Beta-3 adrenergic receptor modulators useful for treating or preventing heart failure and disorders associated therewith

Abstract

The present invention relates to compounds of formula (Ia) and pharmaceutical compositions thereof that modulate the activity of β-3 adrenergic receptors. The compounds and pharmaceutical compositions thereof of the present invention relate to methods for treating β-3 adrenergic receptor-mediated disorders such as heart failure and conditions associated therewith.

Description

Technical Field

[0001] The present invention relates to compounds of formula (Ia) and pharmaceutical compositions thereof that modulate the activity of beta-3 adrenergic receptors. The compounds of the present invention and pharmaceutical compositions thereof are directed to methods for treating disorders mediated by beta-3 adrenergic receptors, such as heart failure; cardiac function during heart failure; mortality, reinfarction, and / or hospitalization associated with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and / or liver damage); heart failure due to left ventricular dysfunction; heart failure with preserved ejection fraction; and cardiovascular death following myocardial infarction. 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; class IV heart failure using the New York Heart Association (NYHA) classification system; left ventricular ejection fraction (LVEF) <40% by radionuclide angiography; LVEF ≤35% by echocardiography or ventricular contraction angiography; and conditions associated therewith. Background Art

[0002] Acute heart failure is a rapid decline in heart function that can lead to a lack of oxygen to tissues, particularly the brain, and thus death. Acute heart failure may occur in previously asymptomatic individuals (e.g., those with pulmonary edema or cardiogenic shock) or in individuals with an acute onset of chronic heart failure.

[0003] In healthy hearts, the effects of β-1 and β-2 adrenergic receptors predominate and act through the Gs-coupled pathway to increase the force and frequency of myocardial contractions, while β-3 adrenergic receptors act through the Gi-coupled eNOS pathway to exert a weak negative inotropic effect. In failing hearts, β-1 and β-2 adrenergic receptors are downregulated or desensitized, while β-3 adrenergic receptors are upregulated, emphasizing the negative effect of β-3 agonism on cardiac contractility. Morimoto, Am J Physiol Heart Circ Physiol, 286: H2425-H2433, 2004; Kulandavelu, J Am College Cardiology, 59(22): 1988-90, 2012.

[0004] In individuals experiencing acute heart failure, the short-term goal is to increase contractility and improve hemodynamic status. The current standard of care for acute heart failure includes the administration of positive inotropes - agents that change the force or energy of cardiac contraction. These agents are typically administered in intensive care units by continuous injection. Examples of such agents include epinephrine, dobutamine, dopamine, levosimendan, and norepinephrine. However, the initial improvement in contractility provided by these agents can accelerate mortality. Katz AM and Konstam MA, Heart Failure: Pathophysiology, Molecular Biology and Clinical Management, Lippincott, Williams & Wilkins, 2nd ed., 1999. The excess mortality following administration of these agents is associated with increased tachycardia and increased myocardial oxygen consumption, which leads to arrhythmias and myocardial ischemia. Francis et al., J Am College of Cardiology, 63(20): 2069-2078, 2014. Summary of the Invention

[0005] One aspect of the present invention encompasses certain 1-oxa-8-azaspiro[4.5]dec-3-yl-aminopropyl-ether derivatives selected from the group consisting of compounds having formula (Ia) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

[0006]

[0007] in:

[0008] X is -SO2- or does not exist;

[0009] R 1selected from the group consisting of: aryl, C1-C6-alkylene-aryl, C1-C6-alkylene-heteroaryl, C3-C7 cycloalkyl, heteroaryl and heterocyclyl; each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C7 alkyl, C1-C6 alkylamino, C1-C6 alkylcarboxamide, C1-C6 alkylsulfonamido, C1-C6 alkylsulfonyl, amino, aryloxy, arylsulfonyl, carboxamide, carbamoylamino, carboxyl, cyano, C3-C7 cycloalkyl, C2-C8 dialkylamino, C2-C8 dialkylsulfamoyl, C1-C6 haloalkoxy, C1-C6 halo wherein the C1-C6 alkoxy, C1-C7 alkyl, C1-C6 alkylamino, aryloxy, C3-C7 cycloalkyl and C2-C8 dialkylamino are each optionally substituted with one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylcarboxamide, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted with oxo, C3-C7 cycloalkyl, cyano, C2-C6 dialkylamino, C1-C6 haloalkyl, C1-C6 haloalkylamino, heterocyclyl, hydroxy, oxo and phenyl;

[0010] Y is selected from: -O- and -NH-;

[0011] Z is selected from the group consisting of: C1-C6 alkoxy, amino, C1-C6 alkylamino, cyano, C2-C6 dialkylamino, hydroxy and phenyl;

[0012] R 2a is H or selected from: C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl and heterocyclyl; each optionally substituted with one or more substituents selected from: C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkylenehydroxy, amino, C3-C7 cycloalkyl, cyano, C2-C8 dialkylamino, heterocyclyl optionally substituted with one oxo group, halogen, hydroxy and oxo; and

[0013] R 2b is H or C1-C6 alkyl,

[0014] One aspect of the present invention pertains to a pharmaceutical product selected from the group consisting of a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound of the present invention.

[0015] One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.

[0016] One aspect of the present invention pertains to methods for preparing a pharmaceutical composition comprising the step of admixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0017] One aspect of the present invention pertains to methods for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual, comprising administering to the individual in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0018] One aspect of the present invention pertains to methods for treating or preventing heart failure in an individual, comprising administering to the individual in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0019] One aspect of the present invention pertains to methods for treating hypotension in a subject, comprising administering to said subject in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0020] One aspect of the present invention pertains to methods for treating a critically hypotensive patient, comprising administering to said individual in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0021] One aspect of the present invention pertains to methods of treating a normotensive patient, comprising administering to said individual in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0022] One aspect of the present invention pertains to methods for treating hypertension in a subject, comprising administering to said subject in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0023] One aspect of the present invention pertains to methods of treating a patient post-myocardial infarction, comprising administering to said individual in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0024] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a beta-3 adrenergic receptor mediated disorder in an individual.

[0025] One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for treating or preventing heart failure in an individual.

[0026] One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for treating a patient suffering from hypotension.

[0027] One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for the treatment of critically hypotensive patients.

[0028] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for treating a normotensive patient.

[0029] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for treating a patient with hypertension.

[0030] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for treating a patient post-myocardial infarction.

[0031] One aspect of the present invention pertains to a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method of treatment of the human or animal body by therapy.

[0032] One aspect of the present invention pertains to compounds of the present invention; pharmaceutical products of the present invention; or pharmaceutical compositions of the present invention for use in a method for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual.

[0033] One aspect of the present invention pertains to a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method for treating or preventing heart failure in an individual.

[0034] One aspect of the present invention pertains to a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method for treating a hypotensive patient.

[0035] One aspect of the present invention pertains to a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method for treating a critically hypotensive patient.

[0036] One aspect of the present invention pertains to a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method for treating a normotensive patient.

[0037] One aspect of the present invention pertains to a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method for treating a patient with hypertension.

[0038] One aspect of the present invention pertains to a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method for treating a patient post-myocardial infarction.

[0039] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is selected from the list consisting of: heart failure; cardiac function in heart failure; mortality, reinfarction, and / or hospitalization associated with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and / or liver damage); heart failure due to left ventricular dysfunction; heart failure with preserved ejection fraction; myocardial infarction Cardiovascular mortality after death; cardiovascular mortality 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; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF <40% by radionuclide ventriculography; and LVEF ≤35% by echocardiography or ventricular contraction angiography.

[0040] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is heart failure.

[0041] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is reduced cardiac function in heart failure.

[0042] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is mortality, reinfarction, and / or hospitalization associated with heart failure.

[0043] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is acute heart failure.

[0044] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is acute decompensated heart failure.

[0045] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is congestive heart failure.

[0046] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is severe congestive heart failure.

[0047] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is organ damage associated with heart failure (eg, kidney damage or failure, heart valve problems, heart rhythm problems, and / or liver damage).

[0048] 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 preserved ejection fraction. In some embodiments, the beta-3 adrenergic receptor-mediated disorder is cardiovascular mortality following 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.

[0049] 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.

[0050] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is class II heart failure using the New York Heart Association (NYHA) classification system.

[0051] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is class III heart failure using the New York Heart Association (NYHA) classification system.

[0052] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is class IV heart failure using the New York Heart Association (NYHA) classification system.

[0053] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is a left ventricular ejection fraction (LVEF) < 40% as determined by radionuclide angiography.

[0054] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is a left ventricular ejection fraction (LVEF) of ≤ 35% as determined by echocardiography or ventricular contraction angiography.

[0055] Beta-3 adrenergic receptor antagonists are described herein that are useful for enhancing cardiac contractility. These compounds are selective for beta-3 adrenergic receptors and have a unique mechanism of action that differs from currently prescribed inotropic agents with known cardiotoxic effects.

[0056] Because increased beta-3 adrenergic receptor activity is known to inhibit contractility in failing hearts, studies have been conducted to evaluate the effects of beta-3 adrenergic receptor antagonists on contractile function. As described herein, these studies demonstrate that inhibition of beta-3 adrenergic receptors by beta-3 adrenergic receptor antagonists improves contractile function and hemodynamic status in failing hearts. New agents are needed to increase cardiac contractility while avoiding cardiotoxic effects.

[0057] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 A general synthetic scheme is shown for the preparation of intermediates useful in the preparation of compounds of formula (Ia), wherein PG 1 (ie, protecting group 1) can be various protecting groups known to those skilled in the art, such as a benzyloxycarbamate (ie, CBz) group.

[0059] Figure 2 A general synthetic scheme is shown for the preparation of intermediates useful in the preparation of compounds of formula (Ia), wherein PG 1 (Protective Group 1) and PG 2 (Protective group 2) can be various protective groups known to those skilled in the art, such as benzyloxycarbamate (Cbz) group and tert-butyloxycarbonyl (BOC) group. 1 and PG 2 are different and orthogonal protecting groups, such as PG 1 It is Cbz and PG 2 It's BOC.

[0060] Figure 3 A general synthetic scheme for preparing compounds of formula (Ia) is shown. It will be appreciated that one or more chiral intermediates may be used in the scheme to provide chiral compounds of formula (Ia). For example, the stereochemistry at C(2) of intermediates 3-1 and 3-2 may be (R) or (S), and the stereochemistry at C(3) of intermediate 3-3 may be (R) or (S).

[0061] Figure 4 A general synthetic scheme for preparing compounds of formula (Ia) is shown. It will be appreciated that one or more chiral intermediates may be used in the scheme to provide chiral compounds of formula (Ia). For example, the stereochemistry at C(2) of intermediate 3-2 may be (R) or (S), and the stereochemistry at C(3) of intermediate 1-1 may be (R) or (S). PG 1 and PG 2 is a protecting group such as BOC (tert-butyloxycarbonyl), Cbz (carboxybenzyl or alternatively benzyloxycarbamate), and the like.

[0062] Figure 5A general synthetic scheme for preparing compounds of formula (Ia) is shown. It will be appreciated that one or more chiral intermediates may be used in the scheme to provide chiral compounds of formula (Ia). For example, the stereochemistry at C(2) of intermediate 3-2 may be (R) or (S), and the stereochemistry at C(3) of intermediate 1-1 may be (R) or (S).

[0063] Figure 6 A general synthetic scheme is shown for preparing compounds of formula (Ia) utilizing chiral oxirane intermediate 6-1, wherein C(2) has (S) stereochemistry. It will be appreciated that intermediate 1-1 wherein C(3) is (R) or (S) may be utilized.

[0064] Figure 7 A general synthetic scheme for preparing compounds of formula (Ia-1) is shown, which utilizes chiral oxirane intermediate 6-1 and chiral amine intermediate 1-1A (see Figure 2 ), wherein the compound of formula (Ia-1) has (S) stereochemistry at C(2) and (R) stereochemistry at C(3).

[0065] Figure 8 A general synthetic scheme for preparing compounds of formula (Ia-3) is shown, which utilizes chiral oxirane intermediate 6-1 and chiral amine intermediate 1-1B (see Figure 2 ), wherein the compound of formula (Ia-3) has an (S) stereochemistry at C(2) and an (S) stereochemistry at C(3).

[0066] Figure 9 A general synthetic scheme for preparing compounds of formula (Ia-2) is shown, which utilizes chiral oxirane intermediate 9-1 and chiral amine intermediate 1-1A (see Figure 2 ), wherein the compound of formula (Ia-2) has an (R) stereochemistry at C(2) and an (R) stereochemistry at C(3).

[0067] Figure 10 A general synthetic scheme for preparing compounds of formula (Ia-4) is shown, which utilizes chiral oxirane intermediate 9-1 and chiral amine intermediate 1-1B (see Figure 2 ), wherein the compound of formula (Ia-4) has (R) stereochemistry at C(2) and (S) stereochemistry at C(3).

[0068] Figure 11 A general synthetic scheme for preparing compounds of formula (Ia) is shown. It will be appreciated that one or more chiral intermediates may be used in the scheme to provide chiral compounds of formula (Ia). For example, Figure 11In the synthetic schemes shown, chiral oxirane intermediates 6-1 or 9-1 can replace intermediate 3-2 and / or chiral amine intermediates 1-1A or 1-1B can replace intermediate 1-1.

[0069] Figure 12 A general synthetic scheme for preparing compounds of formula (Ia) is shown. It will be appreciated that one or more chiral intermediates may be used in the scheme to provide chiral compounds of formula (Ia). For example, Figure 12 In the synthetic schemes shown, chiral oxirane intermediates 6-1 or 9-1 can replace intermediate 3-2 and / or chiral amine intermediates 2-1A or 2-1B can replace intermediate 2-1.

[0070] Figure 13 A general synthetic scheme for preparing compounds of formula (Ia) is shown. It will be appreciated that one or more chiral intermediates may be used in the scheme to provide chiral compounds of formula (Ia). For example, Figure 13 In the synthetic scheme shown, chiral amine intermediate 2-1A or 2-1B can replace intermediate 2-1.

[0071] Figure 14 A general synthetic scheme for preparing compounds of formula (Ia) is shown, wherein X is -SO2- and is absent. It will be appreciated that intermediates may be chiral, thereby providing chiral compounds of formula (Ia).

[0072] Figure 15 A general synthetic scheme is shown for the preparation of certain compounds of formula (Ia) wherein R 1 Yes-Ar 1 -Ar 2 It should be understood that Ar 1 and Ar 2 It may be optionally substituted with one or more groups as described herein.

[0073] Figure 16 A general synthetic scheme for preparing certain compounds of formula (Ia) is shown, wherein R 1 Yes-Ar 1 -Ar 2 , where Ar 1 and Ar 2 are independently aryl or heteroaryl as described herein, provided that Ar 1 and Ar 2 The scheme specifically shows that Ar 2 At least one of -CH2OH or -CH2NH-C1-C6 alkyl is substituted. 1 and Ar 2(excluding Ar bonded to -CH2OH or -CH2NH-C1-C6 alkyl) 2 The ring atoms) may be optionally substituted with one or more groups as described herein.

[0074] Figure 17A A general synthetic scheme for preparing certain compounds of formula (Ia) is shown, wherein R 1 Yes-Ar 1 -Ar 2 , where Ar 1 and Ar 2 are independently aryl or heteroaryl as described herein, provided that Ar 1 and Ar 2 The scheme specifically shows that Ar 2 At least one of the following is substituted with -CH2NH2. 1 and Ar 2 (excluding Ar bonded to -CH2NH2 2 The ring atoms) may be optionally substituted with one or more groups as described herein.

[0075] Figure 17B A general synthetic scheme is shown for the preparation of certain compounds of formula (Ia) wherein R 1 Yes-Ar 1 -Ar 2 The scheme specifically shows that Ar 2 At least one is substituted with -CH2NH2. The amine can optionally be coupled with a carboxylic acid to form an amide (ie, -CH2NHC(=O)R 17 , where R 17 is a C1-C6 alkyl group). It should be understood that Ar 1 and Ar 2 (excluding -CH2NH2 or -CH2NHC(=O)R 17 Bonded Ar 2 The ring atoms) may be optionally substituted with one or more groups as described herein.

[0076] Figure 18 A general synthetic scheme is shown for the preparation of certain compounds of formula (Ia) wherein R 1 It is 4-hydroxy-quinolin-3-yl (or a tautomer thereof, such as 4-oxo-1,4-dihydroquinolin-3-yl) or 1-(C1-C6-alkyl)-4-oxo-1,4-dihydroquinolin-3-yl, such as 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl. It should be understood that the quinolin-3-yl ring (or a tautomer thereof, such as 4-oxo-1,4-dihydroquinolin-3-yl) can be optionally substituted with one or more substituents described herein.

[0077] Figure 19 A general synthetic scheme is shown for the preparation of certain compounds of formula (Ia) wherein R 1 It is 1-(C1-C6-alkyl)-4-oxo-1,4-dihydroquinolin-3-yl, for example 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl. It should be understood that 1,4-dihydroquinolin-3-yl can be optionally substituted with one or more substituents as described herein.

[0078] Figure 20 Compound 505 was shown to inhibit the negative effect of BRL on left ventricular pressure (LVP) in rats with chronic heart failure (CHF) in a dose-dependent manner (Example 4), where Figure 20 “mpkph” means “mg / kg / hr”. DETAILED DESCRIPTION

[0079] definition

[0080] For clarity and consistency, the following definitions will be used throughout this patent document.

[0081] As used herein, "administering" refers to providing a compound of the present invention or other therapy, remedy, or treatment to a subject in need of treatment in a form that can be introduced into the body of that subject in a therapeutically useful form and in a therapeutically useful amount, including but not limited to: oral dosage forms such as tablets, capsules, syrups, suspensions, etc.; injectable dosage forms such as IV, IM, or IP; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, etc.; and rectal suppositories. A healthcare practitioner may provide the compound directly to a subject in the form of a sample, or may provide the compound indirectly to a subject by providing an oral or written prescription for the compound. In addition, for example, a subject may obtain the compound on their own without the involvement of a healthcare practitioner. When the compound is administered to a subject, the body is transformed by the compound in some manner. When a compound of the present invention is provided in combination with one or more other agents, "administering" should be understood to include the compound and the other agents administered simultaneously or at different times. When the combined agents are administered simultaneously, they may be administered together in a single composition, or they may be administered separately.

[0082] As used herein, the term "antagonist" refers to a moiety (e.g., an endogenous ligand) that can competitively bind to the β3-adrenergic receptor as an agonist, but does not activate or substantially reduces the intracellular response compared to the agonist, and thus can inhibit the intracellular response by an agonist or partial agonist. In the absence of an agonist or partial agonist, an "antagonist" does not reduce the baseline intracellular response, or reduces it to a negligible extent.

[0083] The term "composition" refers to a compound or crystalline form thereof, including but not limited to salts, solvates and hydrates of the compounds of the invention, in combination with at least one additional component, such as an obtained composition / compound synthesized during synthesis, preformulation, in-process testing (i.e., TLC, HPLC, NMR samples), etc.

[0084] As used herein, the term "hydrate" refers to a compound of the present invention or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0085] When referring to treatment, the terms "in need of treatment" and "in need thereof" are used interchangeably to refer to a judgment made by a caregiver (e.g., a physician, nurse, nurse practitioner, etc. in the case of humans; a veterinarian in the case of animals (including non-human mammals)) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors within the caregiver's professional knowledge (but including the knowledge that the individual or animal is or will become ill as a result of a disease, condition, or disorder that can be treated with the compounds of the invention). Thus, the compounds of the invention can be used in a protective or preventative manner; or the compounds of the invention can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0086] The term "subject" refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the "subject" refers to a human.

[0087] The term "pharmaceutical composition" refers to a specific composition comprising at least one active ingredient; including but not limited to salts, solvates, and hydrates of the compounds of the present invention, whereby the composition is suitable for investigation of a specific efficacious outcome in a mammal (e.g., but not limited to, a human). One of ordinary skill in the art will understand and appreciate the techniques suitable for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0088] When referring to a compound / compounds as described herein, the phrase "pharmaceutically acceptable salts, solvates and hydrates" encompasses pharmaceutically acceptable solvates and / or hydrates of the compound / compounds, pharmaceutically acceptable salts of the compound / compounds, and pharmaceutically acceptable solvates and / or hydrates of the pharmaceutically acceptable salts of the compound / compounds. It will also be understood that when referring to a compound / compounds described herein as a salt, when the phrase "pharmaceutically acceptable solvates and hydrates" or the phrase "pharmaceutically acceptable solvate or hydrate" is used, it encompasses pharmaceutically acceptable solvates and / or hydrates of such salts. It will also be understood by those of ordinary skill in the art that hydrates are a subgenus of solvates.

[0089] The term "prescribing" refers to ordering, authorizing or recommending the use of a drug or other therapy, remedy or treatment. In some embodiments, a healthcare provider verbally suggests, recommends or authorizes the use of a compound, dosage regimen or other treatment for an individual. A healthcare provider may or may not provide a written prescription for a compound, dosage regimen or treatment. Further, a healthcare provider may or may not provide a compound or treatment to an individual. For example, a healthcare provider may advise an individual where to obtain a compound without providing the compound. In some embodiments, a healthcare provider may provide a written prescription for a compound, dosage regimen or treatment to an individual. The prescription may be written on paper or recorded on electronic media. In addition, the prescription may be (orally) or faxed (in writing) to a pharmacy or clinic. In some embodiments, a sample of the compound or treatment is given to the individual. As used herein, administering a sample of the compound constitutes an implicit prescription for the compound. Different healthcare systems around the world use different methods to prescribe and administer compounds or treatments, and these methods are encompassed in the disclosure herein.

[0090] A healthcare provider can include, for example, a physician, nurse, nurse practitioner, or other healthcare professional who can prescribe or administer a compound (drug) for a disorder disclosed herein. In addition, a healthcare provider can include anyone who can recommend, prescribe, administer, or prevent an individual from receiving a compound or drug, including, for example, an insurance provider.

[0091] The term "prevent (prevent, preventing and prevention)" refers to eliminating or reducing the occurrence or onset of one or more symptoms associated with a particular disorder. For example, the term "prevent (prevent, preventing and prevention)" can refer to administering therapy to an individual who may eventually exhibit at least one symptom of an obstacle but has not yet been treated on a prophylactic (prophylactic or preventative) basis. Such individuals can be identified based on the presence of risk factors such as biomarkers known to be associated with the subsequent occurrence of the disease. Alternatively, preventive therapy can be administered as a preventive measure without the need to identify risk factors in advance. Delaying the onset of at least one paroxysmal symptom and / or condition of an obstacle can also be considered as prevention (prevention or prophylaxis).

[0092] As used herein, the term "solvate" refers to a compound of the invention or a salt thereof that further comprises 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.

[0093] The term "treatment" refers to the individual administration of therapy to at least one symptom that has been shown or has been shown for a disease, disorder, illness, dependence or behavior. For example, "treatment" can include any of the following about a disease, disorder, illness, dependence or behavior: alleviate, weaken, alleviate, improve, suppress (for example, prevent development), alleviate or cause regression. "Treatment" can also include the potential physiological causes of treating symptoms, preventing additional symptoms, preventing symptoms, or stopping the symptoms (preventive and / or therapeutic) of a disease, disorder, illness, dependence or behavior. For example, the term "treatment" about an obstacle refers to a reduction in the severity of one or more symptoms related to a specific obstacle. Therefore, treating an obstacle does not necessarily mean that the severity of all symptoms related to the obstacle is reduced, and does not necessarily mean that the severity of one or more symptoms related to the obstacle is reduced completely.

[0094] The term "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by an individual, researcher, veterinarian, physician or other clinician, which may include one or more of the following:

[0095] (1) prevention of a disorder, such as preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who does not yet experience or exhibit the relevant pathology or symptomatology;

[0096] (2) suppressive disorders, such as suppressing a disease, disorder, or condition in an individual who is experiencing or exhibiting the associated pathology or symptomatology (i.e., preventing further development of the pathology and / or symptomatology); and

[0097] (3) Amelioration of a disorder, such as ameliorating a disease, condition, or disorder in an individual who is experiencing or exhibiting the associated pathology or symptomology (ie, reversing the pathology and / or symptomology).

[0098] Chemical group, moiety or free radical

[0099] The term "C1-C6 alkylene" refers to a group consisting of a straight or branched saturated aliphatic divalent group having 1 to 6 carbon atoms. Some embodiments contain 1 to 5 carbon atoms (i.e., "C1-C5 alkylene"). Some embodiments contain 1 to 4 carbon atoms (i.e., "C1-C6 alkylene"). Some embodiments contain 1 to 3 carbon atoms (i.e., "C1-C3 alkylene"). Some embodiments contain 1 or 2 carbon atoms (i.e., "C1-C2 alkylene"). Some embodiments contain 1 carbon atom (i.e., -CH2-). Examples include methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2-), n-propylene (i.e., -CH2CH2CH2-), propane-1,1-diyl [i.e., -CH(CH2CH3)-], propane-1,2-diyl [i.e., -CH2CH(CH3)-], n-butylene (i.e., -CH2CH2CH2CH2-), n-pentylene (i.e., -CH2CH2CH2CH2CH2-), n-hexylene, and the like.

[0100] The term "C1-C6 alkoxy" refers to a free radical consisting of a C1-C6 alkyl group directly bonded to an oxygen atom, wherein C1-C6 alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbon atoms (i.e., C1-C5 alkoxy). Some embodiments contain 1 to 4 carbon atoms (i.e., C1-C4 alkoxy). Some embodiments contain 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Some embodiments contain 1 or 2 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, and the like.

[0101] The term "C1-C6 alkoxycarbonyl" refers to a group consisting of a single C1-C6 alkoxy group bound to the carbon of a carbonyl group, wherein C1-C6 alkoxy has the same definition as found herein. Alkoxycarbonyl can be represented by:

[0102]

[0103] Term " C1-C7 alkyl " refers to the straight chain or branched carbon radical containing 1 to 7 carbon.Some embodiments are 1 to 6 carbon (that is, C1-C6 alkyl), some embodiments are 1 to 5 carbon (that is, C1-C5 alkyl), some embodiments are 1 to 4 carbon (that is, C1-C4 alkyl), some embodiments are 1 to 3 carbon (that is, C1-C3 alkyl), and some embodiments are 1 or 2 carbon.Example comprises methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl, the tert-butyl, amyl, isopentyl, tert-amyl, neopentyl, 1-methylbutyl [that is, CH (CH ) CH 2 CH 2 CH 3 ], 2-methylbutyl [that is, CH 2 CH (CH ) CH 2 CH 3 ], n-hexyl, n-heptyl etc.

[0104] The term "C1-C6 alkylamino" refers to a radical consisting of a C1-C6 alkyl group bound to an NH group, wherein C1-C6 alkyl has the same meaning as described herein. Some embodiments are "C1-C2 alkylamino". Some examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, and the like.

[0105] The term "C1-C6 alkylcarboxamide" refers to a group consisting of a single C1-C6 alkyl group bound to the carbon or nitrogen of an amide group, wherein C1-C6 alkyl has the same definition as found herein. A C1-C6 alkylcarboxamide group can be represented by:

[0106]

[0107] Examples include N-methylformamide, N-ethylformamide, N-n-propylformamide, N-isopropylformamide, N-n-butylformamide, N-sec-butylformamide, N-isobutylformamide, N-tert-butylformamide and the like.

[0108] The term "C1-C6 alkylenearyl" refers to a radical consisting of an aryl group bonded to a C1-C6 alkylene radical, wherein aryl and C1-C6 alkylene have the same definitions as described herein. Examples include benzyl (i.e., -CH2-phenyl), phenethyl (i.e., -CH2CH2-phenyl), and the like.

[0109] The term "C1-C6 alkylene heteroaryl" refers to a radical consisting of a heteroaryl group bonded to a C1-C6 alkylene radical, wherein heteroaryl and C1-C6 alkylene have the same definitions as described herein. Examples include pyridinyl-4-ylmethyl [i.e., -CH2-(pyridin-4-yl)], pyridin-3-ylmethyl [i.e., -CH2-(pyridin-3-yl)], 2-(pyridin-4-yl)ethyl [i.e., -CH2CH2-(pyridin-4-yl)], 2-(pyridin-2-yl)ethyl [i.e., -CH2CH2-(pyridin-2-yl)], and the like.

[0110]

[0111] The term "C1-C6 alkylene hydroxyl" refers to a radical consisting of a hydroxyl group bonded to a C1-C6 alkylene radical, wherein hydroxyl and C1-C6 alkylene have the same definitions as described herein. Examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, and the like.

[0112] The term "C1-C6 alkylsulfonyl" refers to a group consisting of a single C1-C6 alkyl group bonded to the sulfur or nitrogen of a -SO2-NH- group, wherein the C1-C6 alkyl group has the same definition as herein, and the C1-C6 alkylsulfonyl group can be represented by the following formula:

[0113]

[0114] Examples include -NHSO2CH3, -NHSO2CH2CH3, -NHSO2CH2CH2CH3, -SO2NHCH3, -SO2NHCH2CH3, -SO2NHCH2CH2CH3, and the like.

[0115] The term "C1-C6 alkylsulfonyl" refers to a group consisting of a C1-C6 alkyl group bonded to the sulfur of a sulfone group of the formula -S(=O)2-, wherein C1-C6 alkyl has the same definition as described herein. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, and the like.

[0116] The term "amino" refers to the group -NH2.

[0117] The term "aryl" refers to a ring system containing 6 to 12 carbon atoms, which may contain a single ring, two fused rings, or two rings bonded by a single bond (i.e., biphenyl), and wherein at least one ring is aromatic. Examples include phenyl, biphenyl, indanyl, tetrahydronaphthyl, naphthyl, and the like. Examples of biphenyl groups include: [1,1'-biphenyl]-2-yl (i.e., biphenyl-2-yl), [1,1'-biphenyl]-3-yl (i.e., biphenylpyridin-3-yl), or [1,1'-biphenyl]-4-yl (i.e., biphenyl-4-yl), each having the following structures:

[0118]

[0119] When substituents are present on an aryl ring, the substituents may be bonded at any available ring carbon.

[0120] The term "aryloxy" refers to a group consisting of an aryl group directly bonded to an oxygen atom, wherein aryl has the same definition as found herein. Examples include phenoxy, naphth-2-yloxy, [1,1'-biphenyl]-4-yloxy, and the like.

[0121] The term "arylsulfonyl" refers to a group consisting of an aryl group bonded to the sulfur of a sulfone group of the formula -S(=O)2-, wherein aryl has the same definition as described herein. Examples include phenylsulfonyl, naphth-2-ylsulfonyl, and the like.

[0122] The term "carbamylamino" refers to the following group:

[0123]

[0124] The term "carbamide" refers to the group -CONH2.

[0125] The term "carboxy" or "carboxyl" refers to the group -CO2H; also known as a carboxylic acid group.

[0126] The term "cyano" refers to the group -CN.

[0127] The term "C3-C7 cycloalkyl" refers to a radical consisting of a saturated ring radical containing 3 to 7 carbon atoms. Some embodiments contain 3 to 6 carbon atoms (i.e., C3-C6 cycloalkyl). Some embodiments contain 3 to 5 carbon atoms (i.e., C3-C5 cycloalkyl). Some embodiments contain 5 to 7 carbon atoms (i.e., C5-C7 cycloalkyl). Some embodiments contain 3 to 4 carbon atoms (i.e., C3-C4 cycloalkyl). Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0128] The term "C2-C8 dialkylamino" refers to a radical consisting of an amino radical substituted with two alkyl radicals, which may be the same or different, provided that the two alkyl radicals do not exceed a total of 8 carbon atoms between the two alkyl radicals. Some embodiments are C2-C6 dialkylamino. Some embodiments are C2-C4 dialkylamino. Some examples include dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylbutylamino, methylpentylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino, and the like.

[0129] The term "C2-C8 dialkylsulfamoyl" is a sulfonamide group in which the nitrogen is substituted with two alkyl groups, which may be the same or different, provided that the two alkyl groups do not exceed a total of 8 carbon atoms between the two alkyl groups. C1-C6 alkyl has the same definition as described herein. Examples include -SON(CH3)2, -SON(CH3)(CH2CH3), -SON(CH3)(CH2CH2CH3), -SON(CH2CH3)2, -SON(CH2CH3)(CH2CH2CH3), and the like.

[0130] The term "C1-C6 haloalkoxy" refers to a group consisting of a C1-C6 haloalkyl group directly bonded to an oxygen atom, wherein the C1-C6 haloalkyl group has the same definition as herein. Some embodiments contain 1 to 5 carbon atoms (i.e., C1-C5 haloalkoxy). Some embodiments contain 1 to 4 carbon atoms (i.e., C1-C4 haloalkoxy). Some embodiments contain 1 to 3 carbon atoms (i.e., C1-C3 haloalkoxy). Some embodiments contain 1 or 2 carbon atoms. Examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 4,4,4-trifluorobutoxy, etc.

[0131] The term "C1-C6 haloalkyl" refers to a group consisting of a C1-C6 alkyl group substituted by one or more halogens, wherein C1-C6 alkyl and halogen have the same definitions as described herein. The C1-C6 haloalkyl group may be fully substituted, in which case it may be represented by the formula C n L 2n+1 , wherein L is a halogen and "n" is 1, 2, 3, 4, 5 or 6. When there is more than one halogen, they may be the same or different and be selected from: fluorine, chlorine, bromine and iodine. In some embodiments, the haloalkyl group contains 1 to 5 carbon atoms (i.e., C1-C5 haloalkyl). In some embodiments, the haloalkyl group contains 1 to 4 carbon atoms (i.e., C1-C4 haloalkyl). In some embodiments, the haloalkyl group contains 1 to 3 carbon atoms (i.e., C1-C3 haloalkyl). In some embodiments, the haloalkyl group contains 1 or 2 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, etc.

[0132] The term "C1-C6 haloalkylamino" refers to a radical consisting of a C1-C6 haloalkyl group bound to an NH group, wherein C1-C6 haloalkyl has the same meaning as described herein. Some embodiments are "C1-C2 haloalkylamino." Some examples include 2-fluoroethylamino, 2,2,2-trifluoroethylamino, (1,1,1-trifluoropropyl-2-yl)amino, 3,3,3-trifluoropropylamino, 2,2,2-trifluoropropylamino, and the like.

[0133] The term "halogen" refers to a fluorine, chlorine, bromine, or iodine group. In some embodiments, halogen is fluorine, chlorine, or bromine. In some embodiments, halogen is fluorine or chlorine. In some embodiments, halogen is fluorine.

[0134] The term "heteroaryl" refers to a ring system containing 5 to 18 ring atoms, which may include a single ring, two fused rings, two rings connected by a single bond, three rings connected by a single bond, three fused rings, two fused rings connected by a single bond, and a single ring, wherein at least one ring atom is a heteroatom selected from O, S, N, and NH, and at least one ring is aromatic. It will be understood that in the context of this definition, a fused ring includes two rings that share one common ring atom (i.e., spiro) or two common ring atoms. Examples of two rings that share one common ring atom and two common ring atoms include the following, respectively:

[0135]

[0136] When a heteroaryl group is substituted with an oxo group, the oxo group may be on any available ring atom, such as a ring carbon forming a carbonyl group, a ring nitrogen forming an N-oxide, and a ring sulfur forming either a sulfoxide (i.e., -S(=O)-) or a sulfone (i.e., -S(=O)2-). Some embodiments contain 5 to 6 ring atoms, such as furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like. Some embodiments contain 8 to 14 ring atoms, e.g., quinolizinyl, quinolinyl, isoquinolinyl, quinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, piperidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phenyloxazinyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothiophenyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, furanyl, 4H-benzo[1,3]dioxinyl, 3,4-dihydro-1H-isoquinolinyl, 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridinyl, 7,8-dihydro-5H-[1,6]naphthyridinyl, 5,6-dihydro8H-imidazo[1,2,4]triazolo[4,3-a]pyrazinyl, benzo[1,3]dioxolyl, pyrazolo[1,5-a]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, etc. When "heteroaryl" is a ring system containing two rings joined by a single bond, it is understood that the two rings may be joined at any available ring carbon or available nitrogen atom. Some embodiments include (corresponding to the following chemical structures) 3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 5-phenylthiophen-2-yl, 3-(pyridin-3-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 5-(phenyl)pyridin-3-yl, 5-(1H-pyrazol-4-yl)pyridin-3-yl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(pyridin-2-yl)phenyl, and the like.

[0137]

[0138] In some embodiments, "heteroaryl" 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[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1H-pyrazolyl, oxazolo[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-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, chromanyl, isoquinolinyl, isoxazolyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl and thiazolyl.In some embodiments, "heteroaryl" is selected from the group consisting of: 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-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]dihydro- oxacyclohexeno[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, 1,4-dihydroquinolin-3-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-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl 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-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1H- pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenylthiophen-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, quinolin-6-yl, quinolin-7-yl, and thiazol-4-yl. When referring to heteroaryl groups, it is understood that the terms thienyl, thien-2-yl, thien-3-yl, etc. refer to the following heteroaryl groups, respectively:

[0139]

[0140] The term "heterocyclyl" refers to a non-aromatic cyclic group containing 3 to 8 ring atoms, wherein one, two or three of the ring atoms are heteroatoms selected from, for example, O, S and N, wherein N is optionally substituted with H, C1-C4 acyl or C1-C4 alkyl. In some embodiments, "heterocyclyl" refers to a non-aromatic cyclic group containing 3 to 8 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from, for example, O, S and NH. Examples of heterocyclyl groups include aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, imidazolidinyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, [1,4]oxazepanyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, etc.

[0141] The term "hydroxycarbamoylamino" refers to a group consisting of a hydroxyl group bonded to one of the nitrogen atoms of a carbamoylamino group. The hydroxycarbamoylamino group can be represented by:

[0142]

[0143] The term "hydroxy" refers to the group -OH.

[0144] The term "phenyl" refers to the aromatic ring group C6H5-.

[0145] The term "oxo" refers to a divalent =0.

[0146] The term "sulfamoyl" refers to the group -S(=O)2NH2.

[0147] Compounds of the present invention

[0148] One aspect of the present invention encompasses certain 1-oxa-8-azaspiro[4.5]dec-3-yl-aminopropyl-ether derivatives selected from compounds having formula (Ia) and pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof, among others:

[0149]

[0150] where R 1 (and with R 1 Related Y and Z), X, R 2a and R 2bAll have the same definitions as described above and below herein. It will be understood that certain features of the invention described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, different features of the invention described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable sub-combination. Variables (e.g., R) included in the formulae disclosed in the general chemical formulae described herein, such as Formulae (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ib-1), (Ib-2), (Ic), and the accompanying drawings may be used interchangeably. 1 , Y, Z, X, R 2a and R 2 ) are specifically encompassed by the present invention, as if each and every combination were individually and specifically recited, to the extent that such combinations result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of chemical groups listed in the embodiments describing such variables, as well as all subcombinations of uses and medical indications described herein, are also specifically encompassed by the present invention, as if each and every subcombination of chemical groups and uses and medical indications were individually and specifically recited herein.

[0151] As used herein, "substituted" indicates that at least one hydrogen atom of a chemical group is replaced by a non-hydrogen substituent or group, which can be monovalent or divalent. When the substituent or group is divalent, it should be understood that the group is further substituted by another substituent or group. When a chemical group herein is "substituted", it can have a substitution value that reaches complete; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, etc. Similarly, "substituted by one or more substituents" refers to replacing a group with a substituent to the total number of substituents physically allowed by the group. In addition, when a group is substituted by more than one group, they can be the same or different.

[0152] The compounds of the present invention may also contain tautomeric forms, such as keto-enol tautomers, etc. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It should be understood that various tautomeric forms are within the scope of the compounds of the present invention. One example relates to compounds containing the groups described herein, such as 4-hydroxyquinolin-3-yl, such as compound 548. Even if a compound is shown as a single tautomer, such as the compounds shown in Table A, it should be understood that the compound encompasses all such tautomers; the following are representative tautomers of 4-hydroxyquinolin-3-yl:

[0153]

[0154] It will be understood and appreciated that compounds of formula (Ia) and related formulae may have one or more chiral centers and may therefore exist as enantiomers and / or diastereomers. The present invention is understood to extend to and encompass all such enantiomers, diastereomers, and mixtures thereof, including but not limited to racemates.

[0155] In some embodiments, the compounds of the present invention may have the following defined stereochemistry as shown in Formula (Ia-1):

[0156]

[0157] Where: R 1 , X, R 2a and R 2b has the same definitions as described herein above and below, and wherein the carbon at C(3) designated as the aza-azaspiro[4.5]decyl group bonded to the nitrogen has an (R) stereochemistry, and the carbon at C(2) designated as the propyl group bonded to the hydroxy group has an (S) stereochemistry.

[0158] In some embodiments, the compounds of the present invention may have the following defined stereochemistry as shown in Formula (Ia-2):

[0159]

[0160] Where: R 1 , X, R 2a and R 2b has the same definitions as described herein above and below, and wherein the carbon at C(3) designated as the aza-azaspiro[4.5]decyl group bonded to the nitrogen has an (R) stereochemistry, and the carbon at C(2) designated as the propyl group bonded to the hydroxy group has an (R) stereochemistry.

[0161] In some embodiments, the compounds of the present invention may have the following defined stereochemistry as shown in Formula (Ia-3):

[0162]

[0163] Where: R 1 , X, R 2a and R 2b has the same definitions as described herein above and below, and wherein the carbon at C(3) designated as the aza-azaspiro[4.5]decyl group bonded to the nitrogen has an (S) stereochemistry, and the carbon at C(2) designated as the propyl group bonded to the hydroxy group has an (S) stereochemistry.

[0164] In some embodiments, the compounds of the present invention may have the following defined stereochemistry as shown in Formula (Ia-4):

[0165]

[0166] Where: R 1 , X, R 2a and R 2b has the same definitions as described herein above and below, and wherein the carbon at C(3) designated as the aza-azaspiro[4.5]decyl group bonded to the nitrogen has an (S) stereochemistry, and the carbon at C(2) designated as the propyl group bonded to the hydroxy group has an (R) stereochemistry.

[0167] It should be understood that any formula described herein that does not specifically indicate stereochemistry can be written to specifically indicate the stereochemistry of C(3) and C(2) as (R) and (S), (R) and (R), (S) and (S), or (S) and (R), respectively, in a similar manner, as Formulas (Ia-1), (Ia-2), (Ia-3), and (Ia-4) indicate the stereochemistry of Formula (Ia) above. Similarly, any chemical name described herein that does not specifically indicate stereochemistry can alternatively be qualified using the language of Formulas (Ia-1), (Ia-2), (Ia-3), and Ia-4) as described above to define the stereochemistry of the chemical name as (R) and (S), (R) and (R), (S) and (S), and / or (S) and (R), respectively.

[0168] Thus, in some embodiments, the stereochemistry of the C(3) carbon of the oxa-azaspiro[4.5]decyl group that is bound to nitrogen is (R). In some embodiments, the stereochemistry of the C(3) carbon of the oxa-azaspiro[4.5]decyl group that is bound to nitrogen is (S). In some embodiments, the stereochemistry of the C(2) carbon of the propyl group that is bound to the hydroxyl group is (S). In some embodiments, the stereochemistry of the C(2) carbon of the propyl group that is bound to the hydroxyl group is (R). In some embodiments, the stereochemistry of the C(3) carbon of the oxa-azaspiro[4.5]decyl group that is bound to nitrogen is (R), and the stereochemistry of the C(2) carbon of the propyl group that is bound to the hydroxyl group is (S). In some embodiments, the stereochemistry of the C(3) carbon of the oxa-azaspiro[4.5]decyl group that is bound to nitrogen is (R), and the stereochemistry of the C(2) carbon of the propyl group that is bound to the hydroxyl group is (R). In some embodiments, the stereochemistry of the C(3) carbon of the oxa-azaspiro[4.5]decyl group bound to the nitrogen is (S), and the stereochemistry of the C(2) carbon of the propyl group bound to the hydroxyl group is (S). In some embodiments, the stereochemistry of the C(3) carbon of the oxa-azaspiro[4.5]decyl group bound to the nitrogen is (S), and the stereochemistry of the C(2) carbon of the propyl group bound to the hydroxyl group is (R).

[0169] Unless specifically stated or shown otherwise, compounds of Formula (Ia) and formulae used throughout this disclosure represent all individual enantiomers and mixtures thereof.

[0170] X Group

[0171] In some embodiments, X is -SO2- or is absent.

[0172] In some embodiments, X is -SO2-.

[0173] In some embodiments, the present invention relates to compounds of formula (Ib-1) and pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof:

[0174]

[0175] Where: R 1 、R 2a and R 2b have the same definitions as described herein above and below, and each can be independently selected from any of the embodiments described herein above and below.

[0176] In some embodiments, X is absent.

[0177] In some embodiments, the present invention relates to compounds of formula (Ib-2) and pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof:

[0178]

[0179] Where: R 1 、R 2a and R 2b have the same definitions as described herein above and below, and each can be independently selected from any of the embodiments described herein above and below.

[0180] Y and Z groups

[0181] The Y and Z groups are related to -Y-C1-C6-alkylene-Z which is optionally substituted with oxo.

[0182] In some embodiments, Y is selected from the group consisting of: -O- and -NH-; and Z is selected from the group consisting of: C1-C6 alkoxy, amino, C1-C6 alkylamino, cyano, C2-C6 dialkylamino, hydroxyl, and phenyl.

[0183] In some embodiments, Y is -NH-; and Z is selected from the group consisting of: C1-C6 alkoxy, amino, cyano, C2-C6 dialkylamino, and hydroxy.

[0184] In some embodiments, Y is selected from the group consisting of: -O- and -NH-; and Z is selected from the group consisting of: C1-C6 alkoxy, amino, cyano, C2-C6 dialkylamino, hydroxy, and phenyl.

[0185] In some embodiments, Y is -O-; and Z is phenyl.

[0186] Y is selected from: -O- and -NH-.

[0187] In some embodiments, Y is -O-.

[0188] In some embodiments, Y is -NH-.

[0189] In some embodiments, Z is selected from the group consisting of C1-C6 alkoxy, amino, C1-C6 alkylamino, cyano, C2-C6 dialkylamino, hydroxy, and phenyl. 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 cyano. In some embodiments, Z is C2-C6 dialkylamino. In some embodiments, Z is hydroxy. In some embodiments, Z is phenyl.

[0190] R 1 Group

[0191] In some embodiments, R 1 Selected from: C1-C6-alkylene-aryl, C1-C6-alkylene-heteroaryl, C3-C7 cycloalkyl, heterocyclyl, aryl and heteroaryl; each optionally substituted with one or more substituents described herein.

[0192] In some embodiments, R 1 selected from the group consisting of: aryl, C1-C6-alkylene-aryl, C1-C6-alkylene-heteroaryl, C3-C7 cycloalkyl, heteroaryl and heterocyclyl; each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C7 alkyl, C1-C6 alkylamino, C1-C6 alkylcarboxamide, C1-C6 alkylsulfonamido, C1-C6 alkylsulfonyl, amino, aryloxy, arylsulfonyl, carboxamide, carbamoylamino, carboxyl, cyano, C3-C7 cycloalkyl, C2-C8 dialkylamino, C2-C8 dialkylsulfamoyl, C1-C6 haloalkoxy, C1-C6 halo wherein the C1-C6 alkoxy, C1-C7 alkyl, C1-C6 alkylamino, aryloxy, C3-C7 cycloalkyl and C2-C8 dialkylamino are each optionally substituted with one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylcarboxamide, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted with oxo, C3-C7 cycloalkyl, cyano, C2-C6 dialkylamino, C1-C6 haloalkyl, C1-C6 haloalkylamino, heterocyclyl, hydroxy, oxo and phenyl;

[0193] Y is selected from: -O- and -NH-; and

[0194] Z is selected from the group consisting of: C1-C6 alkoxy, amino, C1-C6 alkylamino, cyano, C2-C6 dialkylamino, hydroxy and phenyl.

[0195] In some embodiments, R 1selected from the group consisting of: aryl, C1-C6-alkylene-aryl, C1-C6-alkylene-heteroaryl, C3-C7 cycloalkyl, heteroaryl and heterocyclyl; each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C7 alkyl, C1-C6 alkylamino, C1-C6 alkylcarboxamide, C1-C6 alkylsulfonamido, C1-C6 alkylsulfonyl, amino, aryloxy, arylsulfonyl, carboxamide, carbamoylamino, cyano, C3-C7 cycloalkyl, C2-C8 dialkylamino, C2-C8 dialkylsulfamoyl, C1-C6 haloalkoxy, C1-C6 haloalkane wherein the C1-C6 alkoxy, C1-C7 alkyl, C1-C6 alkylamino, aryloxy, C3-C7 cycloalkyl and C2-C8 dialkylamino are each optionally substituted with one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylcarboxamide, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted with oxo, C3-C7 cycloalkyl, cyano, C2-C6 dialkylamino, C1-C6 haloalkyl, C1-C6 haloalkylamino, heterocyclyl, hydroxy, oxo and phenyl;

[0196] Y is selected from: -O- and -NH-; and

[0197] Z is selected from the group consisting of: C1-C6 alkoxy, amino, C1-C6 alkylamino, cyano, C2-C6 dialkylamino, hydroxy and phenyl.

[0198] In some embodiments, R 1selected from the group consisting of: C1-C6-alkylene-aryl, C1-C6-alkylene-heteroaryl, C3-C7 cycloalkyl, heterocyclyl, aryl and heteroaryl; each optionally substituted with one or more substituents selected from the group consisting of: (2-ethyl)(methyl)amino, 4-(trifluoromethyl)phenoxy, acetamido, amino, bromo, carbamoylamino, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, heptyl, hydroxycarbamoylamino, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methoxycarbonyl, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, phenylsulfonyl, piperazinyl, piperidinyl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally substituted with one or more substituents selected from the group consisting of 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, amino, oxo, amino, benzyloxy, carboxyl, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, hydroxy, oxo, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidinyl, thiazolidinyl and trifluoromethyl.

[0199] In some embodiments, R 1selected from the group consisting of: C1-C6-alkylene-aryl, C1-C6-alkylene-heteroaryl, C3-C7 cycloalkyl, heterocyclyl, aryl and heteroaryl; each optionally substituted by one or more substituents selected from the group consisting of: (1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, ( 2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy , 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetamido, acetyl, amino, aminomethyl, benzyl, bromo, carbamoyl, carboxamide, carboxyl, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethyl amino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, heptyl, hydroxycarbamoyl, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxycarbonyl, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl.

[0200] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-3-yl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepinyl, 1',2'-dihydrospiro[cyclopropane] Alkyl-1,3'-pyrido[2,3-b][1,4]oxazin-7'-yl, 1,4-dihydropyridinyl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H-pyrazol-5 -yl)thiophen-3-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl-1H-pyrazolyl, 2-(pyridin-4-yl) ethyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolyl[2,3-b] Pyridinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 2-phenylthiazolyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl , 3-(thiophen-3-yl)phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidinyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidinyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-dihydrobenzofuranyl, 5-phenylpyrimidinyl, 5-phenylthiophen-3-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 6-phenylpyrimidinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]thiadiazolyl isoxazolyl, benzofuranyl, benzyl, biphenyl, chromanyl, cyclohexyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolyl, isoxazolyl, naphthyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl, thiophen-3-yl and thiophen-2-yl; each optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C7 alkyl, C1-C6 alkylamino , C1-C6 alkylformamide, C1-C6 alkylsulfonamido, C1-C6 alkylsulfonyl, amino, aryloxy, arylsulfonyl, carboxamide, carbamoylamino, carboxyl, cyano, C3-C7 cycloalkyl, C2-C8 dialkylamino, C2-C8 dialkylsulfamoyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, halogen, heterocyclyl, hydroxycarbamoyl, hydroxy, oxo and sulfamoyl; wherein said C1-C6 alkoxy, C1-C7 alkyl, C1-C C-C6 alkylamino, aryloxy, C3-C7 cycloalkyl and C2-C8 dialkylamino are each optionally substituted with one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylcarboxamide, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted with oxo, C3-C7 cycloalkyl, cyano, C2-C6 dialkylamino, C1-C6 haloalkyl, C1-C6 haloalkylamino, heterocyclyl, hydroxy, oxo and phenyl;

[0201] Y is selected from: -O- and -NH-; and

[0202] Z is selected from the group consisting of: C1-C6 alkoxy, amino, C1-C6 alkylamino, cyano, C2-C6 dialkylamino, hydroxy and phenyl.

[0203] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-3-yl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepinyl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridinyl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H-pyrazolyl)phenyl 1H-pyrazol-5-yl)thiophen-3-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl-1H-pyrazolyl, 2-(pyridin-4-yl)ethyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolyl[2,3 phenyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophene-5-yl)phenyl phenyl, 3-(thiophen-3-yl)phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidinyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidinyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-dihydrobenzofuranyl, 5-phenylpyrimidinyl, 5-phenylthiophen-3-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 6-phenylpyrimidinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, benzyl, biphenyl, chromanyl, cyclohexyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolyl, isoxazolyl, naphthyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl, thien-3-yl and thien-2-yl; each optionally substituted with one or more substituents selected from the group consisting of: (2-ethyl)(methyl)amino, 4-(trifluoromethyl)phenoxy, acetamido, amino, bromo, carbamoylamino, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, heptyl, hydroxycarbamoylamino, hydroxy, isobutyl , isopropyl, isopropyl(methyl)amino, methoxy, methoxycarbonyl, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, phenylsulfonyl, piperazinyl, piperidinyl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally replaced by one or more selected Substituted from the following substituents: 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, amino, oxo, amino, benzyloxy, carboxyl, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, hydroxy, oxo, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidinyl, thiazolidinyl and trifluoromethyl.

[0204] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-3-yl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepinyl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridinyl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H-pyrazolyl)phenyl 1H-pyrazol-5-yl)thiophen-3-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl-1H-pyrazolyl, 2-(pyridin-4-yl)ethyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolyl[2,3 phenyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophene-5-yl)phenyl phenyl, 3-(thiophen-3-yl)phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidinyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidinyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-dihydrobenzofuranyl, 5-phenylpyrimidinyl, 5-phenylthiophen-3-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 6-phenylpyrimidinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, benzyl, biphenyl, chromanyl, cyclohexyl, furanyl, imidazo[1,2-a]pyridinyl , imidazo[2,1-b]thiazolyl, indolyl, isoxazolyl, naphthyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl, thiophen-3-yl and thiophen-2-yl; each optionally substituted with one or more substituents selected from the group consisting of: (1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, (2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino )methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetylamino, Acetyl, amino, aminomethyl, benzyl, bromo, carbamoylamino, carboxamide, carboxyl, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, heptyl, hydroxycarbamoyl, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxycarbonyl, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl. ,

[0205] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridine]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazolin-8-yl, 1',2'-dihydrospiro[cyclopropane]-1,3'-pyrido[2,3-b][1,4]oxazin-7'-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydroquinolin-3-yl, 1,5-naphthyridin-3-yl, 1,8-naphthyridin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-4-yl yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridine -3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2-(pyridin-4-yl)ethyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-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-pyrazol-4-yl Pyrrolol[2,3-b]pyridin-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3 -(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-oxadiazol-3-yl)biphenyl-3-yl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidin-2-yl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidin-2-yl, 5-(1H -pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-3-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-3-yl, 5-phenyl-2,3-dihydrobenzofuran-7-yl, 5 -phenylpyrimidin-2-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-phenylpyrimidin-2-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzo[c] [1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, benzyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, benzopyran-6-yl, cyclohexyl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b] thiazol-5-yl, indol-5-yl, isoxazol-4-yl, naphth-1-yl, naphth-2-yl, phenyl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinolin-8-yl, thiophen-2-yl and thiophen-3-yl; each optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C7 alkyl, C1-C6 alkylamino, C1-C6 alkylcarboxamide, C1-C6 alkylsulfonamido, C1-C6 alkylsulfonyl, amino, aryloxy, arylsulfonyl, carboxamide, carbamoylamino, carboxyl, cyano, C3-C7 cycloalkyl, C2-C8 dialkyl amino, C2-C8 dialkylsulfamoyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, halogen, heterocyclyl, hydroxycarbamoylamino, hydroxy, oxo and sulfamoyl; wherein the C1-C6 alkoxy, C1-C7 alkyl, C1-C6 alkylamino, aryloxy, C3-C7 cycloalkyl and C2-C8 dialkylamino are each optionally substituted with one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylcarboxamide, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted with oxo, C3-C7 cycloalkyl, cyano, C2-C6 dialkylamino, C1-C6 haloalkyl, C1-C6 haloalkylamino, heterocyclyl, hydroxy, oxo and phenyl;

[0206] Y is selected from: -O- and -NH-; and

[0207] Z is selected from the group consisting of: C1-C6 alkoxy, amino, C1-C6 alkylamino, cyano, C2-C6 dialkylamino, hydroxy and phenyl.

[0208] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridine]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-8-yl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydroquinolin-3-yl, 1,5-naphthyridin-3-yl, 1,8-naphthyridin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-4-yl , 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin- 3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2-(pyridin-4-yl)ethyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2 ,3-dihydro-1H-benzo[d]imidazol-5-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-pyrrole benzo[2,3-b]pyridin-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3- (1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-oxadiazol-3-yl)biphenyl-3-yl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidin-2-yl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidin-2-yl, 5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen- 2-yl, 5,6,7,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenyl-2,3-dihydrobenzofuran-7-yl, 5-phenylpyrimidin-2-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-phenylpyrimidin-2-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1 ,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, benzyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, chromen-6-yl, cyclohexyl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b]thiazol-5-yl, indol-5-yl, isoxazol-4-yl, naphthalen-1-yl, naphthalen-2-yl, phenyl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinoline each optionally substituted with one or more substituents selected from the group consisting of: (2-ethyl)(methyl)amino, 4-(trifluoromethyl)phenoxy, acetamido, amino, bromo, carbamoylamino, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, heptyl, hydroxycarbamoylamino, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methoxycarbonyl, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, benzenesulfonyl, piperazinyl, piperidinyl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally substituted with one or more substituents selected from the group consisting of 2-(dimethylamino)ethylamino, 2,2,2-trifluoro Ethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, amino, oxo, amino, benzyloxy, carboxyl, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, hydroxy, oxo, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidinyl, thiazolidinyl and trifluoromethyl. ,

[0209] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridine]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-8-yl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydroquinolin-3-yl, 1,5-naphthyridin-3-yl, 1,8-naphthyridin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-4-yl , 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin- 3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2-(pyridin-4-yl)ethyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2 ,3-dihydro-1H-benzo[d]imidazol-5-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-pyrrole benzo[2,3-b]pyridin-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3- (1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-oxadiazol-3-yl)biphenyl-3-yl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidin-2-yl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidin-2-yl, 5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5, 6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenyl-2,3-dihydrobenzofuran-7-yl, 5-phenylpyrimidin-2-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-phenylpyrimidin-2-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin- 3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, benzyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, benzopyran-6-yl, cyclohexyl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b]thiazol-5-yl, indol-5-yl, isoxazol- 4-yl, naphthalen-1-yl, naphthalen-2-yl, phenyl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinolin-8-yl, thiophen-2-yl and thiophen-3-yl; each optionally substituted with one or more substituents selected from the group consisting of: (1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetylaminoethyl)(methyl)amino, (2-amino-2-oxoacetylamino)methyl, (2-aminoacetylamino)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2 -morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetamido, acetyl, amino, aminomethyl, benzyl, bromo, carbamoylamino, carboxamide, carboxyl, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, heptyl, hydroxycarbamoylamino, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxycarbonyl, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl. ,

[0210] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (5-isoxazol-3-yl)thiophen-3-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepinyl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridinyl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H-pyridinyl)phenyl oxazol-5-yl)thiophen-2-yl, (1H-pyrazol-5-yl)thiophen-3-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl-1H-pyrazolyl, 2,3-dihydro -[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolyl[2,3-b]pyridinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrohydroxybenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 2-phenylthiazolyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-( thiophen-3-yl)phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-Dihydrobenzofuranyl, 5-phenylthiophen-2-yl, 5-phenylthiophen-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, biphenyl, chromanyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolyl, isoxazolyl, naphthyl, phenyl, pyridinyl, pyrimidine 1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, (2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl )methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetylamino, acetyl, amino, aminomethyl alkyl, benzyl, bromo, carbamoyl, carboxamide, carboxyl, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, heptyl, hydroxycarbamoyl, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl.

[0211] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridine]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-8-yl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydroquinolin-3-yl, 1,5-naphthyridin-3-yl, 1,8-naphthyridin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazole-4 -yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-phenyl imidazol-5-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-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3-(1H-pyrazol-3 phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-oxadiazol-3-yl)biphenyl-3-yl, 4-(2H-tetrazol-5-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-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydronaphthalene-1 -yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenyl-2,3-dihydrobenzofuran-7-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, benzo[c][1, 2,5]oxadiazol-4-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, benzopyran-6-yl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b]thiazol-5-yl, indol-5-yl, isoxazole -4-yl, naphth-1-yl, naphth-2-yl, phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinolin-8-yl, thiophen-2-yl and thiophen-3-yl; each optionally substituted with one or more substituents selected from the group consisting of: (1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, (2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethyl , 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetamido, acetyl, amino, aminomethyl, benzyl, bromo, carbamoylamino, carboxamide, carboxyl, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, hydroxycarbamoylamino, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl.

[0212] In some embodiments, R 1Selected from: (dimethylcarbamoyl)phenyl, 1-(2-(benzyloxy)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-(2-hydroxyethyl)-2,3-dihydro-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-(carboxymethyl)-4-oxo-1,4-dihydroquinolin-3-yl, 1,2-dimethyl-1H-imidazol-4-yl, 1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,3-dimethyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,5-naphthyridin-3-yl, 1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,8-dimethyl-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-dihydropyridin-3-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-5-methyl-1H-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]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-pyrazol-4-yl, 1H-pyrazolo[3,4-b]pyridin- 5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-methyl-1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-8-yl, 1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazin]-7'-yl, 1-methyl-1H-imidazo[4,5-b]pyridin-6-yl, 1-methyl-1H-imidazol-4-yl, 1-methyl-1H-indol-5-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-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-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl, 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-methyl-6-(methylamino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-phenyl 1H-pyrazol-4-yl, 1-propyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2-(dimethylamino)pyridin-3-yl, 2-(methylsulfonyl)phenyl, 2-(pyridin-4-yl)ethyl, 2-(trifluoromethoxy)phenyl, 2-(trifluoromethyl)phenyl, 2,2-dimethylchroman-6-yl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 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-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzofuran- pyridin-5-yl, 2,3-dihydrofuran[2,3-b]pyridin-5-yl, 2,3-dimethylphenyl, 2,3-dioxoindole-5-yl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl, 2,6-difluorophenyl, 2-bromophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-(methylsulfonyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl, 2-chloro-5-fluorophenyl, 2-chlorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-5-methylphenyl, 2-cyanophenyl, 2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl, 2-fluoro -3-methylphenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-5-methylphenyl, 2-fluorophenyl, 2-hydroxypyrimidin-5-yl, 2-methoxy-4-methylphenyl, 2-methoxy-5-methylphenyl, 2-methoxyphenyl, 2-methyl-1H-benzo[d]imidazol-5-yl, 2-methyl-1H-imidazo[4,5-b]pyridin-6-yl, 2-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 2-morpholinopyridin-3-yl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl, 2-oxindol-5-yl, 3'-((dimethylamino)methyl)biphenyl-3-yl, 3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl, 3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)phenyl, 3-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl, 3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, 3-(1-benzyl-1H-pyrazol-4-yl)phenyl, 3-(1-ethyl-1H-pyrazol- 4-yl)phenyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(1-isobutyl-1H-pyrazol-4-yl)phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-methyl-1H-pyrrol-3-yl)phenyl, 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl, 3-(2-(trifluoromethyl)phenoxy)phenyl, 3-(2,4-dimethylthiazol-5-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(2-methoxypyrimidin-5-yl)phenyl, 3-( phenyl, 3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenyl, 3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenyl, 3-(6-(aminomethyl)pyridin-3-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-methylpyridin-3-yl)phenyl, 3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenyl, 3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenyl, 3-(6-(aminomethyl)pyridin-3-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-methylpyridin-3-yl)phenyl 3-(aminomethyl)biphenyl-3-yl, 3-(aminomethyl)phenyl, 3'-(carboxy)biphenyl-3-yl, 3'-(dimethylamino)biphenyl-3-yl, 3-(furan-2-yl)phenyl, 3'-(hydroxymethyl)biphenyl-3-yl, 3-(hydroxymethyl)phenyl, 3'-(methoxymethyl)biphenyl-3-yl, 3'-(methylsulfonyl)biphenyl-3-yl, 3'-(N,N-dimethylsulfamoyl)biphenyl-3-yl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,5-dichlorophenyl, 3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl phenyl, 3-bromo-4-methylphenyl, 3-bromo-5-methylphenyl, 3-bromophenyl, 3-carboxyphenyl, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl, 3-chloro-2-fluorophenyl, 3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-chloro-2-phenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-methoxyphenyl phenyl, 3-chlorophenyl, 3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-cyano-4-methylphenyl, 3'-cyanobiphenyl-3-yl, 3-cyanophenyl, 3-ethyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-fluoro-4-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-methyl-2-oxo-2,3- dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3-phenoxyphenyl, 4'-((1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino)biphenyl-3-yl, 4'-((2-(dimethylamino)ethylamino)methyl)biphenyl-3-yl, 4'-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4'-((2,2-difluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-acetamidoethyl)(methyl)amino)biphenyl-3-yl, 4'-((2-amino-2-oxoacetamido)methyl)biphenyl-3-yl, 4'-((2-aminoacetamido)methyl)biphenyl-3-yl, 4'-((2-fluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-hydroxyethylamino)methyl)biphenyl-3-yl, 4'-((2-methoxyethylamino)methyl)biphenyl-3-yl, 4'-((cyanomethylamino)methyl)biphenyl-3-yl, 4'-((dimethylamino)methyl)biphenyl-4-yl, 4'-((ethylamino)methyl) 4'-( ...4'-(aminomethyl)-4-chlorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methylbiphenyl-3-yl, 4'-(aminomethyl)-5-(trifluoromethyl)biphenyl-3-yl, 4'-(aminomethyl)-5-methoxybiphenyl-3-yl, 4'-(aminomethyl)-4-chlorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methylbiphenyl-3-yl, 4'-(aminomethyl)-5-(trifluoromethyl)biphenyl-3-yl, 4'-(aminomethyl)-5-methoxybiphenyl-3-yl, 4'-( 4'-(aminomethyl)-5-methylbiphenyl-3-yl, 4'-(aminomethyl)-6-methoxybiphenyl-3-yl, 4'-(aminomethyl)-6-methylbiphenyl-3-yl, 4'-(aminomethyl)biphenyl-2-yl, 4'-(aminomethyl)biphenyl-3-yl, 4'-(aminomethyl)biphenyl-4-yl, 4-(aminomethyl)phenyl, 4'-(carboxymethyl)biphenyl-3-yl, 4'-(cyanomethyloxy)biphenyl-3-yl, 4'-(cyanomethyl)biphenyl-3-yl, 4-(hydroxymethyl)phenyl, 4'-(methylsulfonyl)biphenyl-3-yl, 4-(methylsulfonyl)phenyl, 4'-(N'-hydroxycarbamoylamino)biphenyl-3-yl, 4-(phenylsulfonyl)thiophen-2-yl, 4-(pyrrolidone)phenyl 4-(trifluoromethyl)phenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 4,5-dichlorothiophen-2-yl, 4,6-dimethoxypyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, 4-acetamidophenyl, 4-acetylphenyl, 4-aminopyrimidin-2-yl, 4-benzylpyrimidin-2-yl, 4-bromo-3-chlorophenyl, 4-bromo-3-methylphenyl, 4-bromophenyl, 4'-carbamoylamino-biphenyl- 3-yl, 4'-carbamoyl-biphenyl-3-yl, 4-carboxyphenyl, 4-chloro-3-methoxyphenyl, 4-chloro-3-methylphenyl, 4-chlorophenyl, 4-chloropyridin-2-yl, 4-cyanophenyl, 4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3-yl, 4-ethoxyphenyl, 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-fluoro-3-methylphenyl, 4'-fluorobiphenyl-4-yl, 4-fluorophenyl, 4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-6-methylquinolin-8-yl, 4-hydroxy-7-methylquinolin-3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4-isobutyl-3,4-Dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-isopropoxyphenyl, 4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methoxy-1H-indazol-5-yl, 4-methoxy-2,3-dimethylphenyl, 4-methoxy-2-methylphenyl, 4-methoxy-3-methylphenyl, 4-methoxy-5,6,7,8-tetrahydronaphthalen-1-yl, 4-methoxynaphthalen-1-yl, 4-methoxyphenyl, 4-methoxypyrimidin-2-yl, 4-methyl-2-phenylthiazol-5-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methyl-3,4-dihydro-2H-pyrido[3 ,2-b][1,4]oxazin-7-yl, 4-methyl-6-phenylpyrimidin-2-yl, 4-methylpyrimidin-2-yl, 4-oxo-1-propyl-1,4-dihydroquinolin-3-yl, 4-phenylpyrimidin-2-yl, 4-sec-butylphenyl, 4-tert-butylphenyl, 4-tert-pentylphenyl, 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-yl, 5-(4-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-7-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5-(5-(trifluoromethyl)isoxazol-3-yl)thiophen-2-yl, 5-(methoxycarbonyl)pyrimidin-3-yl pyrimidin-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydronaphth-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-benzylpyrimidin-2-yl, 5-bromo-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl, 5-bromo-2,3-dihydrobenzofuran-7-yl, 5-bromo-2-chlorophenyl, 5-bromo-2-methoxyphenyl, 5-bromo-2-methylphenyl, 5-bromopyridin-3-yl, 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 5-chloro-2-cyanophenyl, 5-chloro-2-fluorophenyl, 5-chloro-2-methoxyphenyl, 5- Chloro-2-methylphenyl, 5-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 5-chloronaphthyl, 5-chlorothiophen-2-yl, 5-cyano-2-methylphenyl, 5-ethylpyrimidin-2-yl, 5-fluoro-2-methoxyphenyl, 5-fluoro-2-methylphenyl, 5-heptylpyrimidin-2-yl, 5-methoxy-2-methylpyridin-3-yl, 5-methoxypyridin-3-yl, 5-methyl-1-phenyl-1H-pyrazol-4-yl, 5-methyl-2-(trifluoromethyl)furan-3-yl, 5-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 5-methylbenzo[c][1,2,5]oxadiazol-4-yl, 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylpyrimidin-2-yl, 5-phenylthiophen-2-yl, 5-propylpyrimidin-2-yl, 6-(2-aminoethylamino)pyridin-3-yl, 6-(2-hydroxyethylamino)pyridin-3-yl, 6-(2-methoxyethylamino)pyridin-3-yl, 6'-(aminomethyl)-3,3'-bipyridin-5-yl, 6-(dimethylamino)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-(dimethylamino)pyridin-3-yl, 6-(piperazin-1-yl)pyridin-3-yl, 6-(piperidin-1-yl)pyridin-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-amino-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-chloro-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-chloroimidazo[2,1-b]thiazol-5-yl, 6-chloronaphthalen-2-yl, 6-ethoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-ethoxypyridin-3-yl, 6-fluoro-4-hydroxyquinolin-3-yl, 6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 6- Hydroxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-hydroxypyridin-3-yl, 6-methoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-methoxynaphthalen-2-yl, 6-methoxypyridin-3-yl, 6-morpholinopyridin-3-yl, 6-phenoxypyridin-3-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, 7-amino-1,8-naphthyridin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7-fluoro-4-hydroxyquinolin-3-yl, 7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl -3-yl, 7-methoxybenzo[c][1,2,5]oxadiazol-4-yl, 7-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 8-fluoro-4-hydroxyquinolin-3-yl, 8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 8-methyl-4-oxo-1,4-dihydroquinolin-3-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, benzyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, chroman-6-yl, cyclohexyl, furan-3-yl, imidazo[1,2-a] pyridin-6-yl, m-tolyl, naphthalen-1-yl, naphthalen-2-yl, phenyl, p-tolyl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl N-oxide, pyrimidin-2-yl, pyrimidin-4-yl, quinolin-3-yl, quinolin-6-yl and thiophen-3-yl.

[0213] R 1 Group (aryl)

[0214] One aspect of the present invention relates to wherein R 1 is aryl optionally substituted with one or more substituents described herein.

[0215] In some embodiments, R 1 is an aryl group, which is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy, C1-C7 alkyl, C1-C6 alkylcarboxamide, C1-C6 alkylsulfonamido, C1-C6 alkylsulfonyl, aryloxy, carboxamide, carbamoylamino, carboxyl, cyano, C3-C7 cycloalkyl, C2-C8 dialkylamino, C2-C8 dialkylsulfamoyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, halogen, hydroxycarbamoylamino, and sulfamoyl. wherein the C1-C6 alkoxy, C1-C7 alkyl, aryloxy, and C2-C8 dialkylamino are each optionally substituted by one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylcarboxamide, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted by oxo, cyano, C2-C6 dialkylamino, C1-C6 haloalkyl, C1-C6 haloalkylamino, heterocyclyl, hydroxyl, and oxo;

[0216] Y is -NH-; and

[0217] Z is selected from the group consisting of: C1-C6 alkoxy, amino, cyano, C2-C6 dialkylamino, and hydroxy.

[0218] In some embodiments, R 1is selected from the group consisting of: 5,6,7,8-tetrahydronaphthyl, biphenyl, naphthyl and phenyl; each optionally substituted with one or more substituents selected from the group consisting of: (2-ethyl)(methyl)amino, 4-(trifluoromethyl)phenoxy, acetamido, bromo, carbamoylamino, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, hydroxycarbamoylamino, isopropyloxy, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, methylsulfonylamino, methylsulfonyl, N,N-dimethylsulfamoyl, phenoxy, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino, Cyclopropyl, ethoxy, ethyl, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, and phenoxy are each optionally substituted with one or more substituents selected from 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, carboxyl, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, oxo, pyrrolidin-1-yl, thiazolidin-3-yl, and trifluoromethyl.

[0219] In some embodiments, R 1selected from the group consisting of: 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl and phenyl; each optionally substituted with one or more substituents selected from the group consisting of: (1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, (2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (Ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2-carboxy-N-methylacetamido, 4-(trifluoromethyl)phenoxy, acetamido, acetyl, aminomethyl, bromo, carbamoylamino, carboxamide, carboxy, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, dimethylamino, dimethylcarbamoyl, ethoxy, fluoro, hydroxycarbamoylamino, hydroxymethyl, isopropyloxy, methoxy, methoxymethyl, methyl, methylsulfonamido, methylsulfonyl, N,N-dimethylsulfamoyl, phenoxy, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl.

[0220] In some embodiments, R 1Selected from: (dimethylcarbamoyl)phenyl, 2-(methylsulfonyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-(trifluoromethyl)phenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl, 2,6-difluorophenyl, 2-bromophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-(methylsulfonyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl, 2-chloro-5-fluorophenyl, 2-chlorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-5-methylphenyl, 2-cyano phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-5-methylphenyl, 2-fluorophenyl, 2-methoxy-4-methylphenyl, 2-methoxy-5-methylphenyl, 2-methoxyphenyl, 3'-((dimethylamino)methyl)biphenyl-3-yl, 3-(2-(trifluoromethyl)phenoxy)phenyl, 3-(4-(trifluoromethyl)phenoxy)phenyl, 3'-(aminomethyl)biphenyl-3-yl, 3-(aminomethyl)phenyl, 3'-(carboxy)biphenyl-3-yl, 3'-(dimethylamino)biphenyl-3-yl, 3'-(hydroxymethyl)biphenyl-3-yl, 3-(hydroxymethyl)phenyl, 3'-(methoxymethyl)biphenyl-3-yl, 3'-(methylsulfonyl)biphenyl-3 -yl, 3'-(N,N-dimethylsulfamoyl)biphenyl-3-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl, 3-bromo-4-methylphenyl, 3-bromo-5-methylphenyl, 3-bromophenyl, 3-carboxyphenyl, 3-chloro-2-fluorophenyl, 3-chloro-2-methylphenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-methoxyphenyl, 3-chlorophenyl, 3-cyano-4-methylphenyl, 3'-cyanobiphenyl-3-yl, 3-cyanophenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-phenoxyphenyl, 4 '-((1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino)biphenyl-3-yl, 4'-((2-(dimethylamino)ethylamino)methyl)biphenyl-3-yl, 4'-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4'-((2,2-difluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-acetamidoethyl)(methyl)amino)biphenyl-3-yl, 4'-((2-amino-2-oxoacetamido)methyl)biphenyl-3-yl, 4'-((2-aminoacetamido)methyl)biphenyl-3-yl, 4'-((2-fluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-hydroxyethylamino)methyl)biphenyl-3-yl,4'-((2-methoxyethylamino)methyl)biphenyl-3-yl, 4'-((cyanomethylamino)methyl)biphenyl-3-yl, 4'-((dimethylamino)methyl)biphenyl-4-yl, 4'-((ethylamino)methyl)biphenyl-3-yl, 4'-((isobutylamino)methyl)biphenyl-3-yl, 4'-((isopentylamino)methyl)biphenyl-3-yl, 4'-((isopropylamino)methyl)biphenyl-3-yl, 4'-((methylamino)methyl)biphenyl-3-yl, 4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl, 4'-(1-aminocyclopropyl)biphenyl-3-yl, 4'-(2-carboxy-N-methylacetamido)biphenyl-3-yl, 4'-(aminomethyl)-2 -methoxybiphenyl-3-yl, 4'-(aminomethyl)-2-methylbiphenyl-3-yl, 4'-(aminomethyl)-3-(trifluoromethoxy)biphenyl-4-yl, 4'-(aminomethyl)-4-(trifluoromethoxy)biphenyl-3-yl, 4'-(aminomethyl)-4-chlorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methylbiphenyl-3-yl, 4'-(aminomethyl)-5-(trifluoromethyl)biphenyl-3-yl, 4'-(aminomethyl)-5-methoxybiphenyl-3-yl, 4'-(aminomethyl)-5-methylbiphenyl-3-yl, 4'-(aminomethyl)-6- Methoxybiphenyl-3-yl, 4'-(aminomethyl)-6-methylbiphenyl-3-yl, 4'-(aminomethyl)biphenyl-2-yl, 4'-(aminomethyl)biphenyl-3-yl, 4'-(aminomethyl)biphenyl-4-yl, 4-(aminomethyl)phenyl, 4'-(carboxymethyl)biphenyl-3-yl, 4'-(cyanomethoxy)biphenyl-3-yl, 4'-(cyanomethyl)biphenyl-3-yl, 4-(hydroxymethyl)phenyl, 4'-(methylsulfonyl)biphenyl-3-yl, 4-(methylsulfonyl)phenyl, 4'-(N'-hydroxycarbamoylamino)biphenyl-3-yl, 4'-(sulfamoyl)biphenyl-3-yl, 4'-(thiazolidin-3-ylmethyl)biphenyl-3-yl, 4-(trifluoromethoxy)phenyl , 4'-(trifluoromethyl)biphenyl-4-yl, 4-(trifluoromethyl)phenyl, 4-acetylaminophenyl, 4-acetylphenyl, 4-bromo-3-chlorophenyl, 4-bromo-3-methylphenyl, 4-bromophenyl, 4'-carbamoylamino-biphenyl-3-yl, 4'-carbamoyl-biphenyl-3-yl, 4-carboxyphenyl, 4-chloro-3-methoxyphenyl, 4-chloro-3-methylphenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3-yl, 4-ethoxyphenyl, 4-fluoro-3-methylphenyl, 4'-fluorobiphenyl-4-yl, 4-fluorophenyl, 4-isopropoxyphenyl, 4-methoxy-2,3-dimethylphenyl, 4-methoxy-2-methylphenyl,4-methoxy-3-methylphenyl, 4-methoxy-5,6,7,8-tetrahydronaphthalen-1-yl, 4-methoxynaphthalen-1-yl, 4-methoxyphenyl, 4-sec-butylphenyl, 4-tert-butylphenyl, 4-tert-pentylphenyl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5-bromo-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl, 5-bromo-2-chlorophenyl, 5-bromo-2-methoxyphenyl, 5-bromo-2-methylphenyl, 5 -chloro-2-cyanophenyl, 5-chloro-2-fluorophenyl, 5-chloro-2-methoxyphenyl, 5-chloro-2-methylphenyl, 5-chloronaphth-2-yl, 5-cyano-2-methylphenyl, 5-fluoro-2-methoxyphenyl, 5-fluoro-2-methylphenyl, 6-chloronaphth-2-yl, 6-methoxynaphth-2-yl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, m-tolyl, naphthalen-1-yl, naphthalen-2-yl, phenyl and p-tolyl. ,

[0221] R 1 Group (heteroaryl)

[0222] One aspect of the present invention relates to wherein R 1 is heteroaryl optionally substituted with one or more substituents described herein.

[0223] In some embodiments, R 1 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C7 alkyl, C1-C6 alkylamino, amino, aryloxy, arylsulfonyl, carboxyl, cyano, C2-C8 dialkylamino, C1-C6 haloalkyl, halogen, heterocyclyl, hydroxyl and oxo; and wherein the C1-C6 alkoxy, C1-C7 alkyl and C1-C6 alkylamino are each optionally substituted with one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted with oxo, C3-C7 cycloalkyl, C2-C6 dialkylamino, heterocyclyl, hydroxyl and phenyl;

[0224] Y is -O-; and

[0225] Z is phenyl.

[0226] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (5-isoxazol-3-yl)thiophen-3-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepinyl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H-pyrazol-5-yl)thiophen- 2-yl, (1H-pyrazol-5-yl)thiophen-3-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl-1H-pyrazolyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 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-dihydrobenzo[b][ 1,4-dioxinyl, 2,3-dihydrohydroxybenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 2-phenylthiazolyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl )phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidinyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidinyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-Dihydrobenzofuranyl, 5-phenylpyrimidinyl, 5-phenylthiophen-2-yl, 5-phenylthiophen-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 6-phenylpyrimidinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, chromanyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolyl, isoxazolyl, pyrazinyl, pyridinyl, pyrimidine 1-yl, 1-thiophene-2-yl, and 1-thiophene-3-yl; each optionally substituted with one or more substituents selected from the group consisting of amino, bromo, carboxyl, chloro, cyano, dimethylamino, ethoxy, ethyl, ethylamino, fluoro, heptyl, hydroxy, isobutyl, isopropyl, methoxy, methoxycarbonyl, methyl, methylamino, morpholinooxy, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propoxy, propyl, and trifluoromethyl; and wherein ethyl, ethylamino, methyl, and propoxy are each optionally substituted with one or more substituents selected from the group consisting of amino, benzyloxy, carboxyl, cyclopropyl, dimethylamino, hydroxy, methoxy, morpholino, and phenyl.

[0227] In some embodiments, R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridine]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-8-yl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydroquinolin-3-yl, 1,5-naphthyridin-3-yl, 1,8-naphthyridin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazol-4-yl, 1H-indazol-5-yl, 1H -indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 5-(1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[ 2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-yl, 2,3 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-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4 phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-oxadiazol-3-yl)biphenyl-3-yl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidin-2-yl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(phenyl)pyrimidin-2-yl, 5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenyl-2,3-dihydrobenzene pyrimidin-7-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-phenylpyrimidin-2-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazole-5-yl yl, benzofuran-2-yl, benzofuran-5-yl, benzopyran-6-yl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b]thiazol-5-yl, indol-5-yl, isoxazol-4-yl, piperazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinolin-8-yl, thiophen-2-yl and thiophen-3-yl; each optionally substituted with one or more substituents selected from: 2-(benzyl)-1-[[1,2-a]pyridin-6-yl]-1, 2-(benzyl)-1-[[1,2-a]pyridin-6-yl]-1, 2-(benzyl)-1-[[1,2-a]pyridin-5-yl]-1, 2-(benzyl)-1-[[1,2-a]pyridin-6 ... oxy)ethyl, 2-aminoethylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, amino, aminomethyl, benzyl, bromo, carboxyl, carboxymethyl, chloro, cyano, cyclopropylmethyl, dimethylamino, ethoxy, ethyl, fluoro, heptyl, hydroxy, isobutyl, isopropyl, methoxy, methoxycarbonyl, methyl, methylamino, morpholino, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, and propyl, trifluoromethyl. ,

[0228] In some embodiments, R 1Selected from: 1-(2-(benzyloxy)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-(2-hydroxyethyl)-2,3-dihydro-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-(carboxymethyl)-4-oxo-1,4-dihydroquinolin-3-yl, 1,2-dimethyl-1H-imidazol-4-yl, 1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,3-dimethyl-2,3-dihydro- Hydrogen-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,5-naphthyridin-3-yl, 1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,8-dimethyl-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-pyrazol-4-yl, 1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-6-methyl 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]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-pyrazol-4-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazol 1H-pyrrolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-methyl-1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-8-yl, 1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazin]-7'-yl, 1-methyl-1H-imidazo[4,5-b]pyridin-6-yl, 1-methyl-1H-imidazol-4-yl, 1-methyl-1H-indol-5-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-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-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl, 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-methyl-6-(methylamino)- )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-phenyl-1H-pyrazol-4-yl, 1-propyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2-(dimethylamino)pyridin-3-yl, 2,2-dimethylchroman-6-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-dihydrobenzo[b][1,4]dioxin-6-yl, 2 ,3-dihydrobenzofuran-5-yl, 2,3-dihydrofuran[2,3-b]pyridin-5-yl, 2,3-dioxindol-5-yl, 2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl, 2-hydroxypyrimidin-5-yl, 2-methyl-1H-benzo[d]imidazol-5-yl, 2-methyl-1H-imidazo[4,5-b]pyridin-6-yl, 2-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 2-morpholinopyridin-3-yl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, 2-oxo-2,3-dihydro-1H-imidazo[4 ,5-b]pyridin-6-yl, 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl, 2-oxindol-5-yl, 3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl, 3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)phenyl, 3-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl, 3-(1,3-dimethyl-2,4-dioxo-1,2,3,phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-methyl-1H-pyrrol-3-yl)phenyl, 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl, 3-(2,4-dimethylthiazol-5-yl)phenyl, 3-(2H phenyl, 3-(5-(aminomethyl)thiophen-2-yl)phenyl, 3-(5-cyanopyridin-3-yl)phenyl, 3-(5-methylpyridin-3-yl)phenyl, 3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenyl, 3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenyl, 3-(6-(aminomethyl)pyridin-3-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenyl, 3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenyl, 3-(6-(aminomethyl)pyridin-3-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, phenyl, 3-(6-methylpyridin-3-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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, 3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl, 3,5-dimethyl 3-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl, 3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-ethyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-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-(2H-tetrazol-5-yl)phenyl, 4-(3-methoxyphenyl)pyrimidin-2-yl, 4-carboxypyrimidin-2-yl, 4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-3-yl, 4-(phenylsulfonyl)thiophen-2-yl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 4,5-dichlorothiophen-2-yl, 4,6-dimethoxy 4-Hydroxy-2H-benzo[b][1,4]oxazin-6-yl, 4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-6-methylquinolin-8-yl, 4-hydroxy-7-methylquinolin-3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4-isobutyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, -1H-indazol-5-yl, 4-methoxypyrimidin-2-yl, 4-methyl-2-phenylthiazol-5-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl, 4-methyl-6-phenylpyrimidin-2-yl, 4-methylpyrimidin-2-yl, 4-oxo-1-propyl-1,4-dihydroquinolin-3-yl, 4-phenylpyrimidin-2-yl, 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-yl, 5-(4- phenyl)-2,3-dihydrobenzofuran-7-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5-(5-(trifluoromethyl)isoxazol-3-yl)thiophen-2-yl, 5-(methoxycarbonyl)pyrimidin-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-benzylpyrimidin-2-yl, 5-bromo-2,3-dihydrobenzofuran-7-yl, 5-bromopyridin-3-yl, 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 5-chlorobenzo[c][1,2,5-Chlorothiophen-2-yl, 5-ethylpyrimidin-2-yl, 5-heptylpyrimidin-2-yl, 5-methoxy-2-methylpyridin-3-yl, 5-methoxypyridin-3-yl, 5-methyl-1-phenyl-1H-pyrazol-4-yl, 5-methyl-2-(trifluoromethyl)furan-3-yl, 5-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 5-methylbenzo[c][1,2,5]oxadiazol-4-yl, 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylpyrimidin-2-yl, 5-phenylthiophen-2-yl, 5-propylpyrimidin-2-yl, 6-(2-aminoethylamino)pyridin-3-yl, 6-(2-hydroxy 6-(2-methoxyethylamino)pyridin-3-yl, 6'-(aminomethyl)-3,3'-bipyridin-5-yl, 6-(dimethylamino)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-(dimethylamino)pyridin-3-yl, 6-(piperazin-1-yl)pyridin-3-yl, 6-(piperidin-1-yl)piperidin-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-amino-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-chloro-1-methyl 6-Chloromidazo[2,1-b]thiazol-5-yl, 6-ethoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-ethoxypyridin-3-yl, 6-fluoro-4-hydroxyquinolin-3-yl, 6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 6-hydroxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-hydroxypyridin-3-yl, 6-methoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-methoxypyridin -3-yl, 6-morpholinopyridin-3-yl, 6-phenoxypyridin-3-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, 7-amino-1,8-naphthyridin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7-fluoro-4-hydroxyquinolin-3-yl, 7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 7-methoxybenzo[c][1,2,5]oxadiazol-4-yl, 7-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 8-fluoro-4-hydroxyquinolin-3-yl, 8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 8-methyl-4-oxo-1,4-dihydroquinolin-3-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, benzofuran-6-yl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl N-oxide, pyrimidin-2-yl, pyrimidin-4-yl, quinolin-3-yl, quinolin-6-yl and thiophen-3-yl. ,

[0229] In some embodiments, R 1 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of C1-C7 alkyl, cyano, C1-C6 haloalkyl, halogen, hydroxy and oxo.

[0230] In some embodiments, R 1 selected from the group consisting of: 1H-pyrrolo[3,2-b]pyridinyl, quinolinyl, 1,4-dihydroquinolinyl, 1H-pyrrolo[2,3-b]pyridinyl and 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl; each optionally substituted with one or more substituents selected from the group consisting of: ethyl, methyl, cyano, trifluoromethyl, fluoro, hydroxy and oxo.

[0231] In some embodiments, R 1 is selected from the group consisting of: 1H-pyrrolo[3,2-b]pyridin-6-yl, quinolin-3-yl, 1,4-dihydroquinolin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl and 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl; each optionally substituted with one or more substituents selected from the group consisting of: ethyl, methyl, cyano, trifluoromethyl, fluoro, hydroxy and oxo.

[0232] In some embodiments, R 1 Selected from: 1H-pyrrolo[3,2-b]pyridin-6-yl, 4-hydroxyquinolin-3-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl, 1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl and 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl.

[0233] Some R 1 Group

[0234] One aspect of the present invention relates to certain R 1 In some embodiments, R 1 is (dimethylcarbamoyl)phenyl. In some embodiments, R 1is 1-(2-(benzyloxy)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1-(2-hydroxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1-(carboxymethyl)-4-oxo-1,4-diquinolin-3-yl. In some embodiments, R 1 is 1,2-dimethyl-1H-imidazol-4-yl. In some embodiments, R 1 is 1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1,5-naphthyridin-3-yl. In some embodiments, R 1 is 1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1-ethyl-4-oxo-1,4-dihydropyridin-3-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-1H-pyrazol-4-yl. In some embodiments, R 1 is 1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1 is 1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1 is 1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1 is 1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1is 1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1 In some embodiments, R1 is 1H-benzo[d]imidazol-5-yl. In some embodiments, R 1 is 1H-benzo[d]imidazol-6-yl. In some embodiments, R 1 is 1H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 1H-pyrazol-4-yl. In some embodiments, R 1 is 1H-pyrazolo[3,4-b]pyridin-5-yl. In some embodiments, R 1 is 1H-pyrazolo[4,3-b]pyridin-6-yl. In some embodiments, R 1 is 1H-pyrazolo[2,3-b]pyridin-3-yl. In some embodiments, R 1 is 1H-pyrrolo[2,3-b]pyridin-5-yl. In some embodiments, R 1 is 1H-pyrrolo[3,2-b]pyridin-3-yl. In some embodiments, R 1 is 1H-pyrazolo[3,2-b]pyridin-6-yl. In some embodiments, R 1 is 1-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1-methyl-1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazin-8-yl. In some embodiments, R 1 is 1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl. In some embodiments, R 1 is 1-methyl-1H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 is 1-methyl-1H-imidazol-4-yl. In some embodiments, R 1 is 1-methyl-1H-indol-5-yl. In some embodiments, R 1 is 1-methyl-1H-pyrazol-3-yl. In some embodiments, R 1 is 1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl. In some embodiments, R 1is 1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 is 1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl. In some embodiments, R 1 is 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1 is 1-methyl-6-(methylamino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 In some embodiments, R 1 is 1-propyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 2-(dimethylamino)pyridin-3-yl. In some embodiments, R 1 is 2-(methylsulfonyl)phenyl. In some embodiments, R 1 is 2-(pyridin-4-yl)ethyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 2,2-dimethylchroman-6-yl. In some embodiments, R 1 In some embodiments, R 1 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-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 2,3-dihydrobenzo[b][1,4]dioxin-6-yl. In some embodiments, R 1 is 2,3-dihydrobenzofuran-5-yl. In some embodiments, R 1 is 2,3-dihydrofuro[2,3-b]pyridin-5-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 2-chloro-3-fluorophenyl. In some embodiments, R 1 is 2-chloro-4-cyanophenyl. In some embodiments, R 1 In some embodiments, R 1 is 2-chloro-5-(methylsulfonyl)phenyl. In some embodiments, R 1 is 2-chloro-5-(trifluoromethyl)phenyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 2-methoxy-5-methylphenyl. In some embodiments, R 1 In some embodiments, R 1 is 2-methyl-1H-benzo[d]imidazol-5-yl. In some embodiments, R 1 is 2-methyl-1H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 is 2-methyl-3H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1is 2-morpholinopyridin-3-yl. In some embodiments, R 1 is 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl. In some embodiments, R 1 is 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 is 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl. In some embodiments, R 1 is 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl. In some embodiments, R 1 is 2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl. In some embodiments, R 1 In some embodiments, R 1 is 3'-((dimethylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 is 3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl. In some embodiments, R 1 is 3-(1-benzyl-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(1-ethyl-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(1H-pyrazol-3-yl)phenyl. In some embodiments, R 1 is 3-(1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(1H-pyrrol-3-yl)phenyl. In some embodiments, R 1 is 3-(1-isobutyl-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(1-methyl-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(1-methyl-1H-pyrrol-3-yl)phenyl. In some embodiments, R 1 is 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1is 3-(1-propyl-1H-pyrazol-4-yl)phenyl. In some embodiments, R 1 is 3-(2-(trifluoromethyl)phenoxy)phenyl. In some embodiments, R 1 is 3-(2,4-dimethylthiazol-5-yl)phenyl. In some embodiments, R 1 is 3-(2H-tetrazol-5-yl)phenyl. In some embodiments, R 1 is 3-(2-methoxypyrimidin-5-yl)phenyl. In some embodiments, R 1 is 3-(2-methylpyridin-4-yl)phenyl. In some embodiments, R 1 is 3-(3,5-dimethylisoxazol-4-yl)phenyl. In some embodiments, R 1 is 3-(3-methylthiophen-2-yl)phenyl. In some embodiments, R 1 is 3-(4-(trifluoromethyl)phenoxy)phenyl. In some embodiments, R 1 is 3-(4-methylthiophen-3-yl)phenyl. In some embodiments, R 1 is 3-(5-(aminomethyl)thiophen-2-yl)phenyl. In some embodiments, R 1 is 3-(5-cyanopyridin-3-yl)phenyl. In some embodiments, R 1 is 3-(5-methylpyridin-3-yl)phenyl. In some embodiments, R 1 is 3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenyl. In some embodiments, R 1 is 3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenyl. In some embodiments, R 1 is 3-(6-(aminomethyl)pyridin-3-yl)phenyl. In some embodiments, R 1 is 3-(6-aminopyridin-3-yl)phenyl. In some embodiments, R 1 is 3-(6-methylpyridin-3-yl)phenyl. In some embodiments, R 1 is 3'-(aminomethyl)biphenyl-3-yl. In some embodiments, R 1 is 3-(aminomethyl)phenyl. In some embodiments, R 1 In some embodiments, R 1 is 3'-(dimethylamino)biphenyl-3-yl. In some embodiments, R 1 is 3-(furan-2-yl)phenyl. In some embodiments, R 1 In some embodiments, R 1In some embodiments, R 1 is 3'-(methoxymethyl)biphenyl-3-yl. In some embodiments, R 1 is 3'-(methylsulfonyl)biphenyl-3-yl. In some embodiments, R 1 is 3'-(N,N-dimethylsulfamoyl)biphenyl-3-yl. 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-5-yl)phenyl. In some embodiments, R 1 is 3-(thiophen-3-yl)phenyl. In some embodiments, R 1 is 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl. In some embodiments, R 1 is 3-(trifluoromethyl)phenyl. In some embodiments, R 1 In some embodiments, R 1 is 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl. In some embodiments, R 1 is 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl. In some embodiments, R 1 is 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 3,4-dimethoxyphenyl. In some embodiments, R 1 is 3,4-dimethylphenyl. In some embodiments, R 1 is 3,5-dichlorophenyl. In some embodiments, R 1 is 3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl. In some embodiments, R 1 is 3,5-dimethylisoxazol-4-yl. In some embodiments, R 1 is 3,5-dimethylphenyl. In some embodiments, R 1 is 3-bromo-4-methylphenyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl. In some embodiments, R 1is 3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl. In some embodiments, R 1 is 3-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl. In some embodiments, R 1 In some embodiments, R 1 is 3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl. In some embodiments, R 1 In some embodiments, R 1 is 3-chloro-4-cyanophenyl. In some embodiments, R 1 In some embodiments, R 1 is 3-chlorophenyl. In some embodiments, R 1 is 3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 3-ethyl-3H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl. In some embodiments, R 1 is 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl. In some embodiments, R 1 is 3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 is 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 is 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl. In some embodiments, R 1 In some embodiments, R 1 is 4'-((1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino)biphenyl-3-yl. In some embodiments, R 1is 4'-((2-(dimethylamino)ethylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((2,2-difluoroethylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((2-acetylaminoethyl)(methyl)amino)biphenyl-3-yl. In some embodiments, R 1 is 4'-((2-amino-2-oxoacetamido)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((2-aminoacetamido)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((2-fluoroethylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((2-hydroxyethylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((2-methoxyethylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((cyanomethylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-((dimethylamino)methyl)biphenyl-4-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'-((isopentylamino)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'-(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-carboxyl-N-methylacetamido)biphenyl-3-yl. In some embodiments, R 1 is 4-(2H-tetrazolyl-5-yl)phenyl. In some embodiments, R 1 is 4-(3-methoxyphenyl)pyrimidin-2-yl. In some embodiments, R 1 In some embodiments, R 1is 4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-2-methoxybiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-2-methylbiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-3-(trifluoromethoxy)biphenyl-4-yl. In some embodiments, R 1 is 4'-(aminomethyl)-4-(trifluoromethoxy)biphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-4-chlorobiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-4-methoxybiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-4-methylbiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-5-(trifluoromethyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-5-methoxybiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-5-methylbiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-6-methoxybiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)-6-methylbiphenyl-3-yl. In some embodiments, R 1 is 4'-(aminomethyl)biphenyl-2-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 In some embodiments, R 1 is 4'-(carboxymethyl)biphenyl-3-yl. In some embodiments, R 1 is 4'-(cyanomethoxy)biphenyl-3-yl. In some embodiments, R 1 is 4'-(cyanomethyl)biphenyl-3-yl. In some embodiments, R 1 In some embodiments, R 1 is 4'-(methylsulfonylamino)biphenyl-3-yl. In some embodiments, R 1is 4-(methylsulfonyl)phenyl. In some embodiments, R 1 is 4'-(N'-hydroxycarbamoylamino)-biphenyl-3-yl. In some embodiments, R 1 is 4-(phenylsulfonyl)thiophen-2-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'-(thiazolidin-3-ylmethyl)biphenyl-3-yl. In some embodiments, R 1 is 4-(trifluoromethoxy)phenyl. In some embodiments, R 1 is 4'-(trifluoromethyl)biphenyl-4-yl. In some embodiments, R 1 In some embodiments, R 1 is 4-(trifluoromethyl)pyrimidin-2-yl. In some embodiments, R 1 is 4,5-dichlorothiophen-2-yl. In some embodiments, R 1 is 4,6-dimethoxypyrimidin-2-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 4-benzylpyrimidin-2-yl. In some embodiments, R 1 In some embodiments, R 1 is 4-bromo-3-methylphenyl. In some embodiments, R 1 In some embodiments, R 1 is 4'-carbamoyl-biphenyl-3-yl. In some embodiments, R 1 is 4'-carbamoyl-biphenyl-3-yl. In some embodiments, R 1 In some embodiments, R 1 is 4-chloro-3-methoxyphenyl. In some embodiments, R 1 In some embodiments, R 1 is 4-chlorophenyl. In some embodiments, R 1In some embodiments, R 1 In some embodiments, R 1 is 4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3-yl. In some embodiments, R 1 In some embodiments, R 1 is 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl. In some embodiments, R 1 is 4-fluoro-3-methylphenyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 4-hydroxy-6-methylquinolin-3-yl. In some embodiments, R 1 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 In some embodiments, R 1 is 4-isobutyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl. In some embodiments, R 1 is 4-isopropoxyphenyl. In some embodiments, R 1 is 4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl. In some embodiments, R 1 is 4-methoxy-1H-indazol-5-yl. In some embodiments, R 1 is 4-methoxy-2,3-dimethylphenyl. In some embodiments, R 1 In some embodiments, R 1 is 4-methoxy-3-methylphenyl. In some embodiments, R 1 In some embodiments, R 1 is 4-methoxynaphthalen-1-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 4-methyl-2-phenylthiazol-5-yl. In some embodiments, R 1is 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl. In some embodiments, R 1 is 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 4-methyl-6-phenylpyrimidin-2-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl. In some embodiments, R 1 is 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-yl. In some embodiments, R 1 is 5-(4-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-7-yl. In some embodiments, R 1 is 5-(4-(aminomethyl)phenyl)pyridin-3-yl. In some embodiments, R 1 is 5-(5-(trifluoromethyl)isoxazol-3-yl)thiophen-2-yl. In some embodiments, R 1 is 5-(methoxycarbonyl)pyrimidin-2-yl. In some embodiments, R 1 is 5-(trifluoromethyl)pyrazin-2-yl. In some embodiments, R 1 is 5-(trifluoromethyl)pyrimidin-2-yl. In some embodiments, R 1 is 5,6,7,8-tetrahydro-1,6-naphthyridin-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-benzylpyrimidin-2-yl. In some embodiments, R 1 is 5-bromo-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl. In some embodiments, R 1 is 5-bromo-2,3-dihydrobenzofuran-7-yl. In some embodiments, R 1 In some embodiments, R1 is 5-bromo-2-methoxyphenyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 5-chloro-2-methoxyphenyl. In some embodiments, R 1 In some embodiments, R 1 is 5-chlorobenzo[c][1,2,5]oxadiazol-4-yl. In some embodiments, R 1 In some embodiments, R 1 is 5-chlorothiophen-2-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 5-heptylpyrimidin-2-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 5-methyl-1-phenyl-1H-pyrazol-4-yl. In some embodiments, R 1 is 5-methyl-2-(trifluoromethyl)furan-3-yl. In some embodiments, R 1 is 5-methyl-3H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 is 5-methylbenzo[c][1,2,5]oxadiazol-4-yl. In some embodiments, R 1 is 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl. In some embodiments, R 1 In some embodiments, R 1 is 5-phenylthiophen-2-yl. In some embodiments, R 1 In some embodiments, R 1is 6-(2-aminoethylamino)pyridin-3-yl. In some embodiments, R 1 is 6-(2-hydroxyethylamino)pyridin-3-yl. In some embodiments, R 1 is 6-(2-methoxyethylamino)pyridin-3-yl. In some embodiments, R 1 is 6'-(aminomethyl)-3,3'-bipyridin-5-yl. In some embodiments, R 1 is 6-(dimethylamino)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 6-(dimethylamino)pyridin-3-yl. In some embodiments, R 1 is 6-(piperazin-1-yl)pyridin-3-yl. In some embodiments, R 1 is 6-(piperidin-1-yl)pyridin-3-yl. In some embodiments, R 1 is 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl. In some embodiments, R 1 is 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl. In some embodiments, R 1 is 6-amino-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 6-chloro-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 is 6-chloroimidazo[2,1-b]thiazol-5-yl. In some embodiments, R 1 In some embodiments, R 1 is 6-ethoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 In some embodiments, R 1 is 6-fluoro-4-hydroxyquinolin-3-yl. In some embodiments, R 1 is 6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1 is 6-hydroxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R 1 In some embodiments, R 1 is 6-methoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl. In some embodiments, R1 is 6-methoxynaphthalen-2-yl. In some embodiments, R 1 is 6-methoxypyridin-3-yl. In some embodiments, R 1 In some embodiments, R 1 is 6-phenoxypyridin-3-yl. In some embodiments, R 1 is 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl. In some embodiments, R 1 is 7-amino-1,8-naphthyridin-3-yl. In some embodiments, R 1 is 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl. In some embodiments, R 1 is 7-fluoro-4-hydroxyquinolin-3-yl. In some embodiments, R 1 In some embodiments, R 1 is 7-methoxybenzo[c][1,2,5]oxadiazol-4-yl. In some embodiments, R 1 is 7-methyl-3H-imidazo[4,5-b]pyridin-6-yl. In some embodiments, R 1 In some embodiments, R 1 is 8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1 is 8-methyl-4-oxo-1,4-dihydroquinolin-3-yl. In some embodiments, R 1 is benzo[c][1,2,5]thiadiazol-4-yl. In some embodiments, R 1 is benzo[c][1,2,5]thiadiazol-5-yl. In some embodiments, R 1 is benzo[d]isoxazol-5-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1is imidazo[1,2-a]pyridin-6-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is thien-3-yl.

[0235] R 2 Group (R 2a and R 2b )

[0236] In some embodiments, R 2a is H or selected from: C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl and heterocyclyl; each optionally substituted by one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkylenehydroxy, amino, C3-C7 cycloalkyl, cyano, C2-C8 dialkylamino, heterocyclyl optionally substituted by one oxo group, halogen, hydroxy and oxo.

[0237] In some embodiments, R 2a is H or C1-C6 alkyl, which is optionally substituted by one or more substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkylenehydroxy, amino, C3-C7 cycloalkyl, cyano, C2-C8 dialkylamino, heterocyclyl optionally substituted by one oxo group, halogen, hydroxy and oxo.

[0238] In some embodiments, R 2ais H or selected from: C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl and heterocyclyl; each optionally substituted by one or more substituents selected from the following: amino, cyano, cyclopropyl, dimethylamino, ethoxy, ethyl, fluoro, hydroxy, hydroxymethyl, methoxy, methylamino, oxo, oxopyrrolidinyl and piperidinyl.

[0239] In some embodiments, R 2a is H or selected from: 2-methylpropyl, butyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dimethylbutyl, ethyl, ethylbutyl, isopentyl, isopropyl, methoxy, methyl, pentyl, piperidinyl, propanyl, propyl, sec-butyl, tert-butyl and tetrahydro-2H-pyranyl; each optionally substituted with one or more substituents selected from the following: C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkylenehydroxy, amino, C3-C7 cycloalkyl, cyano, C2-C8 dialkylamino, heterocyclyl optionally substituted with one oxo group, halogen, hydroxy and oxo.

[0240] In some embodiments, R 2a is H or is selected from: 2-methylpropyl, butyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dimethylbutyl, ethyl, ethylbutyl, isopentyl, isopropyl, methoxy, methyl, pentyl, piperidinyl, propanyl, propyl, sec-butyl, tert-butyl and tetrahydro-2H-pyranyl; each optionally substituted with one or more substituents selected from the following: amino, cyano, cyclopropyl, dimethylamino, ethoxy, ethyl, fluoro, hydroxy, hydroxymethyl, methoxy, methylamino, oxo, oxopyrrolidinyl and piperidinyl.

[0241] In some embodiments, R 2a Selected from: H, methyl, propyl, pentyl, (2,2,2-trifluoroethyl), isopropyl, cyclopropylmethyl, 2,2-difluoroethyl, sec-butyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-hydroxypropyl, 2-ethoxyethyl, 1-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, tetrahydro-2H-pyran-4-yl, 3-hydroxypropyl, cyclopropyl, 3-methoxypropyl, 3,3-difluorocyclobutyl, 2-aminoethyl, 3-hydroxy-1-(methylamino)-1- Oxobutan-2-yl, 1-cyclopropylethyl, tert-butyl, 1,3-dihydroxypropan-2-yl, 2-ethylbutyl, isopentyl, 1-(hydroxymethyl)cyclopropyl, 3,3-dimethylbutan-2-yl, ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 1-ethylpiperidin-4-yl, 2,3-dihydroxypropyl, 2-(dimethylamino)ethyl, piperidin-3-ylmethyl, 3-(dimethylamino)propyl, acetyl, 2-fluoroethyl, 2-hydroxycyclopentyl, 2-hydroxycyclohexyl and cyanomethyl.

[0242] In some embodiments, R 2a It is H or C1-C6 alkyl.

[0243] In some embodiments, R 2a It is H, ethyl or methyl.

[0244] In some embodiments, R 2a is H. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a is (2,2,2-trifluoroethyl). In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a is tetrahydro-2H-pyran-4-yl. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a is 3-hydroxy-1-(methylamino)-1-oxobutan-2-yl. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2aIn some embodiments, R 2a is 3,3-dimethylbutan-2-yl. In some embodiments, R 2a In some embodiments, R 2a is 2-(2-oxopyrrolidin-1-yl)ethyl. In some embodiments, R 2a is 1-ethylpiperidin-4-yl. In some embodiments, R 2a In some embodiments, R 2a is 2-(dimethylamino)ethyl. In some embodiments, R 2a In some embodiments, R 2a is 3-(dimethylamino)propyl. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a It is cyanomethyl.

[0245] In some embodiments, R 2b It is H or C1-C6 alkyl.

[0246] In some embodiments, R 2b is selected from the group consisting of: H, ethyl, isopropyl, and methyl. In some embodiments, R 2b In some embodiments, R 2b For H.

[0247] Certain combinations

[0248] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0249]

[0250] Where: R 1 (and with R 1 Related Y and Z), R 2a and R 2b All have the same definitions as described herein above and below.

[0251] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0252]

[0253] in:

[0254] R 1 selected from the group consisting of: aryl, heteroaryl and heterocyclyl; each optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C7 alkyl, C1-C6 alkylamino, C1-C6 alkylcarboxamide, C1-C6 alkylsulfonamido, C1-C6 alkylsulfonyl, amino, aryloxy, arylsulfonyl, carboxamide, carbamoylamino, carboxyl, cyano, C3-C7 cycloalkyl, C2-C8 dialkylamino, C2-C8 dialkylsulfamoyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, halogen, heterocyclyl, hydroxycarbamoylamino, hydroxy, oxo wherein the C1-C6 alkoxy, C1-C7 alkyl, C1-C6 alkylamino, aryloxy, C3-C7 cycloalkyl and C2-C8 dialkylamino are each optionally substituted with one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylcarboxamide, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted with oxo, C3-C7 cycloalkyl, cyano, C2-C6 dialkylamino, C1-C6 haloalkyl, C1-C6 haloalkylamino, heterocyclyl, hydroxy, oxo and phenyl;

[0255] Y is selected from: -O- and -NH-;

[0256] Z is selected from the group consisting of: C1-C6 alkoxy, amino, cyano, C2-C6 dialkylamino, hydroxy and phenyl; and

[0257] R 2a It is H, ethyl or methyl.

[0258] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0259]

[0260] in:

[0261] R 1is selected from the group consisting of aryl, heteroaryl, and heterocyclyl; each optionally substituted with one or more substituents selected from the group consisting of (2-ethyl)(methyl)amino, acetamido, amino, bromo, carbamoylamino, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, hydroxycarbamoylamino, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy, and trifluoromethyl; and wherein (2-ethyl) (methyl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally substituted with one or more substituents selected from the group consisting of 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, benzyloxy, carboxyl, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidin-1-yl, thiazolidin-3-yl and trifluoromethyl; and

[0262] R 2a It is H, ethyl or methyl.

[0263] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0264]

[0265] in:

[0266] R 1selected from the group consisting of: aryl, heteroaryl and heterocyclyl; each optionally substituted by one or more substituents selected from the group consisting of: (1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, (2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2 -aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetamido, acetyl, amino, aminomethyl, benzyl, bromo, carbamoyl, carboxamide, carboxyl, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, hydroxycarbamoyl, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy, and trifluoromethyl; and

[0267] R 2a It is H, ethyl or methyl.

[0268] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0269]

[0270] in:

[0271] R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (5-isoxazol-3-yl)thiophen-3-yl, (pyridin-2-yl)phenyl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepinyl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridinyl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H-pyrazol-5-yl)thiophen- 2-yl, (1H-pyrazol-5-yl)thiophen-3-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl-1H-pyrazolyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 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-dihydrobenzo[b ][1,4]dioxinyl, 2,3-dihydrohydroxybenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 2-phenylthiazolyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen- 3-yl)phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-dihydrobenzofuranyl, 5-phenylthiophen-2-yl, 5-phenylthiophen-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, biphenyl, chromanyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolyl, isoxazolyl, naphthyl, phenyl, pyridyl, pyrimidinyl, quinolinyl, thiophen-2-yl and thiophen-3-yl; R1 is selected from the group consisting of aryl, heteroaryl and heterocyclic; each optionally substituted with one or more substituents selected from the group consisting of (2-ethyl)(methyl)amino, acetamido, amino, bromo, carbamoylamino, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, hydroxycarbamoylamino, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, benzenesulfonyl, piperazin-1-yl, piperidin-1-yl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally substituted by one or more substituents selected from the group consisting of Oxo: 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, benzyloxy, carboxyl, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidin-1-yl, thiazolidin-3-yl and trifluoromethyl; and,

[0272] R 2a It is H, ethyl or methyl.

[0273] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0274]

[0275] in:

[0276] R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (5-isoxazol-3-yl)thiophen-3-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepinyl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridinyl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H-pyridinyl)phenyl oxazol-5-yl)thiophen-2-yl, (1H-pyrazol-5-yl)thiophen-3-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl-1H-pyrazolyl, 2,3-dihydro -[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolyl[2,3-b]pyridinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrohydroxybenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 2-phenylthiazolyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-( thiophen-3-yl)phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-Dihydrobenzofuranyl, 5-phenylthiophen-2-yl, 5-phenylthiophen-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, biphenyl, chromanyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolyl, isoxazolyl, naphthyl, phenyl, pyridinyl, pyrimidine 1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, (2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino) methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetylamino, acetyl, amino, aminomethyl, benzyl, bromo, carbamoyl, carboxamide, carboxyl, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, heptyl, hydroxycarbamoyl, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl; and,

[0277] R 2a It is H, ethyl or methyl.

[0278] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0279]

[0280] in:

[0281] R 1Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridine]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-8-yl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydroquinolin-3-yl, 1,5-naphthyridin-3-yl, 1,8-naphthyridin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazole-4 -yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-phenyl imidazol-5-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-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3-(1H-pyrazol-3 phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-oxadiazol-3-yl)biphenyl-3-yl, 4-(2H-tetrazol-5-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-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydronaphthalene-1 -yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenyl-2,3-dihydrobenzofuran-7-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, benzo[c][1, 2,5]oxadiazol-4-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, benzopyran-6-yl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b]thiazol-5-yl, indol-5-yl, isoxazole -4-yl, naphth-1-yl, naphth-2-yl, phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinolin-8-yl, thiophen-2-yl and thiophen-3-yl; each optionally substituted with one or more substituents selected from the group consisting of: (1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, (2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethyl amino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetamido, acetyl, amino, aminomethyl, benzyl, bromo, carbamoylamino, carboxamide, carboxy, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, hydroxycarbamoylamino, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy, and trifluoromethyl; and,

[0282] R 2a It is H, ethyl or methyl.

[0283] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0284]

[0285] in:

[0286] R 1 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of C1-C7 alkyl, cyano, C1-C6 haloalkyl, halogen, hydroxy and oxo; and

[0287] R 2a is H or C1-C6 alkyl.

[0288] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0289]

[0290] in:

[0291] R 1 is selected from the group consisting of: 1H-pyrrolo[3,2-b]pyridinyl, quinolinyl, 1,4-dihydroquinolinyl, 1H-pyrrolo[2,3-b]pyridinyl, and 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl; each optionally substituted with one or more substituents selected from the group consisting of: ethyl, methyl, cyano, trifluoromethyl, fluoro, hydroxy, and oxo; and

[0292] R 2a is H or C1-C6 alkyl.

[0293] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0294]

[0295] in:

[0296] R 1 is selected from the group consisting of: 1H-pyrrolo[3,2-b]pyridin-6-yl, quinolin-3-yl, 1,4-dihydroquinolin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl and 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl; each optionally substituted with one or more substituents selected from the group consisting of: ethyl, methyl, cyano, trifluoromethyl, fluoro, hydroxy and oxo; and

[0297] R 2a It is H, ethyl or methyl.

[0298] One aspect of the present invention relates to compounds having formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof:

[0299]

[0300] in:

[0301] R 1 Selected from: 1H-pyrrolo[3,2-b]pyridin-6-yl, 4-hydroxyquinolin-3-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl, 1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl and 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl; and

[0302] R 2a It is H or methyl.

[0303] Some embodiments of the present invention include one or more compounds selected from the following group, and each combination of pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein the bold compound number immediately preceding the chemical name is used elsewhere in this disclosure: Compound 1: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 2: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-propylbenzenesulfonamide; Compound 3: 3-((2S)-2 -hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-pentylbenzenesulfonamide; Compound 4: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 5: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(2,2,2-trifluoroethyl)benzenesulfonamide; Compound 6: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide -2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-isopropylbenzenesulfonamide; Compound 7: N-ethyl-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-isopropylbenzenesulfonamide; Compound 8: N-(cyclopropylmethyl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 9: N-(2,2-difluoroethyl)-3-((2S)-2-hydroxy-3-(8- (naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 10: N-sec-butyl-3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 11: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methoxybenzenesulfonamide; Compound 12: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methoxybenzenesulfonamide.5]dec-3-ylamino)propoxy)-N-(2-hydroxyethyl)benzenesulfonamide; Compound 13: 3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(2-methoxyethyl)benzenesulfonamide; Compound 14: 3-((2S)-2-hydroxy-3-(8-(benzenesulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 15: 3-((2S)-3-(8-(3-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methyl Benzenesulfonamide; Compound 16: 3-((2S)-2-hydroxy-3-(8-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 17: 3-((2S)-3-(8-(4-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 18: 3-((2S)-2-hydroxy-3-(8-(4-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 19: 3-( (2S)-3-(8-(3,4-dimethylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 20: 3-((2S)-3-(8-(3-bromophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 21: 3-((2S)-2-hydroxy-3-(8-(m-toluenesulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 22: 3-((2S)-3-(8-(4-sec-butylbenzenesulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide Compound 23: 3-((2S)-3-(8-(3,5-dimethylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 24: 4-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)-N,N-dimethylbenzamide; Compound 25: 3-((2S)-3-(8-(4-acetylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 26: 3-((2S)-3-(8-(4-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 27: 3-((2S)-2-hydroxy-3-(8-(3-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 28: 3-((2S)-3-(8-(3-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methyl Benzenesulfonamide; Compound 29: 3-((S)-2-hydroxy-3-((S)-8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 30: 3-((S)-2-hydroxy-3-((R)-8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 31: 3-((2S)-3-(8-(biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 32: 3-((2S)- 3-(8-(3-cyanophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 33: 3-((2S)-2-hydroxy-3-(8-(2-(trifluoromethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 34: 3-((2S)-3-(8-(2-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 35: 3-((2S)-3-(8-(2-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide -8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 36: 3-((2S)-3-(8-(4-tert-butylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 37: 3-((2S)-2-hydroxy-3-(8-(4-(methylsulfonyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 38: 3-((2S)-2-hydroxy-3-(8-(3-(trifluoromethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.Compound 39: 3-((2S)-3-(8-(2-cyanophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 40: 4-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)benzoic acid; Compound 41: 3-((2S)-3-(8-(chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide Compound 42: N-(4-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)phenyl)acetamide; Compound 43: 3-((2S)-2-hydroxy-3-(8-(2-(methylsulfonyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 44: 3-((2S)-3-(8-(4-cyanophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyl oxy)-N-methylbenzenesulfonamide; Compound 45: 3-((2S)-2-hydroxy-3-(8-(4-(trifluoromethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 46: 3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(2-hydroxypropyl)benzenesulfonamide; Compound 47: N-(2-ethoxyethyl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide. 1-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 48: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((S)-1-hydroxypropan-2-yl)benzenesulfonamide; Compound 49: N-(1-hydroxy-2-methylpropan-2-yl)-3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 50: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide.5]dec-3-ylamino)propyloxy)-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide; Compound 51: 3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-(3-hydroxypropyl)benzenesulfonamide; Compound 52: 3-((2S)-3-(8-(4-bromophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 53: 3-((2S)-2-hydroxy-3-(8-toluenesulfonyl-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-(3-hydroxypropyl)benzenesulfonamide )-N-methylbenzenesulfonamide; Compound 54: 3-((2S)-3-(8-(2-bromophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 55: 3-((2S)-2-hydroxy-3-(8-(naphthalen-1-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 56: 3-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)benzoic acid; Compound 57: 3-((2S)-3-(8-(2-bromophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide )-2-hydroxy-3-(8-(4-(trifluoromethoxy)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 58: 3-((2S)-2-hydroxy-3-(8-(2-oxo-2,3-dihydrobenzo[d]thiazole-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 59: 3-((2S)-3-(8-(3-(3,5-dimethylisoxazol-4-yl)phenyl ...-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 58: 3-((2S)-2-hydroxy-3-(8-(2-oxo-2,3-dihydrobenzo[d]thiazole-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 59: 3-((2S)-3-(8-(3-(3,5-dimethylisoxazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 60: 3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(2-methoxyethyl)-N-methylbenzenesulfonamide; Compound 61: 3-((2S)-2-hydroxy-3-(8-(3-(1-methyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 62: 3-((2S)-2-hydroxy-3-(8-(3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 63: 3-((2S)-3-(8-(3-(1H-pyrrol-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 64: 3-((2S)-3-(8-(3-(1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 65: 3-((2S)-2-hydroxy-3-(8-(3'-(methoxymethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide. -3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 66: 3-((2S)-2-hydroxy-3-(8-(3-(thien-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 67: 3-((2S)-3-(8-(3'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 68: 3-((2S)-3-(8-(3-(1,3-dimethyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide 3-((2S)-2-hydroxy-3-(8-(3-(1-ethyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 69: 3-((2S)-3-(8-(3-(1-ethyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 70: 3-((2S)-2-hydroxy-3-(8-(3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 71: 3-((2S)-2-hydroxy-3-(8-(3'-(methylsulfonyl)biphenyl-3-ylsulfonyl)-1-oxa -8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 72: 3-((2S)-3-(8-(3'-cyanobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 73: 3-((2S)-3-(8-(3-(2,4-dimethylthiazol-5-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 74: N-cyclopropyl-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 75: 3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(3-methoxypropyl)benzenesulfonamide; Compound 76: 3-((2S)-2-hydroxy-3-(8-(3-(1-methyl-1H-pyrrol-3-yl)benzenesulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 77: 3-((2S)-3-(8-(3-(1-benzyl-1H-pyrazol-4-yl)phenylsulfonyl)-1- oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 78: 3-((2S)-3-(8-(3-(furan-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 79: 3-((2S)-3-(8-(4'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 80: 3-((2S)-2-hydroxy-3-(8-(3-(1- Compound 82: 3-((2S)-3-(8-(3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 81: 3-((2S)-2-hydroxy-3-(8-(3-(1-isobutyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 82: 3-((2S)-3-(8-(3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide Benzenesulfonamide; Compound 83: 3-((2S)-3-(8-(3'-(dimethylamino)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 84: 3-((2S)-3-(8-(3-(1H-pyrazol-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 85: 3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide.5]dec-8-ylsulfonyl)biphenyl-4-yl)acetic acid; Compound 88: 3-((2S)-2-hydroxy-3-(8-(4'-(methylsulfonamido)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 87: 2-(3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-yl)acetic acid; Compound 88: 3-((2S)-2-hydroxy-3-(8-(3-(pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5] dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 89: N-(3,3-difluorocyclobutyl)-3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 90: N-cyclopropyl-3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 91: N-(2-aminoethyl)-3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide Compound 92: (2S,3R)-3-hydroxy-2-(3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamido)-N-methylbutanamide; Compound 93: N-((R)-1-cyclopropylethyl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 94: N-tert-butyl-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5] dec-3-ylamino)propoxy)benzenesulfonamide; Compound 95: N-(1,3-dihydroxypropan-2-yl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 96: 3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((R)-1-hydroxypropan-2-yl)benzenesulfonamide; Compound 97: N-(2-ethylbutyl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 98: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-isopentylbenzenesulfonamide; Compound 99: 3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(1-(hydroxymethyl)cyclopropyl)benzenesulfonamide; Compound 100: N-((R)-3,3-dimethylbutan-2-yl)-3-((2S)-2-hydroxy-3-(8-(naphthalene-2-ylsulfonyl)-1-oxa-8-azaspiro[4 .5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 101: N-ethyl-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 102: 3-((2S)-2-hydroxy-3-(8-(3-(pyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 103: 3-((2S)-3-(8-(3-(6-aminopyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-2-hydroxypropoxy Compound 104: 3-((2S)-2-hydroxy-3-(8-(3-(pyrimidin-5-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 105: 3-((2S)-3-(8-(3'-((dimethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 106: 3-((2S)-2-hydroxy-3-(8-(3-(pyridin-4-yl)phenylbenzenesulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide. 1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 107: 3-((2S)-2-hydroxy-3-(8-(3-(2-methylpyridin-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 108: 3-((2S)-2-hydroxy-3-(8-(3-(2-methoxypyrimidin-5-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 109: 3-((2S)-2-hydroxy-3-(8-(3-(4-methylthiophen-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-amino)propoxy)-N-methylbenzenesulfonamide; Compound 110: 3-((2S)-2-hydroxy-3-(8-(3-(5-methylpyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 111: 3-((2S)-2-hydroxy-3-(8-(3-(6-methylpyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 112: 3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy Compound 113: 3-((2S)-3-(8-(3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 114: 3-((2S)-3-(8-(4'-(cyanomethoxy)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 115 : 3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)-N,N-dimethylbiphenyl-3-sulfonamide; Compound 116: 3-((2S)-2-hydroxy-3-(8-(3-(3-methylthiophen-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 117: 3-((2S)-3-(8-(4'-(cyanomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2- 1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 118: 3-((2S)-2-hydroxy-3-(8-(3'-(hydroxymethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 119: 3-((2S)-3-(8-(1,2-dimethyl-1H-imidazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 120: 3-((2S)-2-hydroxy-3-(8-(4-tert-pentylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 121: 3-((2S)-2-hydroxy-3-(8-(4'-(trifluoromethyl)biphenyl-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 122: 3-((2S)-3-(8-(4'-fluorobiphenyl-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 123: 3-((2S)-3-(8-(biphenyl-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide Compound 124: 3-((2S)-2-hydroxy-3-(8-(3-phenoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 125: 3-((2S)-3-(8-(cyclohexylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 126: 3-((2S)-2-hydroxy-3-(8-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide oxy)-N-methylbenzenesulfonamide; Compound 127: 3-((2S)-3-(8-(2,2-dimethylchroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 128: 3-((2S)-3-(8-(Benzo[c][1,2,5]thiadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 129: 3-((2S)-3-(8-(6-chloroimidazo[2,1-b]thiazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5] dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 130: 3-((2S)-2-hydroxy-3-(8-(6-phenoxypyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 131: 3-((2S)-3-(8-(1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 132: 3-((2S)-2-hydroxy-3-(8-(5-methyl-1-phenyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 133: 3-((2S)-3-(8-(2-chloro-5-(trifluoromethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 134: 3-((2S)-3-(8-(2,4-difluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 135: 3-((2S)-2-hydroxy-3-(8-(2-methoxy-4-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino) Compound 137: 3-((2S)-2-hydroxy-3-(8-(4-isopropoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 138: 3-((2S)-3-(8-(3,5-dichlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 139: 3 -((2S)-3-(8-(3-chloro-2-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 140: 3-((2S)-3-(8-(2,5-dichlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 141: 3-((2S)-3-(8-(3,4-difluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 142: 3-((2S)-3-(8-(2,3-dichlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide 1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 143: 3-((2S)-3-(8-(3-chloro-2-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 144: 3-((2S)-3-(8-(5-chloro-2-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 145: 3-((2S)-3-(8-(5-chloro-2-cyanophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 146: 3-((2S)-3-(8-(1H-benzo[d]imidazol-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 147: 3-((2S)-2-hydroxy-3-(8-(4-methoxy-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 148: 3-((2S)-3-(8-(5-chloro-2-methoxyphenylsulfonyl)-1-oxa-8-azaspiro [4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 149: 3-((2S)-3-(8-(4-fluoro-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 150: 3-((2S)-3-(8-(2-fluoro-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 151: 3-((2S)-3-(8-(4-chloro-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5 ]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 152: 3-((2S)-2-hydroxy-3-(8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 153: 3-((2S)-3-(8-(3,4-dimethoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 154: 3-((2S)-3-(8-(2,5-dimethylphenylsulfonyl)-1-oxa-8 -azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 155: 3-((2S)-3-(8-(4-bromo-3-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 156: 3-((2S)-3-(8-(2,6-difluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 157: 3-((2S)-3-(8-(2-chloro-4-cyanophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 158: 3-((2S)-3-(8-(2,4-dichlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 159: 3-((2S)-3-(8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 160: 3-((2S)-3-(8-(2-fluoro-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy 1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 161: 3-((2S)-2-hydroxy-3-(8-(3-(4-(trifluoromethyl)phenoxy)benzenesulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 162: 3-((2S)-2-hydroxy-3-(8-(5-methyl-2-(trifluoromethyl)furan-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 163: 3-((2S)-3-(8-(5-chloro-1,3-dimethyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide. 1-Oxypyrrolidin-1-yl)ethyl)benzenesulfonamide; Compound 165: N-(1-ethylpiperidin-4-yl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 166: N-((S)-2,3-dihydroxypropyl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide. -oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 167: N-(2-(dimethylamino)ethyl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 168: 3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(piperidin-3-ylmethyl)benzenesulfonamide; Compound 169: 3-((2S)-2-hydroxy-3-(8-(6-methoxynaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 170: 3-((2S)-2-hydroxy-3-(8-(3-(2-(trifluoromethyl)phenoxy)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 171: 3-((2S)-2-hydroxy-3-(8-(2-(trifluoromethoxy)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 172: 3-((2S)-3-(8-(benzylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2 -hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 173: 3-((2S)-2-hydroxy-3-(8-(7-methoxybenzo[c][1,2,5]oxadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 174: 3-((2S)-3-(8-(biphenyl-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 175: 3-((2S)-2-hydroxy-3-(8-(5-methylbenzo[c][1,2,5]oxadiazol-4-ylsulfonyl)-1-oxa- 8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 176: 3-((2S)-2-hydroxy-3-(8-(2-methoxy-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 177: 3-((2S)-3-(8-(Benzo[c][1,2,5]thiadiazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 178: 3-((2S)-3-(8-(4,5-dichlorothiophen-2-ylsulfonyl)-1-oxa- 8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 179: 3-((2S)-3-(8-(3-fluoro-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 180: 3-((2S)-3-(8-(2-cyano-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 181: 3-((2S)-3-(8-(5-chlorothiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 182: 3-((2S)-2-hydroxy-3-(8-(2-oxoindole-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 183: 3-((S)-3-((S)-8-(chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 184: 3-((S)-3-((R)-8-(chroman-6-ylsulfonyl)-1-oxa- 8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 185: 3-((2S)-3-(8-(7-chlorobenzo[c][1,2,5]oxadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 186: 3-((2S)-2-hydroxy-3-(8-(4-methyl-2-phenylthiazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 187: 3-((2S)-2-hydroxy-3-( 8-(5-phenylthiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 188: 3-((2S)-3-(8-(3,5-dimethylisoxazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 189: 3-((2S)-2-hydroxy-3-(8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide Sulfonamide; Compound 190: 3-((2S)-2-hydroxy-3-(8-(4-(phenylsulfonyl)thiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 191: 3-((2S)-2-hydroxy-3-(8-(5-(1-methyl-3-(trifluoromethyl))-1H-pyrazol-5-yl)thiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 192: 3-((2S)-3-(8-(furan-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 193: 3-((2S)-2-hydroxy-3-(8-(1-methyl-1H-pyrazol-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 194: 3-((2S)-2-hydroxy-3-(8-(1-methyl-1H-imidazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 195: 3-((2S)-3-(8-(3-fluoro-4-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide Compound 196: 3-((2S)-2-hydroxy-3-(8-(thiophen-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 197: 3-((2S)-3-(8-(5-chlorobenzo[c][1,2,5]thiadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 198: 3-((2S)-3-(8-(3-cyano-4-methylphenylsulfonyl)-1-oxa -8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 199: 3-((2S)-3-(8-(2-chloro-3-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 200: 3-((2S)-3-(8-(2-chloro-4-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 201: 3-((2S)-3-(8-(2,3-difluorophenylsulfonyl)-1-oxa-8-azaspiro[4 .5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 202: 3-((2S)-3-(8-(2-chloro-5-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 203: 3-((2S)-3-(8-(2-chloro-5-(methylsulfonyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 204: 3-((2S)-3-(8-(5-fluoro-2-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 205: 3-((2S)-3-(8-(2,5-difluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 206: 3-((2S)-3-(8-(4-chloro-3-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 207: 3-((2S)-3-(8-(3-chloro-4-methoxyphenylsulfonyl)-1-oxa-8-azaspiro [4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 208: 3-((2S)-2-hydroxy-3-(8-(5-(trifluoromethyl)isoxazol-3-yl)thiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 209: N-ethyl-3-((2S)-3-(8-(3-(1-ethyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 210: 3-((2S)-3-( 8-(4'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-ethylbenzenesulfonamide; Compound 211: 3'-(3-((S)-3-(3-(N-ethylsulfamoyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-sulfonamide; Compound 212: 3-((2S)-3-(8-(3-(6-aminopyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-ethylbenzenesulfonamide; Compound Compound 213: 3-((2S)-3-(8-(4'-(cyanomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-ethylbenzenesulfonamide; Compound 214: 3-((2S)-3-(8-(4'-(cyanomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-ethylbenzenesulfonamide; Compound 215: 3-((S)-2-hydroxy-3-((R)-8-(3-(1-methyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 216: 3-((S)-2-hydroxy-3-((S)-8-(3-(1-methyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 217: 3-((2S)-3-(8-(5-cyano-2-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 218: 3-((2S)-3-(8-(3-bromo-4-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide Compound 219: 3-((2S)-3-(8-(3-bromo-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 220: 3-((2S)-3-(8-(5-bromo-2-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 221: 3-((2S)-2-hydroxy-3-(8-(1-methyl-1H-indol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide Compound 222: 3-((2S)-2-hydroxy-3-(8-(4-methoxy-5,6,7,8-tetrahydronaphthalen-1-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 223: 3-((2S)-3-(8-(5-chloronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 224: 3-((2S)-3-(8-(3-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide 5-[4.5]dec-3-ylamino]-2-hydroxypropoxy)-N-ethylbenzenesulfonamide; Compound 225: N-ethyl-3-((2S)-2-hydroxy-3-(8-(4-methoxy-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-amino)propoxy)benzenesulfonamide; Compound 226: N-ethyl-3-((2S)-3-(8-(2-fluoro-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-amino)-2-hydroxypropoxy)benzenesulfonamide; Compound 227: 3-((2S)-3-(8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-amino)propoxy)benzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-ethylbenzenesulfonamide; Compound 228: N-ethyl-3-((2S)-2-hydroxy-3-(8-(3-oxa-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 229: 3-((2S)-3-(8-(Benzo[c][1,2,5]thiadiazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-ethylbenzenesulfonamide; Compound 230: N-ethyl-3-((2S)-2 -hydroxy-3-(8-(5-methyl-1-phenyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 231: N-ethyl-3-((2S)-2-hydroxy-3-(8-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 232: 3-((2S)-3-(8-(3,5-dimethylisoxazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-ethylbenzenesulfonamide; Compound 2 Compound 33: N-ethyl-3-((2S)-2-hydroxy-3-(8-(5-phenylthiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 234: N-ethyl-3-((2S)-2-hydroxy-3-(8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 235: 3-((2S)-3-(8-(7-chlorobenzo[c][1,2,5]oxadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5 ]dec-3-ylamino)-2-hydroxypropoxy)-N-ethylbenzenesulfonamide; Compound 236: 3-((2S)-2-hydroxy-3-(8-(4-methoxy-2-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 237: 3-((2S)-3-(8-(5-bromo-2-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 238: 3-((2S)-3-(8-(5-fluoro-2-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 239: 3-((2S)-3-(8-(3-chloro-4-cyanophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 240: 3-((2S)-3-(8-(5-chloro-2-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 241: 3-((2S)-3-(8-(2-fluoro-5-methoxyphenylsulfonyl)-1- Compound 243: 3-((2S)-2-hydroxy-3-(8-(1-phenyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 244: 3-((S)-3-((S) -8-(Benzo[c][1,2,5]thiadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 245: 3-((S)-3-((R)-8-(Benzo[c][1,2,5]thiadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 246: 3-((2S)-3-(8-(3-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)- N,N-dimethylbenzenesulfonamide; Compound 247: 3-((2S)-2-hydroxy-3-(8-(4-methoxy-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 248: 3-((2S)-3-(8-(2-fluoro-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N,N-dimethylbenzenesulfonamide; Compound 249: 3-((2S)-3-(8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.Compound 251: 3-((2S)-3-(8-(Benzo[c][1,2,5]thiadiazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N,N-dimethylbenzenesulfonamide; Compound 252: 3-((2S)-2-hydroxy-3-(8-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 253: 3-((2S)-2-hydroxy-3-(8-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 254: 3-((2S)-2-hydroxy-3-(8-(Benzo[c][1,2,5]thiadiazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide -3-(8-(5-methyl-1-phenyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 253: 3-((2S)-2-hydroxy-3-(8-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 254: 3-((2S)-3-(8-(3,5-dimethylisoxazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N,N-dimethylbenzenesulfonamide; Compound 255: 3-((2S)-3-(8-(3,5-dimethylisoxazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 256: 3-((2S)-3-(8-(3,5-dimethylisoxazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 257: 3-((2S)-3-(8-(3,5-dimethylisoxazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 258: 3-((2S)-3-(8-(3,5-dimethylisoxazol-4-yl Compound 255: 3-((2S)-2-hydroxy-3-(8-(5-phenylthiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 256: 3-((2S)-2-hydroxy-3-(8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N,N-dimethylbenzenesulfonamide; Compound 257: 3-((2S)-3-(8-(7-chlorobenzo[c][1,2,5]oxadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5 ]dec-3-ylamino)-2-hydroxypropoxy)-N,N-dimethylbenzenesulfonamide; Compound 258: 3-((2S)-2-hydroxy-3-(8-(4-methoxynaphthalen-1-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 259: 3-((2S)-3-(8-(5-bromo-2-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 260: 3-((2S)-3-(8-(5-bromo-2,3-dihydrobenzofuran-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 261: 3-((2S)-3-(8-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 262: 3-((2S)-3-(8-(5-chlorobenzo[c][1,2,5]oxadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 263: 3-((2S)-3-(8-(2-cyano-5-methoxyphenylsulfonyl)- Compound 264: 3-((2S)-3-(8-(6-chloronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 265: 3-((2S)-3-(8-(2,3-dimethylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 266: 3-((S)-2-hydroxy-3-((S)-8-(4-methoxy-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide 3-((S)-2-hydroxy-3-((R)-8-(4-methoxy-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 267: 3-((S)-2-hydroxy-3-((R)-8-(4-methoxy-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 268: 3-((S)-3-((S)-8-(2-fluoro-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 269: 3-((S)-3-((R)-8-(2-fluoro-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5] dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 270: 3-((S)-3-((S)-8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 271: 3-((S)-3-((R)-8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 272: 3-((2S)-3-(8-(3-(1-ethyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropyloxy)-N,N-dimethylbenzenesulfonamide; Compound 273: 3-((2S)-3-(8-(4'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N,N-dimethylbenzenesulfonamide; Compound 274: 3'-(3-((S)-3-(3-(N,N-dimethylsulfamoyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-sulfonamide; Compound 275: 3-((2S)-3-(8-(3-(6-aminopyridin-3-yl)phenylsulfonyl)-1-oxa-8 -azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N,N-dimethylbenzenesulfonamide; Compound 276: 3-((2S)-3-(8-(4'-(cyanomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N,N-dimethylbenzenesulfonamide; Compound 277: 3-((2S)-3-(8-(4'-(cyanomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N,N-dimethylbenzenesulfonamide; Compound 278: 3-((S)-2-hydroxy-3-((S)-8-(3-oxo-3,4-dimethylbenzenesulfonamide Compound 279: 3-((S)-2-hydroxy-3-((R)-8-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 280: 3-((S)-2-hydroxy-3-((S)-8-(5-methyl-1-phenyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide Benzenesulfonamide; Compound 281: 3-((S)-2-hydroxy-3-((R)-8-(5-methyl-1-phenyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 282: 3-((S)-3-((S)-8-(3-(1-ethyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 283: 3-((S)-3-((R)-8-(3-(1-ethyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 284: 3-((S)-2-hydroxy-3-((S)-8-(3-(pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 285: 3-((S)-2-hydroxy-3-((R)-8-(3-(pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 286: 3-((S)-3-((S)-8-(3-(6-aminopyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide Compound 287: 3-((S)-3-((R)-8-(3-(6-aminopyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 288: 3-((S)-3-((S)-8-(4'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 289: 3-(( S)-3-((R)-8-(4'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 290: 3-((2S)-3-(8-(4-(aminomethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N,N-dimethylbenzenesulfonamide; Compound 291: 3'-((S)-3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl Benzene-4-sulfonamide; Compound 292: 3'-((R)-3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-sulfonamide; Compound 293: 3-((S)-3-((S)-8-(4'-(cyanomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 294: 3-((S)-3-((R)-8-(4'-(cyanomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 295: 3-((S)-3-((S)-8-(3-(1H-pyrazol-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 296: 3-((S)-3-((R)-8-(3-(1H-pyrazol-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 297: 3-((S)-3-((S)-8-(4'-(cyanomethoxy)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide. -8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 298: 3-((S)-3-((R)-8-(4'-(cyanomethoxy)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 299: 3-((S)-2-hydroxy-3-((S)-8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 300: 3-((S)-2-hydroxy-3-(( 3-((2S)-2-hydroxy-3-(8-(4'-((methylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 302: 3-((2S)-3-(8-(4'-((ethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide. Sulfonamide; Compound 303: 3-((2S)-2-hydroxy-3-(8-(4'-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 304: 3-((2S)-2-hydroxy-3-(8-(4'-((2-hydroxyethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 305: 3-((2S)-3-(8-(4'-((2-(dimethylamino)ethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 306: 3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 307: 3-((2S)-3-(8-(3-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-(3-(dimethylamino)propyl)benzenesulfonamide; Compound 308: N-(3-(dimethylamino)propyl)-3-((2S)-2-hydroxy-3-(8-(4-methoxy-3 -methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)benzenesulfonamide; Compound 309: N-(3-(dimethylamino)propyl)-3-((2S)-3-(8-(2-fluoro-5-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)benzenesulfonamide; Compound 310: 3-((2S)-3-(8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-(3-(dimethylamino)propyl)benzenesulfonamide; Compound 311: N-( 3-(dimethylamino)propyl)-3-((2S)-2-hydroxy-3-(8-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)benzenesulfonamide; Compound 312: 3-((2S)-3-(8-(Benzo[c][1,2,5]thiadiazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-(3-(dimethylamino)propyl)benzenesulfonamide; Compound 313: N-(3-(dimethylamino)propyl)-3-((2S)- 2-hydroxy-3-(8-(5-methyl-1-phenyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 314: N-(3-(dimethylamino)propyl)-3-((2S)-2-hydroxy-3-(8-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 315: N-(3-(dimethylamino)propyl)-3-((2S)-2-hydroxy-3-(8-(5-phenylthiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide.5]dec-3-ylamino)propyloxy)benzenesulfonamide; Compound 316: N-(3-(dimethylamino)propyl)-3-((2S)-2-hydroxy-3-(8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)benzenesulfonamide; Compound 317: N-(3-(dimethylamino)propyl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)benzenesulfonamide; Compound 318: N-(3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)benzenesulfonamide 1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)phenylsulfonyl)acetamide; Compound 319: 3-((2S)-2-hydroxy-3-(8-(4'-((isobutylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 320: 3-((2S)-2-hydroxy-3-(8-(4'-((isopentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 321: 3-((2S)-2-hydroxy-3-(8-(4'-((isobutylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide. -((2,2,2-trifluoroethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 322: 3-((2S)-2-hydroxy-3-(8-(pyridin-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 323: 3-((2S)-2-hydroxy-3-(8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 324: 3-((2S)-2-hydroxy-3-(8-(pyridin-3- 5-Ylamino)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 325: 3-((2S)-3-(8-(1H-indazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 326: 3-((2S)-3-(8-(Benzofuran-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 327: 3-((2S)-3-(8-(Benzo[d]isoxazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 328: 3-((2S)-3-(8-(1H-indazol-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 329: 3-((2S)-3-(8-(1-ethyl-5-methyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 330: 3-((2S)-3-(8-(2,3-dihydrobenzofuran-5-ylsulfonyl)- 1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 331: 3-((2S)-3-(8-(Benzofuran-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 332: 3-((2S)-3-(8-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 333: 3-((2S)-3-(8-(4 -ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 334: 3-((2S)-2-hydroxy-3-(8-(4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 335: 3-((S)-2-hydroxy-3-((S)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide -3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 336: 3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 337: 3-((2S)-3-(8-(5-bromopyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 338: 3-((2S)-3-(8-(4'-((cyanomethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 339: 3-((2S)-3-(8-(4'-((2,2-difluoroethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 340: 3-((2S)-2-hydroxy-3-(8-(4'-((2-methoxyethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 341: 3- ((2S)-3-(8-(5-(4-(aminomethyl)phenyl)pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 342: 3-((2S)-2-hydroxy-3-(8-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 343: 3-((S)-2-hydroxy-3-((S)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide. 5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 344: 3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 345: (2S)-3-hydroxy-2-((3'-(3-((S))-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-yl)methylamino)propanamide; Compound 346: 3-((2S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide -(8-(4'-(thiazolidin-3-ylmethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 347: 3-((2S)-3-(8-(4'-((2-fluoroethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 348: N-(2-((3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamideCompound 349: 3-((2S)-2-hydroxy-3-(8-(4-isobutyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 350: 3-((S)-3-((S)-8-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 351: 3-((S)-3-((R)-8-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide -2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 352: 3-((3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-yl)methylamino)-3-oxopropanoic acid; Compound 353: 2-amino-N-((3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-yl)methyl)acetamide; Compound 354: N. 1-((3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-yl)methyl)oxalamide; Compound 355: 3-((2S)-3-(8-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 356: N-(2-fluoroethyl)-3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3 -ylamino)propyloxy)benzenesulfonamide; Compound 357: 3-((2S)-3-(8-(4'-(aminomethyl)-4-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 358: 3-((2S)-3-(8-(5-(4-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 359: 3-((S)-2-hydroxy-3-((S)-8-(4'-((isopropylamino)methyl) Compound 360: 3-((S)-2-hydroxy-3-((S)-8-(4'-((isobutylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 361: 3-((S)-2-hydroxy-3-((S)-8-(4'-((isopentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 362: 3 -((S)-2-hydroxy-3-((R)-8-(4'-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 363: 3-((S)-2-hydroxy-3-((R)-8-(4'-((isobutylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 364: 3-((S)-2-hydroxy-3-((R)-8-(4'-((isopentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 365: 3-((2S)-3-(8-(4'-(aminomethyl)-4-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 366: 3-((2S)-3-(8-(4'-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 367: 3-((2S)-3-(8-(4'-(aminomethyl)-5-(trifluoromethyl)biphenyl-3 -ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 368: 3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-carboxamide; Compound 369: 3-((2S)-3-(8-(3-(5-(aminomethyl)thiophen-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 370: 3-((2S)-3-(8-(3-(5-cyanomethyl)thiophen-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide 3-((2S)-2-Hydroxy-3-(8-(3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 371: 3-((2S)-2-Hydroxy-3-(8-(3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 372: 3-((2S)-3-(8-(3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-2-hydroxypropoxy)-N-methylbenzenesulfonamide Amine; Compound 373: 3-((2S)-3-(8-(4'-(aminomethyl)-5-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 374: 3-((S)-3-((S)-8-(5-(4-(aminomethyl)phenyl)pyridinyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 375: 3-((S)-3-((R)-8-(5-(4-(aminomethyl)phenyl)pyridinyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 376: 3-((2S)-3-(8-(4'-(aminomethyl)-6-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 377: 3-((2S)-3-(8-(4'-(aminomethyl)-4-chlorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 378: 3-((2S)-2-hydroxy-3-(8-(2-(pyridin-4-yl) Compound 379: (Z)-N′-hydroxy-3′-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-carboximide; Compound 380: 3-((2S)-2-hydroxy-3-(8-(4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 381: 3-((2S)-3-(8-(4'-(aminomethyl)biphenyl-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 382: 3-((2S)-3-(8-(4'-(aminomethyl)biphenyl-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 383: 3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-carboximide ; Compound 384: 3-((S)-3-((S)-8-(4'-(aminomethyl)-4-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 385: 3-((S)-3-((R)-8-(4'-(aminomethyl)-4-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 386: 3-((2S)-2-hydroxy-3-(8-(5-methoxypyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 387: 3-((2S)-3-(8-(3-(6-(aminomethyl)pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 388: 3-((2S)-3-(8-(6'-(aminomethyl)-3,3'-bipyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 389: 3-((2S)-3-(8-(3-(aminomethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide. -8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 390: 3-((2S)-2-hydroxy-3-(8-(3-(hydroxymethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 391: 3-((2S)-3-(8-(4-(aminomethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 392: 3-((2S)-2-hydroxy-3-(8-(4-(hydroxymethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide 3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 393: N-(2-fluoroethyl)-3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 394: N-(2-fluoroethyl)-3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 395: 3-((2S)-2-hydroxy-3-(8-(6-hydroxypyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide 3-((2S)-2-hydroxy-3-(8-(6-methoxypyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 396: 3-((2S)-2-hydroxy-3-(8-(6-methoxypyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 397: 3-((2S)-2-hydroxy-3-(8-(5-methoxy-2-methylpyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 398: 3-((2S)-2-hydroxy-3-(8-(2-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 399: 3-((2S)-2-hydroxy-3-(8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 400: 3-((2S)-3-(8-(6-chloro-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 401: 3-(( 2S)-3-(8-(6-ethoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 402: 3-((2S)-2-hydroxy-3-(8-(4-(pyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 403: 3-((2S)-3-(8-(4'-(aminomethyl)-3-(trifluoromethoxy)biphenyl-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3 -ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 404: 3-((2S)-3-(8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 405: 3-((S)-3-((R)-8-(4'-((dimethylamino)methyl)biphenyl-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 406: 3-((2S)-2-hydroxy-3-(8-(6-morpholinopyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide 3-((2S)-2-hydroxy-3-(8-(4-(pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 407: 3-((2S)-2-hydroxy-3-(8-(4-(pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 408: 3-((2S)-2-hydroxy-3-(8-(4-(pyridin-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 409: 3-((2S)-3-(8-(3-(2H-tetrazol-5-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 410: 3-((2S)-3-(8-(4-(2H-tetrazol-5-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 411: 3-((2S)-3-(8-(4'-(aminomethyl)-4-(trifluoromethoxy)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 412: 3-((2S)-3-(8-(5-bromo-2-(2-(pyrrolidin-1-yl)ethoxy) phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 413: 3-((S)-2-hydroxy-3-((S)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 414: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide Compound 415: 3-((S)-3-((S)-8-(4'-(aminomethyl)-4-(trifluoromethoxy)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 416: 3-((S)-3-((R)-8-(4'-(aminomethyl)-4-(trifluoromethoxy)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 417: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrrolidone) 1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(2-hydroxyethyl)benzenesulfonamide; Compound 418: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((R)-1-hydroxypropan-2-yl)benzenesulfonamide; Compound 419: 3-((S)-3-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(2-hydroxyethyl)benzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 420: 3-((S)-3-((R)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 421: 3-((2S)-2-hydroxy-3-(8-(6-(piperidin-1-yl)pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 422: 3-((2S)-3-(8-(6-( Compound 423: 3-((2S)-3-(8-(1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 424: 3-((S)-3-((S)-8-(4'-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)- Compound 426: 3-((2S)-2-hydroxy-3-(8-(6-(2-methoxyethylamino)pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 427: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((1S,2S)-2-hydroxycyclopentyl)benzenesulfonamide; Compound 428: 3-((2S)-2-hydroxy-3-(8-(6-(2-hydroxyethylamino)pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 429: 3-((2S)-3-(8-(6-(2-aminoethylamino)pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.Compound 431: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 432: 3-((S)-2-Hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((S)-1-hydroxypropan-2-yl)benzenesulfonamide; Compound 433: 3-((2S)-3-(8-(4-chloropyridin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide Compound 434: 3-((S)-2-Hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide 4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((S)-2-hydroxypropyl)benzenesulfonamide; Compound 435: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((1R,2S)-2-hydroxycyclohexyl)benzenesulfonamide; Compound 436: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin- 7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((R)-2-hydroxypropyl)benzenesulfonamide; Compound 437: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide; Compound 438: 3-((S)-3-((S)-8-(4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 439: 3-((S)-3-((R)-8-(4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 440: 3-((S)-2-hydroxy-3-((R)-8-(4'-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 441: 3-((2S)-3-(8-(2-(dimethylamino)pyridin-3-ylsulfonyl) Compound 443: 3-((S)-2-hydroxy-3-((R)-8-(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 444: 3-((S)-3-( (R)-8-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 445: 3-((2S)-3-(8-(6-ethoxypyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 446: 3-((S)-3-((S)-8-(4'-(1-aminocyclopropyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide Sulfonamide; Compound 447: 3-((S)-3-((S)-8-(4'-(aminomethyl)-2-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 448: 3-((S)-3-((S)-8-(4'-(aminomethyl)-2-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 449: 3-((S)-3-((S)-8-(4'-(aminomethyl)-5-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 450: 3-((S)-3-((S)-8-(6-ethoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 451: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5] dec-3-ylamino)propoxy)-N-methoxybenzenesulfonamide; Compound 452: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-6-(methylamino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 453: 3-((S)-3-((R)-8-(6-(dimethylamino)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 454: 3-((S)-3-((R)-8-(6-(dimethylamino)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide 5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 454: 3-((S)-2-hydroxy-3-((R)-8-(6-hydroxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 455: 3-((S)-3-((R)-8-(6-amino-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide -3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 456: N-ethyl-3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)benzenesulfonamide; Compound 457: N-(2-fluoroethyl)-3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3]-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)benzenesulfonamide.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 458: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 459: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-(2-methoxyethyl)benzenesulfonamide; Compound 4 Compound 60: N-(cyanomethyl)-3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 461: N-(2,2-difluoroethyl)-3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 462: 3-((S)-3-((R )-8-(1-(2-(benzyloxy)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 463: 3-((S)-3-((S)-8-(4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 464: 3-((S)-3-(R)-8-(4'-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylamino) Compound 465: 3-((S)-2-hydroxy-3-((R)-8-(1-(2-hydroxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 466: 3-((S)-3-(R)-8-(1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 467: 3-((S)-3-((R)-8-(1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 468: 3-((S)-3-((R)-8-((R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide Benzenesulfonamide; Compound 469: 3-((S)-2-hydroxy-3-((R)-8-(1-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 470: 3-((S)-2-hydroxy-3-((R)-8-(1-propyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 471: 3-((S)-2-hydroxy-3-((R)-8-(1 -(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 472: 3-((S)-3-((R)-8-((S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 473: 3-((S)-2-hydroxy-3-((R)-8-(1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; [2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 474: 3-((S)-2-hydroxy-3-((R)-8-(1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazin-7'-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 475: 3-((S)-2-hydroxy-3-((R)-8-(3-methyl-3H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.Compound 476: 3-((S)-2-hydroxy-3-((R)-8-(6-methoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 477: 3-((S)-2-hydroxy-3-((R)-8-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 47 8: 3-((S)-2-hydroxy-3-((R)-8-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 479: 3-((S)-2-hydroxy-3-((R)-8-(5,6,7,8-tetrahydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 480: 3-((S)-3-((R)-8-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl)- Compound 481: 3-((S)-2-hydroxy-3-((R)-8-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 482: 3-((S)-3-((R)-8-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-2-hydroxypropoxy)-N-methylbenzenesulfonamide Amide; Compound 483: 3-((S)-3-((R)-8-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 484: 3-((S)-2-hydroxy-3-((R)-8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 485: 3-((S)-3-((R)-8-(1,5-naphthyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.Compound 486: 3-((S)-2-hydroxy-3-((R)-8-(2-methyl-1H-imidazo[4,5-b]pyridine-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 487: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-8-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound Compound 488: 3-((S)-3-((R)-8-(7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 489: 3-((S)-3-((R)-8-(7-amino-1,8-naphthyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 490: 3-((S)-3-((R)-8-(1H-pyrazolo[3,4-b]pyridin-5-ylsulfonyl)-1-oxa-8 -azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 491: 3-((S)-3-((R)-8-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 492: 3-((S)-3-((R)-8-(1-ethyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 493: 3-((S)- 3-((R)-8-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 494: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 495: 3-((S)-3-((R)-8-(1H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 496: 3-((R)-3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)pyridine 1-oxide; Compound 497: 3-((S)-2-hydroxy-3-((R)-8-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 498: 3-((S)-3-((R)-8-(2,3-dioxoindole-5-ylsulfonyl)- Compound 499: 3-((S)-2-hydroxy-3-((R)-8-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 500: 3-((S)-3-((R)-8-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 501: 3- ((S)-2-Hydroxy-3-((R)-8-(2-methyl-1H-benzo[d]imidazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 502: 3-((S)-3-((R)-8-(1H-pyrazolo[4,3-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 503: 3-((S)-3-((R)-8-(1H-benzo[d]imidazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide. Methylbenzenesulfonamide; Compound 504: 3-((S)-3-(R)-8-(2,3-dihydrofuro[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 505: 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 506: 3-((S)-3-((R)-8-(1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 507: 3-((S)-3-((R)-8-(1H-pyrrolo[2,3-b]pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 508: 3-((S)-2-hydroxy-3-((R)-8-(4-methoxy-1H-indazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 509: 3-((S)-2-hydroxy-3-((R)-8-(3-(trifluoromethyl)-1H-indazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide. 5-Methyl)-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 510: 3-((S)-3-((R)-8-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 511: 3-((S)-3-((R)-8-(3-ethyl-3H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-2-methylbenzenesulfonamide. Compound 512: 3-((S)-2-hydroxy-3-((R)-8-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 513: 3-((S)-3-((R))-8-(3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 514: 3-((S)-2-hydroxy-3-((R)-8-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; (2-Oxa-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 515: 3-((S)-3-((R)-8-(2-ethyl-3H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 516: 3-((S)-2-hydroxy-3-((R)-8-(5-methyl-3H-imidazo[4,5-b]pyridin-6-ylsulfonyl]-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 517: 3-((S)-3-((R)-8-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 518: 3-((S)-2-hydroxy-3-((R)-8-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 519: 3-((S) -2-hydroxy-3-((R)-8-(7-methyl-3H-imidazo[4,5-b]pyridin-6-sulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 520: 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-ethylbenzenesulfonamide; Compound 521: 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)- 2-Hydroxypropyloxy)-N-(2-hydroxyethyl)benzenesulfonamide; Compound 522: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 523: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-1H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 524: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-1H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide 3-((S)-3-((R)-8-(4-oxo-1-propyl-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 525: 3-((S)-3-((R)-8-(1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 526: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 527: 3-((S)-3-((R)-8-(3-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 528: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxy-8-methylquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 529: 3-((S)-3-((R) -8-(1H-pyrrolo[3,2-b]pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 530: 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-(2-methoxyethyl)benzenesulfonamide; Compound 531: 3-((S)-3-((R)-8-(1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8 -azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 532: 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 533: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxy-6-methylquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 534: 3-((S)-3-((R)-8 -(6-fluoro-4-hydroxyquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 535: 3-((S)-3-((R)-8-(1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 536: 3-((S)-3-((R)-8-(1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 537: 3-((S)-2-hydroxy-3-((R)-8-(imidazo[1,2-a]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 538: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxy-7-methylquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 539: 3-((S)-3-((R)-8-(7-fluoro-4-hydroxyquinolin-3-ylsulfonyl) -1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 540: 3-((S)-3-((R)-8-(8-fluoro-4-hydroxyquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 541: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxyquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 542: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxy-7- Compound 543: 3-((S)-3-((R)-8-(1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 544: 2-(3-((R)-3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)-4-oxoquinolin-1(4H)-yl)acetic acid; Compound 545: 3-(( S)-3-((R)-8-(1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 546: 3-((S)-3-(R)-8-(1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 547: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxy-6-methylquinolin-8-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 548: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxyquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 549: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 550: 3-((S)-3-((R)-8-(1-ethyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)- 1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 551: 3-((S)-2-hydroxy-3-((R)-8-(4-oxo-1-propyl-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 552: 3-((S)-3-((R)-8-(6-fluoro-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 553: 3-((S)-2-hydroxy-3-((R)-8- 3-((S)-3-((R)-8-(8-fluoro-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 554: 3-((S)-3-((R)-8-(8-fluoro-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 555: 3-((S)-3-((R)-8-(7-fluoro-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 55 6: 3-((S)-2-hydroxy-3-((R)-8-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 557: 3-((S)-3-((R)-8-(1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 558: 3-((S)-2-hydroxy-3-((R)-8-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 559: 3-((S)-2-hydroxy-3-((R)-8-(2-methyl-3H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 560: 3-((S)-2-hydroxy-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 561: 3-((S)-2-hydroxy-3-((R)-8-(pyridin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3 -ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 562: 3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)benzenesulfonamide; Compound 563: 3-((S)-3-((S)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)benzenesulfonamide; Compound 564: 3-((S)-2-hydroxy-3-((R)-8-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-ylsulfonyl)-1 -oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 565: 3-((S)-3-(R)-8-(chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 566: 3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 567: 3-((S)-3-((R)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide 5-Benzylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 568: 3-((S)-2-hydroxy-3-((R)-8-(4-methoxypyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 569: 3-((S)-3-((R)-8-(4-aminopyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 570: 3-((S)-3-((R)-8-(5-benzylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 571: 3-((S)-3-((R)-8-(5-ethylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 572: 3-((S)-2-hydroxy-3-((R)-8-(4-phenylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 573: 3-((S)-3-((R)-8-(4-benzylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3 -ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 574: 3-((S)-2-hydroxy-3-((R)-8-(4-(trifluoromethyl)pyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 575: 3-((S)-2-hydroxy-3-((R)-8-(4-methylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 576: 3-((S)-2-hydroxy-3-((R)-8-(pyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide. Compound 577: 3-((S)-3-((R)-8-(4,6-dimethylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 578: 3-((S)-3-((R)-8-(5-heptylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 579: 3-((S)-2-Hydroxy-3-((R)-8-(5-propylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide 5-Methylamino)-2-((R)-3-((S)-2-Hydroxy-3-((R)-8-(5-phenylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 581: methyl 2-((R)-3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-yl)pyrimidine-5-carboxylate; Compound 582: methyl 2-((R)-3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-yl)pyrimidine-5-carboxylate.5]dec-8-yl)pyrimidine-4-carboxylic acid; Compound 583: 3-((S)-2-hydroxy-3-((R)-8-(5-(trifluoromethyl)pyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 584: 3-((S)-3-((R)-8-(4,6-dimethoxypyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 585: 3-((S)-2-hydroxy-3-((R)-8-(5-(trifluoromethyl)pyrazin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide Compound 586: 3-((S)-2-hydroxy-3-((R)-8-(pyrazin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 587: 3-((S)-3-((R)-8-(1-ethyl-4-oxo-1,4-dihydropyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 588: 3-((S)-3-((R)-8-(1-ethyl-4-oxo-1,4-dihydropyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide -3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 589: 3-((S)-2-hydroxy-3-((R)-8-(pyrimidin-4-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 590: 3-((S)-3-((R)-8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide; Compound 591: 3-((S)-3-((R)-8-(3-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide Compound 592: 3-((S)-3-((R)-8-(3-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide; Compound 593: 3-((S)-2-hydroxy-3-((R)-8-(4-(3-methoxyphenyl)pyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; and Compound 594: 3-((S)-2-hydroxy-3-((R)-8-(4-methyl-6-phenylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.

[0304] Some embodiments of the present invention comprise one or more compounds selected from the following group, and each combination of pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein the bold compound number immediately preceding the chemical name is used elsewhere in the disclosure: Compound 61: 3-((2S)-2-hydroxy-3-(8-(3-(1-methyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 172: 3-((2S)-3-(8-(benzylsulfonyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 300: 3-((S)-2-hydroxy-3-((R)-8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 303: 3-((2S)-2-hydroxy-3-(8-(4'-((isopropylamino)methyl)biphenyl-3- Compound 320: 3-((2S)-2-hydroxy-3-(8-(4'-((isopentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 336: 3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide )propyloxy)-N-methylbenzenesulfonamide; Compound 339: 3-((2S)-3-(8-(4'-((2,2-difluoroethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 344: 3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propyloxy)-N-methylbenzenesulfonamide; Compound 354: N 1-((3'-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-yl)methyl)oxalamide; Compound 419: 3-((S)-3-((S)-8-(4'-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 437: 3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8 -azaspiro[4.5]dec-3-ylamino)propyloxy)-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide; Compound 468: 3-((S)-3-((R)-8-((R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 493: 3-((S)-3-((R)-8-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methyl Benzenesulfonamide; Compound 496: 3-((R)-3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)pyridine 1-oxide; Compound 505: 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropyloxy)-N-methylbenzenesulfonamide; Compound 509: 3-((S)-2-hydroxy-3-((R)-8-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)- 5-Decan-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 532: 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-2-hydroxypropoxy)benzenesulfonamide; Compound 541: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxyquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; Compound 548: 3-((S)-2-hydroxy-3-((R)-8-(4-hydroxyquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 550: 3-((S)-3-((R)-8-(1-ethyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide; Compound 568: 3-((S)-2-hydroxy-3-((R)-8-(4-methoxypyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide; and Compound 573: 3-((S)-3-((R)-8-(4-benzylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-2-hydroxypropoxy)-N-methylbenzenesulfonamide.

[0305] Additionally, the chemical genera and individual compounds of the present invention, such as those found in Table A (including diastereomers and enantiomers thereof), encompass all pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof.

[0306] The compound with formula (Ia) of the present invention can be prepared according to the relevant open literature program used by those skilled in the art. The exemplary reagents and procedures for these reactions are shown in the working examples below. Protection and deprotection can be carried out by methods generally known in the art (see, for example, Greene, TW and Wuts, PGM, " Protecting Groups in Organic Synthesis," 3rd edition, 1999 [Wiley (Wiley)]).

[0307] It should be understood that the present invention encompasses each isomer, each diastereomer, each enantiomer, and mixtures thereof of each compound and formula disclosed herein, as if each were individually disclosed with a specific stereochemical name for each chiral carbon. Monomeric isomers and enantiomers can be prepared by selective synthesis, such as by enantioselective synthesis; or they can be obtained using separation techniques well known to practitioners in the art, such as by HPLC (including normal phase, reverse phase, and chiral), recrystallization (i.e., mixtures of diastereomers), and the like.

[0308] Disorders and treatments

[0309] The compounds disclosed herein can be used to treat or prevent several diseases, disorders, conditions, and / or indications (collectively referred to herein as "disorders"). One skilled in the art will recognize that when a disorder or a method of treatment or prevention is disclosed herein, such disclosure encompasses a secondary medical use (e.g., a compound for treating a disorder, the use of a compound for treating a disorder, and the use of a compound for use in the manufacture of a medicament for treating a disorder).

[0310] In some embodiments, the compounds disclosed herein can be used to treat or prevent disorders. In some embodiments, the compounds disclosed herein can be used to treat or prevent subtypes of disorders. In some embodiments, the compounds disclosed herein can be used to treat or prevent symptoms of disorders.

[0311] Provided herein are methods for treating or preventing beta-3 adrenergic receptor mediated disorders. In some embodiments, the compounds disclosed herein are useful for preventing beta-3 adrenergic receptor mediated disorders.

[0312] In some embodiments, the compounds disclosed herein are useful for treating or preventing beta-3 adrenergic receptor mediated disorders.

[0313] One aspect of the present invention pertains to methods for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual, comprising administering to the individual in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0314] One aspect of the present invention pertains to methods for treating or preventing heart failure in an individual, comprising administering to the individual in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention.

[0315] One aspect of the present invention pertains to methods for treating a hypotensive or borderline hypotensive subject, comprising administering to said subject in need thereof: a therapeutically effective amount of a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention. One aspect of the present invention pertains to use of a compound of the present invention in the manufacture of a medicament for treating or preventing a beta-3 adrenergic receptor-mediated disorder in a subject.

[0316] One aspect of the present invention pertains to the use of compounds of the present invention in the manufacture of a medicament for treating or preventing heart failure in an individual.

[0317] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for treating a hypotensive or critically hypotensive patient.

[0318] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for treating a normotensive patient.

[0319] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for treating a patient with hypertension.

[0320] One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for treating a patient post-myocardial infarction.

[0321] One aspect of the present invention pertains to a compound of the present invention; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method of treatment of the human or animal body by therapy.

[0322] One aspect of the present invention pertains to compounds of the present invention; pharmaceutical products of the present invention; or pharmaceutical compositions of the present invention for use in a method for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual.

[0323] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is selected from the list consisting of: heart failure; reduced heart function in heart failure; mortality, reinfarction, and / or hospitalization associated with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and / or liver damage); heart failure due to left ventricular dysfunction; heart failure with preserved ejection fraction; post-myocardial infarction Cardiovascular mortality; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; post-myocardial infarction condition; 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; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF <40% by radionuclide ventriculography; and LVEF ≤35% by echocardiography or ventricular contraction angiography.

[0324] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is heart failure.

[0325] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is reduced cardiac function in heart failure.

[0326] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is mortality, reinfarction, and / or hospitalization associated with heart failure.

[0327] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is acute heart failure.

[0328] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is acute decompensated heart failure.

[0329] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is congestive heart failure.

[0330] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is severe congestive heart failure.

[0331] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is organ damage associated with heart failure (eg, kidney damage or failure, heart valve problems, heart rhythm problems, and / or liver damage).

[0332] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is heart failure due to left ventricular dysfunction.

[0333] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is heart failure with preserved ejection fraction.

[0334] In some embodiments, the beta-3 adrenergic receptor mediated disorder is cardiovascular mortality after myocardial infarction. In some embodiments, the beta-3 adrenergic receptor mediated disorder is reducing cardiovascular mortality after myocardial infarction or a reduction thereof.

[0335] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction.

[0336] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is post-myocardial infarction.

[0337] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is left ventricular failure.

[0338] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is left ventricular dysfunction.

[0339] Doctors can classify a patient's heart failure according to the severity of their 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 the degree of limitation during physical activity.

[0340]

[0341]

[0342] 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.

[0343] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is class III heart failure using the New York Heart Association (NYHA) classification system.

[0344] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is class IV heart failure using the New York Heart Association (NYHA) classification system.

[0345] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is an LVEF of <40% as determined by radionuclide angiography.

[0346] In some embodiments, the beta-3 adrenergic receptor-mediated disorder is LVEF ≤ 35% as determined by echocardiography or ventricular contraction angiography.

[0347] Polymorphs and pseudopolymorphs

[0348] Polymorphism is the ability of a substance to exist as two or more crystalline phases with different arrangements and / or conformations of molecules in the crystal lattice. Polymorphs exhibit identical properties in the liquid or gaseous state, but they can behave differently in the solid state.

[0349] In addition to single-component polymorphs, drugs can also exist as salts and other multi-component crystalline phases. For example, solvates and hydrates can each contain a host API and a solvent or water molecule as a guest. Similarly, when the guest compound is solid at room temperature, the resulting form is often referred to as a cocrystal. Salts, solvates, hydrates, and cocrystals can also exhibit polymorphism. Crystalline phases that share the same API host but differ in their guest can be referred to as pseudopolymorphs of each other.

[0350] Solvates contain solvent molecules that crystallize in a defined lattice. Solvates in which the solvent of crystallization is water are called hydrates. Because water is a component of the atmosphere, hydrates of drugs can form quite easily.

[0351] For example, Stahly published a polymorph screening of 245 compounds consisting of "multiple structural types," which showed that about 90% of the compounds exhibited multiple solid forms. Overall, about half of the compounds were polymorphic, typically with one to three forms. About one-third of the compounds formed hydrates, and about one-third formed solvates. Data from a cocrystal screening of 64 compounds showed that 60% formed cocrystals other than hydrates or solvates. (GPStahly, Crystal Growth & Design, (2007), 7(6), 1007-1026).

[0352] isotope

[0353] The present disclosure encompasses all isotopes of atoms present in the compounds provided herein. Isotopes include those atoms having the same atomic number but different mass numbers. It is understood that certain features of the present invention encompass every combination of one or more atoms in the compounds provided herein that are substituted with atoms having the same atomic number but a different mass number. One such example is the replacement of the most naturally abundant isotope of an atom found in one of the compounds provided herein, such as 1 H or 12 C, which has different atoms that are not the most naturally abundant isotopes, e.g. 2 H or 3 H (replace 1 H), or 11 、 13 C or 14 C (replace 12 C). Compounds in which such substitutions have occurred are generally referred to as isotopically labeled. Isotopic labeling of the compounds of the present invention may be accomplished using any of a variety of synthetic methods known to those skilled in the art, who will readily appreciate the synthetic methods and available reagents for such labeling. By way of general example and not limitation, isotopes of hydrogen include 2 H (deuterium) and 3 H (deuterium). Carbon isotopes include 11 C. 13 C and 14 C. Nitrogen isotopes include 13 N and 15 N. Isotopes of oxygen include 15 O. 17 O and 18 O. Fluorine isotopes include 18 F. Sulfur isotopes include 35 S. Isotopes of chlorine include 36 Cl. Isotopes of bromine include 75 Br, 76 Br, 77 Br and 82 Br. Iodine isotopes include 123 I. 124 I. 125 I and 131Also provided are compositions, such as those prepared during synthesis, preformulation, and the like, and pharmaceutical compositions, such as those intended for use in a mammal to treat one or more of the disorders described herein, comprising one or more of the compounds of the invention, wherein naturally occurring perturbations in the composition are perturbed. Also provided are compositions and pharmaceutical compositions comprising the compounds of the invention as described herein, wherein the salt is enriched at one or more positions with an isotope other than the most naturally abundant isotope. Methods are readily available for measuring such isotopic perturbations or enrichments, such as mass spectrometry, and for radioisotopes, additional methods can be used, such as radiation detectors used in conjunction with HPLC or GC.

[0354] A challenge in drug development is to improve absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties while maintaining the desired pharmacological profile. Structural changes that improve ADMET properties often alter the pharmacology of the lead compound. While the effect of deuterium substitution on ADMET properties is unpredictable, in selected cases, deuterium can improve the ADMET properties of a compound while minimally interfering with its pharmacology. Two examples of therapeutic entities where deuterium can improve performance are CTP-347 and CTP-354. CTP-347 is a deuterated form of paroxetine that has a reduced potential for the mechanism-based CYP2D6 inactivation observed clinically with paroxetine. CTP-354 is a deuterated form of a promising preclinical gamma-aminobutyric acid A receptor (GABAA) modulator (L-838417), which was not developed due to poor pharmacokinetic (PK) properties. In both cases, deuterium substitution results in improved ADMET spectra, which provide the potential for improved safety, efficacy and / or tolerability without significantly changing the biochemical potency and selectivity relative to the full hydrogen compound. The deuterium substituted compounds of the present invention have improved ADMET characteristics and have substantially similar biochemical potency and selectivity relative to the corresponding full hydrogen compound.

[0355] Other utilities

[0356] Another object of the present invention relates to radiolabeled compounds of the present invention, which will be useful not only in radioimaging but also in in vitro and in vivo assays for localizing and quantifying beta-3 adrenergic receptors in tissue samples, including humans, and for identifying beta-3 adrene...

Claims

1. A compound selected from the group consisting of compounds of formula (Ia) and pharmaceutically acceptable salts thereof: in: X is -SO2- or does not exist; R 1 is selected from the group consisting of: aryl, C1-C6-alkylene-aryl, C1-C6-alkylene-heteroaryl, C3-C7 cycloalkyl, heteroaryl and heterocyclyl; each optionally substituted by one or more substituents selected from the group consisting of: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C7 alkyl, C1-C6 alkylamino, C1-C6 alkylcarboxamide, C1-C6 alkylsulfonamido, C1-C6 alkylsulfonyl, amino, aryloxy, arylsulfonyl, carboxamide, iminocarbamoyl, carboxyl, cyano, C3-C7 cycloalkyl, C2-C8 dialkylamino, C2-C8 dialkylsulfamoyl, C1-C6 haloalkoxy, C1-C6 halo wherein the C1-C6 alkoxy, C1-C7 alkyl, C1-C6 alkylamino, aryloxy, C3-C7 cycloalkyl and C2-C8 dialkylamino are each optionally substituted by one or more substituents selected from the group consisting of amino, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylcarboxamide, carboxyl, -Y-C1-C6-alkylene-Z optionally substituted by oxo, C3-C7 cycloalkyl, cyano, C2-C6 dialkylamino, C1-C6 haloalkyl, C1-C6 haloalkylamino, heterocyclyl, hydroxy, oxo and phenyl; Y is selected from: -O- and -NH-; Z is selected from the group consisting of: C1-C6 alkoxy, amino, C1-C6 alkylamino, cyano, C2-C6 dialkylamino, hydroxyl and phenyl; R 2a is H or selected from: C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl and heterocyclyl; each optionally substituted by one or more substituents selected from: C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkylenehydroxy, amino, C3-C7 cycloalkyl, cyano, C2-C8 dialkylamino, heterocyclyl optionally substituted by one oxo, halogen, hydroxy and oxo; and R 2b is H or C1-C6 alkyl, in: The term "aryl" refers to phenyl, biphenyl, indanyl, tetrahydronaphthyl or naphthyl; The term "aryloxy" refers to a group consisting of an aryl group directly bonded to an oxygen atom; The term "heteroaryl" refers to a ring system containing 5 to 18 ring atoms, wherein at least one ring atom is a heteroatom selected from O, S, N and NH, and at least one ring is aromatic; The term "heterocyclyl" refers to a non-aromatic ring radical containing 3 to 8 ring atoms, wherein one, two or three of the ring atoms are heteroatoms selected from O, S and N, wherein N is optionally substituted by H, C1-C4 acyl or C1-C4 alkyl.

2. The compound according to claim 1, wherein X is -SO2-.

3. The compound according to claim 1, wherein X is absent.

4. A compound according to any one of claims 1 to 3, wherein R 1 selected from: C1-C6-alkylene-aryl, C1-C6-alkylene-heteroaryl, C3-C7 cycloalkyl, heterocyclyl, aryl and heteroaryl; each optionally substituted by one or more substituents selected from the following: (2-ethyl)(methyl)amino, 4-(trifluoromethyl)phenoxy, acetamido, amino, bromo, iminocarbamoyl, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy yl, ethyl, ethylamino, fluoro, heptyl, hydroxycarbamoyl, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methoxycarbonyl, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, benzenesulfonyl, piperazinyl, piperidinyl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-pentyl and wherein (2-ethyl)(methyl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally substituted with one or more substituents selected from the group consisting of 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, amino, oxo, amino, benzyloxy, carboxyl, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, hydroxy, oxo, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidinyl, thiazolidinyl and trifluoromethyl.

5. A compound according to any one of claims 1 to 3, wherein R 1 Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-3-yl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepine 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridinyl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H-pyrazol-5-yl)thiophen-3-yl, (1H-pyrazol-5-yl)thiophen-2-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl 2-(pyridin-4-yl)ethyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolyl[2,3-b]pyridinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofurano[2,3-b]pyridinyl, 2-phenylthiazolyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazolyl-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(phenyl)pyrimidinyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidinyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-dihydrobenzofuranyl, 5-phenylpyrimidinyl, 5-phenylthiophen-3-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 6-phenylpyrimidinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, benzyl, biphenyl, chromanyl, cyclohexyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolinyl, isoxazolyl, naphthyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolyl, thiophen-3-yl and thiophen-2-yl; each optionally substituted by one or more selected from the following substituents: Substituted: (1-amino-3-hydroxy-1-oxopropane-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetylaminoethyl)(methyl)amino, (2-amino-2-oxoacetylamino)methyl, (2-aminoacetylamino)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetylamino, acetyl, amino, aminomethyl, benzyl, bromine, iminocarbamoyl, carboxamide , carboxyl, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, heptyl, hydroxyimidocarbamoyl, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxycarbonyl, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, benzenesulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl. , 6. A compound according to any one of claims 1 to 3, wherein R 1 Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepine 1H-Benzo[d]imidazol-5-yl, 1H-Benzo[d]imidazol-6-yl, 1H-imidazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, (1H-pyrazol-5-yl)thiophene-2-yl, 1H-pyrazolo[3,4-b]pyridin ... 1H-pyrazol-5-yl, 1H-pyrazol-6-yl, 1H-pyrazol-5-yl, 1H-pyrazol-6-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-pyrazol-3-yl pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2-(pyridin-4-yl)ethyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-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-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuran[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazolyl-5-yl)phenyl phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-(2H-tetrazolyl)phenyl, 4-(phenyl)pyrimidin-2-yl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidin-2-yl, 5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydronaphthyl-1-yl, 5,6,7,8-tetrahydronaphthyl-2-yl, 5,6,7,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenyl-2,3-dihydrobenzofuran-7-yl, 5-phenylpyrimidin-2-yl, 5-phenylthiophene-2-yl, 6,7- dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-phenylpyrimidin-2-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, benzyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, chroman-6-yl, cyclohexyl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b] thiazol-5-yl, indolin-5-yl, isoxazol-4-yl, naphth-1-yl, naphth-2-yl, phenyl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinolin-8-yl, thien-2-yl and thien-3-yl; each optionally substituted with one or more substituents selected from the group consisting of (2-ethyl)(methyl)amino, 4-(trifluoromethyl)phenoxy, acetamido, amino, bromo, imidocarbamoyl, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, heptyl, hydroxyimidocarbamoyl, hydroxy, isobutyl , isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methoxycarbonyl, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, benzenesulfonyl, piperazinyl, piperidinyl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally substituted with one or more substituents selected from the group consisting of 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, amino, oxo, amino, benzyloxy, carboxyl, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, hydroxy, oxo, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidinyl, thiazolidinyl and trifluoromethyl. , 7. A compound according to any one of claims 1 to 3, wherein R 1 selected from: 5,6,7,8-tetrahydronaphthyl, biphenyl, naphthyl and phenyl; each optionally substituted by one or more substituents selected from: (2-ethyl)(methyl)amino, 4-(trifluoromethyl)phenoxy, acetamido, bromo, imidocarbamoyl, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, hydroxyimidocarbamoyl, isopropoxy, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, methylsulfonylamino, methylsulfonyl, N,N-dimethylsulfamoyl, phenoxy, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino )amino, cyclopropyl, ethoxy, ethyl, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, and phenoxy are each optionally substituted with one or more substituents selected from the group consisting of 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, carboxy, cyano, cyanomethylamino, dimethylamino, ethylamino, hydroxy, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, oxo, pyrrolidin-1-yl, thiazolidin-3-yl, and trifluoromethyl.

8. A compound according to any one of claims 1 to 3, wherein R 1 selected from the group consisting of: 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl and phenyl; each optionally substituted by one or more substituents selected from the group consisting of: (1-amino-3-hydroxy-1-oxopropane-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetamidoethyl)(methyl)amino, (2-amino-2-oxoacetamido)methyl, (2-aminoacetamido)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl 4-(trifluoromethyl)phenoxy, acetamido, acetyl, aminomethyl, bromo, carbamoyl, carboxamide, carboxy, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, dimethylamino, dimethylcarbamoyl, ethoxy, fluoro, hydroxycarbamoyl, hydroxymethyl, isopropyloxy, methoxy, methoxymethyl, methyl, methylsulfonamido, methylsulfonyl, N,N-dimethylsulfamoyl, phenoxy, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy and trifluoromethyl.

9. A compound according to any one of claims 1 to 3, wherein R 1 Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (5-isoxazol-3-yl)thiophen-3-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepine yl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl, 1H-indolyl, (1H -pyrazol-5-yl)thiophen-2-yl, (1H-pyrazol-5-yl)thiophen-3-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl-1H-pyrazolyl, 2,3-di 2,3-dihydro-1H-pyrido[2,3-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolyl[2,3-b]pyridinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofurano[2,3-b]pyridinyl, 2-phenylthiazolyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-( phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 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, 4'-(1,2,4-oxadiazol-3-yl)biphenyl, 4- phenyl, 4-(phenyl)pyrimidinyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-phenylpyrimidinyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-dihydrobenzofuranyl, 5-phenylpyrimidinyl, 5-phenylthiophen-2-yl, 5-phenylthiophen-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 6-phenylpyrimidinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, chromanyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolinyl, isoxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolyl, thiophen-2-yl and thiophen-3-yl; each optionally substituted with one or more substituents selected from the group consisting of amino, bromo, carboxyl, chloro, cyano, dimethylamino, ethyl oxy, ethyl, ethylamino, fluoro, heptyl, hydroxy, isobutyl, isopropyl, methoxy, methoxycarbonyl, methyl, methylamino, morpholino, oxo, phenoxy, benzenesulfonyl, piperazin-1-yl, piperidin-1-yl, propoxy, propyl, and trifluoromethyl; and wherein ethyl, ethylamino, methyl, and propoxy are each optionally substituted with one or more substituents selected from amino, benzyloxy, carboxyl, cyclopropyl, dimethylamino, hydroxy, methoxy, morpholino, and phenyl. , 10. A compound according to any one of claims 1 to 3, wherein R 1 Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepine 1H-Benzo[d]imidazol-5-yl, 1H-Benzo[d]imidazol-6-yl, 1H-imidazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 5-(1H-pyrazol-5-yl)thiophene-2-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl , 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-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-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuran[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazolyl-5-yl)phenyl, 3 phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-(2H-tetrazolyl-5-yl)phenyl, 4-(phenyl)pyrimidin-2-yl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(phenyl)pyrimidin-2-yl, 5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenyl-2,3-dihydrobenzofuran-7-yl, 5-phenylpyrimidin- 2-yl, 5-phenylthiophene-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-phenylpyrimidin-2-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b]thiazol-5-yl, indolin-5-yl, isoxazol-4-yl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinolin-8-yl, thiophen-2-yl and thiophen-3-yl; each optionally substituted with one or more substituents selected from: 2-(benzyloxy) ethyl, 2-aminoethylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino, 2-morpholinoethylamino, 3-(dimethylamino)propoxy, amino, aminomethyl, benzyl, bromo, carboxyl, carboxymethyl, chloro, cyano, cyclopropylmethyl, dimethylamino, ethoxy, ethyl, fluoro, heptyl, hydroxy, isobutyl, isopropyl, methoxy, methoxycarbonyl, methyl, methylamino, morpholino, oxo, phenoxy, benzenesulfonyl, piperazin-1-yl, piperidin-1-yl, and propyl, trifluoromethyl. , 11. A compound according to any one of claims 1 to 3, wherein R 1 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of C1-C7 alkyl, cyano, C1-C6 haloalkyl, halogen, hydroxy and oxo.

12. A compound according to any one of claims 1 to 3, wherein R 1 selected from: 1H-pyrrolo[3,2-b]pyridinyl, quinolinyl, 1,4-dihydroquinolinyl, 1H-pyrrolo[2,3-b]pyridinyl and 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl; each optionally substituted with one or more substituents selected from: ethyl, methyl, cyano, trifluoromethyl, fluoro, hydroxy and oxo.

13. A compound according to any one of claims 1 to 3, wherein R 1 Selected from: (dimethylcarbamoyl)phenyl, 1-(2-(benzyloxy)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-(2-hydroxyethyl)-2,3-dihydro-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-(carboxymethyl)-4-oxo-1,4-dihydroquinolin-3-yl, 1,2-dimethyl-1H-imidazol-4-yl, 1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1, 4]oxazin-7-yl, 1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,5-naphthyridin-3-yl, 1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,8-dimethyl-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-dihydropyridin-3-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl 1-ethyl-5-methyl-1H-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]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-imidazo[4,5-b]pyrazol-4-yl pyridin-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-pyrazol-4-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-methyl-1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepine -8-yl, 1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1-methyl-1H-imidazo[4,5-b]pyridin-6-yl, 1-methyl-1H-imidazo[4,5-b]pyridin-4-yl, 1-methyl-1H-indol-5-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-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-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl, 1-Methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-methyl-6-(methylamino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-phenyl-1H-pyrazol-4-yl, 1-propyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2-(dimethylamino)pyridin-3-yl, 2-(methylsulfonyl)phenyl, 2-(pyridin-4-yl)ethyl, 2-(trifluoromethoxy)phenyl, 2-(trifluoromethyl)phenyl, 2,2-dimethylchroman-6-yl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl, 2,3-dimethylphenyl, 2,3-dioxoindolin-5-yl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl, 2,6-difluorophenyl, 2-bromophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-(methylsulfonyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl phenyl, 2-chloro-5-fluorophenyl, 2-chlorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-5-methylphenyl, 2-cyanophenyl, 2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl, 2-fluoro-3-methylphenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-5-methylphenyl, 2-fluorophenyl, 2-hydroxypyrimidin-5-yl, 2-methoxy-4-methylphenyl, 2-methoxy-5-methylphenyl, 2-methoxyphenyl, 2-methyl-1H-benzo[d]imidazol-5-yl, 2-methyl-1H-imidazo[4,5-b]pyridin-6-yl, 2-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 2-morpholinopyridin-3-yl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl, 2-oxoindol-5-yl, 3'-((dimethylamino)methyl)biphenyl-3-yl, 3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl, 3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)phenyl, 3-(1,3-dimethyl phenyl, 3-(1-methyl-1H-pyrrol-3-yl)phenyl, 3-(1-isobutyl-1H-pyrazole-4-yl)phenyl, 3-(1-methyl-1H-pyrazole-4-yl)phenyl, 3-(1-methyl-1H-pyrrol-3-yl)phenyl, 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)phenyl, 3-(1-methyl-1H-pyrrol-3-yl)phenyl, 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)phenyl, 3-(1 3-(2-(trifluoromethyl)phenoxy)phenyl, 3-(2,4-dimethylthiazol-5-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(2-methoxypyrimidin-5-yl)phenyl, 3-(2-methylpyridin-4-yl)phenyl, 3-(3,5-dimethylisoxazol-4-yl)phenyl, 3-(3-methylthiophen-2-yl)phenyl, 3-(4-(trifluoromethyl)phenoxy)phenyl, 3-(4-methylthiophen-3-yl)phenyl, 3-(5-(aminomethyl)thiophen-2-yl)phenyl, 3-(5-cyanopyridin-3-yl)phenyl, 3-(5-methylpyridin-3-yl)phenyl, 3-(6-( phenyl, 3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenyl, 3-(6-(aminomethyl)pyridin-3-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-methylpyridine)-3-yl)phenyl, 3'-(aminomethyl)biphenyl-3-yl, 3-(aminomethyl)phenyl, 3'-(carboxy)biphenyl-3-yl, 3'-(dimethylamino)biphenyl-3-yl, 3-(furan-2-yl)phenyl, 3'-(hydroxymethyl)biphenyl-3-yl, 3-(hydroxymethyl)phenyl, 3'-(methoxymethyl)biphenyl-3-yl, 3'-(methylsulfonyl)biphenyl-3-yl, 3'-(N,3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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 , 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,5-dichlorophenyl, 3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethylphenyl, 3-bromo-4-methylphenyl, 3-bromo-5-methylphenyl, 3-bromophenyl, 3-carboxyphenyl, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl, 3-chloro-2-fluorophenyl, 3-chloro-2-methyl-1 H-pyrrolo[2,3-b]pyridin-5-yl, 3-chloro-2-methylphenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-methoxyphenyl, 3-chlorophenyl, 3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-cyano-4-methylphenyl, 3'-cyanobiphenyl-3-yl, 3-cyanophenyl, 3-ethyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-fluoro-4-methoxyphenyl, 3-fluoro-5-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-b]pyridin-5-yl, 3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3-phenoxyphenyl, 4'-((1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino)biphenyl-3-yl, 4'-((2-(dimethylamino)ethylamino)methyl)biphenyl-3-yl, 4'-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4'-((2,2-difluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-acetylaminoethyl)(methyl)amino)biphenyl-3-yl, 4'-((2-amino-2-oxoacetamido)methyl)biphenyl-3-yl, 4'-((2-aminoacetamido)methyl)biphenyl-3-yl, 4'-((2-fluoroethylamino)methyl)biphenyl-3-yl, 4'-((2-hydroxyethylamino)methyl)biphenyl-3-yl, 4'-((2-methoxyethylamino)methyl)biphenyl-3-yl, 4'-((cyanomethylamino)methyl)biphenyl-3-yl, 4'-((dimethylamino)methyl)biphenyl-4-yl, 4'-((ethylamino)methyl 4'-( ...4'-(aminomethyl)-2-methoxybiphenyl-3-yl, 4'-(aminomethyl)-2-methylbiphenyl-3-yl, 4'-(aminomethyl)-3-(trifluoromethoxy)biphenyl-4-yl, 4'-(aminomethyl)-4-(trifluoromethoxy)biphenyl-3-yl, 4'-(aminomethyl)-4-chlorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methylbiphenyl-3-yl, 4'-(aminomethyl)-5-(trifluoromethyl)biphenyl-3-yl, 4'-(aminomethyl)-5-methoxybiphenyl-3-yl, 4'-(aminomethyl)-4-chlorobiphenyl-3-yl, 4'-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methoxybiphenyl-3-yl, 4'-(aminomethyl)-4-methylbiphenyl-3-yl, 4'-(aminomethyl)-5-(trifluoromethyl)biphenyl-3-yl, 4'-(aminomethyl)-5-methoxybiphenyl-3-yl, 4'-(aminomethyl)- 4'-(aminomethyl)-5-methylbiphenyl-3-yl, 4'-(aminomethyl)-6-methoxybiphenyl-3-yl, 4'-(aminomethyl)-6-methylbiphenyl-3-yl, 4'-(aminomethyl)biphenyl-2-yl, 4'-(aminomethyl)biphenyl-3-yl, 4'-(aminomethyl)biphenyl-4-yl, 4-(aminomethyl)phenyl, 4'-(carboxymethyl)biphenyl-3-yl, 4'-(cyanomethoxy)biphenyl-3-yl, 4'-(cyanomethyl)biphenyl-3-yl, 4-(hydroxymethyl)phenyl, 4'-(methylsulfonamido)biphenyl-3-yl, 4-(methylsulfonyl)phenyl, 4'-(N'-hydroxycarbamoyl)-biphenyl-3-yl, 4-(phenylsulfonyl)thiophen-2-yl, 4-(pyrrolidone)- 4-(trifluoromethyl)phenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 4,5-dichlorothiophen-2-yl, 4,6-dimethoxypyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, 4-acetamidophenyl, 4-acetylphenyl, 4-aminopyrimidin-2-yl, 4-benzylpyrimidin-2-yl, 4-bromo-3-chlorophenyl, 4-bromo-3-methylphenyl, 4-bromophenyl, 4'-carbamoyl-biphenyl- 3-yl, 4'-carbamoyl-biphenyl-3-yl, 4-carboxyphenyl, 4-chloro-3-methoxyphenyl, 4-chloro-3-methylphenyl, 4-chlorophenyl, 4-chloropyridin-2-yl, 4-cyanophenyl, 4-ethoxy-4'-((isopropylamino)methyl)biphenyl-3-yl, 4-ethoxyphenyl, 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-fluoro-3-methylphenyl, 4'-fluorobiphenyl-4-yl, 4-fluorophenyl, 4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-6-methylquinolin-8-yl, 4-hydroxy-7-methylquinolin-3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4-isobutyl-3,4-Dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-isopropoxyphenyl, 4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methoxy-1H-indazol-5-yl, 4-methoxy-2,3-dimethylphenyl, 4-methoxy-2-methylphenyl, 4-methoxy-3-methylphenyl, 4-methoxy-5,6,7,8-tetrahydronaphthalen-1-yl, 4-methoxynaphthalen-1-yl, 4-methoxyphenyl, 4-methoxypyrimidin-2-yl, 4-methyl-2-phenylthiazol-5-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methyl-3,4-dihydro-2H-pyrido[3, 2-b][1,4]oxazin-7-yl, 4-methyl-6-phenylpyrimidin-2-yl, 4-methylpyrimidin-2-yl, 4-oxo-1-propyl-1,4-dihydroquinolin-3-yl, 4-phenylpyrimidin-2-yl, 4-sec-butylphenyl, 4-tert-butylphenyl, 4-tert-pentylphenyl, 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-yl, 5-(4-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-7-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5-(5-(trifluoromethyl)isoxazol-3-yl)thiophen-2-yl, 5-(methoxycarbonyl)pyrimidin-3-yl pyrimidin-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydronaphthyridin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-benzylpyrimidin-2-yl, 5-bromo-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl, 5-bromo-2,3-dihydrobenzofuran-7-yl, 5-bromo-2-chlorophenyl, 5-bromo-2-methoxyphenyl, 5-bromo-2-methylphenyl, 5-bromopyridin-3-yl, 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 5-chloro-2-cyanophenyl, 5-chloro-2-fluorophenyl, 5-chloro-2-methoxyphenyl, 5- Chloro-2-methylphenyl, 5-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 5-chloronaphthyl, 5-chlorothien-2-yl, 5-cyano-2-methylphenyl, 5-ethylpyrimidin-2-yl, 5-fluoro-2-methoxyphenyl, 5-fluoro-2-methylphenyl, 5-heptylpyrimidin-2-yl, 5-methoxy-2-methylpyridin-3-yl, 5-methoxypyridin-3-yl, 5-methyl-1-phenyl-1H-pyrazol-4-yl, 5-methyl-2-(trifluoromethyl)furan-3-yl, 5-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 5-methylbenzo[c][1,2,5]oxadiazol-4-yl, 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylpyrimidin-2-yl, 5-phenylthiophene-2-yl, 5-propylpyrimidin-2-yl, 6-(2-aminoethylamino)pyridin-3-yl, 6-(2-hydroxyethylamino)pyridin-3-yl, 6-(2-methoxyethylamino)pyridin-3-yl, 6'-(aminomethyl)-3,3'-bipyridin-5-yl, 6-(dimethylamino)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-(dimethylamino)pyridin-3-yl, 6-(piperazin-1-yl)pyridin-3-yl, 6-(piperidin-1-yl)pyridin-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 6-amino-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-chloro-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-chloroimidazo[2,1-b]thiazol-5-yl, 6-chloronaphth-2-yl, 6-ethoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-ethoxypyridin-3-yl, 6-fluoro-4-hydroxyquinolin-3-yl, 6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 6- Hydroxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-hydroxypyridin-3-yl, 6-methoxy-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-methoxynaphthalen-2-yl, 6-methoxypyridin-3-yl, 6-morpholinopyridin-3-yl, 6-phenoxypyridin-3-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, 7-amino-1,8-naphthyridin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7-fluoro-4-hydroxyquinolin-3-yl, 7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl quinolin-3-yl, 7-methoxybenzo[c][1,2,5]oxadiazol-4-yl, 7-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 8-fluoro-4-hydroxyquinolin-3-yl, 8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 8-methyl-4-oxo-1,4-dihydroquinolin-3-yl, benzo[c][1,2,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, benzyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, chroman-6-yl, cyclohexyl, furan-3-yl, imidazo[1,2-a] pyridin-6-yl, m-tolyl, naphthalen-1-yl, naphthalen-2-yl, phenyl, p-tolyl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl N-oxide, pyrimidin-2-yl, pyrimidin-4-yl, quinolin-3-yl, quinolin-6-yl and thiophen-3-yl. , 14. A compound according to any one of claims 1 to 13, wherein R 2a is H or C1-C6 alkyl, which is optionally substituted by one or more substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkylenehydroxy, amino, C3-C7 cycloalkyl, cyano, C2-C8 dialkylamino, heterocyclyl optionally substituted by one oxo, halogen, hydroxy and oxo.

15. A compound according to any one of claims 1 to 13, wherein R 2a is H or is selected from: 2-methylpropyl, butyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dimethylbutyl, ethyl, ethylbutyl, isopentyl, isopropyl, methoxy, methyl, pentyl, piperidinyl, propanyl, propyl, sec-butyl, tert-butyl and tetrahydro-2H-pyranyl; each optionally substituted by one or more substituents selected from: amino, cyano, cyclopropyl, dimethylamino, ethoxy, ethyl, fluoro, hydroxy, hydroxymethyl, methoxy, methylamino, oxo, oxopyrrolidinyl and piperidinyl.

16. A compound according to any one of claims 1 to 13, wherein R 2a Selected from: H, methyl, propyl, pentyl, (2,2,2-trifluoroethyl), isopropyl, cyclopropylmethyl, 2,2-difluoroethyl, sec-butyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-hydroxypropyl, 2-ethoxyethyl, 1-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, tetrahydro-2H-pyran-4-yl, 3-hydroxypropyl, cyclopropyl, 3-methoxypropyl, 3,3-difluorocyclobutyl, 2-aminoethyl, 3-hydroxy-1-(methylamino)-1-oxo butan-2-yl, 1-cyclopropylethyl, tert-butyl, 1,3-dihydroxypropan-2-yl, 2-ethylbutyl, isopentyl, 1-(hydroxymethyl)cyclopropyl, 3,3-dimethylbutan-2-yl, ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 1-ethylpiperidin-4-yl, 2,3-dihydroxypropyl, 2-(dimethylamino)ethyl, piperidin-3-ylmethyl, 3-(dimethylamino)propyl, acetyl, 2-fluoroethyl, 2-hydroxycyclopentyl, 2-hydroxycyclohexyl and cyanomethyl.

17. A compound according to any one of claims 1 to 13, wherein R 2a It is H, ethyl or methyl.

18. A compound according to any one of claims 1 to 17, wherein R 2b Selected from: H, ethyl, isopropyl and methyl.

19. A compound according to any one of claims 1 to 17, wherein R 2b For H.

20. The compound according to claim 1, which is selected from the compound having formula (Ic) and pharmaceutically acceptable salts thereof: in: R 1 selected from: aryl, heteroaryl and heterocyclyl; each optionally substituted by one or more substituents selected from the group consisting of: (2-ethyl)(methyl)amino, acetamido, amino, bromo, imidocarbamoyl, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, hydroxyimidocarbamoyl, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, benzenesulfonyl, piperazin-1-yl, piperidin-1-yl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino, acetamido, amino, bromo, imidocarbamoyl, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, hydroxyimidocarbamoyl, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, benzenesulfonyl, piperazin-1-yl, piperidin-1-yl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; yl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally substituted with one or more substituents selected from the group consisting of 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, benzyloxy, carboxy, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidin-1-yl, thiazolidin-3-yl and trifluoromethyl; and R 2a It is H, ethyl or methyl.

21. The compound according to claim 1, which is selected from the compound having formula (Ic) and pharmaceutically acceptable salts thereof: in: R 1 Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (5-isoxazol-3-yl)thiophen-3-yl, (pyridin-2-yl)phenyl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepine yl, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-7'-yl, 1,4-dihydropyridinyl, 1,4-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, 1H-benzo[d]imidazolyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazolyl, 1H-indazolyl , 1H-indolyl, (1H-pyrazol-5-yl)thiophen-2-yl, (1H-pyrazol-5-yl)thiophen-3-yl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-phenyl- 1H-pyrazolyl, 2,3-dihydro-[1,4]dioxinol[2,3-b]pyridinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 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-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 2-phenylthiazolyl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-( 1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 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, 4'-(1, 2,4-oxadiazol-3-yl)biphenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1H-pyrazol-4-yl)pyridinyl, 5-(phenyl)pyridinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5-phenyl-2,3-dihydrobenzofuranyl, 5-phenylthiophen-2-yl, 5-phenylthiophen-3-yl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, benzofuranyl, biphenyl, chromanyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indolinyl, isoxazolyl, naphthyl, phenyl, pyridinyl, pyrimidinyl, quinolyl, thiophen-2-yl and thiophen-3-yl; R, 1 selected from: aryl, heteroaryl and heterocyclyl; each optionally substituted by one or more substituents selected from the following: (2-ethyl)(methyl)amino, acetamido, amino, bromo, imidocarbamoyl, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, hydroxyimidocarbamoyl, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, benzenesulfonyl, piperazin-1-yl, piperidin-1-yl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; and wherein (2-ethyl)(methyl)amino, acetamido, amino, bromo, imidocarbamoyl, carboxamide, carboxyl, chloro, cyano, cyclopropyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, ethylamino, fluoro, hydroxyimidocarbamoyl, hydroxy, isobutyl, isopropoxy, isopropyl, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, methylamino, methylsulfonylamino, methylsulfonyl, morpholino, N,N-dimethylsulfamoyl, oxo, phenoxy, benzenesulfonyl, piperazin-1-yl, piperidin-1-yl, propoxy, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, trifluoromethoxy and trifluoromethyl; yl)amino, cyclopropyl, ethoxy, ethyl, ethylamino, isopropyl(methyl)amino, methoxy, methyl, methyl(propyl)amino, phenoxy and propoxy are each optionally substituted with one or more substituents selected from the group consisting of 2-(dimethylamino)ethylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, 2-amino-2-oxoacetamido, 2-aminoacetamido, 2-fluoroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, acetamido, amino, benzyloxy, carboxy, cyano, cyanomethylamino, cyclopropyl, dimethylamino, ethylamino, hydroxy, isobutylamino, isopentylamino, isopropylamino, methoxy, methylamino, morpholino, oxo, phenyl, pyrrolidin-1-yl, thiazolidin-3-yl and trifluoromethyl; and R 2a It is H, ethyl or methyl.

22. The compound according to claim 1, which is selected from the compound having formula (Ic) and pharmaceutically acceptable salts thereof: in: R 1 Selected from: (1,2,3,4-tetrahydropyrimidin-5-yl)phenyl, (5-isoxazol-3-yl)thiophen-2-yl, (pyridin-2-yl)phenyl, [3,3'-bipyridyl]-5-yl, 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepine 1H-Benzo[d]imidazol-5-yl, 1H-Benzo[d]imidazol-6-yl, 1H-imidazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, (1H-pyrazol-5-yl)thiophene-2-yl, 1H-pyrazolo[3,4- b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-phenyl-1H-pyrazol-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-benzo[d]imidazol-5-yl, 2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6 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-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[d]thiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-7-yl, 2,3-dihydrofuran[2,3-b]pyridin-5-yl, 2-phenylthiazol-5-yl, 3-(1H-pyrazol-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1H-pyrrol-3-yl)phenyl, 3-(2H-tetrazol-5-yl)phenyl , 3-(furan-2-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(thiophen-2-yl)phenyl, 3-(thiophen-3-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-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-6-yl, 4'-(1,2,4-(2H-tetrazolyl)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-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydro naphthyl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenyl-2,3-dihydrobenzofuran-7-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzo[c][1,2 ,5]thiadiazol-4-yl, benzo[c][1,2,5]thiadiazol-5-yl, benzo[d]isoxazol-5-yl, benzofuran-2-yl, benzofuran-5-yl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl, chroman-6-yl, furan-3-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[2,1-b]thiazol-5-yl, indolin-5-yl, isoxazol-4-yl, naphthalene-1-yl, yl, naphth-2-yl, phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, quinolin-3-yl, quinolin-6-yl, quinolin-8-yl, thiophen-2-yl and thiophen-3-yl; each optionally substituted by one or more substituents selected from the group consisting of (1-amino-3-hydroxy-1-oxopropan-2-yl)(methyl)amino, (2-(dimethylamino)ethylamino)methyl, (2,2,2-trifluoroethylamino)methyl, (2,2-difluoroethylamino)methyl, (2-acetylaminoethyl)(methyl)amino, (2-amino-2-oxoacetylamino)methyl, (2-aminoacetylamino)methyl, (2-fluoroethylamino)methyl, (2-hydroxyethylamino)methyl, (2-methoxyethylamino)methyl, (cyanomethylamino)methyl, (dimethylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopentylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, 1-aminocyclopropyl, 2-(benzyloxy)ethyl, 2-(pyrrolidin-1-yl)ethoxy, 2-(trifluoromethyl)phenoxy, 2-aminoethylamino, 2-carboxy-N-methylacetamido, 2-hydroxyethyl, 2-hydroxyethylamino, 2-methoxyethyl, 2-methoxyethylamino , 2-morpholinoethylamino, 3-(dimethylamino)propoxy, 4-(trifluoromethyl)phenoxy, acetamido, acetyl, amino, aminomethyl, benzyl, bromo, carbamoyl, carboxamide, carboxy, carboxymethyl, chloro, cyano, cyanomethoxy, cyanomethyl, cyclopropylmethyl, dimethylamino, dimethylcarbamoyl, ethoxy, ethyl, fluoro, hydroxycarbamoyl, hydroxy, hydroxymethyl, isobutyl, isopropoxy, isopropyl, methoxy, methoxymethyl, methyl, methylamino, methylsulfonamido, methylsulfonyl, morpholino, N,N-dimethylsulfonyl, oxo, phenoxy, phenylsulfonyl, piperazin-1-yl, piperidin-1-yl, propyl, sec-butyl, sulfamoyl, tert-butyl, tert-amyl, thiazolidin-3-ylmethyl, trifluoromethoxy, and trifluoromethyl; and, R 2a It is H, ethyl or methyl.

23. The compound according to claim 1, which is selected from the compound having formula (Ic) and pharmaceutically acceptable salts thereof: in: R 1 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of C1-C7 alkyl, cyano, C1-C6 haloalkyl, halogen, hydroxy and oxo; and R 2a It is H or C1-C6 alkyl.

24. The compound according to claim 1, which is selected from the compound having formula (Ic) and pharmaceutically acceptable salts thereof: in: R 1 is selected from the group consisting of: 1H-pyrrolo[3,2-b]pyridinyl, quinolinyl, 1,4-dihydroquinolinyl, 1H-pyrrolo[2,3-b]pyridinyl and 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl; each optionally substituted with one or more substituents selected from the group consisting of: ethyl, methyl, cyano, trifluoromethyl, fluoro, hydroxy and oxo; and R 2a It is H or C1-C6 alkyl.

25. The compound according to claim 1, which is selected from the compound having formula (Ic) and pharmaceutically acceptable salts thereof: in: R 1 Selected from: 1H-pyrrolo[3,2-b]pyridin-6-yl, 4-hydroxyquinolin-3-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl, 1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl and 3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl; and R 2a It is H or methyl.

26. A compound according to any one of claims 1 to 25, wherein the stereochemistry of the C(3) carbon of the oxa-azaspiro[4.5]decyl 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) or (R).

27. A compound according to any one of claims 1 to 25, wherein the stereochemistry of the C(3) carbon of the oxa-azaspiro[4.5]decyl 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) or (R).

28. The compound according to claim 1, which is selected from the following compounds and pharmaceutically acceptable salts thereof: 3-((2S)-2-hydroxy-3-(8-(3-(1-methyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 61); 3-((2S)-3-(8-(Benzylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide, (Compound 172); 3-((S)-2-hydroxy-3-((R)-8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 300); 3-((2S)-2-hydroxy-3-(8-(4′-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 303); 3-((2S)-2-hydroxy-3-(8-(4′-((isopentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 320); 3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 336); 3-((2S)-3-(8-(4′-((2,2-difluoroethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide, (Compound 339); 3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 344); N 1 -((3′-(3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)biphenyl-4-yl)methyl)oxalamide, (Compound 354); 3-((S)-3-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide, (Compound 419); 3-((S)-2-Hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-((1R,2S)-2-hydroxycyclopentyl)benzenesulfonamide, (Compound 437); 3-((S)-3-((R)-8-((R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide, (Compound 468); 3-((S)-3-((R)-8-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide, (Compound 493); 3-((R)-3-((S)-2-hydroxy-3-(3-(N-methylsulfamoyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]dec-8-ylsulfonyl)pyridine 1-oxide, (Compound 496); 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide, (Compound 505); 3-((S)-2-hydroxy-3-((R)-8-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 509); 3-((S)-3-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide, (Compound 532); 3-((S)-2-Hydroxy-3-((R)-8-(4-hydroxyquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 541); 3-((S)-2-Hydroxy-3-((R)-8-(4-hydroxyquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)benzenesulfonamide, (Compound 548); 3-((S)-3-((R)-8-(1-ethyl-4-oxo-1,4-dihydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)benzenesulfonamide, (Compound 550); 3-((S)-2-hydroxy-3-((R)-8-(4-methoxypyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)propoxy)-N-methylbenzenesulfonamide, (Compound 568); and 3-((S)-3-((R)-8-(4-Benzylpyrimidin-2-yl)-1-oxa-8-azaspiro[4.5]dec-3-ylamino)-2-hydroxypropoxy)-N-methylbenzenesulfonamide, (Compound 573).

29. A pharmaceutical product selected from the group consisting of: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound according to any one of claims 1 to 28.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 and a pharmaceutically acceptable carrier.

31. Use of a compound according to any one of claims 1 to 28 for the preparation of a pharmaceutical composition comprising the step of admixing the compound and a pharmaceutically acceptable carrier.

32. Use of a compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in a subject.

33. Use of a compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual; wherein the beta-3 adrenergic receptor mediated disorder is selected from the group consisting of: heart failure; cardiac function in heart failure; mortality, reinfarction and / or hospitalization associated with heart failure; organ damage associated with heart failure; cardiovascular mortality after myocardial infarction; conditions after myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; LVEF <40% by radionuclide ventriculography; and LVEF ≤35% by echocardiography or ventricular contraction angiography.

34. Use of a compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual; wherein the beta-3 adrenergic receptor mediated disorder is selected from the group consisting of: acute heart failure; congestive heart failure; heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; 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; and class IV heart failure using the New York Heart Association (NYHA) classification system.

35. Use of a compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual; wherein the beta-3 adrenergic receptor mediated disorder is acute decompensated heart failure.

36. Use of a compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual; wherein the beta-3 adrenergic receptor mediated disorder is severe congestive heart failure.

37. The use according to claim 33, wherein the organ damage associated with heart failure is selected from the group consisting of kidney damage or failure, heart valve problems, heart rhythm problems and liver damage.

38. Use of a compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 in the preparation of a medicament for treating a patient following myocardial infarction.

39. Use of a compound according to any one of claims 1 to 28 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in a subject.

40. Use of a compound according to any one of claims 1 to 28 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual, wherein the beta-3 adrenergic receptor mediated disorder is selected from the group consisting of: heart failure; cardiac function in heart failure; mortality, reinfarction and / or hospitalization associated with heart failure; organ damage associated with heart failure; cardiovascular mortality after myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; conditions after myocardial infarction; left ventricular failure; left ventricular dysfunction; LVEF <40% by radionuclide ventriculography; and LVEF ≤35% by echocardiography or ventricular contraction angiography.

41. Use of a compound according to any one of claims 1 to 28 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual; wherein the beta-3 adrenergic receptor mediated disorder is selected from the group consisting of: acute heart failure; congestive heart failure; heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; 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; and class IV heart failure using the New York Heart Association (NYHA) classification system.

42. Use of a compound according to any one of claims 1 to 28 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in a subject; wherein the beta-3 adrenergic receptor mediated disorder is acute decompensated heart failure.

43. Use of a compound according to any one of claims 1 to 28 in the preparation of a medicament for treating or preventing a beta-3 adrenergic receptor mediated disorder in a subject; wherein the beta-3 adrenergic receptor mediated disorder is severe congestive heart failure.

44. The use according to claim 40, wherein the organ damage associated with heart failure is selected from the group consisting of kidney damage or failure, heart valve problems, heart rhythm problems and liver damage.

45. Use of a compound according to any one of claims 1 to 28 for the preparation of a medicament for treating a patient following a myocardial infarction.

46. ​​A compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 for use in a method of treating a human or animal by therapy.

47. A compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 for use in a method of treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual.

48. A compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 for use in a method of treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual; wherein the beta-3 adrenergic receptor mediated disorder is selected from the group consisting of: heart failure; cardiac function in heart failure; mortality, reinfarction and / or hospitalization associated with heart failure; organ damage associated with heart failure; cardiovascular mortality after myocardial infarction; conditions after myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; LVEF <40% by radionuclide ventriculography; and LVEF ≤35% by echocardiography or ventricular contraction angiography.

49. A compound according to any one of claims 1 to 28 for use in a method of treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual; The pharmaceutical product of claim 29; or the pharmaceutical composition of claim 30; wherein the beta-3 adrenergic receptor mediated disorder is selected from the group consisting of: acute decompensated heart failure; congestive heart failure; heart failure due to left ventricular dysfunction; Heart failure with normal ejection fraction; 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; and class IV heart failure using the New York Heart Association (NYHA) classification system.

50. A compound according to any one of claims 1 to 28; a pharmaceutical product according to claim 29; or a pharmaceutical composition according to claim 30 for use in a method of treating or preventing a beta-3 adrenergic receptor mediated disorder in an individual; wherein the beta-3 adrenergic receptor mediated disorder is severe congestive heart failure.

51. The compound, pharmaceutical product or pharmaceutical composition for use according to claim 48, wherein the organ damage associated with heart failure is selected from the group consisting of kidney damage or failure, heart valve problems, heart rhythm problems and liver damage.

52. A compound according to any one of claims 1 to 28 for use in a method of treating a patient following a myocardial infarction; The pharmaceutical product according to claim 29; or the pharmaceutical composition according to claim 30.

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