56 (m, 2H), 7.78 (t, J= 7.83 Hz, 1H), 7.81 (d, J=7.07 Hz, 1H), 7.87-7.91 (m, 1H), 8.15 (t, J=7.96 Hz, 1H), 8.21-8.26(m, 1H), 8.39-8.44(m, 1H), 8.49-8.52(m, 1H).

Compound 126: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.58-1.70 (m, 2H), 1.72-1.78 (m, 2H), 1.80-1.86 (m, 2H), 2.09 (dd, J=13.14 , 7.83 Hz, 1H), 2.72-2.91 (m, 4H), 3.37-3.46 (m, 4H), 3.53 (quin, J=5.81 Hz, 1H) , 3.60 (dd, J=9.22, 5.43 Hz, 1H), 3.85 (t, J=6.19 Hz, 2H), 3.91 (dd, J=9.35, 6 .06 Hz, 1H), 3.98-4.12 (m, 3H), 7.28 (ddd, J=5.18, 2.53, 2.40 Hz, 1H), 7.45-7, 50 (m, 1H), 7.50-7.56 (m, 2H), 7.67 (dd, J=6.82, 5.05 Hz, 1H), 7.79 (t, J=7, 71 Hz, 1H), 7.88-7.92 (m, 1H), 7.95-8.00 (m, 1H), 8.04 (d, J=1.77 Hz, 1H), 8, 51 (d, J=5.05 Hz, 1H), 8.59 (d, J=2.78 Hz, 1H).

- 112 041181

Compound 127: 1H NMR (400 MHz, CD3OD) δ ppm 1.61-1.69 (m, 2H), 1.72-1.79 (m, 1H), 1.81-1.86 (m,

2H), 2.12 (dd, J=13.26, 7.71 Hz, 1H), 2.61 (s, 3H), 2.77-2.88 (m, 3H), 2.92-2 .96 (m, 1H), 3.40 (t, J=6.19 Hz,

2H), 3.39-3.44 (m, 2H), 3.56-3.66 (m, 2H), 3.84 (t, J=6.32 Hz, 2H), 3.89-3 .94 (m, 1H), 4.01-4.12 (m, 3H), 7.257.31 (m, 2H), 7.44-7.47 (m, 1H), 7.48-7.55 (m, 2H), 7.72 (t, J=7.71 Hz, 1H), 7.70 (d, J=7.58 Hz, 1H), 7.77-7.84 (m, 2H) , 8.24 (ddd, J=7.71, 1.52, 1.39 Hz, 1H), 8.35 (t, J=1.64 Hz, 1H).

Compound 128: 1H NMR (400 MHz, CD3OD) δ ppm 1.61 (dd, J=13.01, 5.94 Hz, 1H), 1.67 (dd, J=10.48, 4.17 Hz, 1H), 1.72-1.77 (m, 1H), 1.80-1.84 (m, 2H), 2.09 (dd, J=13.14, 7.58 Hz, 1H), 2.41 (s, 3H), 2.72-2 .91 (m, 4H), 3.37-3.43 (m, 2H), 3.40 (t, J=6.19 Hz, 2H), 3.51-3.63 (m, 2H), 3.84 (t, J=6.32 Hz, 2H), 3.90 (dd, J=9.22, 5.94 Hz, 1H), 4.00-4.10 (m, 3H), 7 .27 (dt, J=7.14, 2.37 Hz, 1H), 7.45-7.47 (m, 1H), 7.48-7.55 (m, 2H), 7.72 (t , J=7.71 Hz, 1H), 7.75-7.79 (m, 1H), 7.79-7.82 (m, 1H), 7.82-7.85 (m, 1H), 8.23 (dt, J=7.77, 1.42 Hz, 1H), 8.34 (t, J=1.52 Hz, 1H), 8.51 (d, J=2.27 Hz, 1H ).

Compound 129: 1H NMR (400 MHz, CD3OD) δ ppm 1.61-1.70 (m, 2H), 1.73-1.79 (m, 1H), 1.80-1.85 (m, 2H), 2.12 (dd, J=13.26 , 7.45 Hz, 1H), 2.47 (s, 3H), 2.76-2.88 (m, 3H), 2.92-2.97 (m, 1H), 3.40 (t, J=6.19Hz, 2H), 3.41-3.45(m, 2H), 3.58-3.66(m, 2H), 3.84(t, J=6.32Hz, 2H ), 3.88-3.95 (m, 1H), 4.01-4.12 (m, 3H), 7.267.30 (m, 2H), 7.46 (d, J=2.02 Hz, 1H), 7.48-7.56 (m, 2H), 7.73 (t, J=7.83 Hz, 1H), 7.78 (brs, 1H), 7.82-7.85 (m, 1H), 8.24 (dt, J=7.83, 1.39 Hz, 1H), 8.34 (t, J=1.64 Hz, 1H), 8.51 (d, J= 5.05 Hz, 1H).

Compound 134: 1H NMR (400 MHz, CD3OD) δ ppm 1.58 (dd, J=13.01, 6.19 Hz, 1H), 1.63-1.70 (m, 1H), 1.70-1.77 (m, 1H), 1.78- 1.86 (m, 2H), 2.07 (dd, J=13.01, 7.71 Hz, 1H), 2.71 (dd, J=12.13, 7.33 Hz, 1H), 2.762 .88 (m, 3H), 3.36-3.43 (m, 2H), 3.40 (t, J=6.19 Hz, 2H), 3.45-3.53 (m, 1H), 3.57 (t, J=4.55 Hz, 1H), 3.84 (t, J=6.32 Hz, 2H), 3.89 (dd, J=9.22, 5.94 Hz, 1H ), 3.98-4.08 (m, 3H), 7.06 (dd, J=8.08, 2.53 Hz, 1H), 7.27 (dd, J=7.39, 2.34 , 2.15 Hz, 1H), 7.44-7.47 (m, 1H), 7.48-7.56 (m, 2H), 7.73 (t, J=7.83 Hz, 1H) , 7.84 (ddd, J=8.08, 1.39, 1.14 Hz, 1H), 7.89 (dd, J=7.58, 2.27 Hz, 1H), 8.04 (kv , J=8.08 Hz, 1H), 8.32 (dt, J=7.83, 1.39 Hz, 1H), 8.41 (t, J=1.64 Hz, 1H).

Compound 136: 1H NMR (400 MHz, CDCl·,) δ ppm 1.03-1.08 (m, 2H), 1.55-1.63 (m, 3H), 1.69-1.74 (m, 2H), 1.82-1.89 (m, 2H ), 2.01 (dd, J=13.01, 7.45 Hz, 1H), 2.69-2.76 (m, 1H), 2.77-2.87 (m, 3H), 3, 37-3.45 (m, 1H), 3.53 (dd, J=9.22, 4.93 Hz, 1H), 3.57-3.63 (m, 2H), 3.65 (s, 2H), 3.82 (dd, J=9.09, 5.81 Hz, 1H), 4.02 (s, 3H), 7.14-7.20 (m, 1H), 7.39-7 .42 (m, 1H), 7.43-7.49 (m, 2H), 7.66-7.74 (m, 1H), 7.90 (ddd, J=8.46, 6.95, 1.26 Hz, 1H), 7.96 (d, J=8.08 Hz, 1H), 8.20 (d, J=8.34 Hz, 1H), 8.60 (d, J=2, 02 Hz, 1H), 9.17 (d, J=2.27 Hz, 1H).

Compound 146: 1H NMR (400 MHz, CD3OD) δ ppm 1.68-1.78 (m, 1H), 1.82-2.01 (m, 2H), 2.24-2.47 (m, 5H), 2.89-3.06 (m, 2H ), 3.11-3.19 (m, 1H), 3.24-3.28 (m, 1H), 3.45-3.55 (m, 1H), 3.63 (t, J=12 .63 Hz, 2H), 3.873.94 (m, 1H), 3.99-4.06 (m, 2H), 4.07-4.16 (m, 3H), 4.22-4.31 ( m, 1H), 7.30 (dd, J=8.21, 1.64 Hz, 1H), 7.40 (s, 1H), 7.46 (d, J=7.83 Hz, 1H), 7.55 (t, J=7.96 Hz, 1H), 8.00 (t, J=7.45 Hz, 1H), 8.22 (t, J=7.58 Hz, 1H), 8.288, 35 (m, 1H), 8.41 (d, J=8.08 Hz, 1H), 9.35 (d, J=1.01 Hz, 1H), 9.44 (d, J=1.77 Hz, 1H).

Compound 147: 1H NMR (400 MHz, CD3OD) δ ppm 1.05-1.12 (m, 2H), 1.46-1.51 (m, 2H), 1.64-1.75 (m, 1H), 1.79-1.98 (m, 4H ), 2.33 (dd, J=13.89, 7.83 Hz, 1H), 2.77-2.92 (m, 2H), 3.16 (d, J=9.60 Hz, 1H) , 3.24-3.29 (m, 1H), 3.53-3.65 (m, 2H), 3.71 (s, 2H), 3.83-3.89 (m, 1H), 3 .97-4.03 (m, 2H), 4.05-4.14 (m, 2H), 4.18-4.28 (m, 1H), 7.28 (ddd, J=7.77, 2.59, 1.52 Hz, 1H), 7.46 (d, J=2.27 Hz, 1H), 7.47-7.57 (m, 2H), 8.03 (dd, J=8 .46, 4.93 Hz, 1H), 8.27-8.33 (m, 1H), 8.34-8.40 (m, 1H), 8.72 (d, J=1.77 Hz, 1H), 9.07 (d, J=8.59 Hz, 1H), 9.25 (d, J=1.01 Hz, 1H).

Compound 148: 1H NMR (400 MHz, CD3OD) δ ppm 1.64-1.74 (m, 1H), 1.80-1.98 (m, 4H), 2.33 (dd, J=13.89, 7.83 Hz, 1H), 2.77- 2.92 (m, 2H), 3.15 (dd, J=13.01, 9.73 Hz, 1H), 3.24-3.29 (m, 1H), 3.55-3.67 ( m, 2H), 3.82-3.90 (m, 1H), 3.96-4.04 (m, 2H), 4.06-4.11 (m, 2H), 4.11-4, 19 (m, 2H), 4.25 (dd, J=9.47, 3.16 Hz, 1H), 7.43 (dt, J=7.77, 2.05 Hz, 1H), 7.49 -7.52 (m, 1H), 7.57-7.66 (m, 2H), 8.12 (dd, J=8.46, 5.18 Hz, 1H), 8.33-8.43 (m, 2H), 8.78 (d, J=1.52 Hz, 1H), 9.20 (d, J=8.59 Hz, 1H), 9.31 (dd, J=5.05, 1.52 Hz, 1H).

Compound 155: 1H NMR (400 MHz, CD3OD) δ ppm 1.05-1.13 (m, 2H), 1.46-1.52 (m, 2H), 1.62-1.73 (m, 1H), 1.82-1.94 (m, 4H ), 2.32-2.41 (m, 1H), 2.76-2.92 (m, 2H), 3.04 (s, 3H), 3.14-3.22 (m, 1H), 3.49 (brs, 4H), 3.59 (d, J=5.31 Hz, 1H), 3.63-3.69 (m, 2H), 3.72 (s, 2H), 3 .75 (d, J=1.01 Hz, 1H), 3.94 (d, J=7.58 Hz, 1H), 4.00-4.17 (m, 4H), 4.28 (br. s, 1H), 4.63 (br s, 2H), 7.26 (s, 1H), 7.30 (d, J=7.58 Hz, 1H), 7.48-7.51 (m , 2H), 7.49-7.57 (m, 1H), 7.83 (brs, 1H).

Compound 156: 1H NMR (400 MHz, CD3OD) δ ppm 1.63-1.73 (m, 1H), 1.83-1.96 (m, 4H), 2.35 (dd, J=13.52, 8.21 Hz, 1H), 2.75- 2.84 (m, 1H), 2.84-2.91 (m, 1H), 3.02 (s, 3H), 3.18 (dd, J=12.63, 9.60 Hz, 1H) , 3.413.53 (m, 2H), 3.56-3.61 (m, 2H), 3.63-3.69 (m, 3H), 3.71-3.76 (m, 2H), 3 .90-3.95 (m, 1H), 3.98-4.10 (m, 2H), 4.10-4.19 (m, 3H) 4.28 (td, J=4.74, 3 .16 Hz, 1H), 4.60 (d, J=4.55 Hz, 2H), 7.24 (d, J=2.02 Hz, 1H), 7.42-7.47 (m, 1H ), 7.53 (s, 1H), 7.58-7.67 (m, 2H), 7.81 (br s, 1H).

Compound 157: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.47-1.51 (m, 2H), 1.63-1.73 (m, 1H), 1.81-1.96 (m, 3H ), 2.33 (dd, J=13.64, 8.08 Hz, 1H), 2.71-2.85 (m, 2H), 3.16 (dd, J=12.63, 9.60 Hz, 1H), 3.24-3.28 (m, 1H), 3.43-3.54 (m, 2H), 3.56-3.60 (m, 2H), 3.64-3, 68 (m, 3H), 3.71-3.76 (m, 3H), 3.88-3.94 (m, 1H), 3.98-4.06 (m, 2H), 4.10 ( dd, J=4.93, 2.15 Hz, 2H), 4.19 (s, 2H), 4.23-4.30 (m, 1H), 7.29 (dt, J=8.53, 1.55 Hz, 1H), 7.44-7.50 (m, 1H), 7.50-7.56 (m, 2H), 7.61 (d, J=8.08 Hz, 2H), 7.69-7.82 (m, 4H), 7.94-7.99 (m, 2H).

Compound 158: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.49 (t, J=6.95 Hz, 3H), 1.481.52 (m, 2H), 1.60-1.68 (m, 1H) , 1.78-1.80 (m, 1H), 1.81-1.91 (m, 3H), 2.37 (dd, J=13.77, 8.21 Hz, 1H), 3.07 - 113 041181

3.22(m, 2H), 3.51-3.62(m, 3H), 3.63-3.69(m, 2H), 3.72(s, 2H), 3.74-3, 76 (m, 1H), 3.94-3.99 (m, 1H), 4.01-4.07 (m, 1H), 4.08-4.14 (m, 2H), 4.16 ( s, 2H), 4.23-4.28 (m, 2H), 4.26-4.31 (m, 1H), 7.30 (d, J=8.59 Hz, 2H), 7.477.50 (m, 1H), 7.51-7.57 (m, 4H), 7.69 (d, J=8.34 Hz, 2H), 7.87 (dd, J=8.72, 2.40 Hz, 1H), 8.08 (d, J=2.53 Hz,

1H).

Compound 161: 1H NMR (400 MHz, CD3OD) δ ppm 1.48 (t, J=6.82 Hz, 3H), 1.59-1.68 (m, 1H), 1.771.91 (m, 3H), 2.37 (dd, J=13.26, 7.71 Hz, 1H), 3.08-3.23 (m, 2H), 3.51-3.56 (m, 1H), 3.56-3.60 (m, 2H), 3.633.69 (m, 4H), 3.72-3.76 (m, 2H), 3.95-4.01 (m, 1H), 4.03-4.08 (m, 1H), 4.08-4 .12 (m, 1H), 4.12-4.15 (m, 2H), 4.17 (s, 2H) 4.25 (kv, J=6, 99 Hz, 2H), 4.29-4 .35 (m, 1H), 7.29 (d, J=8.59 Hz, 1H), 7.46 (d, J=7.83 Hz, 1H), 7.53 (s, 1H) 7, 56 (d, J=8.08 Hz, 2H), 7.59-7.66 (m, 2H), 7.69 (d, J=8.34 Hz, 2H), 7.87 (dd, J = 8.59, 2.27 Hz, 1H), 8.07 (d, J=2.27 Hz, 1H).

Compound 162: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.11 (m, 2H), 1.47-1.51 (m, 2H), 1.67 (t, J=10.23 Hz, 1H), 1.84 (d, J= 13.89 Hz, 1H), 1.89-1.95 (m, 3H), 2.36 (dd, J=13.77, 7.96 Hz, 1H), 2.95-3.09 (m , 2H), 3.16 (dd, J=12.38, 9.85 Hz, 1H), 3.56-3.61 (m, 2H), 3.63-3.69 (m, 2H), 3.71-3.75 (m, 4H), 3.91-3.96 (m, 1H), 4.00-4.11 (m, 2H), 4.12 (d, J=5.05 Hz, 2H), 4.19 (s, 2H), 4.27-4.33 (m, 1H), 7.27-7.32 (m, 1H), 7.42-7.51 (m, 3H), 7.52-7.56 (m, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.73 (d, J=8.08 Hz, 2H), 7, 97 (ddd, J=8.46, 4.42, 2.27 Hz, 1H), 8.02 (dd, J=6.32, 2.27 Hz, 1H).

Compound 164: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.10 (m, 2H), 1.46-1.52 (m, 2H), 1.64-1.73 (m, 1H), 1.80-1.98 (m, 3H ), 2.31 (dd, J=13.89, 7.83 Hz, 1H), 2.69-2.85 (m, 2H), 3.13 (dd, J=12.13, 10.36 Hz, 1H), 3.44-3.55 (m, 2H), 3.72 (s, 2H), 3.87 (d, J=6.06 Hz, 1H), 3.97-4.06 (m, 2H), 4.07-4.14 (m, 2H), 4.19 (s, 2H), 4.23-4.30 (m, 1H), 7.29 (d, J=7 .83 Hz, 1H), 7.45-7.56 (m, 3H), 7.60 (d, J=8.08 Hz, 2H), 7.73 (t, J=7.58 Hz, 1H ), 7.75-7.80 (m, 1H), 7.77 (d, J=8.34 Hz, 2H), 7.95-7.99 (m, 2H).

Compound 168: 1H NMR (400 MHz, DMSO46) δ ppm 1.39 (t, J=6.95 Hz, 3H), 1.56 (ddd, J=13.83, 10.29, 3.92 Hz, 1H), 1.64-1.71 (m, 1H), 1.74-1.82 (m, 2H), 1.87 (dd, J=12.76, 6.95 Hz, 1H), 2.19 (dd, J=13.01, 8, 21 Hz, 1H), 2.92-3.10 (m, 3H), 3.12-3.22 (m, 1H), 3.35-3.43 (m, 1H), 3.44-3 .53 (m, 2H), 3.63-3.73 (m, 2H), 3.80-3.86 (m, 1H), 3.87-3.94 (m, 1H), 3.95 -4.00(m, 1H), 4.01-4.14(m, 3H), 4.17-4.28(m, 1H), 4.23(kv, J=6, 82Hz, 2H ), 4.61 (brs, 1H), 5.95 (d, J=4.80 Hz, 1H), 6.11 (t, J=6.57 Hz, 1H), 7.35 (d , J=8.84 Hz, 1H), 7.43 (d, J=1.77 Hz, 1H), 7.51 (dd, J=8.21, 1.89 Hz, 1H), 7.54 -7.61 (m, 1H), 7.57 (d, J=8.08 Hz, 2H), 7.67-7.73 (m, 1H), 7.71 (d, J=8.34 Hz, 2H), 7.94 (dd, J=8.59, 2.27 Hz, 1H), 7.98 (d, J=2.53 Hz, 1H), 8.36 (broad s, 2H ), 8.98 (brs, 1H), 9.34 (brs, 1H).

Compound 169: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.04-1.10 (m, 2H), 1.33-1.38 (m, 2H), 1.57-1.74 (m, 2H), 1.77-1.90 (m, 2H ), 2.21 (dd, J=13.39, 7.83 Hz, 1H), 2.82-3.04 (m, 2H), 3.07-3.18 (m, 1H), 3, 44-3.53 (m, 3H), 3.62 (s, 2H), 3.65-3.73 (m, 3H), 3.82-3.99 (m, 3H), 4.03- 4.11 (m, 1H), 4.08 (t, J=5.05 Hz, 2H), 4.23 (dd, J=8.72, 3.66 Hz, 1H), 7.30 (dd , J=8.21, 1.89 Hz, 1H), 7.35-7.36 (m, 1H), 7.45 (d, J=8.34 Hz, 1H), 7.56 (t, J=7.96Hz, 1H), 7.59-7.65(m, 3H), 7.77(d, J=8.34Hz, 2H), 7.95(dd, J=6.57 , 2.27 Hz, 1H), 8.08 (ddd, J=8.59, 4.55, 2.53 Hz, 1H), 8.47 (br. s, 2H), 9.15 (br. s, 1H), 9.40 (brs, 1H).

Compound 170: 1H NMR (400 MHz, DMSO-T) δ ppm 1.03-1.09 (m, 2H), 1.33-1.37 (m, 2H), 1.56-1.65 (m, 1H), 1.66-1.74 (m, 1H ), 1.77-1.86 (m, 3H), 2.16 (dd, J=13.26, 7.96 Hz, 1H), 2.37 (s, 3H), 2.57-2, 71 (m, 2H), 2.92-3.02 (m, 1H), 3.04-3.17 (m, 1H), 3.44-3.53 (m, 1H), 3.62 ( d, J=2.78 Hz, 2H), 3.65-3.73 (m, 1H), 3.75-3.82 (m, 1H), 3.85-3.93 (m, 2H) , 4.05 (d, J=5.05 Hz, 2H), 4.15-4.22 (m, 1H), 4.84-4.96 (m, 1H), 5.91 (d, J =4.80 Hz, 1H), 7.26-7.36 (m, 4H), 7.42-7.47 (m, 1H), 7.55 (t, J=7.96 Hz, 1H) , 7.64 (d, J=8.34 Hz, 2H), 7.68-7.77 (m, 2H), 7.87-7.91 (m, 1H), 8.01 (dt, J =7.01, 1.80 Hz, 1H), 9.02 (brs, 1H), 9.19 (brs, 1H).

Compound 172: 1H NMR (400 MHz, CD3OD) δ ppm 1.05-1.12 (m, 2H), 1.31-1.36 (m, 2H), 1.41-1.45 (m, 2H), 1.46-1.52 (m, 3H ), 1.58-1.72(m, 1H), 1.77-1.93(m, 3H), 2.36(brs, 1H), 3.08-3.23(m, 2H ), 3.50-3.60 (m, 1H), 3.59 (q, J=4.72 Hz, 2H), 3.65 (s, 3H), 3.70-3.76 (m, 3H), 3.98 (d, J=9.09 Hz, 1H), 4.03-4.18 (m, 4H), 4.22-4.29 (m, 2H), 4.30 (breadth .s, 1H), 7.27-7.34 (m, 2H), 7.44-7.55 (m, 3H), 7.57 (d, J=8.08 Hz, 2H), 7, 68 (d, J=8.08 Hz, 2H), 7.87 (d, J=7.33 Hz, 1H), 8.07 (d, J=1.52 Hz, 1H).

Compound 174: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.12 (m, 2H), 1.45-1.52 (m, 5H), 1.64 (t, J=10.36 Hz, 1H), 1.81 (d, J= 13.64 Hz, 1H), 1.85-1.92 (m, 3H), 2.37 (dd, J=13.64, 7.83 Hz, 1H), 3.07-3.20 (m , 2H), 3.48-3.55 (m, 1H), 3.56-3.60 (m, 3H), 3.63-3.69 (m, 7H), 3.71-3.77 (m, 3H), 3.95-4.00 (m, 1H), 4.06 (brs, 1H), 4.08-4.16 (m, 3H), 4.25 (q, J = 6.82 Hz, 2H), 4.28-4.33 (m, 1H), 7.29 (t, J=8.59 Hz, 1H), 7.28-7.33 (m, 1H) , 7.46-7.52 (m, 3H), 7.55 (d, J=8.34 Hz, 2H), 7.65 (d, J=8.34 Hz, 2H), 7.86 ( dd, J=8.59, 2.27 Hz, 1H), 8.07 (d, J=2.27 Hz, 1H).

Compound 175: 1H NMR (400 MHz, CD3OD) δ ppm 1.05-1.12 (m, 2H), 1.48 (d, J=6.57 Hz, 5H), 1.581.67 (m, 1H), 1.77-1.92 (m, 3H) , 2.05 (s, 3H), 2.36 (dd, J=13.77, 7.96 Hz, 1H), 2.88 (t, J=7.33 Hz, 2H), 3.063.22 ( m, 3H), 3.51 (t, J=7.33 Hz, 2H), 3.48-3.55 (m, 1H), 3.56-3.60 (m, 2H), 3.63 -3.69 (m, 3H), 3.71-3.76 (m, 3H), 3.94-4.00 (m, 1H), 4.01-4.06 (m, 1H), 4 .07-4.16 (m, 2H), 4.23 (q, J=6.91 Hz, 2H), 4.27-4.33 (m, 1H), 7.247.31 (m, 2H), 7.32 (d, J=8.08 Hz, 2H), 7.46-7.50 (m, 1H), 7.50-7.56 (m, 4H), 7.82 (dd, J= 8.72, 2.40 Hz, 1H), 8.03 (d, J=2.27 Hz, 1H).

Compound 176: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.52 (m, 9H), 1.60-1.69 (m, 1H), 1.77-1.95 (m, 3H ), 2.36 (dd, J=13.64, 8.34 Hz, 1H), 3.06-3.20 (m, 3H), 3.55-3.60 (m, 4H), 3, 63-3.69 (m, 2H), 3.71-3.76 (m, 4H), 3.94 (dd, J=10.11, 4.29 Hz, 1H), 4.01-4, 08 (m, 1H), 4.09-4.14 (m, 3H), 4.22-4.28 (m,

- 114 041181

2H), 4.26-4.32(m, 1H), 7.29-7.33(m, 1H), 7.46-7.50(m, 1H), 7.50-7.54( m, 2H), 7.55 (d, J=7.07 Hz, 2H), 7.647.67 (m, 2H), 7.86 (dd, J=8.59, 2.27 Hz, 1H), 8.07 (d, J=2.27 Hz, 1H).

Compound 177: ¹ H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.45-1.52 (m, 5H), 1.59-1.68 (m, 1H), 1.80 (d, J=13.89 Hz, 1H), 1.84-1.92 (m, 3H), 1.99 (s, 3H), 2.36 (dd, J=13.52, 8.21 Hz, 1H), 2.86 (t, J=7.33 Hz, 2H), 3.06-3.21 (m, 3H), 3.47 (t, J=7.33 Hz, 2H), 3.59 (d, J= 5.05 Hz, 2H), 3.63-3.69 (m, 2H), 3.71-3.76 (m, 3H), 3.94 (dd, J=10.11, 4.29 Hz , 1H), 4.00-4.07 (m, 1H), 4.07-4.15 (m, 2H), 4.23 (q, J=6.99 Hz, 2H), 4.26- 4.31 (m, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.28-7.32 (m, 1H), 7.32 (d, J=8.34 Hz , 2H), 7.46-7.50 (m, 1H), 7.50-7.56 (m, 2H), 7.53 (d, J=8.08 Hz, 2H), 7.82 ( dd, J=8.59, 2.27 Hz, 1H), 8.03 (d, J=2.53 Hz, 1H).

Compound 180: 1H NMR (400 MHz, CD3OD) δ ppm 1.04-1.12(m, 2H), 1.49(s, 6H), 1.62-1.73(m, 1H), 1.79-1.97(m, 4H), 2, 32 (dd, J=13.26, 7.71 Hz, 1H), 2.70-2.85 (m, 2H), 3.09-3.19 (m, 1H), 3.24 (s, 2H), 3.41-3.53 (m, 2H), 3.59 (d, J=5.31 Hz, 1H), 3.63-3.69 (m, 2H), 3.70-3 .76 (m, 2H), 3.85-3.91 (m, 1H), 3.98-4.07 (m, 2H), 4.08-4.14 (m, 2H), 4.23 -4.30 (m, 1H), 7.26-7.32 (m, 1H), 7.41-7.56 (m, 3H), 7.60 (d, J=8.08 Hz, 2H ), 7.69-7.79 (m, 4H), 7.93-7.99 (m, 2H).

Compound 181: 1H NMR (400 MHz, CD3OD) δ ppm 1.05-1.12 (m, 2H), 1.49-1.50 (m, 6H), 1.68 (t, J=11.12 Hz, 1H), 1.80-1.96 ( m, 4H), 2.27-2.38 (m, 1H), 2.69-2.85 (m, 2H), 3.10-3.19 (m, 1H), 3.25 (s, 2H), 3.423.53 (m, 2H), 3.56-3.59 (m, 1H), 3.63-3.69 (m, 2H), 3.71-3.77 (m, 2H) , 3.90 (d, J=6.57 Hz, 1H), 3.97-4.06 (m, 2H), 4.07-4.14 (m, 2H), 4.27 (br.s , 1H), 7.29 (d, J=7.58 Hz, 1H), 7.44-7.56 (m, 3H), 7.60 (d, J=8.08 Hz, 2H), 7 .68-7.78 (m, 4H), 7.94-7.98 (m, 2H).

Compound 182: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.47-1.51 (m, 2H), 1.61-1.73 (m, 1H), 1.80-1.98 (m, 4H ), 2.33 (dd, J=13.39, 7.83 Hz, 1H), 2.71-2.85 (m, 2H), 3.10-3.17 (m, 1H), 3, 44-3.55 (m, 2H), 3.64-3.76 (m, 1H), 3.72 (s, 2H), 3.85-3.91 (m, 1H), 3.97- 4.07 (m, 2H), 4.08-4.14 (m, 2H), 4.26 (s, 2H), 4.254.30 (m, 1H), 7.26-7.31 (m, 1H), 7.44-7.56 (m, 3H), 7.57-7.68 (m, 3H), 7.74 (t, J=7.96 Hz, 1H), 7.83 (d , J=7.83 Hz, 1H), 7.96-8.01 (m, 2H).

Compound 184: 1H NMR (400 MHz, CD3OD) δ ppm 1.05-1.11 (m, 2H), 1.34-1.39 (m, 2H), 1.40-1.44 (m, 2H), 1.46-1.52 (m, 2H ), 1.62-1.73 (m, 1H), 1.79-1.97 (m, 4H), 2.32 (dd, J=13.64, 8.08 Hz, 1H), 2, 69-2.84 (m, 2H), 3.13 (dd, J=12.63, 9.60 Hz, 1H), 3.42-3.55 (m, 2H), 3.63-3, 76 (m, 1H), 3.72 (s, 2H), 3.85-3.90 (m, 1H), 3.96-4.07 (m, 1H), 4.08-4.14 ( m, 2H), 4.21-4.29 (m, 1H), 7.29 (ddd, J=7.71, 2.53, 1.64 Hz, 1H), 7.45-7.56 ( m, 3H), 7.58-7.63 (m, 2H), 7.69-7.81 (m, 4H), 7.94-7.98 (m, 2H).

Compound 185: 1H NMR (400 MHz, CD3OD) δ ppm 1.09 (dd, J=12.13, 1.01 Hz, 1H), 1.47-1.53 (m, 2H), 1.63-1.73 (m, 1H), 1.79- 1.97 (m, 3H), 2.34 (dd, J=13.77, 8.21 Hz, 1H), 2.72-2.90 (m, 2H), 3.17 (dd, J= 12.88, 9.60 Hz, 1H), 3.46-3.60 (m, 3H), 3.62-3.76 (m, 1H), 3.72 (s, 2H), 3.86 -3.95 (m, 1H), 3.98-4.14 (m, 4H), 4.21-4.29 (m, 1H), 7.29 (dt, J=8.59, 1, 64 Hz, 1H), 7.45-7.58 (m, 3H), 8.37 (t, J=2.02 Hz, 1H), 8.89 (brs, 1H), 8.96 ( br.s, 1H).

Compound 186: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.12 (m, 2H), 1.47-1.52 (m, 2H), 1.67 (ddd, J=13.89, 10.99, 4.17 Hz, 1H), 1.79-1.95 (m, 4H), 2.34 (dd, J=13.52, 8.21 Hz, 1H), 2.73-2.89 (m, 2H), 3.15 ( dd, J=12.76, 9.47 Hz, 1H), 3.29-3.35 (m, 1H), 3.44-3.56 (m, 2H), 3.56-3.60 ( m, 2H), 3.66 (d, J=5.31 Hz, 3H), 3.703.77 (m, 4H), 3.86-3.92 (m, 1H), 3.98-4.14 (m, 4H), 4.21-4.29 (m, 1H), 7.30 (dt, J=7.64, 2.12 Hz, 1H), 7.45-7.58 (m, 3H ), 8.37 (t, J=2.02 Hz, 1H), 8.89 (s, 1H), 8.96 (s, 1H).

Compound 187: 1H NMR (400 MHz, CD3OD) δ ppm 1.29 (s, 6H), 1.49 (t, J=6.95 Hz, 3H), 1.60-1.69 (m,

1H), 1.78-1.84 (m, 1H), 1.85-1.92 (m, 3H), 2.36 (dd, J=13.64, 8.34 Hz, 1H), 3 .06-3.22(m, 2H), 3.30-3.37(m,

1H), 3.50-3.62 (m, 3H), 3.65-3.76 (m, 2H), 3.94 (dd, J=10.23, 4.42 Hz, 1H), 4 .00-4.07 (m, 1H), 4.08-4.15 (m,

3H), 4.16 (s, 2H), 4.22-4.31 (m, 3H), 7.29 (d, J=8.59 Hz, 1H), 7.34 (dd, J=6 .95, 1.39 Hz, 1H), 7.41-7.45 (m, 1H),

7.47-7.50 (m, 1H), 7.53-7.59 (m, 3H), 7.69 (d, J=8.08 Hz, 2H), 7.87 (dd, J= 8.59, 2.53 Hz, 1H), 8.08 (d, J=2.53 Hz, 1H).

Compound 188: 1H NMR (400 MHz, CD3OD) δ ppm 1.05-1.11 (m, 2H), 1.30-1.37 (m, 2H), 1.39-1.43 (m, 2H), 1.45-1.53 (m, 2H ), 1.48 (t, J=6.06 Hz, 3H), 1.59-1.69 (m, 1H), 1.78-1.93 (m, 4H), 2.36 (dd, J=13.64, 8.34 Hz, 1H), 3.05-3.22 (m, 3H), 3.50-3.62 (m, 3H), 3.63-3.69 (m, 3H), 3.71-3.77 (m, 4H), 3.94 (dd, J=9.98, 4.17 Hz, 1H), 4.00-4.07 (m, 1H), 4 .08-4.16 (m, 3H), 4.20-4.31 (m, 1H), 4.25 (kv, J=6.82 Hz, 2H), 7.26-7.33 (m , 3H), 7.467.56 (m, 3H), 7.56 (d, J=8.34 Hz, 2H), 7.69 (d, J=8.34 Hz, 2H), 7.87 (dd , J=8.59, 2.27 Hz, 1H), 8.07 (d, J=2.27 Hz, 1H).

Compound 190: 1H NMR (400 MHz, CD3OD) δ ppm 1.08 (d, J=2.02 Hz, 2H), 1.47-1.52 (m, 2H), 1.621.76 (m, 2H), 1.79-1.91 (m, 3H) , 1.92 (s, 3H), 2.30 (dd, J=13.64, 8.34 Hz, 1H), 2.70-2.83 (m, 2H), 2.85 (t, J = 7.33 Hz, 2H), 3.12 (dd, J=12.00, 10.48 Hz, 1H), 3.28 (d, J=3.03 Hz, 1H), 3.44 (t , J=7.45 Hz, 2H), 3.43-3.52 (m, 3H), 3.71 (s, 2H), 3.83-3.88 (m, 1H), 3.95- 4.05 (m, 2H), 4.06-4.13 (m, 2H), 4.20-4.27 (m, 1H), 7.25-7.31 (m, 1H), 7. 36 (d, J=8.34 Hz, 2H), 7.43-7.47 (m, 1H), 7.48-7.56 (m, 2H), 7.60 (d, J=8, 34 Hz, 2H), 7.69 (d, J=7.83 Hz, 1H), 7.73 (dt, J=7.83, 1.52 Hz, 1H), 7.90-7.95 ( m, 2H).

Compound 191: 1H NMR (400 MHz, CD3OD) δ ppm 1.05-1.10 (m, 2H), 1.47-1.52 (m, 2H), 1.61-1.74 (m, 2H), 1.79-1.90 (m, 4H ), 1.92 (s, 3H), 2.31 (dd, J=13.89, 8.08 Hz, 1H), 2.70-2.83 (m, 2H), 2.85 (t, J=7.45 Hz, 2H), 3.15 (dd, J=12.63, 9.60 Hz, 1H), 3.27 (dd, J=12.76, 3.16 Hz, 1H), 3.44 (t, J=7.33 Hz, 2H), 3.42-3.52 (m, 2H), 3.71 (s, 2H), 3.85-3.90 (m, 1H) , 3.95-4.04 (m, 2H), 4.06-4.12 (m, 2H), 4.18-4.26 (m, 1H), 7.28 (ddd, J=5, 31, 2.53, 2.27 Hz, 1H), 7.36 (d, J=8.34 Hz, 2H), 7.42-7.47 (m, 1H), 7.48-7.56 (m, 2H), 7.60 (d, J=8.34 Hz, 2H), 7.69

- 115 041181 (d, J=8.08 Hz, 1H), 7.73 (dt, J=7.83, 1.52 Hz, 1H), 7.89-7.96 (m, 2H).

Compound 192: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.12 (m, 2H), 1.48-1.52 (m, 2H), 1.60-1.69 (m,

1H), 1.78-1.93 (m, 4H), 2.37 (dd, J=13.77, 8.21 Hz, 1H), 2.70 (s, 3H), 3.03-3 .23 (m, 3H), 3.39-3.51 (m, 2H),

3.63-3.69 (m, 1H), 3.72 (s, 2H), 3.73-3.76 (m, 1H), 3.94-3.99 (m, 1H), 4, 01-4.07 (m, 1H), 4.08-4.16 (m, 3H),

4.23-4.30 (m, 1H), 7.25-7.33 (m, 2H), 7.46-7.58 (m, 3H), 7.87 (d, J=8.08 Hz, 1H), 7.92 (d, J=7.83 Hz, 1H).

Compound 193: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.48-1.52 (m, 2H), 1.61-1.70 (m, 1H), 1.79-1.94 (m, 3H ), 2.32 (dd, J=13.77, 8.21 Hz, 1H), 2.64-2.80 (m, 2H), 3.11-3.20 (m, 1H), 3, 27 (d, J=3.03 Hz, 1H), 3.36-3.46 (m, 2H), 3.55-3.61 (m, 1H), 3.63-3.69 (m, 1H), 3.72 (s, 2H), 3.73-3.76 (m, 1H), 3.87-3.93 (m, 1H), 3.96-4.05 (m, 1H) , 3.98 (s, 3H), 4.07-4.14 (m, 2H), 4.22-4.28 (m, 1H), 7.24 (d, J=8.59 Hz, 1H ), 7.29 (dt, J=7.64, 2.12 Hz, 1H), 7.45-7.57 (m, 3H), 7.75 (dd, J=8.84, 2.27 Hz, 1H), 7.90 (d, J=2.27 Hz, 1H).

Compound 194: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.11 (m, 2H), 1.48-1.52 (m, 2H), 1.60-1.70 (m, 1H), 1.77-1.94 (m, 3H ), 2.32 (dd, J=13.89, 8.08 Hz, 1H), 2.49 (s, 3H), 2.66-2.81 (m, 2H), 3.13-3, 20 (m, 1H), 3.27 (d, J=3.03 Hz, 1H), 3.38-3.49 (m, 1H), 3.56-3.60 (m, 1H), 3 .63-3.68 (m, 1H), 3.72 (s, 2H), 3.73-3.76 (m, 1H), 3.87-3.92 (m, 1H), 3.96 -4.06 (m, 1H), 4.06-4.14 (m, 2H), 4.20-4.27 (m, 1H), 7.29 (dt, J=7.52, 2, 05 Hz, 1H), 7.447.57 (m, 4H), 7.68 (d, J=2.02 Hz, 1H), 7.80 (d, J=8.34 Hz, 1H).

Compound 195: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.52 (m, 2H), 1.65-1.75 (m, 1H), 1.81-1.96 (m, 3H ), 2.36 (dd, J=13.64, 7.83 Hz, 1H), 2.85-2.99 (m, 2H), 3.14-3.22 (m, 1H), 3, 53-3.62 (m, 3H), 3.64-3.68 (m, 1H), 3.72 (s, 2H), 3.73-3.77 (m, 1H), 3.89- 3.96 (m, 1H), 4.01-4.09 (m, 1H), 4.08-4.16 (m, 2H), 4.28 (dd, J=8.72, 2.91 Hz, 1H), 7.30 (d, J=7.83 Hz, 1H), 7.44-7.58 (m, 3H), 8.06 (dd, J=7.58, 5.56 Hz , 1H), 8.66 (d, J=8.08 Hz, 1H), 9.02 (broad s, 1h), 9.18 (broad s, 1H).

Compound 196: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.48-1.52 (m, 2H), 1.61-1.70 (m, 1H), 1.79-1.95 (m, 4H ), 2.32 (dd, J=13.64, 8.08 Hz, 1H), 2.49 (s, 3H), 2.67-2.80 (m, 2H), 3.14 (dd, J=12.76, 9.47 Hz, 1H), 3.37-3.50 (m, 2H), 3.56-3.60 (m, 1H), 3.63-3.69 (m, 1H), 3.72 (s, 2H), 3.73-3.76 (m, 1H), 3.85-3.90 (m, 1H), 3.98-4.07 (m, 1H) , 4.09-4.14 (m, 2H), 4.21-4.29 (m, 1H), 7.29 (dt, J=8.59, 1.64 Hz, 1H), 7.45 -7.57 (m, 4H), 7.68 (d, J=1.77 Hz, 1H), 7.80 (d, J=8.34 Hz, 1H).

Compound 197: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.12 (m, 2H), 1.49-1.52 (m, 2H), 1.63-1.73 (m, 1H), 1.78-1.97 (m, 4H ), 2.39 (dd, J=13.52, 8.21 Hz, 1H), 2.44 (s, 3H), 3.09-3.25 (m, 3H), 3.32-3, 38 (m, 1H), 3.44-3.56 (m, 2H), 3.63-3.69 (m, 1H), 3.73 (s, 2H), 3.73-3.76 ( m, 1H), 3.93-4.00 (m, 1H), 4.02-4.09 (m, 1H), 4.10-4.17 (m, 3H), 4.20 (s, 2H), 4.24-4.31 (m, 1H), 7.31 (ddd, J=7.71, 2.53, 1.39 Hz, 1H), 7.39 (d, J=8, 08 Hz, 2H), 7.43-7.47 (m, 2H), 7.47-7.54 (m, 2H), 7.56 (d, J=8.34 Hz, 2H), 7, 92-7, 97 (m, 1H).

Compound 198: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.11 (m, 2H), 1.33-1.39 (m, 2H), 1.41-1.46 (m, 2H), 1.47-1.52 (m, 2H ), 1.67 (t, J=10.23 Hz, 1H), 1.79-1.97 (m, 4H), 2.35-2.43 (m, 1H), 2.44 (s, 3H), 3.10-3.24 (m, 3H), 3.33-3.38 (m, 1H), 3.48 (t, J=13.39 Hz, 2H), 3.56-3 .60 (m, 2H), 3.63-3.68 (m, 2H), 3.73 (s, 2H), 3.733.76 (m, 2H), 3.98 (dd, J=9.98 , 3.92 Hz, 1H), 4.07 (broad s, 1H), 4.10-4.18 (m, 2H), 4.27-4.34 (m, 1H), 7.31 ( d, J=7.33 Hz, 1H), 7.38 (d, J=8.08 Hz, 2H), 7.43-7.46 (m, 2H), 7.47-7.55 (m , 3H), 7.59 (d, J=8.08 Hz, 2H), 7.927.99 (m, 1H).

Compound 200: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.11 (m, 2H), 1.48-1.53 (m, 2H), 1.60-1.68 (m, 1H), 1.79-1.91 (m, 4H ), 2.37 (dd, J=13.64, 8.34 Hz, 1H), 2.70 (s, 3H), 3.04-3.20 (m, 3H), 3.32-3, 37 (m, 1H), 3.40-3.51 (m, 2H), 3.56-3.60 (m, 1H), 3.63-3.69 (m, 1H), 3.72 ( s, 2H), 3.72-3.76 (m, 1H), 3.92-3.97 (m, 1H), 4.00-4.08 (m, 1H), 4.09-4, 16 (m, 2H), 4.24-4.30 (m, 1H), 7.26-7.33 (m, 2H), 7.47-7.58 (m, 3H), 7.87 ( dd, J=8.08, 1.01 Hz, 1H), 7.91 (d, J=8.08 Hz, 1H).

Compound 201: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.11 (m, 2H), 1.48-1.52 (m, 2H), 1.65 (dd, J=13.64, 6.82 Hz, 1H), 1.78- 1.93 (m, 4H), 2.32 (dd, J=13.64, 8.08 Hz, 1H), 2.65-2.79 (m, 2H), 3.14 (dd, J= 12.63, 9.60 Hz, 1H), 3.35-3.46 (m, 2H), 3.56-3.59 (m, 1H), 3.63-3.68 (m, 1H) , 3.72 (s, 2H), 3.73-3.76 (m, 1H), 3.86-3.90 (m, 1H), 3.98 (s, 3H), 4.01-4 .07 (m, 1H), 4.08-4.14 (m, 2H), 4.22-4.29 (m, Hz, 1H), 7.24 (d, J=8.84 Hz, 1H ), 7.277.31 (m, 1H), 7.46-7.50 (m, 1H), 7.51-7.57 (m, 2H), 7.75 (dd, J=8.84, 2 .27 Hz, 1H), 7.90 (d, J=2.27 Hz, 1H).

Compound 202: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.11 (m, 2H), 1.47-1.51 (m, 2H), 1.65-1.76 (m, 1H), 1.83-1.97 (m, 4H ), 2.36 (brs, 1H), 2.84-2.99 (m, 2H), 3.12-3.20 (m, 1H), 3.52-3.61 (m, 2H ), 3.63-3.69 (m, 1H), 3.72 (s, 2H), 3.72-3.77 (m, 1H), 3.92 (d, J=8.34 Hz, 1H), 4.01-4.17 (m, 3H), 4.29 (broad s, 1H), 7.31 (d, J=7.33 Hz, 1H), 7.44-7.57 (m, 3H), 8.10 (brs, 1H), 8.69 (d, J=7.58 Hz, 1H), 9.06 (brs, 1H), 9.22 (brs). s, 1H).

Compound 203: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.12 (m, 2H), 1.48-1.52 (m, 2H), 1.63-1.72 (m, 1H), 1.79-1.95 (m, 3H ), 2.40 (dd, J=13.77, 8.21 Hz, 1H), 2.44 (s, 3H), 3.10-3.25 (m, 4H), 3.32-3, 35 (m, 1H), 3.43-3.54 (m, 2H), 3.56-3.60 (m, 1H), 3.63-3.69 (m, 2H), 3.73 ( s, 2H), 3.72-3.76 (m, 1H), 3.96-4.01 (m, 1H), 4.02-4.09 (m, 1H), 4.09-4, 16 (m, 3H), 4.20 (s, 2H), 4.25-4.32 (m, 1H), 7.31 (dt, J=7.83, 2.02 Hz, 1H), 7 .39 (d, J=8.34 Hz, 2H), 7.43-7.47 (m, 2H), 7.48-7.51 (m, 1H), 7.51-7.59 (m , 4H), 7.92-7.98 (m, 1H).

Compound 204: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.11 (m, 2H), 1.34-1.39 (m, 2H), 1.40-1.45 (m, 2H), 1.48-1.53 (m, 2H ), 1.63-1.72 (m, 1H), 1.79-1.95 (m, 3H), 2.40 (dd, J=13.89, 8.34 Hz, 1H), 2, 44 (s, 3H), 3.10-3.24 (m, 3H), 3.44-3.55 (m, 2H), 3.56-3.59 (m, 1H), 3.63- 3.69 (m, 2H), 3.73 (s, 2H), 3.72-3.76 (m, 1H), 3.96-4.01 (m, 1H), 4.02-4, 09 (m, 1H), 4.09-4.16 (m, 3H), 4.25-4.31 (m, 1H), 7.31 (ddd, J=7.77, 2.59, 1 .52 Hz, 1H), 7.39 (d, J=8.34 Hz, 2H), 7.43-7.46 (m, 2H), 7.47-7.51 (m, 1H), 7 .51-7.56 (m, 2H), 7.58 (d, J=8.34 Hz, 2H),

- 116 041181

7.94 (d, J=4.29 Hz, 1H).

Compound 207: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.48-1.51 (m, 2H), 1.63-1.71 (m, 1H), 1.79-1.96 (m, 3H ), 2.33 (dd, J=13.52, 8.21 Hz, 1H), 2.68-2.81 (m, 2H), 3.14 (dd, J=12.63, 9.60 Hz, 1H), 3.32-3.34 (m, 1H), 3.38-3.49 (m, 2H), 3.56-3.60 (m, 1H), 3.64-3, 68 (m, 2H), 3.70-3.76 (m, 1H), 3.72 (s, 2H), 3.88 (t, J=3.03 Hz, 1H), 3.90 (s , 3H), 3.97-4.07 (m, 2H), 4.08-4.15 (m, 2H), 4.17 (s, 2H), 4.24-4.30 (m, 1H ), 7.27-7.31 (m, 1H), 7.32 (d, J=8.84 Hz, 1H), 7.46-7.48 (m, 1H), 7.49-7, 55 (m, 4H), 7.57-7.61 (m, 2H), 7.64 (d, J=2.27 Hz, 1H), 7.79 (dd, J=8.72, 2, 40 Hz, 1H).

Compound 208: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.47-1.51 (m, 2H), 1.63-1.72 (m, 1H), 1.80-1.96 (m, 3H ), 2.33 (dd, J=13.77, 8.21 Hz, 1H), 2.67-2.83 (m, 2H), 3.16 (dd, J=12.63, 9.60 Hz, 1H), 3.26-3.33 (m, 1H), 3.39-3.48 (m, 2H), 3.56-3.60 (m, 1H), 3.63-3, 69 (m, 2H), 3.72 (s, 2H), 3.73-3.76 (m, 1H), 3.88-3.93 (m, 1H), 3.90 (s, 2H) , 3.97-4.06 (m, 2H), 4.08-4.14 (m, 2H), 4.17 (s, 3H), 4.22-4.29 (m, 1H), 7 .27-7.31 (m, 1H), 7.32 (d, J=0.84 Hz, 1H), 7.45-7.48 (m, 1H), 7.49-7.55 (m , 4H), 7.56-7.61 (m, 2H), 7.64 (d, J=2.27 Hz, 1H), 7.79 (dd, J=8.72, 2.40 Hz, 1H).

Compound 210: 1H NMR (400 MHz, CD3OD) δ ppm 1.63-1.72 (m, 1H), 1.79-1.98 (m, 4H), 2.32 (dd, J=13.64, 8.08 Hz, 1H), 2.70- 2.86 (m, 2H), 3.03 (t, J=7.71 Hz, 2H), 3.13 (dd, J=12.76, 9.47 Hz, 1H), 3.23 (t , J=7.83 Hz, 2H), 3.28-3.30 (m, 1H), 3.42-3.54 (m, 2H), 3.85-3.89 (m, 1H), 3.95-4.06 (m, 2H), 4.14 (t, J=14.40 Hz, 2H), 4.11 (d, J=5.56 Hz, 2H), 7.43 (d , J=8.08 Hz, 2H), 7.43-7.46 (m, 1H), 7.50-7.53 (m, 1H), 7.58-7.66 (m, 2H), 7.68 (d, J=8.08 Hz, 2H), 7.71 (d, J=7.83 Hz, 1H), 7.75 (dt, J=7.83, 1.39 Hz, 1H ), 7.91-7.98 (m, 2H).

Compound 211: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.51 (m, 2H), 1.63-1.72 (m, 1H), 1.79-1.97 (m, 4H ), 2.32 (dd, J=13.77, 8.21 Hz, 1H), 2.69-2.85 (m, 2H), 3.03 (t, J=7.71 Hz, 2H) , 3.13 (dd, J=12.63, 9.60 Hz, 1H), 3.23 (t, J=7.83 Hz, 2H), 3.43-3.54 (m, 2H), 3.63-3.76 (m, 1H), 3.72 (s, 2H), 3.84-3.91 (m, 1H), 3.95-4.06 (m, 2H), 4, 07-4.15 (m, 2H), 4.23-4.29 (m, 1H), 7.29 (dt, J=8.59, 1.64 Hz, 1H), 7.43 (d, J=8.34 Hz, 2H), 7.45-7.47(m, 1H), 7.48-7.51(m, 1H), 7.51-7.56(m, 1H), 7 .68 (d, J=8.34 Hz, 2H), 7.71 (d, J=7.83 Hz, 1H), 7.75 (dt, J=7.83, 1.52 Hz, 1H) , 7.92-7.97 (m, 2H).

Compound 212: 1H NMR (400 MHz, CD 3 OD) δ ppm 1.06-1.11 (m, 2H), 1.47-1.51 (m, 2H), 1.63-1.72 (m, 1H), 1.78-1.96 (m, 4H ), 2.32 (dd, J=13.77, 8.21 Hz, 1H), 2.71-2.84 (m, 2H), 3.03 (t, J=7.83 Hz, 2H) , 3.15 (dd, J=12.76, 9.73 Hz, 1H), 3.23 (t, J=7.71 Hz, 2H), 3.27 (d, J=3.03 Hz, 1H), 3.42-3.53 (m, 2H), 3.72 (s, 2H), 3.863.94 (m, 1H), 3.97-4.05 (m, 2H), 4.06 -4.15 (m, 2H), 4.22-4.29 (m, 1H), 7.29 (dt, J=6.88, 1.74 Hz, 1H), 7.44 (d, J = 8.34 Hz, 2H), 7.45-7.48 (m, 1H), 7.48-7.51 (m, 1H), 7.52 (d, J=7.83 Hz, 1H) , 7.67 (d, J=8.08 Hz, 2H), 7.71 (d, J=7.83 Hz, 1H), 7.74-7.79 (m, 1H), 7.91- 7.98 (m, 2H).

Compound 213: 1H NMR (400 MHz, CD3OD) δ ppm 1.63-1.72 (m, 1H), 1.79-1.96 (m, 4H), 2.32 (dd, J=13.89, 8.08 Hz, 1H), 2.70- 2.84 (m, 2H), 3.03 (t, J=7.71 Hz, 2H), 3.16 (dd, J=12.63, 9.60 Hz, 1H), 3.23 (t , J=7.71 Hz, 2H), 3.26 (d, J=3.03 Hz, 1H), 3.43-3.53 (m, 2H), 3.87-3.92 (m, 1H), 3.97-4.06 (m, 2H), 4.09-4.13 (m, 2H), 4.14 (t, J=14.40 Hz, 2H), 4.22-4 .30 (m, 1H), 7.42-7.46 (m, 1H), 7.43 (d, J=8.08 Hz, 2H), 7.51-7.52 (m, 1H), 7.58-7.61 (m, 1H), 7.62 (d, J=7.83 Hz, 1H), 7.68 (d, J=8.08 Hz, 2H), 7.71 (d , 1H), 7.75 (dt, J=8.08, 1.39 Hz, 1H), 7.92-7.96 (m, 2H).

Compound 214: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.44-1.53 (m, 2H), 1.48 (t, J=6, 95 Hz, 3H), 1.60-1.69 ( m, 1H), 1.79-1.92 (m, 4H), 2.36 (dd, J=13.64, 8.34 Hz, 1H), 3.01 (t, J=7.71 Hz , 2H), 3.073.24 (m, 5H), 3.35 (d, J=2.78 Hz, 1H), 3.50-3.61 (m, 2H), 3.72 (s, 2H) , 3.94 (dd, J=10.23, 4.17 Hz, 1H), 4.004.07 (m, 1H), 4.08-4.15 (m, 2H), 4.25 (q, J =6.99Hz, 2H), 4.25-4.31(m, 1H), 7.28(d, J=8.84Hz, 1H), 7.29-7.33(m, 1H) , 7.38 (d, J=8.08 Hz, 2H), 7.46-7.49 (m, 1H), 7.49-7.52 (m, 1H), 7.53 (d, J = 7.83 Hz, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.84 (dd, J=8.72, 2.40 Hz, 1H), 8.05 (d , J=2.27 Hz, 1H).

Compound 215: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.10 (m, 2H), 1.47-1.52 (m, 2H), 1.68 (dd, J=11.12, 4.04 Hz, 1H), 1.79- 1.96 (m, 4H), 2.32 (d, J=5.56 Hz, 1H), 2.67-2.82 (m, 2H), 3.02 (t, J=7.71 Hz , 2H), 3.14 (dd, J=12.63, 9.60 Hz, 1H), 3.23 (t, J=7.71 Hz, 2H), 3.33 (d, J=3, 03 Hz, 1H), 3.37-3.50 (m, 2H), 3.72 (s, 2H), 3.86-3.90 (m, 1H), 3.90 (s, 3H), 3.98-4.07 (m, 2H), 4.08-4.15 (m, 2H), 4.23-4.30 (m, 1H), 7.29 (d, J=8.84 Hz, 2H), 7.36 (d, J=8.08 Hz, 2H), 7.46-7.57 (m, 5H), 7.62 (d, J=2.27 Hz, 1H), 7.76 (dd, J=8.72, 2.40 Hz, 1H).

Compound 216: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.10 (m, 2H), 1.47-1.51 (m, 2H), 1.64-1.72 (m, 1H), 1.80-1.97 (m, 4H ), 2.34 (dd, J=13.52, 7.96 Hz, 1H), 2.71-2.87 (m, 2H), 3.17 (dd, J=12.51, 9.73 Hz, 1H), 3.28 (d, J=2.53 Hz, 1H), 3.43-3.54 (m, 2H), 3.72 (s, 2H), 3.92 (d, J = 6.06 Hz, 1H), 3.99-4.07 (m, 2H), 4.08-4.14 (m, 2H), 4.21 (s, 2H), 4.27 (dd, J=8.84, 2.78 Hz, 1H), 7.27-7.33(m, 1H), 7.44-7.50(m, 2H), 7.51(s, 1H), 7 .53 (d, J=7.83 Hz, 1H), 7.59-7.63 (m, 2H), 7.65-7.70 (m, 2H), 7.82-7.90 (m , 2H).

Compound 217: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.35-1.40 (m, 2H), 1.41-1.46 (m, 2H), 1.47-1.52 (m, 2H ), 1.61-1.73 (m, 1H), 1.79-1.97 (m, 4H), 2.34 (dd, J=13.64, 7.58 Hz, 1H), 2, 65-2.85 (m, 2H), 3.17 (dd, J=12.51, 9.73 Hz, 1H), 3.28 (d, J=2.53 Hz, 1H), 3.39 -3.54 (m, 2H), 3.72 (s, 2H), 3.88-3.96 (m, 1H), 3.98-4.07 (m, 2H), 4.08-4 .15 (m, 2H), 4.22-4.31 (m, 1H), 7.30 (dt, J=7.77, 1.93 Hz, 1H), 7.45-7.50 (m , 2H), 7.50-7.52 (m, 1H), 7.53 (d, J=7.58 Hz, 1H), 7.60-7.63 (m, 2H), 7.65- 7.70 (m, 2H), 7.80-7.90 (m, 2H).

Compound 218: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.52 (m, 2H), 1.61-1.73 (m, 1H), 1.81-1.98 (m, 4H ), 2.34 (dd, J=13.39, 8.08 Hz, 1H), 2.70-2.85 (m, 2H), 3.14 (dd, J=12.76, 9.47 Hz, 1H), 3.32-3.35 (m, 1H), 3.43-3.55 (m, 2H), 3.72 (s, 2H), 3.86-3.92 (m, 1H), 3.97-4.09 (m, 2H), 4.08-4.14 (m, 2H), 4.20 (s, 2H), 4.23-4.31 (m, 1H) , 7.30 (td, J=7.77, 2.59, 1.52 Hz, 1H), 7.45-7.50 (m, 2H), 7.50-7.52 (m, 1H) , 7.52-7.57

- 117 041181 (m, 1H), 7.59-7.63 (m, 2H), 7.65-7.69 (m, 2H), 7.81-7.90 (m, 2H).

Compound 219: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.35-1.40 (m, 2H), 1.42-1.47 (m, 2H), 1.47-1.52 (m, 2H ), 1.61-1.72 (m, 1H), 1.79-1.97 (m, 4H), 2.33 (dd, J=13.77, 6.69 Hz, 1H), 2, 66-2.86 (m, 2H), 3.08-3.20 (m, 1H), 3.32-3.35 (m, 1H), 3.42-3.53 (m, 2H), 3.72 (s, 2H), 3.86-3.93 (m, 1H), 3.98-4.07 (m, 2H), 4.09-4.16 (m, 2H), 4. 23-4.31 (m, 1H), 7.27-7.32 (m, 1H), 7.44-7.49 (m, 2H), 7.50-7.56 (m, 2H), 7.60-7.63 (m, 2H), 7.65-7.69 (m, 2H), 7.80-7.90 (m, 2H).

Compound 220: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.53 (m, 5H), 1.59-1.71 (m, 1H), 1.82 (d, J=14.15 Hz, 1H), 1.85-1.93 (m, 3H), 2.37 (dd, J=13.52, 8.21 Hz, 1H), 3.07-3.22 (m, 3H) , 3.56-3.60 (m, 2H), 3.63-3.68 (m, 2H), 3.72 (s, 2H), 3.72-3.76 (m, 1H), 3 .91-3.97 (m, 1H), 4.01-4.07 (m, 1H), 4.09-4.16 (m, 3H), 4.21-4.32 (m, 5H) , 7.31 (d, J=8.59 Hz, 2H), 7.46-7.62 (m, 6H), 7.90 (dd, J=8.72, 2.40 Hz, 1H), 8.09 (d, J=2.53 Hz, 1H).

Compound 221: 1H NMR (400 MHz, CD3OD) δ ppm 1.07-1.12 (m, 2H), 1.48-1.52 (m, 2H), 1.63-1.73 (m, 1H), 1.80-1.98 (m, 4H ), 2.35 (d, J=5.56 Hz, 1H), 2.77-2.85 (m, 1H), 2.85-2.92 (m, 1H), 3.14-3, 22 (m, 1H), 3.28 (d, J=3.03 Hz, 1H), 3.47-3.60 (m, 2H), 3.73 (s, 2H), 3.90-3 .95 (m, 1H), 3.98-4.08 (m, 2H), 4.08-4.15 (m, 2H), 4.22-4.30 (m, 1H), 7.30 (ddd, J=7.64, 2.59, 1.64 Hz, 1H), 7.45-7.49 (m, 1H), 7.49-7.53 (m, 1H), 7.54 (d, J=7.83 Hz, 1H), 8.47 (d, J=2.27 Hz, 1H), 8.72 (d, J=2.27 Hz, 1H).

Compound 223: 1H NMR (400 MHz, CD3OD) δ ppm 1.31 (s, 6H), 1.64-1.74 (m, 1H), 1.81-1.99 (m, 4H), 2.33 (d, J=13.39 Hz, 1H) , 2.69-2.83 (m, 2H), 3.16 (dd, J=12.38, 9.60 Hz, 1H), 3.34-3.36 (m, 1H), 3.41 -3.51(m, 3H), 3.68-3.70(m, 1H), 3.87-3.92(m, 1H), 3.92(s, 3H), 3.99-4 .10 (m, 2H), 4.09-4.16 (m, 2H), 4.19 (s, 2H), 4.254.33 (m, 1H), 7.30-7.37 (m, 2H ), 7.43-7.46 (m, 1H), 7.48-7.52 (m, 1H), 7.52-7.63 (m, 5H), 7.65 (d, J=2 .27 Hz, 1H), 7.81 (dd, J=8.72, 2.15 Hz, 1H).

Compound 224: 1H NMR (400 MHz, CD3OD) δ ppm 1.31 (s, 6H), 1.34-1.40 (m, 2H), 1.40-1.47 (m, 2H), 1.63-1.72 (m, 1H), 1. 81-1.98 (m, 4H), 2.34 (dd, J=13.39, 8.08 Hz, 1H), 2.68-2.84 (m, 2H), 3.16 (dd, J=12.63, 9.60 Hz, 1H), 3.35 (d, J=3.03 Hz, 1H), 3.39-3.50 (m, 2H), 3.68-3.71 (m, 1H), 3.87-3.91 (m, 2H), 3.92 (s, 3H), 3.994.10 (m, 2H), 4.10-4.16 (m, 2H), 4.26-4.33 (m, 1H), 7.33 (d, J=8.84 Hz, 1H), 7.33-7.37 (m, 1H), 7.43-7.46 ( m, 1H), 7.49-7.52 (m, 1H), 7.54-7.61 (m, 5H), 7.65 (d, J=2.27 Hz, 1H), 7.80 (dd, J=8.72, 2.40 Hz, 1H).

Compound 225: 1H NMR (400 MHz, CD3OD) δ ppm 1.06-1.12 (m, 2H), 1.33-1.38 (m, 2H), 1.39-1.45 (m, 2H), 1.47-1.52 (m, 2H ), 1.62-1.72 (m, 1H), 1.79-1.96 (m, 4H), 2.33 (dd, J=13.52, 8.21 Hz, 1H), 2, 68-2.82 (m, 2H), 3.14 (dd, J=12.63, 9.60 Hz, 1H), 3.32-3.35 (m, 1H), 3.38-3, 50 (m, 2H), 3.72 (s, 2H), 3.86-3.89 (m, 1H), 3.91 (s, 3H), 3.98-4.07 (m, 2H) , 4.07-4.15 (m, 2H), 4.23-4.32 (m, 1H), 7.27-7.34 (m, 2H), 7.46-7.48 (m, 1H), 7.49-7.60 (m, 6H), 7.63 (d, J=2.53 Hz, 1H), 7.79 (dd, J=8.72, 2.40 Hz, 1H ).

Compound 233: 1H NMR (400 MHz, CD3OD) δ ppm 1.58-1.67 (m, 3H), 1.68-1.76 (m, 1H), 1.82-2.00 (m, 4H), 2.34 (dd, J=13.77 , 7.96 Hz, 1H), 2.88-3.01 (m, 2H), 3.15 (dd, J=12.88, 9.60 Hz, 1H), 3.24-3.30 ( m, 1H), 3.56-3.67 (m, 2H), 3.85-3.92 (m, 1H), 3.97-4.05 (m, 2H), 4.06-4, 14 (m, 2H), 4.22-4.30 (m, 1H), 5.45-5.62 (m, 1H), 7.37 (ddd, J=8.08, 2.53, 1 .01 Hz, 1H), 7.46 (t, J=2.02 Hz, 1H), 7.51-7.56 (m, 1H), 7.59 (d, J=8.08 Hz, 1H ), 7.93-8.00 (m, 1H), 8.18 (ddd, J=8.59, 7.07, 1.52 Hz, 1H), 8.28 (d, J=8.59 Hz, 1H), 8.36 (d, J=8.08 Hz, 1H), 9.25 (d, J=1.77 Hz, 1H), 9.38 (d, J=2.02 Hz, 1H).

Compound 234: 1H NMR (400 MHz, CD3OD) δ ppm 1.58-1.67 (m, 3H), 1.68-1.76 (m, 1H), 1.82-2.00 (m, 4H), 2.34 (dd, J=13.77 , 7.96 Hz, 1H), 2.88-3.01 (m, 2H), 3.15 (dd, J=12.88, 9.60 Hz, 1H), 3.24-3.30 ( m, 1H), 3.56-3.67 (m, 2H), 3.85-3.92 (m, 1H), 3.97-4.05 (m, 2H), 4.06-4, 14 (m, 2H), 4.22-4.30 (m, 1H), 5.45-5.62 (m, 1H), 7.37 (ddd, J=8.08, 2.53, 1 .01 Hz, 1H), 7.46 (t, J=2.02 Hz, 1H), 7.51-7.56 (m, 1H), 7.59 (d, J=8.08 Hz, 1H ), 7.93-8.00 (m, 1H), 8.18 (ddd, J=8.59, 7.07, 1.52 Hz, 1H), 8.28 (d, J=8.59 Hz, 1H), 8.36 (d, J=8.08 Hz, 1H), 9.25 (d, J=1.77 Hz, 1H), 9.38 (d, J=2.02 Hz, 1H).

Compound 235: 1H NMR (400 MHz, CD3OD) δ ppm 1.64 (dd, J=23.75, 6.57 Hz, 3H), 1.68-1.74 (m, 1H), 1.82-1.96 (m, 4H), 2.38 ( dd, J=13.52, 7.96 Hz, 1H), 2.84-2.99 (m, 2H), 3.10 (s, 3H), 3.15-3.23 (m, 1H) , 3.32-3.35 (m, 1H), 3.44-3.54 (m, 2H), 3.59 (t, J=4.42 Hz, 2H), 3.91-3.97 (m, 1H), 4.01-4.10 (m, 2H), 4.10-4.17 (m, 2H), 4.26-4.34 (m, 1H), 4.75 (t , J=4.42 Hz, 2H), 5.49 (dq, J=47.49, 6.32 Hz, 1H), 7.37-7.42 (m, 2H), 7.47-7, 51 (m, 1H), 7.54-7.56 (m, 1H), 7.61 (t, J=7.96 Hz, 1H), 7.87 (d, J=1.52 Hz, 1H ).

Example 2 IC ₅₀ Determination of cAMP Antagonist (Cyclic Adenosine Monophosphate) Assays by Homogeneous Time Resolved Fluorescence (HTRF®)

cAMP assays by HTRF were performed according to the manufacturer's instructions (Cisbio, cAMP Dynamic 2 Assay Kit; #62AM4PEJ). CHO-K1 cells stably expressing the recombinant receptor were harvested and suspended in warm PBS to give a reaction mass of 300,000 cells/ml. This cell suspension was dispensed into 384 assay well plates (PerkinElmer ProxiPlate #6008280) at 5 μl per well (1500 cells/well) along with a cAMP (cyclic adenosine monophosphate) calibration curve.

The compounds were dissolved and serially diluted (5 times) in DMSO to obtain a 10-point dose-dependent effect of the reaction mass. The reaction mass was then diluted 100-fold in assay buffer (PBS containing 1 mM IBMX) before a volume of 2.5 μl was added to the cells (final upper concentration of the compound in a dose-dependent effect is typically 10 or 100 μM). After a short incubation, 2.5 μl of isoproterenol reaction mass was added to the wells,

- 118 041181 obtained at a concentration of 4 times its EC90 at the receptor of interest. EC90 for isoproterenol, a beta-adrenergic agonist, was determined in separate experiments using standard methods for measuring agonist potencies.

After a 1 hour incubation at room temperature, 5 µl of CAMP-D2 reagent diluted in lysis buffer was added to each well followed by 5 µl of cryptate reagent. The plates were further incubated at room temperature for 1 hour before reading. Time-resolved fluorescence measurements were collected on a suitable, HTRF-enabled spectrophotometer for reading plates.

Counts from a plate reader were matched to a standard cAMP curve on an assay plate to determine cAMP concentrations in each well and these values were used to plot dose-response curves to derive IC ₅₀ values.

Table B IC ₅₀ values for beta-3-adrenergic receptor

Connection No. 1C _5O 5 33.31 nM 88 25.12 nM 123 53.17 nM 136 18.83 nM 154 17.5 nM 161 21.14 nM 163 17.31 nM 169 17.47 nM 199 25.01 nM 210 22.43 nM 211 2 6.18 nM 217 28.43 nM

Connection No. 1C ₅₀ 225 33.1 nM 227 17.9 nM 229 11.58 nM 230 14.99 nM 232 16.63 nM 234 10.19 nM 240 31.69 nM 241 21.06 nM 243 35.01 nM 244 27.83 nM 245 18.38 nM 247 33.47 nM

It has been noted that each of the compounds specifically described herein had a beta-3 adrenergic receptor IC ₅₀ value in the range of about 3.0 nM to about 2.0 μM.

Specific IC ₅₀ values for specific compounds are given below, with the number of the immediately preceding IC ₅₀ value referring to the compound number (for example, 1: 4.42 nM refers to compound 1 with an IC ₅₀ value of 4.42 nM): 1: 4 .42 nM; 2: 44.79 nM; 3: 5.47 nM; 4: 4.45 nM; 6: 16.46 nM; 7: 34.24 nM; 8: 12.08 nM; 9: 24.25 nM; 10: 25.05 nM; 11: 35.52 nM; 12: 130.50 nM; 13: 97.85 nM; 14: 56.71 nM; 15: 5.70 nM; 16: 132.70 nM; 17: 38.76 nM; 18: 48.93 nM; 19: 66.74 nM; 20: 76.21 nM; 21: 252.30 nM; 22: 302.00 nM; 23: 242.00 nM; 24: 23.63 nM; 25: 54.56 nM; 26: 5.25 nM; 27: 19.33 nM; 28: 18.52 nM; 29: 16.09 nM; 30: 34.28 nM; 31: 49.26 nM; 32: 21.06 nM; 33: 189.20 nM; 34: 31.24 nM; 35: 20.26 nM; 36: 21.51 nM; 37: 9.37 nM; 38: 3.99 nM; 39: 70.81 nM; 40: 20.33 nM; 41: 13.68 nM; 42: 18.68 nM; 43: 32.42 nM; 44: 21.51 nM; 45: 23.64 nM; 46: 87.03 nM; 47: 82.09 nM; 48: 46.11 nM; 49: 33.13 nM; 50: 42.23 nM; 51: 17.36 nM; 52: 61.20 nM; 53: 23.93 nM; 54: 45.94 nM; 55: 30.55 nM; 56: 1988.00 nM; 57: 486.90 nM; 58: 109.30 nM; 59: 12.30 nM; 60: 17.37 nM; 61: 29.81 nM; 62: 24.46 nM; 63: 17.20 nM; 64: 921.70 nM; 65: 710.50 nM; 66: 981.60 nM; 67: 821.90 nM; 68: 4 93.60 nM; 69: 21.25 nM; 70: 24.43 nM; 71: 38.95 nM; 72: 328.70 nM; 73: 23.95 nM; 74: 37.97 nM; 75: 26.70 nM; 76: 35.91 nM; 77: 35.08 nM; 78: 41.93 nM; 79: 42.20 nM; 80: 38.10 nM; 81: 27.79 nM; 82: 43.23 nM; 83: 53.47 nM; 84: 54.69 nM; 85: 17.84 nM; 86: 9.10 nM; 87: 41.12 nM; 89: 110.10 nM; 90: 354.30 nM; 91: 37.14 nM; 92: 26.93 nM; 93: 75.04 nM; 94: 113.50 nM; 95: 21.09 nM; 96: 410.60 nM; 97: 212.10 nM; 98: 89.00 nM; 99: 287.30 nM; 100: 92.16 nM; 101: 466.20 nM; 102: 113.80 nM; 103: 1195.00 nM; 104: 36.50 nM; 105: 277.40 nM; 106: 36.24 nM; 107: 25.73 nM; 108: 325.30 nM; 109: 144.60 nM; 110: 68.65 nM; 111: 31.07 nM; 112: 39.47 nM; 113: 26.79 nM; 114: 51.96 nM; 115: 120.50 nM; 116: 319.70 nM; 117: 171.60 nM; 118: 10.44 nM; 119: 11.64 nM; 120: 177.30 nM; 121: 562.40 nM; 122: 7.81 nM; 124: 78.20 nM; 125: 48.81 nM; 126: 126.50 nM; 127: 156.60 nM; 128: 108.50 nM; 129: 485.00 nM; 130: 12.00 nM; 131: 23.72 nM; 132: 739.30 nM; 133: 443.00 nM; 134: 55.13 nM; 135: 88.77 nM; 137: 349.50 nM; 138: 20.41 nM; 139: 36.18 nM; 140: 45.89 nM; 141: 11.63 nM; 142: 106.00 nM; 143: 13.23 nM; 144: 7.77 nM; 145: 81.89 nM; 146: 103.60 nM; 147: 53.32 nM; 148: 21.76 nM; 149: 97.26 nM; 150: 226.60 nM; 151: 40.85 nM; 152: 24.68 nM; 153: 18.80 nM; 155: 48.24 nM; 156: 24.78 nM; 157: 25.73 nM;

158: 27.29 nM; 159: 177.90 nM; 160: 11.58 nM; 162: 29.51 nM; 164: 27.73 nM; 165: 64.38 nM; 166: 51.18 nM; 167: 15.79 nM; 168: 15.38 nM; 170: 416.40 nM; 171: 25.03 nM; 172: 50.34 nM; 173: 31.25 nM; 174: 699.30 nM; 175: 715.60 nM; 176: 58.42 nM; 177: 50.59 nM; 178: 84.61 nM; 179: 49.11 nM; 180: 30.67 nM;

181: 179.70 nM; 182: 24.74 nM; 183: 1600.00 nM; 184: 26.72 nM; 185: 257.80 nM; 186: 78.60 nM; 187: 33.40 nM; 188: 35.02 nM; 189: 10.31 nM; 190: 31.27 nM; 191: 439.90 nM; 192: 298.30 nM; 193: 26.90 nM; 194: 13.65 nM; 195: 1530.00 nM; 196: 34.61 nM; 197: 84.99 nM; 198: 62.23 nM; 200: 72.38 nM; 201: 41.80 nM; 202: 345.90 nM; 203: 1111.00 nM; 204: 503.80 nM; 205: 92.19 nM; 206: 402.80 nM; 207: 51.11 nM; 208: 34.76 nM; 209: 8.79 nM; 212: 25.96 nM; 213: 18.62 nM; 214: 36.66 nM; 215: 38.42 nM; 216: 26.42 nM; 218:

- 119 041181

29.32 nM; 219: 21.59 nM; 220: 27.50 nM; 221: 20.57 nM; 222: 47.57 nM; 223: 83.59 nM; 224: 73.16 nM; 226: 12.46 nM; 228: 29.07 nM; 231: 19.61 nM; 233: 9.72 nM; 235: 14.97 nM; 236: 368.60 nM; 237: 81.97 nM; 238: 22.84 nM; 239: 30.94 nM; 242: 35.50 nM; 246: 48.29 nM; 248: 72.39 nM; 249: 224.40 nM; 250: 335.70 nM; 251: 51.62 nM; 252: 29.26 nM; 253: 29.15 nM; 254: 41.77 nM; 255: 27.94 nM; 256: 32.64 nM; 257: 37.84 nM; 258: 27.73 nM; 259: 158.30 nM; 260: 177.90 nM; 261: 38.77 nM; 262: 981.90 nM; 263: 754.60 nM; 264: 979.70 nM; 265: 374.30 nM; 266: 1291.00 nM; 267: 442.30 nM; 268: 138.30 nM; 269: 399.70 nM; 270: 92.31 nM; 271: 205.50 nM; 272: 566.10 nM; 273: 29.35 nM; 274: 38.43 nM; 275: 62.29 nM; 276: 1808.00 nM; 277: 16.46 nM; 278: 585.90 nM; 279: 39.75 nM; 280: 96.39 nM; 281: 57.87 nM; 282: 23.74 nM; 283: 68.93 nM; 284: 106.40 nM; 285: 303.30 nM; 286: 56.94 nM; 287: 150.50 nM; 288: 176.50 nM; 289: 65.82 nM; 290: 34.18 nM; 291: 69.80 nM; 292: 90.25 nM; 293: 130.20 nM; 294: 109.80 nM; 295: 143.20 nM; 298: 82.52 nM; 299: 44.31 nM; 301: 357.00 nM; 302: 696.00 nM; 303: 17.11 nM; 304: 69.02 nM; 305: 17.11 nM; 306: 62.90 nM; 307: 59.18 nM; 308: 34.50 nM; 311: 43.50 nM; 312: 31.55 nM; 313: 141.50 nM; 314: 269.70 nM; 315: 23.94 nM; 316: 63.76 nM; 317: 104.00 nM; 318: 95.17 nM; 319: 16.51 nM; 323: 49.56 nM; 324: 22.46 nM; 325: 34.05 nM; 328: 35.37 nM; 330: 70.08 nM; 332: 42.26 nM; 333: 16.28 nM; 334: 79.94 nM; 335: 14.45 nM; 336: 101.70 nM; 337: 1689.00 nM; and 338: 32.15 nM.

Example 3: Determination of Ki by Radioligand Binding.

Radioligand binding assays were performed using the commercially available [ ¹²⁵ I] adrenergic receptor agonist cyanopindolol as the radioligand and non-specific binding was determined in the presence of unlabeled L-748337 at a saturation concentration of 10 μM. For the beta-3 adrenergic receptor, the radioligand is used in the assay at a final concentration of 0.4 nM. Membrane beads derived from Cho-Κι cells stably expressing recombinant beta-3 adrenergic receptors were prepared using standard methods and stored at -80°C. The membranes were thawed on ice and resuspended in assay buffer (20 mM HEPES, pH 7.4, 10 mM MgCl2) by homogenization in a Dounce homogenizer. Competitive experiments consist of adding 145 µl of membranes, 50 µl of stock radioligand, and 5 µl of test compound diluted in DMSO to 96-well microtiter plates. The plates were incubated for one hour at room temperature and the assay was terminated by Perkin ElmerGF/C rapid filtration, the plates were pre-treated with 0.5% PEI under vacuum pressure using a Packard 96-well filtration device. The plates were quickly washed several times with ice-cold assay buffer and then dried overnight at 45°C. Finally, 25 µl of BetaScint scintillation cocktail was added to each well and the plates were counted in a Packard TopCount scintillation counter. In each competitive study, test compounds were dosed at eight to ten concentrations with three determinations at each test concentration. A reference compound, typically isoproterenol, is included in each experiment for quality control purposes.

The raw readings from the scintillation counters exactly fit the non-linear least-squares fitting program to obtain the ICj^ values. The Ki values are determined from the IC ₅₀ values using the Cheng-Prusoff equation and radioligand Kd. Mean Ki values and 95% confidence intervals are calculated from the mean value of log(Ki).

Example 4 Beta-3 Adrenergic Receptor Antagonists in Healthy and Chronic Heart Failure Models.

Beta-3 receptor antagonists have been evaluated for effects on cardiac contractility in healthy rats and rats with chronic heart failure (CHF). Because beta-3 adrenergic receptor expression is weak in healthy rat heart, the compounds were evaluated for the ability to attenuate the negative contractile effects of the beta-3 adrenergic receptor agonist BRL 37344 (Tocris Bioscience, Bristol, UK) in healthy rats. Since beta-3-adrenergic receptor expression is higher in the rat heart with CHF (chronic heart failure), the compound was evaluated for its ability to improve contractility from baseline in this CHF rat model.

Myocardial infarction was induced in male Sprague-Dawley rats by performing ligation of the left descending coronary artery. Rats were anesthetized using an isoflurane vaporizer (Summit Medical, 5% induction and 2-3% intraoperatively), intubated, and placed on a ventilator (p/n 55-0000, Harvard Apparatus, Holliston, Massachusetts), feeding 2-3% isoflurane in oxygen at an inspiratory volume of 2.5 ml/beat at a rate of 70 beats per minute. A 2 cm incision was made to open the chest using a hemostat. The left descending coronary artery was ligated using 7-0 Prolene suture 3 mm from the origin of the left descending coronary artery. The chest was then closed with 4-0 silk suture (Cat. No. 1677G, Ethicon, Somerville, NJ) and the rats were taken off the ventilator and placed in a home cage after spontaneous breathing had begun.

Heart failure was assessed weekly after surgery by means of

Claims (48)

total testing of left ventricular dysfunction using echocardiography. Left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) were measured over at least three consecutive cardiac cycles in long axis images. The ejection fraction (EF%) was calculated using the following formula: EF%=(LVEDVLVESV)/LVEDV. An ejection fraction <30% has been used in the termination of heart failure. Direct determination of left ventricular function was used in all rats to evaluate the effect of compounds on left ventricular contractility. Catheterization of the right carotid artery was used to measure contractility. Rats were anesthetized with an intraperitoneal injection of INACTIN® (Cat. No. T-133, Sigma, St. Louis, MO) (100 mg/kg body weight) and a Millar MIKRO-TIP® pressure catheter (Cat. No. SPR-320NR, Millar, Inc.). , Houston, Texas) passed through the carotid artery into the left ventricle. Left ventricular pressure (LVP) was monitored using LabChart with POWERLAB® data acquisition system (ADInstruments, Sydney, Australia). Jugular vein catheterization was used to administer the compound. A silastic catheter (p/n 427411, BD, Franklin Lake, NJ) was inserted into the jugular vein, and the right venous catheter was connected to an automated drug delivery system (11 Plus Syringe Pump, Harvard Apparatus, Holliston, Massachusetts). Healthy rats were administered 3 mg/kg, 10 mg/kg, 30 mg/kg or 60 mg/kg of test compounds starting 30-45 minutes after catheter implantation. A bolus injection of BRL 37344 (3 ng/kg) was administered via the left jugular vein 15-20 minutes after the start of the test compound infusion and five minutes before the termination of the compound infusion. A blood sample (800 cl) was taken from the left venous catheter five minutes after the bolus injection of BRL 37 34 4 (Fig. 25). The development of CHF was monitored by echocardiography in rats after an operation-induced myocardial infarction. When the EF% fell below 30% (typically 3-5 months after arterial ligation), each animal was prepared for drug testing. The carrier was injected within 10 minutes after stabilization. Then, 10 mg/kg of test compound was administered over 10 minutes, followed by 30 mg/kg over 10 minutes. Then, immediately after each 10-minute drip infusion of the drug, a blood sample (800 microliters of whole blood) was taken from the left venous catheter to monitor the plasma concentrations of the test compound (Fig. 26). Compound 123 (Figure 27), compound 310 (Figure 28), compound 163 (Figure 29), compound 154 (Figure 30), and compound 88 (Figure 31) dose-dependently inhibited the negative effect of adrenergic receptor-3 BRL agonist against LVP in healthy rats. In addition, compound 88 showed a tendency to improve contractility with increasing dosage in the CHF rat (FIG. 32). Those skilled in the art will appreciate that various modifications, additions, substitutions, and variations on the illustrative examples set forth herein may be made without departing from the spirit. CLAIM 1. A compound selected from compounds of formula (Ia) and their pharmaceutically acceptable salts Where X represents -SO ₂ -, -C(=O)- or -CH ₂ C(=O)-; W is absent or is C1-C3 alkylene; R ¹ is aryl or heteroaryl, each optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkyl, amino, cyano, _C3 - _C7 cycloalkyl, C1-C6 haloalkyl, halogen , hydroxyl, oxo and sulfamoyl; and wherein said C1-C6 alkyl and _C3 - _C7 cycloalkyl are each optionally substituted with one or more substituents selected from amino, _C1 - _C6 alkoxy, C1- _C6 alkylcarboxamide, -U- _C3 -C ₇ -cycloalkyl, -Y-C1-C6 alkylene-Z, C1-C ₆ alkylamino, C1-C6 haloalkylamino and heterocyclyl; Y is independently selected from -O-, -NH- and -X-(C1-C ₄ -alkyl)-; Z is independently _selected from hydroxyl, _C1-6 alkoxy, amino, _C1-6 alkylamino and _C2-6 dialkylamino; R ² is selected from C ₂ -C ₆ alkenyl, C 1 -C 6 alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl and C 1 -C 6 haloalkyl; each optionally substituted with one or more substituents selected from C1- _C6 alkoxy, C1-C6 alkylene hydroxyl, amino, aryl, _C3 - _C7 cycloalkyl, cyano, _C3 - _C7 halocycloalkyl, hydroxyl and oxo; and R ^3a , R ^3b , R ^3c and R ^3d are each independently H or halogen; where aryl refers to a ring system containing from 6 to 12 carbon atoms, which may contain one ring, two fused rings or two rings connected via a single bond and at the same time - 121 041181 at least one ring is aromatic; and heteroaryl refers to a ring system containing from 5 to 14 ring atoms, which may contain one ring, two fused rings, two rings connected by a single bond, or three fused rings, and where at least one ring atom is a heteroatom selected from O, S and N, where N is optionally substituted by H, C ₁ -C ₄ acyl or C ₁ -C ₄ alkyl and at least one ring is aromatic; and heterocyclyl refers to a non-aromatic ring radical containing from 3 to 8 ring atoms, where one, two or three ring atoms are heteroatoms selected from O, S and N, where N is optionally substituted with H, C ₁ -C ₄ acyl or C ₁ -C ₄ alkyl. 2. A compound according to claim 1, characterized in that X is -SO2-. 3. A compound according to claim 1 or 2, characterized in that W is absent. 4. A compound according to any one of claims 1 to 3, characterized in that Y is -NH-. 5. A compound according to any one of claims 1 to 4, characterized in that Z is C ₁ -C ₆ alkoxy. 6. The compound according to any one of claims 1 to 5, characterized in that R ¹ is aryl, optionally substituted with one or more substituents selected from C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, cyano, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, halogen and sulfamoyl; and wherein said C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl are each optionally substituted with one or more substituents selected from amino, C ₁ -C ₆ alkylcarboxamide, -NH-C ₃ -C ₇ -cycloalkyl, -NH-C ₁ -C ₆ alkylene-NH ₂ , -NH-C ₁ -C ₆ -alkylene-O-C ₁ -C ₆ -alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ haloalkylamino and heterocyclyl. 7. The compound according to any one of claims 1 to 5, characterized in that R ¹ is selected from 5,6,7,8 tetrahydronaphthalene, biphenyl, naphthalenyl and phenyl; each optionally substituted with one or more substituents selected from 2-methylpropan-2-yl, bromine, chlorine, cyano, cyclopropyl, ethoxy, ethyl, fluorine, isopropoxy, methoxy, methyl, propan-2-yl, sulfamoyl and trifluoromethyl; and wherein said 2-methylpropan-2-yl, cyclopropyl, ethyl, methyl and propan-2-yl are each optionally substituted with one or more substituents selected from 2,2,2trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino, 3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methylamino, morpholino, propylamino, t-butylamino and t-pentylamino. 8. The compound according to any one of claims 1 to 5, characterized in that R ¹ is selected from 5,6,7,8 tetrahydronaphthalene, biphenyl, naphthalenyl and phenyl; each optionally substituted with one or more substituents selected from (2,2,2-trifluoroethylamino)methyl, (2aminoethylamino)methyl, (2-methoxyethylamino)methyl, (3-aminopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tertpentylamino)methyl, 1-amino-2-methylpropane- 2-yl, 1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl, aminomethyl, azetidin-1-ylmethyl, bromine, chlorine, cyano, ethoxy, fluorine, isopropoxy, methoxy, methyl, morpholinomethyl, sulfamoyl and trifluoromethyl. 9. The compound according to any one of claims 1 to 5, characterized in that R ¹ is selected from 5,6,7,8 tetrahydronaphthalene-2-yl, biphenyl-3-yl, biphenyl-4-yl, naphthalene-2-yl and phenyl; each optionally substituted with one or more substituents selected from (2,2,2trifluoroethylamino)methyl, (2-aminoethylamino)methyl, (2-methoxyethylamino)methyl, (3aminopropylamino)methyl, (butylamino)methyl, (cyclobutylamino )methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl, 1-amino-2-methylpropane-2- yl, 1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl, aminomethyl, azetidin-1-ylmethyl, bromine, chlorine, cyano, ethoxy, fluorine, isopropoxy, methoxy, methyl, morpholinomethyl, sulfamoyl, and trifluoromethyl. 10. The compound according to any one of claims 1 to 5, characterized in that R ¹ is selected from 1-ethoxynaphthalen-2-yl, 3-(trifluoromethyl)phenyl, 3-bromo-2-methylphenyl, 3-bromo-4-methoxyphenyl , 3-bromophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methoxyphenyl, 4'-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-aminoethylamino)methyl )biphenyl-3-yl, 4'-((2-methoxyethylamino)methyl)biphenyl-3-yl, 4'-((3-aminopropylamino)methyl)biphenyl-3-yl, 4'-((butylamino)methyl) biphenyl-3yl, 4'-((cyclobutylamino)methyl)biphenyl-3-yl, 4'-((ethylamino)methyl)biphenyl-3-yl, 4'-((isobutylamino)methyl)biphenyl-3-yl, 4 '-((isopropylamino)methyl)biphenyl-3-yl, 4'-((methylamino)methyl)biphenyl-3-yl, 4'-((propylamino)methyl)biphenyl-3-yl, 4'-((tert -butylamino)methyl)biphenyl-3-yl, 4'-((tert-pentylamino)methyl)biphenyl-3-yl, 4'-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl , 4'-(1-Amino-2-methylpropan-2-yl)biphenyl-3-yl, 4'-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl, 4'-(1-aminocyclopropyl)-4-ethoxybiphenyl -3-yl, 4'-(1-aminocyclopropyl)-6-fluorob iphenyl-3-yl, 4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl)biphenyl-3-yl, 4'-(2-acetamidoethyl)-4-ethoxybiphenyl-3- yl, 4'-(2-acetamidoethyl)biphenyl-3-yl, 4'-(2-aminoethyl)-4-ethoxybiphenyl3-yl, 4'-(2-aminoethyl)-6-methoxybiphenyl-3-yl, 4' -(2-aminoethyl)biphenyl-3-yl, 4'-(2-aminopropan-2yl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-2-methoxybiphenyl-3-yl, 4'-( aminomethyl)-2-methylbiphenyl - 122 041181 3-yl, 4'-(aminomethyl)-3'-fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxy-3'-fluorobiphenyl-3-yl, 4'(aminomethyl)-4-ethoxybiphenyl- 3-yl, 4'-(aminomethyl)-4-fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-isopropoxybiphenyl-3-yl, 4'-(aminomethyl)-5-methoxybiphenyl-3-yl, 4 '-(aminomethyl)-6-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-6-fluorobiphenyl-3-yl, 4'-(aminomethyl)-6-methoxybiphenyl-3-yl, 4'-(aminomethyl) biphenyl-3-yl, 4'-(aminomethyl)biphenyl-4-yl, 4'-(azetidin-1-ylmethyl)biphenyl-3-yl, 4'-(morpholinomethyl)biphenyl-3-yl, 4'-( sulfamoyl)biphenyl-3-yl, 4-bromo-3-methylphenyl, 4-ethoxy-4'((isopropylamino)methyl)biphenyl-3-yl, 4'-methylbiphenyl-3-yl, 5,6,7,8 -tetrahydronaphthalen-2-yl, 5-chloronaphthalen-2-yl, 6-chloronaphthalen-2-yl, m-tolyl, naphthalen-2-yl and phenyl. 11. The compound according to any one of claims 1 to 5, characterized in that R ¹ is heteroaryl, optionally substituted with one or more substituents selected from C 1 -C 6 alkoxy, C ₁ -C ₆ alkyl, amino, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, halogen, hydroxyl and oxo; and wherein said C ₁ -C ₆ alkyl is optionally substituted with one or more substituents selected from amino and C 1 -C 6 alkoxy. 12. The compound according to any one of claims 1 to 5, characterized in that R ¹ is selected from (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3, 4-tetrahydropyrido[3,2b]pyrazinyl, 1,2-dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1Hindazolyl, 1H-indolyl, 1-pyrazolo[4,3-b]pyridinyl, 1H- pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3 -dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2, 3b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2Нpyrano[2,3-b]pyridinyl, 3,4-dihydro -2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7'- dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, chromanil, isoquinolinyl, isoxazolyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2-a ]pyrimidinyl, quinolinyl and ti azolyl; each optionally substituted with one or more substituents selected from amino, bromine, chlorine, cyclopropyl, ethyl, fluorine, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl; and wherein said ethyl and methyl are each optionally substituted with one or more substituents selected from: amino and methoxy. 13. The compound according to any one of claims 1 to 5, characterized in that R ¹ is selected from (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3, 4-tetrahydropyrido[3,2b]pyrazinyl, 1,2-dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1-pyrazole[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrole[2,3-b]pyridinyl, 1Hpyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3 -dihydro-1H-imidazo[4,5b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3- b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3.4 -dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl, 6.7 '-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, chromanil, isoquinolinyl, isoxazolyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2 -a] pyrimidinyl, quinolinyl and thia ash; each optionally substituted with one or more substituents selected from 2-methoxyethyl, amino, aminomethyl, bromine, chlorine, cyclopropyl, ethyl, fluorine, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl. 14. The compound according to any one of claims 1 to 5, characterized in that R ¹ is selected from 1,2,3,4 tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,2-dihydroquinolin-6-yl, 1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5- yl, 1H-indol6-yl, 1H-pyrazol-4-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1Hpyrrolo[ 3,2-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-imidazo[4,5 -b]pyridin-6-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 2,3-dihydro-1H-pyrido[2,3b] [1,4]oxazin-7-yl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2,3-dihydrobenzofuran-5-yl, 3-(1Hpyrazol-4- yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3(pyrimidin-5-yl)phenyl, 3.4 -dihydro-2H-benzo[b] [ 1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b] [ 1,4]oxazin-7-yl, 3,4-dihydro-2H -pyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazin-7yl, 3H-imidazo[4,5-b] pyridin-5-yl, 3H-imidazo[4, 5-b]pyridin-6-yl, 4-(pyridin-2-yl)phenyl, 4(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1H-pyrazol-4 -yl)pyridin-3-yl, 5-(phenyl)pyridin3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-pyrrolo[ 3,4-b]pyridin-3yl, benzo[c][1,2,5]oxadiazol-4-yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl , isoquinolin-5-yl, isoxazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl , quinolin-7-yl and thiazol-4-yl; each optionally substituted with one or more substituents selected from 2-methoxyethyl, amino, aminomethyl, bromine, chlorine, cyclopropyl, ethyl, fluorine, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl. 15. The compound according to any one of claims 1 to 5, characterized in that R ¹ is selected from (R)-1,3-dimethyl-2,3 - 123 041181 dihydro-III-pyrido[2,3-b][1,4]oxazin-7-yl, (S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin7-yl, 1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,3, 3-trimethyl-2,3-dihydro1H-pyrido[2,3-b][1,4]oxazin-6-yl, 1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b ]pyrazin-7-yl, 1,6dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,8-dimethyl-2,3-dihydro- 1H-pyrido[2,3b][1,4]oxazin-7-yl, 1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl , 1 -ethyl-4-oxo-1,4-dihydroquinolin-3 -yl, 1 -ethyl-5-methyl-1 H-pyrazol-4-yl, 1 -ethyl-6-fluoro-4-oxo-1, 4-dihydroquinolin-3-yl, 1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl , 1-ethyl7-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-8methyl-4 -oxo-1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H -indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, N-pyrrolo [2,3b]pyridin-3-yl, 1 H-pyrrolo [3,2-b]pyridin-6-yl, 1-methyl-2,3-dihydro-1 H-pyrido [2,3-b][ 1,4]oxazin-7yl, 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-7-yl , 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydrobenzofuran-5-yl, 2-aminothiazol-4-yl, 2-oxo- 2,3dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-(1cyclopropyl -1 H-pyrazol-4-yl)phenyl, 3-(1-ethyl-1 H-pyrazol-4-yl)phenyl, 3-(1 H-pyrazol-4-yl)phenyl, 3-(1-methyl -1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl, 3-(2-methylpyridin-4yl)phenyl, 3-(3-fluoropyridin-2-yl) phenyl, 3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2yl)phenyl, 3-(6-(trifluoromethyl)pyridin-2-yl)phenyl, 3-(6-aminopyridin-3 -yl)phenyl, 3-(6fluoropyridin-2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3yl)phenyl, 3 -(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-pyridine-[2,3-b]pyridin6-yl, 3,5-dimethylisoxazol-4-yl , 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5b]pyridin-6-yl, 3-oxo-3,4-dihydro-2H -benzo[b][1,4]oxazin-6-yl, 4-(pyridin-2-yl)phenyl, 4(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4- hydroxy-6-methylquinolin-3-yl, 4-hydroxy-7methylquinolin-3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4-methoxyquinolin-3yl, 4-methyl- 2-oxo-1,2-dihydroquinolin-6-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4methyl-3,4-dihydro-2H -benzo[b][1,4]oxazin-7-yl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl, 4-oxo-1 ,4-dihydroquinolin-3-yl, 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5.6, 7,8-tetrahydroquinolin-3-yl, 5-bromo-6-chloropyridin-3-yl, 5-bromopyridin-3-yl, 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyridin-3-yl, 5-phenylthiophen-2-yl, 6-fluoro-4hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7-fluoro-4-hydroxyquinoline -3-yl, 8fluoro-4-hydroxyquinolin-3-yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chromo man-7-yl, isoquinolin-5-yl, pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl and quinolin-7-yl. 16. The compound according to any one of claims 1 to 15, characterized in that R ² is selected from 1,1-difluoroethyl, 1fluoroethyl, 2-methylpropan-2-yl, 3,3,3-trifluoropropyl, 4,4,4- trifluorobutyl, azetidin-3-yl, cyclobutyl, cyclopentyl, cyclopropyl, ethyl, fluoromethyl, isobutyl, isopentyl, isopropyl, methyl, oxetan-3-yl, propan-1-yl, sec-butyl and vinyl; each optionally substituted with one or more substituents selected from 2,2-difluorocyclopropyl, amino, cyano, cyclobutyl, cyclohexyl, cyclopropyl, ethoxy, hydroxy, hydroxymethyl, methoxy, oxo and phenyl. 17. The compound according to any one of claims 1 to 15, characterized in that R ² is selected from 1-(hydroxymethyl)cyclobutyl, 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-fluoroethyl, 1hydroxy- 2-methylpropan-2-yl, 2-amino-2-oxoethyl, 2-hydroxyethyl, 3-amino-3-oxopropyl, 3hydroxypropyl, 3-methoxypropyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isobutyl, isopropyl, methoxymethyl, methyl and propan-1-yl. 18. A compound according to any one of claims 1 to 17, wherein R ^3a , R ^3b , R ^3c and R ^3d are each independently H or F. 19. A compound according to any one of claims 1 to 17, wherein R ^3a , R ^3b , R ^3c and R ^3d are each H. 20. The compound according to claim 1, selected from compounds of formula (Ig) and their pharmaceutically acceptable salts: n ? ⁿ Ar ¹ —Ar ² —S—NY 4 ^X ' ° R (Ig) R ^3c Where Ar ¹ and Ar ² are independently 1H-pyrazolyl, phenyl, pyridinyl, pyrimidinyl and thiophenyl, each optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkyl, amino, C ₃ -C ₇ cycloalkyl, C1-C6 haloalkyl, halogen and sulfamoyl; and wherein said C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl are each optionally substituted with one or more substituents selected from amino, C 1 -C 6 alkyl carboxamide, -NH-C 3 -C 7 cycloalkyl, -NH-C ₁ -C ₆ -alkylene-NH ₂ , -NH-C ₁ -C ₆ -alkylene-O-C ₁ -C ₆ -alkyl, C1-C6 alkylamino, C1-C6 haloalkylamino and heterocyclyl; - 124 041181 R ² is selected from C1-C6 alkyl, C ₃ -C ₇ cycloalkyl and C1-C6 haloalkyl; each is optionally substituted with one or more substituents selected from C 1 -C ₆ alkoxy, C ₁ -C ₆ alkylene hydroxyl, amino, hydroxyl and oxo; and R ^3a , R ^3b , R ^3c and R ^3d are each independently H or halogen. 21. The compound according to claim 1, selected from compounds of formula (Ig) and their pharmaceutically acceptable salts Where Ar ¹ and Ar ² together form a group selected from (1H-pyrazolyl)phenyl, (1H pyrazolyl)pyridinyl, (phenyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, biphenyl and phenylthiophenyl, each optionally substituted with one or a large number of substituents selected from 2-methylpropan-2-yl, amino, cyclopropyl, ethoxy, ethyl, fluorine, isopropoxy, methoxy, methyl, n-propyl, propan-2-yl, sulfamoyl and trifluoromethyl; and wherein said 2methylpropan-2-yl, cyclopropyl, ethyl, methyl and propan-2-yl are each optionally substituted with 2,2,2trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino, 3-aminopropylamino, acetamido, amino, azetidine 1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, isopropylamino, methylamino, morpholino, propylamino, t-butylamino and t-pentylamino; R ² is selected from 1,1-difluoroethyl, 2-methylpropan-2-yl, cyclopropyl, ethyl, isopropyl and methyl; each is optionally substituted with one or more substituents selected from amino, hydroxy, hydroxymethyl, methoxy, and oxo; and R ^3a , R ^3b , R ^3c and R ^3d are each H. 22. The compound according to claim 1, selected from compounds of formula (Ig) and their pharmaceutically acceptable salts Where Ar ¹ and Ar ² together form a group selected from 3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl, 3-(1ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H- pyrazol-4-yl)phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1propyl-1H-pyrazol-4-yl)phenyl, 3-(2-methylpyridin-4- yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl, 3-(4methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl, 3-(6-(trifluoromethyl)pyridine -2-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3(pyridin- 2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 4((2,2,2-trifluoroethylamino) methyl)biphenyl-3-yl, 4'-((2-aminoethylamino)methyl)biphenyl-3-yl, 4'-((2methoxyethylamino)methyl)biphenyl-3-yl, 4'-((3-aminopropylamino)methyl )biphenyl-3-yl, 4'-((butylamino)methyl)biphenyl-3-yl, 4'-((cyclobutylamino)methyl)biphenyl-3-yl, 4'-((ethylamino)methyl)biphenyl-3yl, 4'-((isobutylamino)methyl)biphenyl-3-yl, 4'-((isopropylamino)methyl)biphenyl-3-yl, 4'-((methylamino)methyl)biphenyl-3-yl, 4'-(( propyl mino)methyl)biiphenyl-3-yl, 4'-((tert-butylamino)methyl)biphenyl-3-yl, 4'-((tert-pentylamino)methyl)biphenyl-3-yl, 4'-(1- amino-2-methylpropan-2-yl)-4ethoxybiphenyl-3-yl, methylbiphenyl-3-yl, fluorobiphenyl-3-yl, 4'-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl, 4'-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl)-24'-(1-aminocyclopropyl)-64'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl)biphenyl-3-yl, 4'-(2-acetamidoethyl)-4-ethoxybiphenyl-3-yl, 4'-(2-acetamidoethyl)biphenyl-3-yl, 4'(2- aminoethyl)-4-ethoxybiphenyl-3-yl, 4'-(2-aminoethyl)-6-methoxybiphenyl-3-yl, 4'-(2-aminoethyl)biphenyl-3-yl, 4'-(2-aminopropan- 2-yl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-2-methoxybiphenyl-3-yl, 4'-(aminomethyl)-2-methylbiphenyl-3-yl, 4'-(aminomethyl)- 3-fluorobiphenyl-3-yl, 4'(aminomethyl)-4-ethoxy-3'-fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)4- fluorobiphenyl-3-yl, 4'-(aminomethyl)-4-isopropoxybiphenyl-3-yl, 4'-(aminomethyl)-5-methoxybiphenyl-3-yl, 4'-(aminomethyl)-6-ethoxybiphenyl-3-yl , 4'-(aminomethyl)-6-fluorobiphenyl-3-yl, 4'-(aminomethyl)-6-methoxybiphenyl-3-yl, 4'-(aminomethyl)biphenyl-3-yl, 4'-(aminomethyl)biphenyl -4-yl, 4'(azetidin-1-ylmethyl)biphenyl-3-yl, 4'-(morpholinomethyl)biphenyl-3yl, 4-(pyridin-2-yl)phenyl, 4(pyridin-3-yl) phenyl, 4-(pyridin-4-yl)phenyl, 4'-(sulfamoyl)biphenyl-3-yl, 4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3 - yl, 4'-methylbiphenyl-3-yl, 5-(1-methyl-1 H-pyrazol-4-yl)pyridin-3-yl, 5 (4-(aminomethyl)phenyl)pyridin-3-yl and 5- phenylthiophen-2-yl; R ² is selected from 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-hydroxy-2methylpropan-2-yl, 2-amino-2-oxoethyl, 2-hydroxyethyl, cyclopropyl, ethyl, isopropyl, methoxymethyl and methyl; and R ^3a , R ^3b , R ^3c and R ^3d are each H. 23. The compound according to claim 1, selected from compounds of formula (Ii) and their pharmaceutically acceptable - 125 041181 where R ² is selected from C1-C6 alkyl, C ₃ -C ₇ cycloalkyl and C1-C6 haloalkyl; each optionally substituted with one or more substituents selected from C1-C6 alkoxy, C1-C6 alkylene hydroxyl and salts hydroxyl; R ^3a , R ^3b , R ^3c and R ^3d each independently represents H or halogen; R ⁴ is H or C1-C6 alkyl; and R5 ^a , R5 ^b , R5 ^c and R5 ^d are independently H, C1-C6 alkyl and halo. 24. A compound according to claim 23 selected from compounds of formula (Ii) and their pharmaceutically acceptable salts Where R ² is selected from 1,1-difluoroethyl, 2-methylpropan-2-yl, cyclopropyl, ethyl, 1-fluoroethyl, isopropyl and methyl; each is optionally substituted with one or more substituents selected from: hydroxy, hydroxymethyl and methoxy; R ^3a , R ^3b , R ^3c and R ^3d each represents H; R ⁴ is selected from H, methyl and ethyl and R ^5a , R ^5b , R ^5c and R ^5d are independently H, methyl and fluoro. 25. A compound according to claim 23 selected from compounds of formula (Ii) and their pharmaceutically acceptable salts Where R ² is selected from 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-fluoroethyl, 1hydroxy-2-methylpropan-2-yl, cyclopropyl, isopropyl, methoxymethyl and methyl; R ^3a , R ^3b , R ^3c and R ^3d each represents H; R ⁴ is selected from H, methyl and ethyl; R ^5a , R ^5b and R ^5c are independently H, methyl and fluoro and R ^5d is H. 26. The compound according to any one of claims 1 to 25, characterized in that the stereochemistry of the C(3) carbon of the oxaazaspiro[4.5]decanyl group associated with nitrogen is (R), and the stereochemistry of the C(2) carbon of the propyl group associated with a hydroxyl group is (S). 27. The compound according to any one of claims 1 to 25, characterized in that the stereochemistry of the C(3) carbon of the oxaazaspiro[4.5]decanyl group associated with nitrogen is (R) and the stereochemistry of the C(2) carbon of the propyl group associated with hydroxyl group is (R). 28. The compound according to any one of claims 1 to 25, characterized in that the stereochemistry of the carbon C(3) of the oxaazaspiro[4.5]decanyl group associated with nitrogen is (S) and the stereochemistry of the carbon C(2) of the propyl group associated with a hydroxyl group is (S). 29. The compound according to any one of claims 1 to 25, characterized in that the stereochemistry of the carbon C(3) of the oxaazaspiro[4.5]decanyl group associated with nitrogen is (S), and the stereochemistry of the carbon C(2) of the propyl group associated with a hydroxyl group is (R). 30. The compound according to claim 1, selected from the following compounds and their pharmaceutically acceptable salts: (2S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2- ol (compound 5); (S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino) propan-2-ol (compound 88); (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-amino ) propan-2-ol (compound 136); (S)-1 -(3 -(cyclopropylsulfonyl)phenoxy)-3 -((R)-8-(1-methyl-2,3-dihydro-1 H-pyrido [2,3-b][1,4 ]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 154); (S)-1-((R)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3- (1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol (compound 161); (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- 126 041181 ylamino)-3 -(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 163); (S)-1-((R)-8-(4'-(aminomethyl)-4-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3 - (1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 169); (S)-1-((R)-8-(4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3 -(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 199); (S)-1-((S)-8-(4'-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3(3- (1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol (compound 210); (S)-1-((S)-8-(4'-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3(3- (1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 211); (S)-1-((R)-8-(4'-(1-aminocyclopropyl)-6-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3 -( 3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 217); (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxy-3'-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino )-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 220); (S)-1-((S)-8-(4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3 -(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 225); (S)-1-((S)-8-(4'-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3- (cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 227); (S)-1-((S)-8-(4'-(aminomethyl)-5-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3- (cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 229); (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3- (methoxymethylsulfonyl)phenoxy)propan-2-ol (compound 230); (S)-1-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3- (isopropylsulfonyl)phenoxy)propan-2-ol (compound 232); (2S)-1-(3-(1-fluoroethylsulfonyl)phenoxy)-3 -((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino) propan-2-ol (compound 234); (S)-1-((S)-8-(4'-((tert-butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-( 3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 240); (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4'-((tert-pentylamino)methyl)biphenyl-3-ylsulfonyl)-1- oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 241); (S)-1-((S)-8-(4'-(azetidin-1-ylmethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3 -(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 243); (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4'-((propylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa- 8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 244); (S)-1-((S)-8-(4'-((butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3ylamino)-3-(3- (1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 245); (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4'-((2-methoxyethylamino)methyl)biphenyl-3-ylsulfonyl)-1- oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (compound 247); 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethylquinoline -4(1H)-one (compound 297); (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1oxa-8-azaspiro[4.5]decan-3-amino ) propan-2-ol (compound 300); (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3( 3-(cyclopropylsulfonyl)phenoxy)propan-2-ol (compound 309); 1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl )quinoline-4(1H)-one (compound 310); (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3( 3-(methylsulfonyl)phenoxy)propan-2-ol (compound 320); (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3( 3-(isopropylsulfonyl)phenoxy)propan-2-ol (compound 321); 1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8azaspiro[4.5]decan-8 -ylsulfonyl)quinoline-4(1H)-one (compound 322); 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4( 1H)-one (compound 326); 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8-methylquinoline -4-ol (compound 327); 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-7-fluoroquinoline -4-ol (compound 329); and 1 -ethyl-8-fluoro-3 -((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8azaspiro[4.5]decan-8 -ylsulfonyl)quinoline-4(1H)-one (compound 331). 31. The compound according to claim 1, selected from the following compound and its pharmaceutically acceptable salts: (S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl )-1-oxa-8-azaspi- - 127 041181 ro[4.5]decan-3-ylamino)propan-2-ol (Compound 88). 32. The compound according to claim 1, selected from the following compound and its pharmaceutically acceptable salts: 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1- oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethylquinolin-4(1H)-one (Compound 297). 33. The compound according to claim 1, selected from the following compound and its pharmaceutically acceptable salts: (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1 -oxa-8-azaspiro[4.5]decan-3-ylamino)3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 309). 34. A compound according to claim 1 selected from the following compound and its pharmaceutically acceptable salts: 1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy) propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 310). 35. The compound according to claim 1, selected from the following compound and its pharmaceutically acceptable salts: 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1- oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-8-methylquinolin-4(1H)-one (Compound 315). 36. The compound according to claim 1, selected from the following compound and its pharmaceutically acceptable salts: 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1- oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 326). 37. The compound according to claim 1, selected from the following compound and its pharmaceutically acceptable salts: 3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1- oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-8-fluoroquinolin-4(1H)-one (Compound 333). 38. The compound of claim 1, wherein the compound is 1-ethyl-3-((R)-3-((S)-2-hydroxu-3-(3(methylsulfonyl)phenoxy)propylamino)-1-oxa- 8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 310). 39. The compound of claim 1, wherein the compound is 3-((R)-3-((S)-3-(3(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5 ]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 326). 40. The compound of claim 1, wherein the compound is 3-((R)-3-((S)-3-(3(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5 ]decan-8-ylsulfonyl)-1-ethyl-8-fluoroquinolin-4(1H)-one (Compound 333). 41. The compound of claim 1 wherein the compound is 1-ethyl-8-fluoro-3((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino hydrochloride salt )-1-oxa-8-azaspiro[4.5]decan-8ylsulfonyl)quinolin-4(1Н)-one (compound 322). 42. The compound of claim 1, wherein the compound is a salt of methanesulfonic acid and 1ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1 -oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 310) 43. The compound of claim 1 wherein the compound is 3-((R)-3-((S)-3-(3(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro hydrochloride salt [4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 326). 44. The compound of claim 1, wherein the compound is 3-((R)-3-((S)-3-(3(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro hydrochloride salt [4.5]decan-8-ylsulfonyl)-1-ethyl-8-fluoroquinolin-4(1H)-one (Compound 333). 45. A pharmaceutical composition containing a compound according to any one of claims 1 to 44 and a pharmaceutically acceptable carrier. 46. A method for preparing a pharmaceutical composition, comprising the step of mixing a compound according to any one of claims 1 to 44 with a pharmaceutically acceptable carrier. 47. A method of treating or preventing a beta-3-adrenergic receptor-mediated disorder in a patient, comprising administering to said patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 44; or a pharmaceutical composition according to claim 45. 48. A method of treating or preventing a beta-3 adrenergic receptor-mediated disorder in a patient, comprising administering to said patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 44; or a pharmaceutical composition according to claim 45; wherein the beta-3 adrenergic receptor mediated disorder is selected from the list consisting of the following: heart failure; re-infarction; acute heart failure; acute decompensated heart failure; chronic heart failure; severe chronic heart failure; organ damage associated with heart failure, where organ damage is selected from kidney damage or kidney failure, heart valve problems, heart rhythm problems, and/or liver damage; heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; left ventricular failure; left ventricular dysfunction; heart failure class II using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; heart failure class IV using the system - 128 -