Beta-adrenergic agonists and methods of using same

Abstract

The present disclosure is directed to compounds and uses of such compounds in the treatment of diseases associated with adrenergic receptors. In certain embodiments of the methods disclosed herein, the methods comprise administering to a subject a compound described herein and a peripherally acting P blocker (PABRA). TIFF2022527769000257.tif75158

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 824,876, filed March 27, 2019, and U.S. Provisional Patent Application No. 62 / 934,482, filed November 12, 2019, the contents of each of which are incorporated herein by reference.

[0002] Field FIELD OF THE DISCLOSURE The present disclosure relates generally to compounds and, in some embodiments, to beta-adrenergic agonists and their use in treating diseases associated with adrenergic receptors. [Background technology]

[0003] background PCT Application Publication No. WO2017 / 197324 (Patent Document 1) discloses "an adrenergic receptor-modulating compound and a method of treating a subject for a disease or condition associated with an adrenergic receptor, comprising administering a therapeutically effective amount of the compound."

[0004] U.S. Patent Application Publication No. 2013 / 0096126 (Patent Document 2) discloses "a method for enhancing learning or memory, or both, in a mammal having impaired learning or memory, or both, due to a neurodegenerative disorder, comprising the step of administering at least one compound that is a β1-adrenergic receptor agonist, partial agonist, or receptor ligand, or a salt thereof, in an amount effective to improve learning or memory, or both, in the mammal."

[0005] U.S. Patent Application Publication No. 2014 / 0235726 (Patent Document 3) discloses "a method of improving cognition in patients with Down syndrome, comprising administering to the patient one or more beta-2 adrenergic receptor agonists in an amount and at a frequency effective to improve the patient's cognition as measured by a contextual learning test."

[0006] U.S. Patent Application Publication No. 2016 / 0184241 (Patent Document 4) discloses "a method of improving cognition in patients with Down's syndrome, comprising intranasally administering to the patient one or more β2-ADR agonists or pharmaceutically acceptable salts of either or both in an amount and at a frequency effective to improve the patient's cognition as measured by a contextual learning test." [Prior art documents] [Patent documents]

[0007] [Patent Document 1] PCT Application Publication Number WO2017 / 197324 [Patent Document 2] U.S. Patent Application Publication No. 2013 / 0096126 [Patent Document 3] U.S. Patent Application Publication No. 2014 / 0235726 [Patent Document 4] U.S. Patent Application Publication No. 2016 / 0184241 Summary of the Invention

[0008] overview The present disclosure is based, at least in part, on the identification of compounds that modulate adrenergic receptors and methods of using same to treat diseases associated with adrenergic receptors. Disclosed herein are compounds according to formula (I) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF0007682097000001.tif29128

[0009] In some embodiments, each A, B, and X is independently nitrogen or carbon. In some embodiments, each R is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. In some embodiments, m is an integer selected from 0 to 4.

[0010] In some embodiments, R2, R3, and R4 are independently selected from H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, TIFF0007682097000002.tif60156, or R2 and R3 together with the carbons form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0011] In some embodiments, L is an optionally substituted C1-C5 alkyl linker; each Y1, Y2, Y3, and Y4 is independently a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; and Z is O or S.

[0012] In some embodiments, R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R5 and R6 together with Y2 are cyclically bonded to form an optionally substituted cycloalkyl or heterocycle, and each R7 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0013] In some embodiments, n is an integer selected from 0 to 4, R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino.

[0014] Also disclosed herein are compounds according to formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. TIFF0007682097000003.tif30128

[0015] In some embodiments, each A, B, and X is independently nitrogen or carbon. In some embodiments, each R is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. In some embodiments, m is an integer selected from 0 to 4.

[0016] In some embodiments, R2, R3, and R4 are independently selected from H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, TIFF0007682097000004.tif60156, or R2 and R3 together with the carbons form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0017] In some embodiments, L is an optionally substituted C1-C5 alkyl linker; each Y1, Y2, Y3, and Y4 is independently a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; and Z is O or S.

[0018] In some embodiments, R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R5 and R6 together with Y2 are cyclically bonded to form an optionally substituted cycloalkyl or heterocycle, and each R7 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0019] In some embodiments, n is an integer selected from 0 to 4; R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl; and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino.

[0020] Further disclosed herein are compounds according to formula (III) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. TIFF0007682097000005.tif26128

[0021] In some embodiments, each R is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. m is an integer selected from 0 to 4.

[0022] In some embodiments, R2, R3, and R4 are independently selected from H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, TIFF0007682097000006.tif60156, or R2 and R3 together with the carbons form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0023] In some embodiments, L is an optionally substituted C1-C5 alkyl linker; each X1, X2, X3, and X4 is independently a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; and Y is O or S.

[0024] In some embodiments, R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R5 and R6 together with Y2 are cyclically bonded to form an optionally substituted cycloalkyl or heterocycle, and each R7 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0025] In some embodiments, n is an integer selected from 0 to 4, R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino.

[0026] Additionally, compounds according to formula (I'): TIFF0007682097000007.tif32128 or a pharmaceutically acceptable salt thereof. [In the formula, A', B', and X' are each independently nitrogen or carbon; Each R 1’ are independently halogen, -R', -CN, -NO2, -SF5, -OR x , -NR x 2, -NHR x , -SO2R', -C(O)R', -C(O)NR'2; Each R' is independently hydrogen or C 1~6an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R x are independent, C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R 2’ , R 3’ , and R 4’ are each independently a halogen, -R', -CN, -NO2, -OR', -NR'2, TIFF0007682097000008.tif60161, or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is optionally substituted C 1~5 is alkylene; Y 1’ , Y 2’ , Y 3’ , and Y 4’ each independently represents a covalent bond, carbon, oxygen, or hydrogen, or an optionally substituted C 1~6 is nitrogen optionally substituted with alkyl or an optionally substituted 3- to 7-membered saturated carbocyclic ring; Z' is O or S; R 5’ and R 6’ are each independently hydrogen or optionally substituted alkyl, or R 5’ and R 6’ is Y 2’ and are cyclically bonded together to form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7’ are independently -R', halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, —CN, an optionally substituted alkyl, or an optionally substituted aryl ring; and Each R 9’ are independently hydrogen, halogen, -CN, -OR x , —NR′2, or optionally substituted alkyl; and R 10’ and R 11’ each independently represents hydrogen or an optionally substituted C 1~2 aliphatic].

[0027] Additionally, compounds according to formula (I″): TIFF0007682097000009.tif32128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, A', B', and X' are each independently nitrogen or carbon; Each R 1’ are independently halogen, -R', -CN, -NO2, -SF5, -OR x , -NR x 2, -NHR x , -SO2R', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'CO2R', or -CO2R'; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R x are independent, C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R 2’ , R 3’ , and R 4’are each independently a halogen, -R', -CN, -NO2, -OR', -NR'2, TIFF0007682097000010.tif60162, or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is optionally substituted C 1~5 is alkylene; Y 1’ , Y 2’ , Y 3’ , and Y 4’ each independently represents a covalent bond, carbon, oxygen, or hydrogen, or an optionally substituted C 1~6 is nitrogen optionally substituted with alkyl or an optionally substituted 3- to 7-membered saturated carbocyclic ring; Z' is O or S; R 5’ and R 6’ are each independently hydrogen or optionally substituted alkyl, or R 5’ and R 6’ is Y 2’ and are cyclically bonded together to form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7’ are independently -R', halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, —CN, an optionally substituted alkyl, or an optionally substituted aryl ring; and Each R 9’ are independently hydrogen, halogen, -CN, -OR x , —NR′2, or optionally substituted alkyl; and R 10’ and R 11’ each independently represents hydrogen or an optionally substituted C 1~2 aliphatic].

[0028] Additionally, compounds having the following structural formula: TIFF0007682097000011.tif17128 or a pharmaceutically acceptable salt thereof is disclosed herein.

[0029] Additionally, compounds having the following structural formula: TIFF0007682097000012.tif16128 or a pharmaceutically acceptable salt thereof is disclosed herein.

[0030] Additionally, compounds having the following structural formula: TIFF0007682097000013.tif16128 or a pharmaceutically acceptable salt thereof is disclosed herein.

[0031] Also disclosed herein is a pharmaceutical composition comprising a compound described herein, i.e., a compound having a structural formula of Formula (I), Formula (II), Formula (III), Formula (I'), Formula (I''), Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), Formula (VII'), Formula (VIII'), Formula (IX'), Formula (X'), Formula (XI'), Formula (XII'), Formula (XIII'), Formula (XIV'), Formula (XV'), Formula (XVI'), Formula (XVII'), Formula (XVIII'), Formula (XIX'), Formula (XX'), Formula (XXI'), Formula (XXII'), Formula (XXIII'), Formula (XXIV'), and Formula (XXV'), and a pharmaceutically acceptable excipient.

[0032] In certain embodiments, the compounds described herein are agonists, partial agonists, or antagonists of adrenergic receptors; in some embodiments, the compounds are β1-adrenergic receptor agonists, β2-adrenergic receptor agonists, or non-selective β1 / β2-adrenergic receptor agonists; in some embodiments, the compounds are β1-adrenergic receptor agonists; in some embodiments, the compounds are β2-adrenergic receptor agonists; in some embodiments, the compounds are compounds that are non-selective β1 / β2-adrenergic agonists.

[0033] Also disclosed is a method of treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound described herein, i.e., a compound having a structural formula of Formula (I), Formula (I"), Formula (II), Formula (III), Formula (I'), Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), Formula (VII'), Formula (VIII'), Formula (IX'), Formula (X'), Formula (XI'), Formula (XII'), Formula (XIII'), Formula (XIV'), Formula (XV'), Formula (XVI'), Formula (XVII'), Formula (XVIII'), Formula (XIX'), Formula (XX'), Formula (XXI'), Formula (XXII'), Formula (XXIII'), Formula (XXIV'), or Formula (XXV'). In some embodiments, the disease is an adrenergic receptor-associated disease. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the subject is a human.

[0034] In some embodiments, the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedreich's ataxia, ataxia-telangiectasia, spinal muscular dystrophies, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipozygosinosis. In some embodiments, the compound is administered to a subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal routes.

[0035] In some embodiments, the disease is MCI (mild cognitive impairment), MCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome). and Alzheimer's disease (AD), early AD, and Down's syndrome (DS). In some embodiments, the disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke's syndrome), The neurodegenerative disease is one or more selected from the group consisting of Korsakoff's syndrome; alcoholic dementia & thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not have Alzheimer's disease (AD). In some embodiments, the subject does not have Down's syndrome.

[0036] In certain embodiments of the methods disclosed herein, the method comprises administering to a subject a compound described herein and a peripherally acting beta blocker (PABRA).

[0037] As used herein, the term "peripherally acting beta-blocker (PABRA)" refers to a beta-adrenergic receptor antagonist or simply a beta-, beta-, or non-selective beta-blocker. In certain embodiments, examples of selective peripherally acting beta-blockers (PABRA) that can be used in the methods disclosed herein include nadolol, atenolol, sotalol, and labetalol. In certain embodiments, the beta-blocker that can be used in the methods herein is one or more selected from the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, and nebivolol; in other embodiments, the methods do not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, or nebivolol as the beta-blocker.

[0038] In certain embodiments, a peripherally acting beta blocker (PABRA) is administered to a subject prior to administration of a compound of the present disclosure; in other embodiments, a peripherally acting beta blocker (PABRA) is administered to a subject simultaneously with administration of a compound of the present disclosure.

[0039] In certain embodiments of the compositions and methods provided herein, one or more peripherally acting beta-blockers (PABRAs) are administered prior to or concurrently with the compounds of the present disclosure to inhibit or eliminate agonism of peripheral beta- and / or beta-adrenergic receptors by the compounds of the present disclosure. In various embodiments, blocking peripheral beta- and / or beta-adrenergic receptors in accordance with the compositions and methods of the present disclosure is preferred to eliminate, or at least minimize, any adverse peripheral cardiac, metabolic, or muscular effects in the treated human.

[0040] In some embodiments of the methods provided herein, in addition to a compound described herein, a beta 1 agonist and / or a beta 2 agonist, or a non-selective beta 1 / beta 2 agonist, is administered to the patient.

[0041] As used herein, the term "β1 agonist" refers to a β1-adrenergic receptor agonist or a β1-ADR agonist. In certain embodiments, the term β1 agonist is understood to include compounds that are primarily β1 agonists but may also exhibit some peripheral agonism at other adrenergic receptors, such as the β2-adrenergic receptor. In this application, the terms "β1-adrenergic receptor agonist," "β1-ADR agonist," "β1AR agonist," and "β1 agonist" may be used interchangeably. In certain embodiments, the term "β1-ADR agonist" expressly encompasses both selective and partial agonists, as well as biased and unbiased agonists. Examples of β1-adrenergic agonists include, for example, xamoterol, noradrenaline, isoprenaline, dopamine, pindolol, and dobutamine, as well as pharmaceutically acceptable salts of any of the above. Partial agonists and ligands of β1-ADR are known. Furthermore, using the methodology of Kolb et al., but instead for β1-ADR, those skilled in the art could determine new ligands by structure-based discovery. See Proc. Natl. Acad. Sci. USA 2009, 106, 6843-648.

[0042] As used herein, the term β2 agonist refers to a β2-adrenergic receptor agonist or a β2-ADR agonist. In certain embodiments, the term β2 agonist is understood to encompass compounds that are primarily β2 agonists but may also exhibit some peripheral agonism at other adrenergic receptors, such as β1-adrenergic receptors. In the present application, the terms "β2-adrenergic receptor agonist," "β2-ADR agonist," "β2AR agonist," and "β2 agonist" may be used interchangeably. In some embodiments, the term β2-ADR agonist explicitly encompasses both selective and partial agonists. The β2 agonists that can be used according to various aspects and embodiments of the present disclosure may be short-acting, long-acting, or ultra-long-acting. Examples of short-acting β2 agonists that can be used include salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, oritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and isoetharin.Examples of long-acting β2 agonists that can be used include salmeterol, bambuterol, formoterol, and clenbuterol.Examples of ultra-long-acting β2 agonists include indacaterol, vilanterol, and olodaterol.

[0043] As demonstrated in the Examples section of this specification, it has been unexpectedly found that the compounds of the present disclosure exhibit unexpectedly advantageous properties.For example, it has been unexpectedly found that the compounds of the present disclosure act as low nM (<10 nM) partial agonists of β2 adrenergic receptors.Furthermore, the compounds of the present disclosure exhibit unexpectedly high ability to pass through the blood-brain barrier and accumulate in cerebrospinal fluid.In addition, the compounds of the present disclosure exhibit excellent oral bioavailability and stability, while at the same time exhibiting low toxicity and low potential for drug-drug interactions. [The present invention 1001] A compound according to formula (I') or a pharmaceutically acceptable salt thereof: TIFF0007682097000014.tif32128 During the ceremony, A', B', and X' are each independently nitrogen or carbon; Each R 1’ are independently halogen, -R', -CN, -NO 2 ,-SCIENCE FICTION 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R', -C(O)R', --C(O)NR' 2 and; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R x are independent, C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R 2’ 、R 3’ , and R 4’ are each independently a halogen, -R', -CN, or -NO 2 , -OR', -NR' 2 、 TIFF0007682097000015.tif60162 or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is optionally substituted C 1~5 is alkylene; Y 1’ 、Y 2’ 、Y 3’ , and Y 4’ each independently represents a covalent bond, carbon, oxygen, or hydrogen, or an optionally substituted C 1~6 is nitrogen optionally substituted with alkyl or an optionally substituted 3- to 7-membered saturated carbocyclic ring; Z' is O or S; R 5’ and R 6’ are each independently hydrogen or optionally substituted alkyl, or R 5’ and R 6’ is Y 2’ and are cyclically bonded together to form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7’ are independently -R', halogen, -CN, -NO 2 , -NR' 2 , or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, —CN, an optionally substituted alkyl, or an optionally substituted aryl ring; and Each R 9’ are independently hydrogen, halogen, -CN, -OR x , -NR' 2 or optionally substituted alkyl; and R 10’ and R 11’ each independently represents hydrogen or an optionally substituted C 1~2 It is aliphatic. [The present invention 1002] A compound according to formula (II') or a pharmaceutically acceptable salt thereof: TIFF0007682097000016.tif30128 During the ceremony, A', B', and X' are each independently nitrogen or carbon; Each R 1’ are independently halogen, -R', -CN, -NO 2 ,-SCIENCE FICTION 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R', -C(O)R', --C(O)NR' 2 and; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R x are independent, C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R 2’ 、R 3’ , and R4’ are each independently a halogen, -R', -CN, or -NO 2 , -OR', -NR' 2 、 TIFF0007682097000017.tif60162 or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is optionally substituted C 1~5 is alkylene; Y 1’ 、Y 2’ 、Y 3’ , and Y 4’ each independently represents a covalent bond, carbon, oxygen, or hydrogen, or an optionally substituted C 1~6 is nitrogen optionally substituted with alkyl or an optionally substituted 3- to 7-membered saturated carbocyclic ring; Z' is O or S; R 5’ and R 6’ are each independently hydrogen or optionally substituted alkyl, or R 5’ and R 6’ is Y 2’ and are cyclically bonded together to form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7’ are independently -R', halogen, -CN, -NO 2 , -NR' 2 , or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, —CN, an optionally substituted alkyl, or an optionally substituted aryl ring; and Each R 9’ are independently hydrogen, halogen, -CN, -OR x , -NR' 2 or optionally substituted alkyl. [The present invention 1003] A compound according to formula (III') or a pharmaceutically acceptable salt thereof: TIFF0007682097000018.tif26128 During the ceremony, A', B', and X' are each independently nitrogen or carbon; Each R 1’ are independently halogen, -R', -CN, -NO 2 ,-SCIENCE FICTION 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R', -C(O)R', --C(O)NR' 2 and; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R x are independent, C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R 2’ 、R 3’ , and R 4’ are each independently a halogen, -R', -CN, or -NO 2 , -OR', -NR' 2 、 TIFF0007682097000019.tif60162 or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is optionally substituted C 1~5 is alkylene; Y 1’ 、Y 2’ 、Y 3’ , and Y 4’ each independently represents a covalent bond, carbon, oxygen, or hydrogen, or an optionally substituted C 1~6 is nitrogen optionally substituted with alkyl or an optionally substituted 3- to 7-membered saturated carbocyclic ring; Z' is O or S; R 5’ and R 6’ are each independently hydrogen or optionally substituted alkyl, or R 5’ and R 6’ is Y 2’ and are cyclically bonded together to form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7’ are independently -R', halogen, -CN, -NO 2 , -NR' 2 , or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, —CN, an optionally substituted alkyl, or an optionally substituted aryl ring; and Each R 9’ are independently hydrogen, halogen, -CN, -OR x , -NR' 2 or optionally substituted alkyl. [The present invention 1004] A compound according to formula (XVIII') or a pharmaceutically acceptable salt thereof: TIFF0007682097000020.tif24128 During the ceremony, R 1’ is a halogen, -R', -CN, or -NO 2 and; Each R' is an optionally substituted C 1~6 is aliphatic; and R 2’ 、R 3’ , and R 4’ are each independently a halogen, -R', -CN, or -NO 2 , -OR', or -NR' 2 or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring. [The present invention 1005] A compound according to formula (XXII') or a pharmaceutically acceptable salt thereof: TIFF0007682097000021.tif25128 During the ceremony, R 1’ is a halogen, -R', -CN, or -NO 2 and; Each R' is an optionally substituted C 1~6 is aliphatic; and R 2’ 、R 3’ , and R4’ are each independently a halogen, -R', -CN, or -NO 2 , -OR', or -NR' 2 or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring. [The present invention 1006] R 1’ is halogen, -CN, or optionally substituted C 1~6 The compound of any one of 1001 to 1005 of the present invention, which is aliphatic. [The present invention 1007] R 1’ The compound of the present invention 1006, wherein is -CN. [The present invention 1008] R 1’ may be substituted C 1~6 The compound of the present invention 1006, which is aliphatic. [The present invention 1009] R 1’ The compound of the present invention 1008, wherein is methyl. [The present invention 1010] R 1’ But -CF 3 The compound of the present invention 1008, [The present invention 1011] R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring. [The present invention 1012] R 2’ may be substituted C 1~6 The compound of any one of 1001 to 1010 of the present invention, which is aliphatic. [The present invention 1013] R 2’ is methyl. [The present invention 1014] R 3’ may be substituted C 1~6 The compound of any one of 1001 to 1010 of the present invention, which is aliphatic. [The present invention 1015] R 3’ is methyl. [The present invention 1016] R 4’ may be substituted C 1~6 The compound of any one of 1001 to 1010 of the present invention, which is aliphatic. [The present invention 1017] R 4’ The compound of the present invention 1016, wherein is methyl. [The present invention 1018] The following structural formula: TIFF0007682097000022.tif16128 1001. The compound of the present invention having the formula: or a pharmaceutically acceptable salt thereof. [The present invention 1019] The following structural formula: TIFF0007682097000023.tif17128 1001. The compound of the present invention having the formula: or a pharmaceutically acceptable salt thereof. [The present invention 1020] The following structural formula: TIFF0007682097000024.tif16128 1001. The compound of the present invention having the formula: or a pharmaceutically acceptable salt thereof. [The present invention 1021] The compound of any one of claims 1001 to 1020, which is an agonist, partial agonist or antagonist of an adrenergic receptor. [The present invention 1022] Any of the compounds of inventions 1001 to 1020, which are β1-adrenergic receptor agonists, β2-adrenergic receptor agonists or non-selective β1 / β2-adrenergic receptor agonists. [The present invention 1023] Any of the compounds of the present invention 1001 to 1020, which is a β1-adrenergic receptor agonist. [The present invention 1024] Any of the compounds of the present invention 1001 to 1020, which is a β2-adrenergic receptor agonist. [The present invention 1025] Any of the compounds of the present invention 1001 to 1020, which are non-selective β1 / β2-adrenergic agonists. [The present invention 1026] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1020 and a pharmaceutically acceptable excipient. [The present invention 1027] A method for treating a subject having a disease, comprising the step of administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1020. [The present invention 1028] A method for treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1020, thereby treating the subject. [The present invention 1029] A method for treating a subject having a disease associated with an adrenergic receptor, the method comprising the step of administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1020. [The present invention 1030] The method of any one of claims 1027 to 1029, wherein the disease is a neurodegenerative disease. [The present invention 1031] The diseases include MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; 1030. The method of the present invention, wherein the present invention relates to one or more of the following conditions: Alcoholic Dementia & Thiamine Deficiency, Normal Pressure Hydrocephalus, Hypersomnia / Narcolepsy, ASD (Autism Spectrum Disorder), FXS (Fragile X Syndrome), TSC (Tuberous Sclerosis), Prion-related Disease (such as CJD), Depressive Disorder, DLB (Dementia with Lewy Bodies), PD (Parkinson's Disease), PDD (PD Dementia), ADHD (Attention Deficit Hyperactivity Disorder), Alzheimer's Disease (AD), Early AD, and Down's Syndrome (DS). [The present invention 1032] The method of any one of claims 1027 to 1031, wherein the subject is a human. [The present invention 1033]

[0039] Any of the methods of claims 1027 to 1032, wherein the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal routes. [Brief explanation of the drawings]

[0044] [Figure 1] 1 is a graph summarizing the concentration-dependent inhibition of compounds 03-3 and 03-5 in β1-expressing CHO cells, with isoproterenol as a control. [Figure 2] 1 is a graph summarizing the concentration-dependent inhibition of compounds 03-3 and 03-5 in β2-expressing CHO cells, with isoproterenol as a control. [Figure 3] 1 is a graph summarizing the concentration-dependent inhibition of compounds 03-3 and 03-5 in human astrocytoma cells (1321N1) with isoproterenol as a control. [Figure 4] 1 is a graph summarizing the pharmacokinetic properties of compound 03-3 in male SD rats after oral (1, 3, 5, and 10 mg / kg) and intravenous (1 mg / kg) administration. [Figure 5] 1 is a graph summarizing the pharmacokinetic properties of compound 03-5 in male SD rats after oral (1, 3, 5, and 10 mg / kg) and intravenous (1 mg / kg) administration. [Figure 6]

[0023] Figure 1 is a graph summarizing the pharmacokinetic profile of compound 03-3 in male C57BL / 6J mice after oral (5 mg / kg) and intravenous (1 mg / kg) administration. The trend line with squares represents oral (PO) administration. [Figure 7]

[0023] Figure 1 is a graph summarizing the pharmacokinetic profile of compound 03-5 in male C57BL / 6J mice after oral (5 mg / kg) and intravenous (1 mg / kg) administration. The trend line with squares represents oral (PO) administration. [Figure 8] 1 is a graph summarizing the pharmacokinetic profile of compound 03-3 in male beagle dogs after oral (1 and 2.5 mg / kg) and intravenous (0.1 and 0.3 mg / kg) administration. [Figure 9] 1 is a graph summarizing the pharmacokinetic profile of compound 03-5 in male beagle dogs after oral (0.3 and 1 mg / kg) and intravenous (0.1 and 0.3 mg / kg) administration. [Figure 10] 1 is a graph summarizing the pharmacokinetic properties of compound 03-3 in male cynomolgus monkeys after oral (0.1 and 0.3 mg / kg; "PO_A" and "PO_B", respectively) and intravenous (0.1 mg / kg) administration. [Figure 11] 1 is a graph summarizing the pharmacokinetic properties of compound 03-5 in male cynomolgus monkeys after oral (0.1 and 0.3 mg / kg; "PO_B" and "PO_C", respectively) and intravenous (0.1 mg / kg) administration. [Figure 12] 1 is a graph summarizing the pharmacokinetic properties of compound 03-115 in male SD rats after oral (1, 2, 5, 10, 25 and 100 mg / kg) and intravenous (1 mg / kg) administration. [Figure 13] 1 is a graph summarizing the pharmacokinetic properties of compound 03-115 in male beagle dogs after oral (0.5 and 1.5 mg / kg) and intravenous (0.1 mg / kg) administration. [Figure 14]

[0023] Figure 1 is a graph summarizing the pharmacokinetic profile of compound 03-115 in male C57BL / 6J mice after oral (5 mg / kg) and intravenous (1 mg / kg) administration. The trend line with squares represents oral (PO) administration. [Figure 15] 1 is a graph summarizing the pharmacokinetic properties of compound 03-115 in male cynomolgus monkeys after oral (0.3 mg / kg) and intravenous (0.1 mg / kg) administration. DETAILED DESCRIPTION OF THE INVENTION

[0045] Detailed Description In the following detailed description of embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present disclosure. However, it will be apparent to those skilled in the art that embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0046] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in practicing the disclosure. The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. The term "comprises" means "include." Thus, "including A or B" means "including A, B, or A and B," without excluding additional elements. The term "about" will be understood by those of ordinary skill in the art. All numerical quantities set forth herein, whether or not the term "about" is expressly used, refer to the given value actually set forth, and are also meant to refer to approximations to such set forth value that would be reasonably inferred based on ordinary skill in the art.

[0047] Further, it should be understood that all base or amino acid sizes and all molecular weight or molecular mass values ​​given for nucleic acids or polypeptides are approximate and are given for illustrative purposes only. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.

[0048] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Definitions of common terms in molecular biology can be found in Benjamin Lewin, Genes V, Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).

[0049] Unless otherwise indicated, the naming of substituents not expressly defined herein is obtained by naming the terminal portion of the functional group toward the point of attachment, followed by the adjacent functional group. Those skilled in the art will understand that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with five different groups, a pentavalent carbon, etc.). Such impermissible substitution patterns are readily recognized by those of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. All sequences set forth in the disclosed GenBank accession numbers as they were available on August 11, 2011, are incorporated by reference herein. In case of conflict, the present specification, including explanations of terms, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0050] An alkyl group refers to a monovalent group derived from an alkane by removing a hydrogen atom from any carbon atom, including straight and branched chains containing 1 to 12 carbon atoms, typically 1 to about 10 carbon atoms, or in some embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups. Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl groups. Alkyl groups can be substituted or unsubstituted. Representative substituted alkyl groups can be mono-substituted or substituted more than once, for example, but not limited to, mono-, di-, or tri-substituted. As used herein, the term alkyl refers to both cyclic and acyclic groups, unless otherwise stated.

[0051] The term "cyclic alkyl" or "cycloalkyl" refers to a monovalent group derived from a cycloalkane by removing a hydrogen atom from a ring carbon atom. A cycloalkyl group is a saturated or partially saturated non-aromatic structure containing a single ring or multiple rings, including isolated, fused, bridged, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments, 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, for example, but not limited to, mono-, di-, or tri-substituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of polycyclic ring systems include, but are not limited to, bicycle[4.4.0]decane, bicycle[2.2.1]heptane, spiro[2.2]pentane, and the like. (Cycloalkyl)oxy refers to -O-cycloalkyl. (Cycloalkyl)thio refers to -S-cycloalkyl. The term also includes oxidized forms of sulfur, such as -S(O)-cycloalkyl, or -S(O)2-cycloalkyl.

[0052] Alkenyl groups refer to straight-chain, branched-chain, and cycloalkyl groups, as defined above, having one or more double bonds between two carbon atoms. Alkenyl groups can have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbon atoms, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. Alkenyl groups can be substituted or unsubstituted. Representative substituted alkenyl groups can be mono-substituted or substituted more than once, for example, but not limited to, mono-, di-, or tri-substituted. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0053] An alkynyl group refers to straight-chain, branched-chain, and cycloalkyl groups, as defined above, having one or more triple bonds between two carbon atoms. Alkynyl groups can have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbon atoms, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 1, 2, 3, or 4 carbon atoms. Alkynyl groups can be substituted or unsubstituted. Representative substituted alkynyl groups can be mono-substituted or substituted more than once, for example, but not limited to, mono-, di-, or tri-substituted. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and —C≡C(CH), among others.

[0054] Aryl groups are cyclic aromatic hydrocarbons containing single and multiple ring compounds, including multiple ring compounds containing separate and / or fused aryl groups. Aryl groups may contain 6 to about 18 ring carbons, or in some embodiments, 6 to 14 ring carbons, or even 6 to 10 ring carbons. Aryl groups also include heteroaryl groups, which are aromatic ring compounds containing five or more ring members, one or more of which ring carbon atoms are replaced with heteroatoms, such as, but not limited to, N, O, and S. Aryl groups can be substituted or unsubstituted. Representative substituted aryl groups can be mono-substituted or substituted more than once, for example, but not limited to, mono-, di-, or tri-substituted. Aryl groups include, but are not limited to, phenyl, biphenylenyl, triphenylenyl, naphthyl, anthryl, and pyrenyl groups. Aryloxy refers to -O-aryl. Arylthio refers to -S-aryl, where aryl is as defined herein. The term also includes oxidized forms of sulfur, such as -S(O)-aryl or -S(O)2-aryl. Heteroaryloxy refers to -O-heteroaryl. Heteroarylthio refers to -S-heteroaryl. The term also includes oxidized forms of sulfur, such as -S(O)-heteroaryl or -S(O)2-heteroaryl.

[0055] Suitable heterocyclyl groups include cyclic groups having atoms of at least two different elements as ring members, one or more of which is a heteroatom, for example, but not limited to, N, O, or S. Heterocyclyl groups can contain 3 to about 20 ring members, or in some embodiments, 3 to 18, or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring system in a heterocyclyl group can be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups can be substituted or unsubstituted. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, for example, but not limited to, mono-, di-, or tri-substituted. Exemplary heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, and pyrazolyl. The term includes thiazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolizinyl, cinnolinyl, phthalazinyl, pteridinyl, and benzothiazolyl groups. Heterocyclyloxy refers to -O-heterocyclyl. Heterocyclylthio refers to -S-heterocyclyl. This term also encompasses oxidized forms of sulfur, such as -S(O)-heterocyclyl or -S(O)2-heterocyclyl.

[0056] A polycyclic or polycyclyl group refers to two or more rings in which two or more carbons are common to two adjacent rings, where the rings are "fused rings"; if the rings are joined by one common carbon atom, they are a "spiro" ring system. Rings that are joined through non-adjacent atoms are "bridged" rings. Polycyclic groups can be substituted or unsubstituted. Representative polycyclic groups can be substituted one or more times.

[0057] Halogen groups include F, Cl, Br, and I; nitro groups refer to -NO2; cyano groups refer to -CN; isocyano groups refer to -N≡C; epoxy groups contain essentially cyclic ether structures in which an oxygen atom is directly bonded to two adjacent or non-adjacent carbon atoms in a carbon chain or ring system. Epoxides are cyclic ethers containing a three-atom ring.

[0058] An alkoxy group is a substituted or unsubstituted alkyl group, as defined above, that is single-bonded to oxygen. The alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted once or multiple times. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups.

[0059] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at every position. Combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically viable compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0060] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH) 0~4 R 〇 ;-(CH2) 0~4 OR 〇 ;-O(CH2) 0~4 R o , -O-(CH2) 0~4 C(O)OR 〇 ;-(CH2) 0~4 CH(OR 〇 )2;-(CH2) 0~4 SR 〇 ;R 〇 may be substituted with -(CH2) 0~4 Ph;R 〇 may be substituted with -(CH2) 0~4 O(CH2) 0~1 Ph;R 〇 may be substituted with -CH=CHPh; R 〇 may be substituted with -(CH2) 0~4 O(CH2) 0~1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2)0~4 N(R 〇 )2;-(CH2) 0~4 N(R 〇 )C(O)R 〇 ;-N(R 〇 )C(S)R 〇 ;-(CH2) 0~4 N(R 〇 )C(O)NR 〇 2;-N(R 〇 )C(S)NR 〇 2;-(CH2) 0~4 N(R 〇 )C(O)OR 〇 ;-N(R 〇 )N(R 〇 )C(O)R 〇 ;-N(R 〇 )N(R 〇 )C(O)NR 〇 2;-N(R 〇 )N(R 〇 )C(O)OR 〇 ;-(CH2) 0~4 C(O)R 〇 ;-C(S)R 〇 ;-(CH2) 0~4 C(O)OR 〇 ;-(CH2) 0~4 C(O)SR 〇 ;-(CH2) 0~4 C(O)OSiR 〇 3;-(CH2) 0~4 OC(O)R 〇 ;-OC(O)(CH2) 0~4 SR o ;SC(S)SR 〇 ;-(CH2) 0~4 SC(O)R 〇 ;-(CH2) 0~4 C(O)NR 〇 2;-C(S)NR 〇 2;-C(S)SR 〇 ;-SC(S)SR 〇 ;-(CH2) 0~4 OC(O)NR 〇 2;-C(O)N(OR 〇 )R 〇 ;-C(O)C(O)R 〇 ;-C(O)CH2C(O)R 〇 ;-C(NOR〇 )R 〇 ;-(CH2) 0~4 SSR 〇 ;-(CH2) 0~4 S(O)2R 〇 ;-(CH2) 0~4 S(O)2OR 〇 ;-(CH2) 0~4 OS(O)2R 〇 ;-S(O)2NR 〇 2;-S(O)(NR 〇 )R 〇 ;-S(O)2N=C(NR 〇 2)2;-(CH2) 0~4 S(O)R 〇 ;-N(R 〇 )S(O)NR 〇 2;-N(R 〇 )S(O)2R 〇 ;-N(OR 〇 )R 〇 ;-C(NH)NR 〇 2;-P(O)2R 〇 ;-P(O)R 〇 2;-OP(O)R 〇 2;-OP(O)(OR 〇 )2;-SiR 〇 ;-(C 1~4 Linear or branched alkylene)ON(R 〇 )2; or -(C 1~4 Linear or branched alkylene)C(O)ON(R 〇 )2, where each R 〇 are optionally substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the definition above, R 〇 two independent occurrences of together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0061] R 〇 (or R 〇 Suitable monovalent substituents on the ring formed by two independent occurrences of -(CH2) together with their intervening atoms are independently halogen, -(CH2) 0~2 R ● ;-(Halo R ● );-(CH2) 0~2 OH;-(CH2) 0~2 OR ● ;-(CH2) 0~2 CH(OR ● )2;-O(HaloR ● );-CN;-N3;-(CH2) 0~2 C(O)R ● ;-(CH2) 0~2 C(O)OH;-(CH2) 0~2 C(O)OR ● ;-(CH2) 0~2 SR ● ;-(CH2) 0~2 SH;-(CH2) 0~2 NH2;-(CH2) 0~2 NHR ● ;-(CH2) 0~2 NR ● 2;-NO2, -SiR ● 3;-OSiR ● 3;-C(O)SR ● ;-(C 1~4 Linear or branched alkylene)C(O)OR ● ;or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 R is selected from Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 〇 Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0062] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: =O; =S; =NNR * 2;=NNHC(O)R * ;=NNHC(O)OR * ;=NNHS(O)2R * ;=NR * ;=NOR * ;-O(C(R * 2)) 2~3 O-; or -S(C(R * 2)) 2~3 S-includes; where R * Each independent occurrence of represents hydrogen, optionally substituted C as defined below 1~6 aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2~3 O-, where R * Each independent occurrence of represents hydrogen, optionally substituted C as defined below 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] R * Suitable substituents on the aliphatic group include halogen, -R ● ;-(Halo R ● );-OH, -OR ● ;-O(Halo R ● );-CN;-C(O)OH;-C(O)OR ● ;-NH2;-NHR ● ;-NR ● 2; or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph;-O(CH2) 0~1Ph; or a 5-6 membered saturated; partially unsaturated; or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0064] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † ;-NR † 2;-C(O)R † ;-C(O)OR † ;-C(O)C(O)R † ;-C(O)CH2C(O)R † ;-S(O)2R † ;-S(O)2NR † 2;-C(S)NR † 2;-C(NH)NR † 2; or -N(R † )S(O)2R † where each R † are independently hydrogen, optionally substituted C as defined below 1~6 an aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, R † two independent occurrences of together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0065] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ;-(Halo R ● );-OH;-OR ● ;-O(Halo R ● );-CN;-C(O)OH;-C(O)OR ● ;-NH2;-NHR ● ;-NR ● 2; or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C1~4 Aliphatic, -CH2Ph;-O(CH2) 0~1 Ph; or a 5-6 membered saturated; partially unsaturated; or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0066] Thiol refers to -SH. Thiocarbonyl refers to (=S). Sulfonyl refers to -SO2-alkyl, -SO2-substituted alkyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclyl, and -SO2-substituted heterocyclyl. Sulfonylamino refers to -NR a SO2 alkyl, -NR a SO2-substituted alkyl, -NR a SO2 cycloalkyl, --NR a SO2-substituted cycloalkyl, -NR a SO2 aryl, -NR a SO2-substituted aryl, --NR a SO2 heteroaryl, -NR a SO2-substituted heteroaryl, -NR a SO2 heterocyclyl, -NR a refers to an SO2-substituted heterocyclyl, where each R a are independently as defined herein.

[0067] Carboxyl refers to -COOH or a salt thereof. Carboxy ester refers to -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)β-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclyl, and -C(O)O-substituted heterocyclyl. (Carboxy ester)amino refers to -NR a -C(O)O-alkyl, -NR a -C(O)O-substituted alkyl, -NR a -C(O)O-aryl, -NR a-C(O)O-substituted aryl, -NR a -C(O)β-cycloalkyl, --NR a -C(O)O-substituted cycloalkyl, -NR a —C(O)O-heteroaryl, —NR a -C(O)O-substituted heteroaryl, -NR a -C(O)O-heterocyclyl and -NR a -C(O)O-substituted heterocyclyl, where R a are as enumerated herein. (Carboxy ester)oxy refers to -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)β-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclyl, and -OC(O)O-substituted heterocyclyl. Oxo refers to (=O).

[0068] The terms "amine" and "amino" refer to derivatives of ammonia in which one or more hydrogen atoms are replaced with substituents including, but not limited to, alkyl, alkenyl, aryl, and heterocyclyl groups. In some embodiments, a substituted amino can include -NH-CO-R. A carbamate group refers to -O(C=O)NR1R2, where R1 and R2 are independently hydrogen, an aliphatic group, an aryl group, or a heterocyclyl group.

[0069] Aminocarbonyl is -C(O)N(R b )2, where each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; b may optionally be joined together with the nitrogen to which it is attached to form a heterocyclyl or substituted heterocyclyl group, provided that both R bprovided that both are not hydrogen. Aminocarbonylalkyl is -alkylC(O)N(R b )2, where each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; b may optionally be joined together with the nitrogen to which it is attached to form a heterocyclyl or substituted heterocyclyl group, provided that both R b provided that neither is hydrogen. Aminocarbonylamino is -NR a C(O)N(R b )2, where R a and each R b is as defined herein. Aminodicarbonylamino is —NR a C(O)C(O)N(R b )2, where R a and each R b is as defined herein. Aminocarbonyloxy is —OC(O)N(R b )2, where each R b are independently as defined herein. Aminosulfonyl is —SON(R b )2, where each R b are independently as defined herein.

[0070] Imino is -N=R c where R c may be selected from hydrogen, aminocarbonylalkyloxy, substituted aminocarbonylalkyloxy, aminocarbonylalkylamino, and substituted aminocarbonylalkylamino.

[0071] Additionally, unless otherwise stated, structural formulas depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (e.g., D or H 2) or tritium (e.g., T or H 3 ) for hydrogen, or 13 C- or 14 Compounds having this structural formula containing the replacement of a carbon with a C-enriched carbon are included within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in bioassays, or as therapeutic agents according to the present invention.

[0072] Pharmaceutically acceptable salts of the compounds described herein include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isothioic acid. In other cases, the compounds may contain one or more acidic functional groups and thus may form pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can likewise be prepared in situ during the administration vehicle or dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0073] A "prodrug" refers to a derivative of an active drug that requires conversion within the body to release the active drug. In certain embodiments, the conversion is enzymatic. A prodrug is often, but not necessarily, pharmacologically inactive until converted to an active drug. A "promoiety" refers to a form of protecting group used to mask a functional group within an active drug, converting the active drug into a prodrug. In some cases, the promoiety will be attached to the drug via bond(s) that are cleaved in vivo by enzymatic or non-enzymatic means. Any convenient prodrug form of the present compounds can be prepared by the strategies and methods described, for example, in Rautio et al. ("Prodrugs: design and clinical applications", Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0074] Disclosed herein are compounds according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. TIFF0007682097000025.tif29128

[0075] Each A, B, and X may independently be nitrogen or carbon. Each R may independently be hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. m may be an integer selected from 0 to 4.

[0076] R2, R3, and R4 are independently H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; TIFF0007682097000026.tif67150, or R2 and R3 together with the carbon may form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0077] L can be an optionally substituted C1-C5 alkyl linker, each of Y1, Y2, Y3, and Y4 can independently be a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Z can be O or S.

[0078] R5 and R6 may independently be hydrogen, unsubstituted or substituted alkyl, or R5 and R6 together with Y2 are cyclically bonded to form an optionally substituted cycloalkyl or heterocycle, and each R7 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0079] n can be an integer selected from 0 to 4, R8 can be hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, or unsubstituted or substituted amino.

[0080] Also disclosed herein are compounds according to formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. TIFF0007682097000027.tif31128

[0081] Each A, B, and X may independently be nitrogen or carbon. Each R1 may be hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. m may be an integer selected from 0 to 4.

[0082] R2, R3, and R4 are independently H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; TIFF0007682097000028.tif62150, or R2 and R3 together with the carbons may form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0083] L can be an optionally substituted C1-C5 alkyl linker, each Y1, Y2, Y3, and Y4 can independently be a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Z can be O or S.

[0084] R5 and R6 may independently be hydrogen, unsubstituted or substituted alkyl, or R5 and R6 may be cyclically bonded together with Y2 to form an optionally substituted cycloalkyl or heterocycle, and each R7 may be hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0085] n can be an integer selected from 0 to 4, R8 can be hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, or unsubstituted or substituted amino.

[0086] Further disclosed herein are compounds according to formula (III) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. TIFF0007682097000029.tif27128

[0087] Each R1 can independently be hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. m can be an integer selected from 0 to 4.

[0088] R2, R3, and R4 are independently H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; TIFF0007682097000030.tif62150, or R2 and R3 together with the carbons may form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0089] L can be an optionally substituted C1-C5 alkyl linker, each of X1, X2, X3, and X4 can independently be a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Y can be O or S.

[0090] R5 and R6 may independently be hydrogen, unsubstituted or substituted alkyl, or R5 and R6 may be cyclically bonded together with Y2 to form an optionally substituted cycloalkyl or heterocycle, and each R7 may independently be hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0091] n can be an integer selected from 0 to 4, R8 can be hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, or unsubstituted or substituted amino.

[0092] Additionally, compounds according to formula (I'): TIFF0007682097000031.tif32128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, A', B', and X' are each independently nitrogen or carbon; Each R 1’ are independently halogen, -R', -CN, -NO2, -SF5, -OR x , -NR x 2, -NHR x , -SO2R', -C(O)R', -C(O)NR'2; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R x are independent, C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R 2’ , R 3’ , and R 4’ are each independently a halogen, -R', -CN, -NO2, -OR', -NR'2, TIFF0007682097000032.tif61150, or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is optionally substituted C 1~5 is alkylene; Y 1’ , Y 2’ , Y 3’ , and Y 4’ each independently represents a covalent bond, carbon, oxygen, or hydrogen, or an optionally substituted C 1~6 is nitrogen optionally substituted with alkyl or an optionally substituted 3- to 7-membered saturated carbocyclic ring; Z' is O or S; R 5’ and R 6’ are each independently hydrogen or optionally substituted alkyl, or R 5’ and R 6’ is Y 2’ and are cyclically bonded together to form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7’ are independently -R', halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4; R 8’is hydrogen, —CN, an optionally substituted alkyl, or an optionally substituted aryl ring; Each R 9’ are independently hydrogen, halogen, -CN, -OR x , —NR′2, or optionally substituted alkyl; and R 10’ and R 11’ each independently represents hydrogen or an optionally substituted C 1~2 aliphatic].

[0093] Additionally, compounds according to formula (I″): TIFF0007682097000033.tif32128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, A', B', and X' are each independently nitrogen or carbon; Each R 1’ are independently halogen, -R', -CN, -NO2, -SF5, -OR x , -NR x 2, -NHR x , -SO2R', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'CO2R', or -CO2R'; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R x are independent, C 1~6an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R 2’ , R 3’ , and R 4’ are each independently a halogen, -R', -CN, -NO2, -OR', -NR'2, TIFF0007682097000034.tif60162, or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is optionally substituted C 1~5 is alkylene; Y 1’ , Y 2’ , Y 3’ , and Y 4’ each independently represents a covalent bond, carbon, oxygen, or hydrogen, or an optionally substituted C 1~6 is nitrogen optionally substituted with alkyl or an optionally substituted 3- to 7-membered saturated carbocyclic ring; Z' is O or S; R 5’ and R 6’ are each independently hydrogen or optionally substituted alkyl, or R 5’ and R6’ is Y 2’ and are cyclically bonded together to form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 7’ are independently -R', halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, —CN, an optionally substituted alkyl, or an optionally substituted aryl ring; Each R 9’ are independently hydrogen, halogen, -CN, -OR x , —NR′2, or optionally substituted alkyl; and R 10’ and R 11’ each independently represents hydrogen or an optionally substituted C 1~2 aliphatic].

[0094] As defined above and described herein, A' is nitrogen or carbon. In some embodiments, A' is nitrogen. In some embodiments, A' is carbon.

[0095] In some embodiments, A' is selected from those shown in Table 1 below.

[0096] As defined above and described herein, B' is nitrogen or carbon. In some embodiments, B' is nitrogen. In some embodiments, B' is carbon.

[0097] In some embodiments, B' is selected from those shown in Table 1 below.

[0098] As defined above and described herein, X' is nitrogen or carbon. In some embodiments, X' is nitrogen. In some embodiments, X' is carbon.

[0099] In some embodiments, X' is selected from those shown in Table 1 below.

[0100] As defined above, each R 1’ are independently halogen, -R', -CN, -NO2, -SF5, -OR x , -NR x 2, -NHR x , -SO2R', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'CO2R', or -CO2R'.

[0101] In some embodiments, R 1’ is hydrogen. In some embodiments, R 1’ is a halogen. In some embodiments, R 1’ is -R'. In some embodiments, R 1’ is cyano. In some embodiments, R 1’ is —NO. In some embodiments, R 1’ is -SF. In some embodiments, R 1’ -OR x In some embodiments, R 1’ is -NR x 2. In some embodiments, R 1’ -NHR x In some embodiments, R 1’ is -SO2R'. In some embodiments, R 1’ is —C(O)R′. In some embodiments, R 1’ is —C(O)NR′ 2. In some embodiments, R 1’ is —NR′C(O)R′. In some embodiments, R 1’is -NR'COR'. In some embodiments, R 1’ is -CO2R'.

[0102] In some embodiments, R 1’ is -Br. In some embodiments, R 1’ is -Cl. In some embodiments, R 1’ is -F.

[0103] In some embodiments, R 1’ is -CH3. In some embodiments, R 1’ is -CH2CH3. In some embodiments, R 1’ is -CH(CH3)2.

[0104] In some embodiments, R 1’ is —CF. In some embodiments, R 1’ is -CFH. In some embodiments, R 1’ is -CFH. In some embodiments, R 1’ is -CF2CH3. In some embodiments, R 1’ is —CH 2 CF 3 . In some embodiments, R 1’ is -C≡CCH. In some embodiments, R 1’ is vinyl. In some embodiments, R 1’ is -C≡CCF3. In some embodiments, R 1’ is -CO2H.

[0105] In some embodiments, R 1’ is -CN.

[0106] In some embodiments, R 1’ is —OCH. In some embodiments, R 1’ is —OCH2CH3. In some embodiments, R 1’ is —OCH(CH). In some embodiments, R 1’ is -OCF3. In some embodiments, R 1’ is -NHCH3. In some embodiments, R1’ is -NHCD. In some embodiments, R 1’ is —N(CD3)CO2tBu. In some embodiments, R 1’ is -NHCH2CH3. In some embodiments, R 1’ is —NHCH(CH). In some embodiments, R 1’ is -NHCHCF. In some embodiments, R 1’ is -NHPh. In some embodiments, R 1’ is -NHAc. In some embodiments, R 1’ is —N(CH). In some embodiments, R 1’ teeth, TIFF0007682097000035.tif11128. In some embodiments, R 1’ teeth, TIFF0007682097000036.tif14128. In some embodiments, R 1’ teeth, TIFF0007682097000037.tif6128. In some embodiments, R 1’ teeth, TIFF0007682097000038.tif8128. In some embodiments, R 1’ teeth, TIFF0007682097000039.tif9128. In some embodiments, R 1’ teeth, TIFF0007682097000040.tif9128. In some embodiments, R 1’ teeth, TIFF0007682097000041.tif12128. In some embodiments, R 1’ teeth, TIFF0007682097000042.tif13128. In some embodiments, R 1’ teeth, TIFF0007682097000043.tif9128. In some embodiments, R 1’ teeth, TIFF0007682097000044.tif11128. In some embodiments, R 1’ teeth, TIFF0007682097000045.tif9128. In some embodiments, R 1’ teeth, TIFF0007682097000046.tif11128. In some embodiments, R 1’ teeth, TIFF0007682097000047.tif9128. In some embodiments, R 1’ teeth, TIFF0007682097000048.tif14128. In some embodiments, R 1’ teeth, TIFF0007682097000049.tif9128. In some embodiments, R 1’ teeth, TIFF0007682097000050.tif10128. In some embodiments, R 1’ teeth, TIFF0007682097000051.tif9128. In some embodiments, R 1’ teeth, TIFF0007682097000052.tif10128. In some embodiments, R 1’ teeth, TIFF0007682097000053.tif9128. In some embodiments, R 1’ teeth, TIFF0007682097000054.tif11128. In some embodiments, R 1’ teeth, TIFF0007682097000055.tif10128. In some embodiments, R 1’ teeth, TIFF0007682097000056.tif13128. In some embodiments, R 1’ teeth, TIFF0007682097000057.tif17128. In some embodiments, R 1’ teeth, TIFF0007682097000058.tif12128. In some embodiments, R 1’ teeth, TIFF0007682097000059.tif7128. In some embodiments, R 1’ teeth, TIFF0007682097000060.tif11128. In some embodiments, R 1’ teeth, TIFF0007682097000061.tif10128. In some embodiments, R 1’ teeth, The file is TIFF0007682097000062.tif10128.

[0107] In some embodiments, R 1’ is selected from those shown in Table 1 below.

[0108] As defined above, each R' is independently hydrogen or C 1~6 It is an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0109] In some embodiments, R' is hydrogen.

[0110] In some embodiments, R' is an optionally substituted C 1~6 For example, in some embodiments, R' is -CF3, -CF2H, or -CFH2.

[0111] In some embodiments, R' is an optionally substituted 3-8 membered saturated monocyclic carbocyclic ring.

[0112] In some embodiments, R' is an optionally substituted 3-8 membered partially unsaturated monocyclic carbocyclic ring.

[0113] In some embodiments, R' is an optionally substituted phenyl.

[0114] In some embodiments, R' is an optionally substituted 8-10 membered bicyclic partially unsaturated carbocyclic ring.

[0115] In some embodiments, R' is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.

[0116] In some embodiments, R' is an optionally substituted 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0117] In some embodiments, R' is an optionally substituted 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0118] In some embodiments, R' is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0119] In some embodiments, R' is an optionally substituted 8-10 membered bicyclic partially unsaturated ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0120] In some embodiments, R' is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0121] In some embodiments, R' is selected from those shown in Table 1 below.

[0122] As defined above, each R x are independent, C 1~6 It is an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0123] In some embodiments, R x may be substituted C 1~6 For example, in some embodiments, R x is -CF, -CFH, or -CFH. In some embodiments, R x is C 1~6 It is alkyl.

[0124] As defined above, m' is an integer selected from 0-4.

[0125] In some embodiments, m' is 0. In some embodiments, m' is 1. In some embodiments, m' is 2. In some embodiments, m' is 3. In some embodiments, m' is 4.

[0126] As defined above, R 2’ , R 3’ , and R 4’ are each independently a halogen, -R', -CN, -OH, -OR', -NR'2, -NHR', -NH2, TIFF0007682097000063.tif60162 or R 2’ and R 3’together with the carbon, form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0127] In some embodiments, R 2’ is hydrogen. In some embodiments, R 2’ is a halogen. In some embodiments, R 2’ is -R'. In some embodiments, R 2’ is -CN. In some embodiments, R 2’ is —NO. In some embodiments, R 2’ is —OH. In some embodiments, R 2’ is -OR'. In some embodiments, R 2’ is -NR'. In some embodiments, R 2’ is -NHR'. In some embodiments, R 2’ is -NH2.

[0128] In some embodiments, R 2’ teeth, TIFF0007682097000064.tif16128. In some embodiments, R 2’ teeth, TIFF0007682097000065.tif14128. In some embodiments, R 2’ teeth, TIFF0007682097000066.tif20128. In some embodiments, R 2’ teeth, TIFF0007682097000067.tif19128. In some embodiments, R 2’ teeth, TIFF0007682097000068.tif15128. In some embodiments, R 2’ teeth, TIFF0007682097000069.tif12128. In some embodiments, R 2’ teeth, TIFF0007682097000070.tif13128. In some embodiments, R 2’ teeth, TIFF0007682097000071.tif15128. In some embodiments, R 2’ teeth, TIFF0007682097000072.tif15128. In some embodiments, R 2’ teeth, TIFF0007682097000073.tif14128. In some embodiments, R 2’ teeth, The file is TIFF0007682097000074.tif16128.

[0129] In some embodiments, R 2’ is hydrogen. In some embodiments, R 2’ is deuterium. In some embodiments, R 2’ is -CH3. In some embodiments, R 2’ is -CD3. In some embodiments, R 2’ teeth, The file is TIFF0007682097000075.tif12128.

[0130] In some embodiments, R 3’ is hydrogen. In some embodiments, R 3’ is a halogen. In some embodiments, R 3’ is -R'. In some embodiments, R 3’ is -CN. In some embodiments, R 3’ is —NO. In some embodiments, R 3’ is —OH. In some embodiments, R 3’ is -OR'. In some embodiments, R 3’ is -NR'. In some embodiments, R 3’ is -NHR'. In some embodiments, R3’ is -NH2.

[0131] In some embodiments, R 3’ teeth, TIFF0007682097000076.tif16128. In some embodiments, R 3’ teeth, TIFF0007682097000077.tif14128. In some embodiments, R 3’ teeth, TIFF0007682097000078.tif20128. In some embodiments, R 3’ teeth, TIFF0007682097000079.tif19128. In some embodiments, R 3’ teeth, TIFF0007682097000080.tif15128. In some embodiments, R 3’ teeth, TIFF0007682097000081.tif12128. In some embodiments, R 3’ teeth, TIFF0007682097000082.tif13128. In some embodiments, R 3’ teeth, TIFF0007682097000083.tif15128. In some embodiments, R 3’ teeth, TIFF0007682097000084.tif15128. In some embodiments, R 3’ teeth, TIFF0007682097000085.tif14128. In some embodiments, R 3’ teeth, The file is TIFF0007682097000086.tif16128.

[0132] In some embodiments, R 3’ is hydrogen. In some embodiments, R 3’ is deuterium. In some embodiments, R 3’is -CH3. In some embodiments, R 3’ is -CD3. In some embodiments, R 3’ teeth, The file is TIFF0007682097000087.tif12128.

[0133] In some embodiments, R 2’ and R 3’ together with the carbon, form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0134] In some embodiments, R 2’ and R 3’ together with the carbon, forms an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0135] In some embodiments, R 2’ and R 3’ together with the carbon form an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0136] In some embodiments, R 2’ and R 3’ together with the carbon form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0137] In some embodiments, R 2’ and R 3’ together with carbon, TIFF0007682097000088.tif11128. In some embodiments, R 2’ and R 3’ together with carbon, TIFF0007682097000089.tif13128. In some embodiments, R 2’ and R 3’ together with carbon, TIFF0007682097000090.tif17128. In some embodiments, R 2’ and R 3’ together with carbon, This forms TIFF0007682097000091.tif22128.

[0138] In some embodiments, R 4’ is hydrogen. In some embodiments, R 4’ is a halogen. In some embodiments, R 4’ is -R'. In some embodiments, R 4’ is -CN. In some embodiments, R 4’ is —NO. In some embodiments, R 4’ is —OH. In some embodiments, R 4’ is -OR'. In some embodiments, R 4’ is -NR'. In some embodiments, R 4’ is -NHR'. In some embodiments, R 4’ is -NH. In some embodiments, R 4’ is -CF3.

[0139] In some embodiments, R 4’ teeth, TIFF0007682097000092.tif16128. In some embodiments, R 4’ teeth, TIFF0007682097000093.tif14128. In some embodiments, R 4’ teeth, TIFF0007682097000094.tif20128. In some embodiments, R 4’ teeth, TIFF0007682097000095.tif19128. In some embodiments, R 4’ teeth, TIFF0007682097000096.tif15128. In some embodiments, R 4’ teeth, TIFF0007682097000097.tif12128. In some embodiments, R 4’ teeth, TIFF0007682097000098.tif13128. In some embodiments, R 4’ teeth, TIFF0007682097000099.tif15128. In some embodiments, R 4’ teeth, TIFF0007682097000100.tif15128. In some embodiments, R 4’ teeth, TIFF0007682097000101.tif14128. In some embodiments, R 4’ teeth, The file is TIFF0007682097000102.tif16128.

[0140] In some embodiments, R 4’ is hydrogen. In some embodiments, R 4’ is deuterium. In some embodiments, R 4’ is -CH3. In some embodiments, R 4’ In some embodiments, R 4’ teeth, The file is TIFF0007682097000103.tif12128.

[0141] In some embodiments, R 2’ , R 3’ , and R 4’ are each selected from those shown in Table 1 below.

[0142] As defined above, L' is an optionally substituted C 1~5 It is alkylene.

[0143] In some embodiments, L' is -CH2-.

[0144] In some embodiments, L' is selected from those shown in Table 1 below.

[0145] As defined above, Y 1’ , Y 2’ , Y 3’ , and Y 4’ each independently represents a covalent bond, carbon, oxygen, or hydrogen; optionally substituted C 1~6 It is nitrogen optionally substituted with alkyl or an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0146] In some embodiments, Y 1’ is a covalent bond. 1’ is carbon. In some embodiments, Y 1’ is oxygen. In some embodiments, Y 1’ is hydrogen, optionally substituted C 1~6 It is nitrogen optionally substituted with alkyl, or an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0147] In some embodiments, Y 2’ is a covalent bond. 2’ is carbon. In some embodiments, Y 2’ is oxygen. In some embodiments, Y 2’ is hydrogen, optionally substituted C 1~6 It is nitrogen optionally substituted with alkyl, or an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0148] In some embodiments, Y 3’ is a covalent bond. 3’ is carbon. In some embodiments, Y 3’ is oxygen. In some embodiments, Y 3’ is hydrogen, optionally substituted C 1~6 It is nitrogen optionally substituted with alkyl, or an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0149] In some embodiments, Y 3’ is a covalent bond. 3’ is carbon.

[0150] In some embodiments, Y 4’ is a covalent bond. 4’ is carbon. In some embodiments, Y 4’ is oxygen. In some embodiments, Y 4’ is hydrogen, optionally substituted C 1~6 It is nitrogen optionally substituted with alkyl, or an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0151] In some embodiments, Y 4’ is a covalent bond. 4’ is carbon.

[0152] In some embodiments, Y 1’ , Y 2’ , Y 3’ , and Y 4’ are each selected from those shown in Table 1 below.

[0153] Z' is O or S as defined above.

[0154] In some embodiments, Z' is O. In some embodiments, Z' is S.

[0155] In some embodiments, Z' is selected from those shown in Table 1 below.

[0156] As defined above, R 5’ and R 6’ are each independently hydrogen or optionally substituted alkyl, or R 5’ and R 6’ is Y 2’and are bonded together in a ring to form an optionally substituted 3- to 7-membered saturated carbocyclic ring; an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0157] In some embodiments, R 5’ is hydrogen. In some embodiments, R 5’ may be substituted C 1~6 It is alkyl.

[0158] In some embodiments, R 6’ is hydrogen. In some embodiments, R 6’ may be substituted C 1~6 It is alkyl.

[0159] In some embodiments, R 5’ and R 6’ is Y 2’ are bonded together in a ring to form an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0160] In some embodiments, R 5’ and R 6’ is Y 2’ and are bonded together in a ring to form an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0161] In some embodiments, R 5’ and R 6’ is Y 2’ and are bonded together in a ring to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0162] In some embodiments, R 5’ and R 6’ is Y 2’ and are bonded together in a ring to form an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0163] In some embodiments, R 5 ' and R 6 Each of the ' is selected from those shown in Table 1 below.

[0164] As defined above, each R 7 ' is independently -R', halogen, -CN, -NO2, -OH, -NR'2, -NHR', -NH2, or -OR'.

[0165] In some embodiments, R 7’ is hydrogen. In some embodiments, R 7’ is a halogen. In some embodiments, R 7’ is -CN. In some embodiments, R 7’ is —NO. In some embodiments, R 7’ is —OH. In some embodiments, R 7’ is -NR'. In some embodiments, R 7’ is -NHR'. In some embodiments, R 7’ is -NH. In some embodiments, R 7’ is -OR'.

[0166] In some embodiments, each R 7’ are independently selected from those shown in Table 1 below.

[0167] As defined above, n' is an integer selected from 0-4.

[0168] In some embodiments, n' is 0. In some embodiments, n' is 1. In some embodiments, n' is 2. In some embodiments, n' is 3. In some embodiments, n' is 4.

[0169] As defined above, R 8’ is hydrogen, —CN, an optionally substituted alkyl, or an optionally substituted aryl ring.

[0170] In some embodiments, R 8’ is hydrogen. In some embodiments, R 8’ is -CN. In some embodiments, R 8’ may be substituted C 1~6 In some embodiments, R 8’ is an optionally substituted aryl ring.

[0171] In some embodiments, R 8’ is selected from those shown in Table 1 below.

[0172] As defined above, each R 9’ are independently hydrogen, halogen, -CN, -OR x , -NR'2, or optionally substituted alkyl.

[0173] In some embodiments, R 9’ is hydrogen. In some embodiments, R 9’ is a halogen. In some embodiments, R 9’ is -CN. In some embodiments, R 9’ -OR x In some embodiments, R 9’ is -NR'. In some embodiments, R 9’ is -NHR'. In some embodiments, R 9’ is -NH. In some embodiments, R 9’ may be substituted C 1~6 It is alkyl.

[0174] In some embodiments, R 9’ is selected from those shown in Table 1 below.

[0175] As defined above, R 10’ and R 11’ each independently represents hydrogen or an optionally substituted C 1~2 In some embodiments, R 10’ and R 11’ are each independently hydrogen, methyl, or ethyl.

[0176] In some embodiments, R 10’ is hydrogen. In some embodiments, R 10’ is an optionally substituted C1 aliphatic. In some embodiments, R 10’ is methyl. In some embodiments, R 10’ is an optionally substituted C2 aliphatic. In some embodiments, R 10’ is ethyl.

[0177] In some embodiments, R 10’ is selected from those shown in Table 1 below.

[0178] In some embodiments, R 11’ is hydrogen. In some embodiments, R 11’ is an optionally substituted C1 aliphatic. In some embodiments, R 11’ is methyl. In some embodiments, R 11’ is an optionally substituted C2 aliphatic. In some embodiments, R 11’ is ethyl.

[0179] In some embodiments, R 11’ is selected from those shown in Table 1 below.

[0180] Additionally, compounds according to formula (II'): TIFF0007682097000104.tif28128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, A', B', X', R 1’ , R 2’ , R 3’ , R 4’ and m′, both alone and in combination, are as defined above and as described in the embodiments provided herein.

[0181] Additionally, compounds according to formula (III'): TIFF0007682097000105.tif25128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ , R 2’ , R 3’ , R 4’ and m′, both alone and in combination, are as defined above and as described in the embodiments provided herein.

[0182] Additionally, compounds according to formula (IV'): TIFF0007682097000106.tif25128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ , R 2’ , R 3’ , and R 4’ each of which, both alone and in combination, is as defined above and as described in the embodiments provided herein. In some such embodiments, R 1’ is —CF. In some such embodiments, R 1’ is -CFH. In some such embodiments, R 1’ is -OCF3. In some such embodiments, R 1’ In some such embodiments, R 1’ is —C(O)NR′ 2. In some such embodiments, R 1’is a cyclopropyl group. In some such embodiments, R 1’ is tetrazole. In some such embodiments, R 1’ is phenyl. In some such embodiments, R 1’ In some such embodiments, R 1’ is -CH3.

[0183] Additionally, compounds according to formula (V'): TIFF0007682097000107.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ and m', both alone and in combination, are as defined above and as described in the embodiments provided herein.

[0184] Additionally, compounds according to formula (VI'): TIFF0007682097000108.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ are as defined above and as described in the embodiments provided herein, both alone and in combination].

[0185] Additionally, compounds according to formula (VII'): TIFF0007682097000109.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ , R 2’ , R 3’ , R 4’ and m′, both alone and in combination, are as defined above and as described in the embodiments provided herein.

[0186] Furthermore, compounds according to formula (VIII'): TIFF0007682097000110.tif25128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ , R 2’ , R 3’ , R 4’ and m′, both alone and in combination, are as defined above and as described in the embodiments provided herein.

[0187] Furthermore, compounds according to formula (IX'): TIFF0007682097000111.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ , R 2’ , R 3’ , R 4’ and m′, both alone and in combination, are as defined above and as described in the embodiments provided herein.

[0188] Additionally, compounds according to formula (X'): TIFF0007682097000112.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is halogen, -R x , -CN, -NO2, -SF5, -OR x , -SO2R', or -C(O)R'; R 2’ , R 3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2’ and R 3’ together with the carbons form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring; and R' and R xare as defined above and as described in the embodiments provided herein, both alone and in combination. In some such embodiments, R 1’ is —CF. In some such embodiments, R 1’ is -CFH. In some such embodiments, R 1’ is -OCF3. In some such embodiments, R 1’ In some such embodiments, R 1’ is —C(O)NR′ 2. In some such embodiments, R 1’ is a cyclopropyl group. In some such embodiments, R 1’ is tetrazole. In some such embodiments, R 1’ is phenyl. In some such embodiments, R 1’ In some such embodiments, R 1’ is -CH3.

[0189] Additionally, compounds according to formula (XI'): TIFF0007682097000113.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is halogen, -R', -CN, -NO2, -SF5, -OR x , -SO2R', or -C(O)R'; R 2’ , R 3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2’ and R 3’ together with the carbons form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring; and R' and R x are as defined above and as described in the embodiments provided herein, both alone and in combination].

[0190] Furthermore, compounds according to formula (XII'): TIFF0007682097000114.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is halogen, -R', -CN, -NO2, -SF5, -OR x , -SO2R', or -C(O)R'; and R' and R x are as defined above and as described in the embodiments provided herein, both alone and in combination].

[0191] Furthermore, compounds according to formula (XIII'): TIFF0007682097000115.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is halogen, -R', -CN, -NO2, -SF5, -OR x , -SO2R', or -C(O)R'; and R' and R x are as defined above and as described in the embodiments provided herein, both alone and in combination].

[0192] Additionally, compounds according to formula (XIV'): TIFF0007682097000116.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, -R', -CN, or -NO2; R 2’ , R 3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2 ' and R 3' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring; and R', both alone and in combination, is as defined above and as described in the embodiments provided herein.

[0193] Additionally, compounds according to formula (XV'): TIFF0007682097000117.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, -R', -CN, or -NO2; R 2’ , R 3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring; and R', both alone and in combination, is as defined above and as described in the embodiments provided herein.

[0194] Additionally, compounds according to formula (XVI'): TIFF0007682097000118.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, —R′, —CN, or —NO2; and R', both alone and in combination, is as defined above and as described in the embodiments provided herein.

[0195] Additionally, compounds according to formula (XVII'): TIFF0007682097000119.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, -R', -CN, or -NO2; Each R' is an optionally substituted C 1~6 is aliphatic; and R 2’ , R 3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0196] Furthermore, compounds according to formula (XVIII'): TIFF0007682097000120.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, -R', -CN, or -NO2; Each R' is an optionally substituted C 1~6 is aliphatic; and R 2’ , R 3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0197] Furthermore, compounds according to formula (XIX'): TIFF0007682097000121.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, —R′, —CN, or —NO2; and R' is an optionally substituted C1~6 aliphatic].

[0198] Furthermore, compounds according to formula (XX'): TIFF0007682097000122.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, —R′, —CN, or —NO2; and R' is an optionally substituted C 1~6 aliphatic].

[0199] Furthermore, compounds according to formula (XXI'): TIFF0007682097000123.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, -R', -CN, or -NO2; Each R' is an optionally substituted C 1~6 is aliphatic; and R 2’ , R 3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0200] Furthermore, compounds according to formula (XXII'): TIFF0007682097000124.tif25128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, -R', -CN, or -NO2; Each R' is an optionally substituted C 1~6 is aliphatic; and R 2’ , R3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0201] Furthermore, compounds according to formula (XXIII'): TIFF0007682097000125.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, —R′, —CN, or —NO2; and R' is an optionally substituted C 1~6 aliphatic].

[0202] Furthermore, compounds according to formula (XXIV'): TIFF0007682097000126.tif25128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, R 1’ is a halogen, —R′, —CN, or —NO2; and R' is an optionally substituted C 1~6 aliphatic].

[0203] Furthermore, compounds according to formula (XXV'): TIFF0007682097000127.tif29128 or a pharmaceutically acceptable salt thereof is disclosed herein. [In the formula, A', B', X', R 1’ , R 2’ , R 3’ , R 4’ and m′, both alone and in combination, are as defined above and as described in the embodiments provided herein.

[0204] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both 1) therapeutic treatments or measures that cure, slow, alleviate the symptoms of, and / or halt the progression of a diagnosed pathological condition, disease, or disorder, and 2) as well as prophylactic / preventative measures. Those in need of treatment can include individuals who already have a particular medical disease or disorder, as well as individuals who will eventually acquire the disorder (i.e., those at risk or in need of preventative measures).

[0205] The term "subject" as used herein refers to any individual or patient on whom the present methods are performed. Generally, the subject is a human, although, as will be appreciated by those skilled in the art, the subject may also be an animal.

[0206] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like refer to an amount of the compound that will elicit a desired biological or medical response in a tissue, system, animal, or human upon administration of the compound. Generally, the response is either amelioration of symptoms in a patient or a desired biological outcome. In some embodiments, such an amount should be sufficient to modulate adrenergic receptors.

[0207] In some embodiments, an effective amount of an adrenoceptor-modulating compound is from about 50 ng / ml to 50 pg / ml (e.g., from about 50 ng / ml to 40 pg / ml, from about 30 ng / ml to 20 pg / ml, from about 50 ng / ml to 10 μg / ml, from about 50 ng / ml to 1 μg / ml, from about 50 ng / ml to 800 ng / ml, from about 50 ng / ml to 700 ng / ml, from about 50 ng / ml to 600 ng / ml, from about 50 ng / ml to 500 ng / ml, from about 50 ng / ml to 400 ng / ml, from about 60 ng / ml to 40 The amount is in the range of about 0 ng / ml, about 70 ng / ml to 300 ng / ml, about 60 ng / ml to 100 ng / ml, about 65 ng / ml to 85 ng / ml, about 70 ng / ml to 90 ng / ml, about 200 ng / ml to 900 ng / ml, about 200 ng / ml to 800 ng / ml, about 200 ng / ml to 700 ng / ml, about 200 ng / ml to 600 ng / ml, about 200 ng / ml to 500 ng / ml, about 200 ng / ml to 400 ng / ml, or about 200 ng / ml to about 50 ng / ml).

[0208] In some embodiments, an effective amount of an adrenoceptor-modulating compound is from about 10 pg to 100 mg, e.g., from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1 ng, from about 1 ng to 10 ng, from about 10 ng to 50 ng, from about 50 ng to 150 ng, from about 150 ng to 250 ng The amount is in the range of about 250 ng to 500 ng, about 500 ng to 750 ng, about 750 ng to 1 mg, about 1 pg to 10 pg, about 10 pg to 50 pg, about 50 pg to 150 pg, about 150 pg to 250 pg, about 250 pg to 500 pg, about 500 pg to 750 pg, about 750 pg to 1 mg, about 1 mg to 50 mg, about 1 mg to 100 mg, or about 50 mg to 100 mg. The above amounts may be single doses or total daily amounts. The total daily amount may be in the range of about 10 pg to 100 mg, about 100 mg to 500 mg, or about 500 mg to 1000 mg.

[0209] Also disclosed herein are pharmaceutical compositions comprising compounds described herein, for example, having the structural formulas of Formula (I), Formula (II), Formula (III), Formula (I'), Formula (I"), Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), Formula (VII'), Formula (VIII'), Formula (IX'), Formula (X'), Formula (XI'), Formula (XII'), Formula (XIII'), Formula (XIV'), Formula (XV'), Formula (XVI'), Formula (XVII'), Formula (XVIII'), Formula (XIX'), Formula (XX'), Formula (XXI'), Formula (XXII'), Formula (XXIII'), Formula (XXIV'), and Formula (XXV'). The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be administered to a patient together with a compound of the present disclosure without destroying its pharmacological activity. Pharmaceutically acceptable carriers that can be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0210] For pharmaceutical compositions containing only a compound described herein as an active ingredient, methods for administering these compositions may additionally include administering to the subject an additional drug or treatment. Such treatments include, but are not limited to, anemia treatments, diabetes treatments, hypertension treatments, cholesterol treatments, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, or blood cell production; hormones and antagonists, drugs that affect gastrointestinal function, chemotherapeutics for microbial diseases, and / or chemotherapeutics for neoplastic diseases. Other pharmacological treatments may include any other drug or biological agent found in any drug class. For example, other drug classes may include allergy / cold / ENT treatments, analgesics, anesthetics, anti-inflammatory drugs, antimicrobials, antivirals, asthma / pulmonary treatments, cardiovascular treatments, dermatological treatments, endocrine / metabolic treatments, gastrointestinal treatments, cancer treatments, immunotherapy, neurotherapy, ophthalmology treatments, psychiatric treatments, or rheumatology treatments. Other examples of drugs or treatments that can be administered with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

[0211] The term "therapeutically effective amount," as used herein, refers to an amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, individual, or human that is sought by a researcher, veterinarian, physician, or other clinician, including one or more of: (1) preventing a disease in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or displayed the pathology or symptomology of the disease; e.g., preventing the disease, condition, or disorder; (2) inhibiting a disease in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder; e.g., inhibiting the disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomology); and (3) ameliorating a disease; e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptomology) in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder.

[0212] In some embodiments, the compounds described herein can be adrenergic receptor-modulating compounds (e.g., adrenergic receptor agonists, partial agonists, or antagonists). The adrenergic receptor-modulating compounds of the present disclosure can, in some embodiments, be used to modulate the activity of a target adrenergic receptor in vitro or in vivo. Aspects of the method include contacting a sample with an effective amount of an adrenergic receptor-modulating compound (e.g., as described herein) to determine whether the desired activity is present.

[0213] Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCRs) widely expressed throughout the body and play important roles in regulating multiple physiological processes, including cognition, stress-related behavior, inflammation, and smooth muscle contraction / dilation, myocardial contraction, airway reactivity, and cognition. Adrenergic receptors mediate the central and peripheral actions of noradrenaline (NA) and adrenaline. Multiple ADR subtypes exist, including α- and β-adrenergic receptors. Each subtype is expressed in a distinct pattern and is involved in various physiological processes. Therefore, ligands that selectively target one subtype are valuable both as research tools for identifying the roles of different ADR subtypes and as therapeutic agents for multiple diseases associated with dysfunction of the NA and adrenergic systems.

[0214] β-adrenergic receptors further include three subtypes: β1-adrenergic receptors (β1-ADRs), β2-adrenergic receptors (β2-ADRs), and β3-adrenergic receptors (β3-ADRs). Because these subtypes are expressed in distinct patterns and are involved in different physiological processes, ligands that can selectively target one subtype have therapeutic potential for multiple diseases. However, the discovery of subtype-selective ligands is difficult due to the high level of sequence homology shared by these subtypes. Many existing agonists for β-adrenergic receptors also exhibit poor blood-brain barrier (BBB) ​​penetration, which makes drug discovery for central nervous system (CNS) applications challenging.

[0215] As a group of G protein-coupled receptors, adrenergic receptors signal through G protein- and β-arrestin-dependent pathways. G protein- or β-arrestin signaling can mediate various physiological responses. Recently, it has become clear that agonists can exhibit biased activation of signaling pathways. The ability of a ligand to activate a receptor and generate a pathway-dependent response is referred to as "signaling bias" or "functional selectivity." Because G proteins and β-arrestins mediate distinct physiological processes, biased agonists can provide improved therapeutic selectivity with reduced adverse effects. Therefore, the present disclosure is directed to β-adrenergic receptor subtype-selective agonists with improved blood-brain barrier (BBB) ​​penetration.

[0216] The adrenergic receptor-modulating compound can be an agonist of the target adrenergic receptor. In some cases, the effective amount of the adrenergic receptor-modulating compound is sufficient to activate the activity associated with the adrenergic receptor in a cell by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or even more, compared to a control, for example, a control cell exhibiting a known level of receptor activity.

[0217] Said adrenergic receptor regulating compound can be the partial agonist of target adrenergic receptor.In some cases, the effective amount of adrenergic receptor regulating compound is sufficient to achieve partial agonism of adrenergic receptor in cell, for example, the compound achieves 10% or more activation of receptor, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, compared with control, for example, fully activated receptor.Partial agonism can be evaluated by any convenient method, for example, by using a cell-based assay that uses a known full agonist as 100% activation control, and the relative maximum activation of receptor can be measured compared with full agonist.

[0218] The adrenergic receptor-modulating compound can be an antagonist of the target adrenergic receptor.In some cases, an effective amount of the adrenergic receptor-modulating compound is an amount sufficient to inhibit or reduce the activity of the target adrenergic receptor in a sample by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or even more, compared to a control, for example, a sample not contacted with the compound of interest.

[0219] In some embodiments, compounds of the present disclosure act as low nM partial agonists of β2 adrenergic receptors. For example, in some embodiments, compounds of the present disclosure have an EC of less than about 1 nM, less than about 5 nM, less than about 10 nM, less than about 15 nM, less than about 20 nM, less than 25 nM, less than 30 nM, less than 35 nM, less than 40 nM, less than 45 nM, less than 50 nM, less than 55 nM, less than 60 nM, less than 65 nM, less than 70 nM, less than 75 nM, less than 80 nM, less than 85 nM, less than 90 nM, less than 95 nM, or less than 100 nM. 50In some embodiments, compounds of the present disclosure act as low nM partial agonists of β2 adrenergic receptors and have an EC of about 0.001 nM to about 200 nM, 0.001 nM to about 150 nM, 0.001 nM to about 100 nM, 0.01 nM to about 100 nM, 0.1 nM to about 100 nM, or about 0.1 nM to about 80 nM, or about 0.1 nM to about 60 nM, or about 0.1 nM to about 40 nM, or about 0.1 nM to about 30 nM, or about 0.1 nM to about 20 nM, or about 0.1 nM to about 10 nM. 50 It has.

[0220] In some embodiments, compounds of the present disclosure act as low μM partial agonists of β2 adrenergic receptors. For example, in some embodiments, compounds of the present disclosure have an EC of less than about 0.1 μM, less than about 0.5 μM, less than about 1.0 μM, less than about 1.5 μM, less than about 2.0 μM, less than about 2.5 μM, less than about 3.0 μM, less than about 3.5 μM, less than about 4.0 μM, less than about 4.5 μM, less than about 5.0 μM, less than about 5.5 μM, less than about 6.0 μM, less than about 6.5 μM, less than about 7.0 μM, less than about 7.5 μM, less than about 8.0 μM, less than about 8.5 μM, less than about 9.0 μM, less than about 9.5 μM, or less than about 10.0 μM. 50 It has.

[0221] In some embodiments, compounds of the present disclosure act as low μM partial agonists of β2 adrenergic receptors and have an EC of about 0.01 μM to about 10 μM, about 0.01 μM to about 9.0 μM, about 0.01 μM to about 8.0 μM, about 0.01 μM to about 7.0 μM, about 0.01 μM to about 6.0 μM, about 0.01 μM to about 5.0 μM, about 0.01 μM to about 4.0 μM, about 0.01 μM to about 3.0 μM, about 0.01 μM to about 2.0 μM, about 0.01 μM to about 1.0 μM, about 0.01 μM to about 9.0 μM, or about 0.1 μM to about 1.0 μM. 50 It has.

[0222] In some embodiments of the method, the target adrenergic receptor is a β1-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β2-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β3-adrenergic receptor. In some embodiments, the compound is an agonist for both the β1-adrenergic receptor and the β2-adrenergic receptor. In certain cases, the compound is selective for the β2-adrenergic receptor over the β1-adrenergic receptor.

[0223] The target adrenergic receptor may be responsible for mediating an intracellular signal or pathway in the cell. In some embodiments, the sample comprises a cell, and modulation of the adrenergic receptor regulates a physiological process in the cell. Any convenient physiological process can be targeted for modulation in the cell using the method. In some embodiments, the physiological process is involved in cardiac function, and in certain cases, the physiological process is involved in cognitive function. In certain cases, the physiological process is involved in an inflammatory pathway or condition. The method may provide for mediating the intracellular concentration of a signaling molecule, e.g., cAMP, in the cell. The method may provide partial or complete blockade of the target adrenergic receptor, resulting in modulation (e.g., activation) of cAMP in the sample. In some embodiments, the method does not regulate the beta-arrestin pathway in the cell. In some cases, the cell is an inflammatory cell, and the function of the cell is controlled. The method may result in inhibition of an inflammatory pathway in the cell. In some embodiments, TNF-alpha is inhibited in the cell, e.g., performing the method reduces the concentration or production of TNF-alpha. In certain embodiments of the method, the cell is a neuron. In some embodiments, modulating adrenergic receptors enhances neurogenesis.

[0224] The compounds of the present disclosure can be used in a conventional manner to control, prevent, or treat the diseases described herein, including, but not limited to, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedreich's ataxia, ataxia-telangiectasia, spinal muscular dystrophies, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis, cerebral autosomal dominant arteriopathy with subcortical infarction (CADASIL), and diabetic retinopathy. Such treatment methods, their dosage levels and requirements can be selected by one skilled in the art from available methods and techniques.

[0225] As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the compound can be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form comprising the compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "in combination" when a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "in combination" when a patient or individual simultaneously exhibits therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in the brain, in serum, etc.).

[0226] When the compounds of the present disclosure are administered in combination therapy with other agents, they may be administered sequentially or simultaneously to a patient. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure includes a combination of ivermectin, or any other compound described herein, and another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may also be referred to as "agents appropriate for the disease or condition being treated."

[0227] In some embodiments, the method comprises administering one or more additional active agents in a therapeutically effective amount.Combined therapy means that the adrenergic receptor modulating compound can be used in combination with another therapeutic agent to treat a single disease or condition.In certain embodiments, the compound of the present disclosure is administered simultaneously with the administration of another therapeutic agent, which can be administered as a component of the composition comprising the compound of the present disclosure or as a component of another composition.

[0228] The present compound can be administered in combination with other therapeutic agents in various therapeutic applications.Target therapeutic applications for combination therapy include applications in which the activity of target adrenergic receptors is a causative or aggravating factor in disease progression.Therefore, the present compound can be used in combination therapy in which the inhibition of target adrenergic receptors in subjects is desired.Examples of disease states that can be treated by combination therapy with the present compound include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental diseases, respiratory disorders, asthma, memory disorders, depression, inflammatory diseases, stroke, ischemic brain or tissue damage, and cancer.Target drugs that can be used in combination with the present adrenergic receptor-modulating compound include, but are not limited to, antidepressants, antipsychotics, beta-blockers, vasoconstrictors, antihypertensives, decongestants, chemotherapy drugs, drugs used in Alzheimer's disease, and anti-inflammatory drugs.

[0229] The adrenergic receptor-modulating compounds can be used in combination with any drug useful in treating cardiac conditions such as cardiogenic shock, hypertension, congestive heart failure, ischemic heart disease, arrhythmia, myocardial infarction, or ischemic heart disease. Drugs of interest that can be used in combination with the adrenergic receptor-modulating compounds include, but are not limited to, denopamine, dobutamine, xamoterol, acebutolol, atenolol, betaxolol, bisoprolol, pindolol, esmolol, metoprolol, nebivolol, vortioxetine, carvedilol, labetalol, phentolamine, prazosin, cirazoline, methoxamine, synephrine, etilefrine, metaraminol, midodrine, and coumarin.

[0230] The adrenergic receptor modulating compound can be used in combination with any drug useful in the treatment of neurodegenerative or neurodevelopmental diseases, such as Alzheimer's disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue damage, Down's syndrome, or autism. Drugs of interest that can be used in combination with the adrenergic receptor modulating compound include, but are not limited to, acepromazine. In some embodiments, the adrenergic receptor modulating compound can be used in combination with a cholinesterase inhibitor or an NMDA receptor modulating substance in the treatment of diseases, such as neurodegenerative or neurodevelopmental diseases. Drugs of interest include, but are not limited to, donepezil, Aricept, galantamine, razadine, memantine, namenda, rivastigmine, Exelon, tacrine, and Cognex. Other drugs of interest that can be used in conjunction with the present adrenergic receptor modulating compounds include, but are not limited to, 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tiamenidine, These include azithromycin, tizanidine, tolonidine, xylazine, xylometazoline, aripiprazole, asenapine, atipamezole, cirazoline, clozapine, efaroxan, idazoxan, lurasidone, melperone, mianserin, mirtazapine, napitan, olanzapine, paliperidone, phenoxybenzamine, phentolamine, piribedil, rauwolscine, risperidone, rotigotine, quetiapine, norquetiapine, setiptiline, tolazoline, yohimbine, ziprasidone, and zotepine.Other drugs of interest that may be used in conjunction with the present adrenergic receptor-modulating compounds include, but are not limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levosalbutamol or levalbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol, salbutamol or albuterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, mirveterol, olodaterol, vilanterol, fenoterol, hexoprenaline, isoxsuprine, ritodrine, salbutamol or albuterol, terbutaline, zilpaterol, ICI-118,551, and butoxamine.

[0231] The compounds utilized in the compositions and methods of the present disclosure can also be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and / or alter excretion rate.

[0232] According to a preferred embodiment, the compositions of the present disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human, and such pharmaceutical compositions are used to ameliorate, treat, or prevent any of the diseases described herein in the subject.

[0233] The agents of the present disclosure are often administered as pharmaceutical compositions containing an active therapeutic agent, i.e., and various other pharmaceutically acceptable ingredients. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application. Depending on the desired formulation, the composition may contain a pharmaceutically acceptable non-toxic carrier or diluent, defined as a vehicle commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may contain other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0234] In some embodiments, the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the above compounds formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents for use in the treatment of diseases described herein, including, but not limited to, stroke, ischemia, Alzheimer's disease, ankylosing spondylitis, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, systemic lupus erythematosus, nephritis, ulcerative colitis, and Parkinson's disease. Although the compounds can be administered alone, it is preferred to administer the compounds as pharmaceutical formulations as described herein. By analogy with other pharmaceuticals, the compounds can be formulated for administration in any convenient manner for use in human or veterinary medicine.

[0235] As detailed above, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as sterile solutions or suspensions, or sustained release formulations; topical application, e.g., as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or oral cavity; vaginally or rectally, e.g., as vaginal suppositories, creams, or foams; sublingually; ophthalmically; transdermally; or adapted for nasal, pulmonary, and other mucosal surfaces.

[0236] Wetting agents, emulsifying agents and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition.

[0237] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0238] Formulations for use in accordance with the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. Such formulations may be conveniently presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount ranges from about 1% to about 99% of the active ingredient. In some embodiments, this amount ranges from about 5% to about 70%, from about 10% to about 50%, or from about 20% to about 40%.

[0239] In certain embodiments, a formulation as described herein comprises an additive selected from the group consisting of cyclodextrins, liposomes, micelle-forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present disclosure. In certain embodiments, the formulation makes the compound of the present disclosure orally bioavailable.

[0240] Methods of preparing formulations or compositions containing the compounds include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations can be prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0241] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. Such suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80, etc.) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as those described in the Swiss Pharmacopoeia, or similar alcohols. Other commonly used surfactants, such as Tween, Spann, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0242] In some cases, in order to prolong the effect of a drug, it may be desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the size and crystalline form of the crystal.Alternatively, the absorption of parenterally administered drug forms can be delayed by dissolving or suspending the drug in an oil vehicle.

[0243] Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0244] The pharmaceutical compositions of the present disclosure can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants, such as magnesium stearate, are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.For oral administration of aqueous suspensions and solutions and propylene glycol, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners and / or flavorings and / or coloring agents can be added.

[0245] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (with a flavored base, usually sucrose and gum arabic or tragacanth), powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (with an inert base such as gelatin and glycerin, or sucrose and gum arabic), and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present disclosure as an active ingredient. The compounds described herein may also be administered as a bolus, electuary, or paste.

[0246] Solid dosage forms for oral administration (such as capsules, tablets, pills, dragees, powders, granules, and the like) may comprise the active ingredient in one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum acacia; humectants, such as glycerol; disintegrants, such as agar-agar. , calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard-shell gelatin capsules, using additives such as lactose or milk sugar, as well as high molecular weight polyethylene glycols.

[0247] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets can be made in a suitable machine by moistening a mixture of powdered compounds with an inert liquid diluent. When a solid carrier is used, the preparation can be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier can vary, for example, from about 25 to 800 mg, preferably from about 25 to 400 mg. When a liquid carrier is used, the preparation can be in the form of, for example, a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or non-aqueous liquid suspension. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the above carriers in a hard gelatin capsule shell.

[0248] Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Alternatively, or additionally, they can be formulated using, for example, various ratios of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to achieve the desired release profile, resulting in delayed or controlled release of the active ingredient therein. They can be formulated for rapid release, for example, freeze-dried. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents into the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may optionally contain opacifying agents and can be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0249] Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0250] Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0251] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0252] The pharmaceutical composition of the present disclosure can also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present disclosure with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature, and therefore should melt in the rectum to release the active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycol.

[0253] Topical administration of the pharmaceutical composition of the present disclosure is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present disclosure can also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present disclosure.

[0254] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions may be prepared by techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0255] For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated in an ointment such as petrolatum.

[0256] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present disclosure to the body.Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound through the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0257] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0258] Such compositions may contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. In certain embodiments, it may be desirable to include one or more antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. Alternatively, or in addition, it may be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the composition. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0259] In certain embodiments, the compound or pharmaceutical formulation is administered orally. In other embodiments, the compound or pharmaceutical formulation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0260] When the compounds described herein are administered as pharmaceuticals to humans and animals, they can be given as is or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0261] The preparations described herein can be given orally, parenterally, topically, or rectally. They are, of course, given in a form suitable for the relevant administration route. For example, they are administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by injection, infusion, or inhalation; topically by lotions or ointments; and rectally by suppositories. Oral administration is preferred.

[0262] Such compounds can be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, e.g., by aerosol, rectally, vaginally, parenterally, intracisternally, and bucally and sublingually, and topically, such as by powders, ointments, or drops.

[0263] Regardless of the route of administration selected, the compounds described herein, which may be used in a suitable hydrated form, and / or pharmaceutical compositions of the present disclosure are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0264] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response in a particular patient, composition, and mode of administration without being toxic to the patient.

[0265] Kits containing the disclosed adrenergic receptor-modulating compounds are also provided. The disclosed systems include a collection of active agents, compiled, for example, by a healthcare practitioner, for administration to a subject, such as a patient. Such systems may include an adrenergic receptor-modulating compound and one or more additional active agents disclosed herein. The provided kits containing adrenergic receptor-modulating compounds may include one or more dosages of the adrenergic receptor-modulating compound and, optionally, one or more dosages of one or more additional active agents. Conveniently, the formulations may be provided in unit dosage form. In addition to the formulation(s), e.g., a container containing a unit dose, such kits include an information package insert describing the use of the formulation in the methods described herein, e.g., instructions for using the unit dose to treat a cell proliferative disease condition. These instructions may be present in the systems and kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is as information printed on a suitable medium or substrate within the kit's packaging, e.g., as a piece of paper with the information printed thereon, in a package insert, etc. Another means would be a computer-readable medium on which the information has been recorded, e.g., a floppy disk, CD, etc. Another means that may be present is a website address that can be used via the internet to access the information at a remote location. Any convenient means may be present in the kit.

[0266] Table 1 below illustrates compounds that have been synthesized and characterized in this disclosure. Table 1 also illustrates representative compounds contemplated by this disclosure. Table 1: Compounds of the present disclosure TIFF0007682097000128.tif184143TIFF0007682097000129.tif221143TIFF0007682097000130.tif226143TIFF0007682097000131.tif227143TIFF0007682097000132.tif231143TIFF0007682097000133.tif229143TIFF0007682097000134.tif208143TIFF0007682097000135.tif211143TIFF0007682097000136.tif218143TIFF0007682097000137.tif232143TIFF0007682097000138.tif220143TIFF0007682097000139.tif207143TIFF0007682097000140.tif231143TIFF0007682097000141.tif222143TIFF0007682097000142.tif231143TIFF0007682097000143.tif197143TIFF0007682097000144.tif200143TIFF0007682097000145.tif232143TIFF0007682097000146.tif221143TIFF0007682097000147.tif224143TIFF0007682097000148.tif226143TIFF0007682097000149.tif225143TIFF0007682097000150.tif227143TIFF0007682097000151.tif202143TIFF0007682097000152.tif221143TIFF0007682097000153.tif220143TIFF0007682097000154.tif224143TIFF0007682097000155.tif208143TIFF0007682097000156.tif221143TIFF0007682097000157.tif180143TIFF0007682097000158.tif225143TIFF0007682097000159.tif223143TIFF0007682097000160.tif219143TIFF0007682097000161.tif224143TIFF0007682097000162.tif213143TIFF0007682097000163.tif231143TIFF0007682097000164.ti f219143TIFF0007682097000165.tif213143TIFF0007682097000166.tif228143TIFF0007682097000167.tif222143TIFF0007682097000168.tif2 08143TIFF0007682097000169.tif228143TIFF0007682097000170.tif200143TIFF0007682097000171.tif186143TIFF0007682097000172.tif194 143TIFF0007682097000173.tif229143TIFF0007682097000174.tif226143TIFF0007682097000175.tif230143TIFF0007682097000176.tif61143.

[0267] In some embodiments, the disclosure provides a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0268] Also disclosed herein is a pharmaceutical composition comprising a compound having a structural formula of Formula (I), Formula (II), Formula (III), Formula (I'), Formula (I''), Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), Formula (VII'), Formula (VIII'), Formula (IX'), Formula (X'), Formula (XI'), Formula (XII'), Formula (XIII'), Formula (XIV'), Formula (XV'), Formula (XVI'), Formula (XVII'), Formula (XVIII'), Formula (XIX'), Formula (XX'), Formula (XXI'), Formula (XXII'), Formula (XXIII'), Formula (XXIV'), or Formula (XXV'), and a pharmaceutically acceptable excipient. Further disclosed is a method of treating a subject having a disease associated with an adrenergic receptor, comprising administering to the subject a therapeutically effective amount of a compound having a structural formula of Formula (I), (II), (III), (I'), (I''), (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XV'), (XVI'), (XVII'), (XVIII'), (XIX'), (XX'), (XXI'), (XXII'), (XXIII'), (XXIV'), or (XXV'), thereby treating the subject. In some embodiments, the disease is a neurodegenerative disease and the subject is a human.

[0269] In some embodiments, the disease is selected from the group consisting of myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedreich's ataxia, ataxia-telangiectasia, spinal muscular dystrophies, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipozymosis. In some embodiments, the compound is administered to a subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal routes. In one embodiment, the compound is selected from the compounds shown in Table 1.

[0270] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, and by methods detailed in the Examples herein. In one embodiment, a compound selected from the compounds shown in Table 1 was prepared by the method shown in Scheme A. Scheme A. TIFF0007682097000177.tif18142

[0271] In one embodiment, a compound selected from the compounds shown in Table 1 was prepared by the method shown in Scheme B. Scheme B. TIFF0007682097000178.tif20142

[0272] In one embodiment, a compound selected from the compounds shown in Table 1 was prepared by the method shown in Scheme C. Scheme C. TIFF0007682097000179.tif21142

[0273] In one embodiment, a compound selected from the compounds shown in Table 1 was prepared by the method shown in Scheme D. Scheme D. TIFF0007682097000180.tif18142

[0274] In one embodiment, a compound selected from the compounds shown in Table 1 was prepared by the method shown in Scheme E. Scheme E. TIFF0007682097000181.tif22142

[0275] In one embodiment, a compound selected from the compounds shown in Table 1 was prepared by the method shown in Scheme F. Scheme F. TIFF0007682097000182.tif21139

[0276] In one embodiment, a compound selected from the compounds shown in Table 1 was prepared by the method shown in Scheme G. Scheme G. TIFF0007682097000183.tif17142

[0277] The following examples are provided to further illustrate the advantages and features of the present disclosure, but are not intended to limit the scope of the disclosure. The examples are typical of those that might be used, but other procedures, methods, or techniques known to those skilled in the art may alternatively be used. [Example]

[0278] Example 1: Compound synthesis Scheme 1. Synthesis of compound 03-1. TIFF0007682097000184.tif56151

[0279] Scheme 1 illustrates the synthesis of compound 03-1.

[0280] Step 1: Synthesis of 1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-one To a stirred solution of 2-bromo-3-(trifluoromethyl)pyridine (4.0 g, 17.7 mmol) and tributyl(1-ethoxyvinyl)tin (8.4 g, 23.0 mmol) in dioxane (50 mL) was added Pd(PPh3)4 (1.01 g, 0.88 mmol, 0.05 equiv.). The resulting mixture was purged with N2 (3x) and then heated to 120 °C for 6 h. After cooling, 1.5 N aqueous HCl was introduced into the flask and stirring was continued at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 (30 mL) and then extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 30 / 1 to 5 / 1) to give 1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-one as a yellow oil (2.4 g, 71%). MS (m / z): 190.1 (M+H). + .

[0281] Step 2: Synthesis of 2-bromo-1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-one To a stirred solution of 1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-one (0.5 g, 2.65 mmol) and HBr (40%, 0.5 mL) in AcOH (8 mL) was added pyridinium tribromide (0.85 g, 2.65 mmol). The resulting mixture was stirred at 40 °C overnight, then cooled and quenched with saturated aqueous NaHCO (100 mL). The reaction mixture was subsequently extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 30 / 1 to 3 / 1) to give 2-bromo-1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-one as a yellow oil (0.37 g, 52%). MS(m / z): 267.9(M+H) + .

[0282] Step 3: Synthesis of (R)-2-bromo-1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-ol To a stirred solution of 2-bromo-1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-one (0.37 g, 1.38 mmol) in toluene (4 mL) was added (R)-2-methyl-CBS-oxazaborolidine (0.3 mL, 1N in THF) at −35° C. The resulting mixture was stirred at −35° C. for 30 minutes. Borane-THF (2 mL, 1N in THF) was then added dropwise. The resulting solution was stirred at −15° C. for 2 hours, then quenched with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM / CHOH (silica, 50 / 1 to 15 / 1) to give (R)-2-bromo-1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-ol as a yellow oil (0.12 g, 32%). MS (m / z): 269.9 (M+H). + .

[0283] Step 4: Synthesis of (S)-2-(tert-butylamino)-1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-ol To a stirred solution of (R)-2-bromo-1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-ol (0.12 g, 0.44 mmol) in acetonitrile (3 mL) was added tert-butylamine (3 mL, 2.09 g, 28.6 mmol). The resulting mixture was stirred at 40 °C for 48 hours and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO and brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by HPLC [C18, MeCN / HO (0.1% formic acid), (1% to 100%)] to give compound 03-1, (S)-2-(tert-butylamino)-1-(3-(trifluoromethyl)pyridin-2-yl)ethan-1-ol as a white solid (0.045 g, 39%). TIFF0007682097000185.tif26150

[0284] TIFF0007682097000186.tif23128

[0285] Compound 03-2. TIFF0007682097000187.tif18151

[0286] Scheme 2. Synthesis of compound 03-3. TIFF0007682097000188.tif53152

[0287] Scheme 2 illustrates the synthesis of compound 03-3. TIFF0007682097000189.tif26150

[0288] Scheme 3. Synthesis of compound 03-4. TIFF0007682097000190.tif60153

[0289] Scheme 3 illustrates the synthesis of compound 03-4. TIFF0007682097000191.tif25150

[0290] Scheme 4. Synthesis of compounds 03-5 and 03-48. TIFF0007682097000192.tif50149

[0291] Scheme 4 illustrates the synthesis of compounds 03-5 and 03-48.

[0292] Step 1: Synthesis of 2-cyano-6-vinylpyridine A stirred mixture of 2-chloro-6-cyanopyridine (8.0 g, 69.3 mmol), 1-vinyltri-n-butyltin (21.97 g, 69.29 mmol, 20.34 mL), and Pd(PPh3)4 (3.34 g, 3.61 mmol) in anhydrous toluene (150 mL) was sparged with N2 for 5 minutes and then heated to 80 °C overnight. After cooling, the reaction mixture was poured into an aqueous solution of KF (40 g in 200 mL) and stirred for 30 minutes. The mixture was then filtered through Celite, and the solid was washed with EtOAc (2 × 50 mL). The aqueous phase of the filtrate was separated and extracted with EtOAc (2 × 250 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 95 / 5 to 90 / 10) to give 2-cyano-6-vinylpyridine as a pale yellow liquid (6.5 g, 86%). MS (m / z): 131.1 (M+H). + .

[0293] Step 2: Synthesis of 6-(oxiran-2-yl)picolinonitrile To a stirred solution of 2-cyano-6-vinylpyridine (6.5 g, 49.94 mmol) in DCM (300 mL) was added mCPBA (61.56 g, 249.72 mmol) slowly in small portions over 30 min at 0 °C and stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was cooled to 5 °C, saturated aqueous NaHCO was added, and extracted with DCM (200 mL × 2). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 90 / 10 to 80 / 20) to give 6-(oxiran-2-yl)picolinonitrile as a colorless liquid (3.85 g, 52%). MS (m / z): 147.1 (M+H). + .

[0294] Step 3: Synthesis of (S)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile and (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile To a stirred solution of 6-(oxiran-2-yl)picolinonitrile (3.5 g, 18.2 mmol) in ethanol (25 mL) was added tert-butylamine (6.66 g, 91.0 mmol). The reaction mixture was stirred in a sealed tube at 80° C. for 3 hours, during which the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was evaporated to give a residue, which was purified by reverse-phase chromatography to give the desired product as a racemic mixture. The racemic mixture was separated by SFC (Chiralpak AS-H (30*250) mm, 5μ column, CO:80% co-solvent:20% (0.2% isopropylamine in IPA) as eluent) to give compound 03-5, (S)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile (1.05 g, 26.3%) and compound 03-48, (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile (0.98 g, 24.5%) as white solids. TIFF0007682097000193.tif33162

[0295] Scheme 5. Synthesis of Compound 03-247 TIFF0007682097000194.tif53149

[0296] Scheme 5 illustrates the synthesis of compound 03-247.

[0297] Step 1: Synthesis of 3-methyl-4-vinylpyridine To a solution of 4-bromo-3-methylpyridine (1.0 g, 4.80 mmol) in dioxane / HO (15 mL / 1.5 mL) was added CsCO (4.69 g, 14.39 mmol), potassium vinyltrifluoroborate (0.96 g, 7.19 mmol), and Pd(PPh)Cl (0.20 g, 0.27 mmol). The mixture was stirred under a N atmosphere at 85 °C for 15 h. The resulting mixture was then filtered and washed with EtOAc (2 × 20 mL). The filtrate was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with hexane / EtOAc (silica, 90 / 10 to 75 / 25) to give 3-methyl-4-vinylpyridine as a yellow oil (0.45 g, 79%). MS (m / z): 120 (M+H). + .

[0298] Step 2: Synthesis of (R)-1-(3-methylpyridin-4-yl)ethane-1,2-diol To a solution of (R)-1-(3-methylpyridin-4-yl)ethane-1,2-diol (0.125 g, 0.82 mmol) in CHCl (4 mL), MeC(OCH) (0.30 g, 2.46 mmol) and p-toluenesulfonic acid (0.008 g, 0.048 mmol) were added and stirred at room temperature for 6 hours. The mixture was then concentrated in vacuo. The residue was redissolved in anhydrous CHCl (4 mL), followed by the dropwise addition of TMSBr (0.26 g, 1.71 mmol) at 0° C. The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. To the residue in anhydrous CHOH (4 mL), KCO (0.33 g, 2.40 mmol) was added, and the reaction mixture was stirred at 30° C. for 4 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give crude (R)-3-methyl-4-(oxiran-2-yl)pyridine as an oil (0.08 g, 72%). MS (m / z): 136 (M+H). + .

[0299] Step 4: Synthesis of (R)-2-(tert-butylamino)-1-(3-methylpyridin-4-yl)ethan-1-ol To a solution of (R)-3-methyl-4-(oxiran-2-yl)pyridine (0.08 g, 0.60 mmol) in EtOH / HO (2 mL / 1 mL) was added tert-BuNH (0.24 g, 3.30 mmol). The resulting mixture was stirred at 60 °C for 15 h and concentrated under reduced pressure. The residue was purified by HPLC [C18, MeCN / HO (0.1% trifluoroacetic acid), (1% to 100%)] to give compound 03-247, (R)-2-(tert-butylamino)-1-(3-methylpyridin-4-yl)ethan-1-ol, which was then converted to the diHCl salt as a white solid (0.044 g, 26%). TIFF0007682097000195.tif18150

[0300] Those skilled in the art will recognize that the above synthetic schemes are representative of methods for making the compounds of the present disclosure, and that many other compounds can be synthesized using similar such methods.

[0301] Example 2: Evaluation of synthetic adrenergic receptor agonists cAMP Homogeneous Time-Resolved Fluorescence (HTRF) Compound potency was determined using the cAMP Gs dynamic HTRF assay (Cisbio, Cat. No. 62AM4PEC) largely according to the manufacturer's instructions, also detailed below.

[0302] Compound Preparation. Beta-adrenergic compound candidates dissolved at 10 mM in DMSO were diluted in 1x Stimulation Buffer 1 (Cisbio Part No. 64SB1FDD) containing 1 mM 3-isobutyl-1-methylxanthene (IBMX; Cayman Chemical Company, Catalog No. 13347). Serial dilutions were performed in 96-well V-bottom polypropylene compound microplates (Corning, Catalog No. 3363) in Stimulation Buffer containing 1 mM IBMX to twice the final desired concentration. The standard serial dilution curve was a 10-point, 5-fold dilution starting from a top concentration of 10 μM. Controls present on all assay plates were 0.1% DMSO (vehicle control), 1 μM isoproterenol (full beta-adrenergic agonist control), and 15 μM xamoterol (partial beta-adrenergic agonist control). Five μL from the 2× compound plate was stamped into a white 384 round-well small-volume HiBase assay plate (Greiner Bio-One; catalog number 784075) to obtain four technical replicates per compound per concentration. The assay plate was centrifuged at 500×g for 10 seconds. Compounds and IBMX were prepared at 2× the final volume to compensate for the addition of cells.

[0303] Cell preparation. 1x stimulation buffer, wash PBS (Dulbecco's phosphate-buffered saline, -Mg-Ca; Caisson Labs, catalog number PBL01), assay PBS (Dulbecco's phosphate-buffered saline, +Mg, +Ca; Caisson Labs, catalog number PBL02), and Versene (0.02% EDTA disodium salt solution in PBS without calcium or magnesium; Caisson Labs, catalog number EDL01) were prewarmed to 37°C. Cells expressing beta-adrenergic receptors were washed in wash PBS to remove growth medium and then detached from the surface by incubation with Versene for 5-10 minutes at 37°C. Cells were harvested using assay PBS, counted manually by hemocytometer or automated cell counter, pelleted by centrifugation (200 x g, 5 minutes), and transferred to 1.5 x 10 cells in 1x stimulation buffer at 37°C. 6 The cells were resuspended to a final density of 1000 cells / mL. Five microliters of the suspended cell solution (7500 cells total) was added to every well of a 384-well assay plate, which was then covered with an Axygen® plate seal (Corning PCR-SP) and incubated for 30 minutes in a humidified 37°C environment supplemented with 5% CO2.

[0304] HTRF Reagent Addition, Reading, and Data Analysis. Thirty minutes after cell stimulation with test compounds, the assay plate was centrifuged at 500 × g for 10 seconds, and the incubation was stopped by adding 5 μL of cAMP-D2 acceptor diluted 1:21 in Detection and Lysis Buffer 2 (Cisbio 62CL2FDF) and added to all cells. Subsequently, 5 μL of anti-cAMP-Eu donor diluted 1:21 in Detection and Lysis Buffer 2 was added to the cells. The plate was sealed, and the reaction was gently vortexed at 900 rpm on a Heidolph Titramax 1000 for at least 30 minutes at room temperature. The plate was again centrifuged at 500 × g for 10 seconds, and HTRF was measured using a Tecan Spark plate reader with 50 flashes per well. HTRF ratios (665 nm / 620 nm x 10,000) were determined and plotted in GraphPad Prism to generate concentration-effect curves. Potency estimates (EC 50 ) was obtained from a four-parameter nonlinear regression of the concentration-effect curves, and an estimate of relative efficacy was determined by comparing the magnitude of the test compound HTRF signal window (minimum-maximum dose) with the signal window of the full agonist control, isoproterenol.

[0305] Efficacy data for selected compounds is summarized in Table 2 below.

[0306] Table 2: Pharmacological data for compounds disclosed herein TIFF0007682097000196.tif39128EC 50 (nM): A<10nM; B=10~100nM; C=100nM~1μM; D>1μM

[0307] Certain compounds of the present disclosure have been unexpectedly found to be partial agonists of the β2 adrenergic receptor, particularly in human astrocytoma cells (e.g., 1321N1). Inhibition curves for select compounds are further summarized in Figures 1, 2, and 3. Efficacy data for additional compounds of the invention are found in Example 8.

[0308] Example 3: In vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) studies As described above and herein, the compounds of the present disclosure exhibit unexpectedly favorable properties. For example, as described above, it has been unexpectedly discovered that the compounds of the present disclosure act as low nM (<10 nM) partial agonists of β2-adrenergic receptors. Furthermore, as the following examples demonstrate, the compounds of the present disclosure exhibit unexpectedly high ability to penetrate the blood-brain barrier and accumulate in cerebrospinal fluid. In addition, the compounds of the present disclosure exhibit excellent oral bioavailability and stability, while at the same time exhibiting low toxicity and low potential for drug-drug interactions. The following examples illustrate some of the unexpected results achieved with the compounds of the present disclosure.

[0309] Plasma protein and brain tissue binding Brain tissue binding measurements Thawing of frozen brain tissue homogenate (stored at -80°C). Frozen brain tissue homogenate was thawed immediately in a room temperature bath. Note: Only use brain tissue homogenate that has been thawed no more than once.

[0310] Preparation of working solutions. Working solutions of the test compounds and the control compound propranolol were prepared in DMSO at a concentration of 200 μM. 4 μL of the working solution was then removed and mixed with 796 μL of rat brain tissue homogenate to achieve a final concentration of 1 μM (0.5% DMSO). The brain tissue homogenate sample was vortexed thoroughly.

[0311] Preparation of dialysis membrane: The dialysis membrane was immersed in ultrapure water for 60 minutes to separate the strips, then in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes.

[0312] Procedure for equilibrium dialysis. The dialysis apparatus was assembled according to the manufacturer's instructions. Each cell was filled with 150 μL of brain tissue homogenate sample and dialyzed against an equal volume of dialysis buffer (PBS). Assays were performed in duplicate. The dialysis plate was sealed and incubated in an incubator at 37°C, 5% CO2, and approximately 100 rpm for 6 hours. At the end of dialysis, the seals were removed and 50 μL of sample was transferred from both the buffer and brain tissue homogenate chambers to separate tubes within the plate.

[0313] Procedure for sample analysis. 50 μL of brain tissue homogenate was added to each buffer sample, and an equal volume of PBS was supplemented to the collected brain tissue homogenate samples. 400 μL of room temperature quenching solution (acetonitrile containing internal standard (IS), 100 nM alprazolam, 500 nM labetalol, and 2 μM ketoprofen)) was added to precipitate proteins. The samples in the plate were vortexed for 5 minutes and centrifuged at 3,220 g for 30 minutes at room temperature. Then, 100 μL of the supernatant was transferred to a new 96-well plate containing 100 μL of water for LC-MS / MS analysis.

[0314] Data Analysis. All calculations were performed using Microsoft Excel. The concentrations of test and control compounds in the buffer and brain tissue homogenate chambers were determined from the peak area ratios. The percentage of bound test and control compounds was calculated as follows: Fu 平均 = (peak area ratio バッファーチャンバー / peak area ratio 脳組織ホモジネートチャンバー )+1 / D Undiluted fu = ((1 / Fu 平均 )-1)+1 / D % Binding = (1 - undiluted FU) x 100 Recovery % = (peak area ratio バッファーチャンバー +Peak area ratio 脳組織ホモジネートチャンバー ) / peak area ratio 試料合計 ×100 Fu 平均 = unbound fraction measured in brain tissue homogenates D = dilution factor of brain tissue % bound = % brain tissue bound

[0315] Measurement of plasma protein binding Preparation of 100 mM sodium phosphate and 150 mM NaCl buffer (PBS). A basic solution was prepared by dissolving 14.2 g / L NaHPO and 8.77 g / L NaCl in deionized water, and the solution could be stored at 4°C for up to 7 days. An acidic solution was prepared by dissolving 12.0 g / L NaHPO and 8.77 g / L NaCl in deionized water, and the solution could be stored at 4°C for up to 7 days. The basic solution was titrated to pH 7.4 with the acidic solution, and the solution was stored at 4°C for up to 7 days. The pH was checked on the day of the experiment and adjusted if it deviated from the specification of 7.4 ± 0.1.

[0316] Thawing of frozen plasma (stored at -80°C). Frozen plasma was thawed immediately at room temperature. The plasma was centrifuged at 3,220 g for 10 minutes to remove clots, and the supernatant was collected in a fresh tube. The pH of the plasma was checked and recorded. Note: a) Only use plasma that has been thawed less than twice since arrival. b) Only use plasma within the pH range of 7 to 8.

[0317] Preparation of working solutions. Working solutions of the test compounds and the control compound ketoconazole were prepared in DMSO at a concentration of 200 μM. 3 μL of the working solution was then removed and mixed with 597 μL of rat plasma to achieve a final concentration of 1 μM (0.5% DMSO). The plasma samples were vortexed thoroughly.

[0318] Preparation of dialysis membrane: The dialysis membrane was immersed in ultrapure water for 60 minutes to separate the strips, then in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes.

[0319] Procedure for equilibrium dialysis. The dialysis apparatus was assembled according to the manufacturer's instructions. Each cell was filled with 120 μL of spiked plasma sample and dialyzed against an equal volume of dialysis buffer (PBS). Assays were performed in duplicate. The dialysis plate was sealed and incubated in an incubator at 37°C, 5% CO2, and 100 rpm for 6 hours. At the end of the incubation, the seals were removed and 50 μL of sample was transferred from both the buffer and plasma chambers to wells of a 96-well plate.

[0320] Procedure for sample preparation. 50 μL of blank plasma was added to each buffer sample, and an equal volume of PBS was supplemented to the collected plasma samples. 300 μL of room temperature quench solution (acetonitrile containing internal standard (IS), 100 nM alprazolam, 500 nM labetalol, and 2 μM ketoprofen)) was added to precipitate proteins. The samples in the plate were vortexed for 5 minutes and centrifuged at 3,220 g for 30 minutes at 4°C. Then, 100 μL of the supernatant was transferred to a new 96-well plate containing 100 μL of water for LC-MS / MS analysis.

[0321] Data Analysis. All calculations were performed using Microsoft Excel. The concentrations of test and control compounds in the buffer and plasma chambers were determined from the peak area ratios. The percentage of bound test and control compounds was calculated as follows: Fu% = (peak area ratio バッファーチャンバー / peak area ratio 血漿チャンバー ) x 100 Combine%=100-Fu% Recovery % = (peak area ratio バッファーチャンバー +Peak area ratio 血漿チャンバー ) / peak area ratio 試料合計 ×100

[0322] Peak area ratio バッファーチャンバー means the concentration of the free fraction; peak area ratio 血漿チャンバー means the concentration of both the free and bound fractions; peak area ratio 試料合計 denotes the concentration of the starting sample before incubation.

[0323] Percent plasma protein binding (PPB) and brain tissue binding (BTB) for selected compounds are summarized in Table 3 below.

[0324] Certain compounds of the present disclosure have been found to exhibit a high propensity to bind and accumulate in the central nervous system.

[0325] Table 3. Percentage of unbound fraction of PPB and brain tissue binding TIFF0007682097000197.tif28128

[0326] MDCK-MDR1 permeability assay Preparation of MDCK-MDR1 cells. Cell culture medium was added to each well of the transwell insert (50 μL) and the reservoir (25 mL). The HTS transwell plate was then incubated at 37°C and 5% CO for 1 hour, after which the cells were seeded. MDCK-MDR1 cells were cultured in culture medium at a density of 1.56 × 10 6 The cells were diluted to 1000 cells / mL, and 50 μL of the cell suspension was dispensed into filter wells of a 96-well HTS transwell plate. Cells were cultured for 4–8 days in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity. Cell culture medium was changed every other day, starting within 24 hours of initial plating.

[0327] Preparation of stock solutions. 10 mM stock solutions of test compounds were prepared in DMSO. Positive control stock solutions were prepared in DMSO at a concentration of 10 mM. Metoprolol, prazosin, and imatinib were used as control compounds in this assay.

[0328] Assessment of cell monolayer integrity. The medium was removed from the reservoir and each transwell insert and replaced with fresh, pre-warmed culture medium. The transepithelial electrical resistance (TEER) across the monolayer was measured using a Millicell Epithelial Volt-Ohm measurement system (Millipore, USA). Once the measurement was taken, the plate was returned to the incubator. TEER values ​​should be higher than 42 ohm cm2, indicating a high-quality MDCK-MDR1 monolayer. TEER values ​​were calculated according to the following formula: TEER measurement value (ohm) × membrane area (cm 2 ) = TEER value (ohm cm 2 )

[0329] Assay procedure. MDCK-MDR1 plates were removed from the incubator, washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37°C for 30 minutes. Stock solutions of test compounds and controls were diluted in DMSO to obtain 1 mM solutions, and then diluted with HBSS (10 mM HEPES, pH 7.4) to obtain 5 μM working solutions. The final concentration of DMSO in the incubation system was 0.5%.

[0330] To determine the rate of drug transport from the apical to the basolateral direction, 125 μL of a 5 μM working solution of test and control compounds was added to the transwell insert (apical compartment), and 50 μL of sample (D0 sample) was immediately transferred from the apical compartment to a new 96-well plate. Wells in the receiver plate (basolateral compartment) were filled with 235 μL of HBSS (10 mM HEPES, pH 7.4). Assays were performed in duplicate.

[0331] To determine the rate of drug transport from the basolateral to the apical direction, 285 μL of a 5 μM working solution of the test compound and control compound was added to the reservoir plate wells (basolateral compartment), and 50 μL of sample (D0 sample) was immediately transferred from the basolateral compartment to a new 96-well plate. Wells in the transwell insert (apical compartment) were filled with 75 μL of HBSS (10 mM HEPES, pH 7.4). The plate was incubated at 37°C for 2 h. At the end of the incubation, 50 μL of sample from the donor side (apical compartment for Ap→B1 efflux and basolateral compartment for B1→Ap) and reservoir side (basolateral compartment for Ap→B1 efflux and apical compartment for B1→Ap) was transferred to wells of a new 96-well plate, followed by the addition of 4 volumes of cold methanol containing the appropriate internal standard (IS). The samples were vortexed for 5 min and then centrifuged at 3,220 g for 40 min. An aliquot of 100 μL of the supernatant was mixed with an appropriate volume of ultrapure water before LC-MS / MS analysis.

[0332] To determine Lucifer Yellow leakage after a 2-hour transport period, a stock solution of Lucifer Yellow was prepared in DMSO and diluted with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 100 μM. Lucifer Yellow solution (100 μL) was added to each transwell insert (apical compartment), and then wells in the receiver plate (basolateral compartment) were filled with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plate was incubated at 37°C for 30 minutes, after which 80 μL of sample was removed directly from the apical and basolateral wells (using the basolateral access hole) and transferred to wells of a new 96-well plate. Lucifer Yellow fluorescence (to monitor monolayer integrity) signal was measured in a fluorescent plate reader at 480 nM excitation and 530 nM emission.

[0333] Data Analysis. The apparent permeability coefficient (Papp) in centimeters per second was calculated in the MDCK-MDR1 drug transport assay using the following formula: Papp =(V A ×[drugs] アクセプター ) / (area × time × [drug] 当初、ドナー )

[0334] V A is the volume of the acceptor well (in mL), and Area is the surface area of ​​the membrane (0.143 cm for Transwell 96-well permeable supports). 2 ) and time is the total transport time in seconds.

[0335] The discharge ratio was determined using the following formula: Emission ratio=P app(B-A) / P app(A-B)

[0336] WP app(B-A) denotes the apparent permeability coefficient in the basolateral to apical direction, and P app(A-B) denotes the apparent permeability coefficient in the apical to basolateral direction.

[0337] The recovery rate can be determined using the following formula: Recovery % = (V A ×[drugs] アクセプター +V D ×[drugs] ドナー ) / (V D ×[drugs] 当初、ドナー )

[0338] V A is the volume (in mL) in the acceptor well (0.235 mL for Ap → Bl efflux and 0.075 mL for Bl → Ap), and V D is the volume (in mL) in the donor well (0.075 mL for Ap→Bl outflow and 0.235 mL for Bl→Ap).

[0339] The leakage of Lucifer Yellow in percentage (%) was calculated using the following formula: LY leakage%=100×[LY] アクセプター / ([LY] ドナー +[LY] アクセプター )

[0340] <1% LY leakage is acceptable to represent a quality MDCK-MDR1 monolayer.

[0341] Excretion rates and ratios for selected compounds are summarized in Table 4 below.

[0342] (Table 4) MDCK-MDR1 discharge rate and ratio TIFF0007682097000198.tif32128

[0343] Microsomal and hepatocyte stability Microsome Stability Protocol: A master solution was prepared as follows. TIFF0007682097000199.tif29158

[0344] Two separate experiments were performed as follows: When NADPH was used, 10 μL of 20 mg / mL liver microsomes and 40 μL of 10 mM NADPH were added to the incubation, with final concentrations of microsomes and NADPH of 0.5 mg / mL and 1 mM, respectively. Without NADPH: 10 μL of 20 mg / mL liver microsomes and 40 μL of ultrapure water were added to the incubation. The final concentration of microsomes was 0.5 mg / mL.

[0345] Reactions were initiated by the addition of 4 μL of 3, 10, 30 and 100 μM test compound or control compound solutions to final concentrations of 0.03, 0.1, 0.3 and 1 μM and were carried out at 37°C.

[0346] Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45, and 60 minutes. The reaction was stopped by adding 4 volumes of cold acetonitrile containing IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen). The samples were centrifuged at 3,220 g for 40 minutes. A 100 μL aliquot of the supernatant was mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis.

[0347] Data Analysis: All calculations were performed using Microsoft Excel.

[0348] Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the parent drug retention rate versus incubation time curve.

[0349] In vitro half-life (in vitro t 1 / 2 ) was determined from the slope value: In vitro 1 / 2 =-(0.693 / k)

[0350] In vitro 1 / 2 (min) to in vitro intrinsic clearance (in vitro CL int Conversion to (μL / min / mg protein) was performed using the following formula (mean value of duplicate determinations): TIFF0007682097000200.tif11128

[0351] In vitro 1 / 2 (min) to scale-up unbound intrinsic clearance (scale-up CL int Conversion to % saturation (mL / min / kg) was performed using the following formula (mean of duplicate determinations): TIFF0007682097000201.tif11140

[0352] Scaling factors for predicting intrinsic clearance in liver microsomes. TIFF0007682097000202.tif50155a. Iwatsubo et al, Davies and Morris, 1993, 10 (7) pp 1093-1095. b. Barter et al, 2007, Curr Drug Metab, 8(1), pp 33-45; Iwatsubo et al, 1997, JPET, 283 pp 462-469.

[0353] Microsomal stability results (μL / min / mg protein) for selected compounds are summarized in Table 5 below.

[0354] Table 5. Microsome stability results TIFF0007682097000203.tif21128

[0355] Hepatocyte Stability Protocol: Preparation of working solutions 10 mM and 100 μM stock solutions of test compound(s) and positive control were prepared in the appropriate solvent (DMSO). In separate conical tubes, 10 mM test compound and positive control were diluted to 100 μM by combining 198 μL of 50% acetonitrile / 50% water and 2 μL of the 10 mM stock. 100 μM test compound and positive control were diluted to 30 μM by combining 140 μL of 50% acetonitrile / 50% water and 60 μL of the 100 μM stock solution. 100 μM test compound and positive control were diluted to 10 μM by combining 180 μL of 50% acetonitrile / 50% water and 20 μL of the 100 μM stock solution. 100 μM test compound and positive control were diluted to 3 μM by combining 194 μL of 50% acetonitrile / 50% water and 6 μL of the 100 μM stock solution.

[0356] Preparation of hepatocytes The incubation medium (Williams E medium supplemented with GlutaMAX) and hepatocyte thawing medium were placed in a 37°C water bath and warmed for at least 15 minutes before use. A vial of cryopreserved hepatocytes was then removed from storage, ensuring that the vial was maintained at a cryogenic temperature until the thawing process occurred. The cells were thawed by placing the vial in a 37°C water bath and gently shaking the vial for 2 minutes. After thawing was complete, the vial was sprayed with 70% ethanol and transferred to a biosafety cabinet.

[0357] Using a wide-bore pipette tip, the hepatocytes were transferred to a 50 mL conical tube containing thawing medium. The 50 mL conical tube was placed in a centrifuge and spun at 100 g for 10 minutes. Once spun, the thawing medium was aspirated and the hepatocytes were resuspended in sufficient incubation medium to obtain a total of approximately 1.5 x 10 6 cells / mL were obtained.

[0358] Cells were counted and viable cell density determined using AOPI staining solution. Cells with poor viability (viability <75%) were unacceptable for use. Cells were then diluted with incubation medium to a concentration of 0.5 x 10 viable cells. 6 The cells were diluted to a working cell density of 0.5 x 10 viable cells / mL before being added to the plate as a negative control to rule out enzyme activity, since little or no substrate turnover should be observed. 6 A aliquot of 1 / mL of hepatocytes was boiled for 5 minutes.

[0359] Procedure for determining stability 198 μL of hepatocytes were pipetted into each well of a 96-well uncoated plate. The plate was placed on an orbital shaker in an incubator, and the hepatocytes were warmed for 10 minutes. 2 μL of 3, 10, 30, and 100 μM test compound or positive control was pipetted into each well of the 96-well uncoated plate to initiate the reaction. The final concentrations of test compound or control compound were 0.03, 0.1, 0.3, and 1 μM. The plate was returned to the incubator and placed on the orbital shaker. 25 μL aliquots of well contents were removed at 0, 15, 30, 60, 90, and 120 minutes. The aliquots were then mixed with six volumes (150 μL) of acetonitrile containing internal standards (IS: 100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen) to terminate the reaction. The plates were centrifuged at 3,220 g for 20 min. A 100 μL aliquot of the supernatant was mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis. All incubations were performed in duplicate. Hepatocyte stability results (μL / min / cells 10 6 ) are summarized in Table 6 below.

[0360] Data analysis All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. Regression analysis of the percent disappearance of the parent compound versus time curve yielded the in vitro half-life (t 1 / 2 ) was decided.

[0361] In vitro half-life (in vitro t 1 / 2 ) the gradient value: In vitro 1 / 2 =0.693 / k It was decided from

[0362] In vitro 1 / 2 (in min) to scale-up intrinsic clearance (scale-up CL int Conversion to % saturation (mL / min / kg) was performed using the following formula (mean of duplicate determinations): Scale-up CL int = kV / N × scaling factor; V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1 x 10 6 cell).

[0363] Scaling factors for predicting in vivo intrinsic clearance using hepatocytes from different species are listed below. TIFF0007682097000204.tif57152

[0364] Table 6. Hepatocyte stability results TIFF0007682097000205.tif28144

[0365] hERG cardiotoxicity Table 7: Materials and Instrumentation TIFF0007682097000206.tif149150

[0366] Cell Line and Cell Culture. The HEK293 cell line (catalog number K1236) stably expressing the hERG channel was purchased from Invitrogen. Cells were cultured in 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U / mL penicillin-streptomycin, 5 μg / mL blasticidin, and 400 μg / mL geneticin. Cells were split approximately three times a week using TrypLE™ Express to maintain a confluency between approximately 40% and approximately 80%. Prior to the assay, cells were plated onto coverslips at 5 × 10 5 Cells were plated at 6 cm cell culture dish and induced with 1 μg / mL doxycycline for 48 hours.

[0367] Preparation of solutions. Extracellular solution (in mM): 132 NaCl, 4 KCl, 3 CaCl, 0.5 MgCl, 11.1 glucose, and 10 HEPES (pH adjusted to 7.35 with NaOH), intracellular solution (in mM): 140 KCl, 2 MgCl, 10 EGTA, 10 HEPES, and 5 MgATP (pH adjusted to 7.35 with KOH).

[0368] Preparation of working solutions for test compounds. Test compounds were initially prepared in DMSO at final stock concentrations of 10 or 30 mM. The stock solutions of test compounds were then serially diluted with DMSO (1:3) to prepare additional intermediate solutions containing 10, 3.33, 1.11, and 0.37 mM. Prior to the hERG assay, working solutions were prepared by diluting the 30, 10, 3.33, 1.11, and 0.37 mM intermediate solutions 1000-fold using extracellular solution, thus resulting in final working concentrations of 30, 10, 3.33, 1.11, and 0.37 μM. The final DMSO concentrations of the working solutions were 0.1-0.3% (v / v). IC 50 To determine this, human ERG currents in the presence of five doses were tested.

[0369] Experimental Procedure. The coverslip was removed from the cell culture dish and placed on the microscope stage of the batch chamber. The desired cell was located using a 10x objective. The tip of the electrode was positioned under the microscope by focusing on the cell surface using the 10x objective. Once the tip was in focus, the manipulator's path control was used to advance the lower electrode toward the cell while simultaneously moving the objective to keep the tip in focus. Then, using the fine adjustments of the manipulator, the electrode was gradually moved closer to the cell. Gentle suction was applied through the side of the electrode holder to form a gigaohm seal. C fast The current capacity corresponding to the voltage step was removed using a hysteresis loop. The whole-cell configuration was obtained by repeatedly applying short, strong suction until the membrane patch ruptured. The membrane potential was then set to -60 mV to ensure that the hERG channels were not open. The amplifier then measured the C slow Current spikes were cancelled using a voltage regulator. The holding potential was set at -90 mV for 500 ms, and currents were recorded at 50 kHz and filtered at 10 kHz. Current leakage was monitored at -80 mV for 500 ms.

[0370] hERG current was induced by polarizing at +30mV for 4.8 seconds, and then the voltage was returned to -50mV for 5.2 seconds to remove deactivation and observe the deactivation tail current. The maximum tail current size was used to determine the hERG current amplitude. Current was recorded for 120 seconds to evaluate current stability. Only stable cells that recorded parameters above threshold were applied for drug administration.

[0371] Vehicle control was administered to cells to establish a baseline. After the hERG current was found to be stable for 3 minutes, test compounds were applied. The hERG current in the presence of test compounds was recorded for approximately 5 minutes until a steady state was reached, and then five sweeps were captured. For dose-response testing, five doses of compounds were applied to cells, gradually increasing from low to high concentrations. To ensure good throughput of cultured cells and operation, five dose concentrations of positive control, dofetilide, were also used to test the same batch of cells.

[0372] Data Analysis: The following criteria were used to determine data acceptability. 1) Initial seal resistance >1GΩ; 2) Stable leakage current <100pA at test potential; 3) peak tail amplitude >250 pA; 4) Membrane resistance Rm>500MΩ; 5) Access resistance (Ra)<10MΩ; 6) Apparent run-down of peak current per minute <2.5%.

[0373] Data meeting the above criteria for hERG current characteristics were further analyzed. The percentage of hERG current inhibition was calculated using the following formula: Peak current inhibition = (1-) x 100 Peak Tail Current Medium

[0374] Using Graphpad Prism 6.0, the dose-response curves of the test compounds were plotted against the concentration of the test compound and the percentage of hERG current inhibition, and fitted to a sigmoidal dose-response curve with a variable slope.Peak currents were extracted from the original data using PatchMaster software. Roche et al.A Virtual Screening Method for Prediction of the hERG Potassium Channel Liability of Compound Libraries.(2002)ChemBioChem.3,455-459;Glenn E.Kirsch et al.Variability in the measurement of hERG potassium channel inhibition:effects of temperature and stimulus patter.(2004)Journal of Pharmacological and Toxicological Methods 50,93-101;Roger Marrannes et al.Computer programs to facilitate the estimation of time-dependent drug effects on ion channels.(2004)Computer Methods and Programs in Biomedicine 74,167-181;SOP-ADMET-MAN-007:The Standard Operating Procedure for Compound Management.

[0375] hERG manual patch clamp IC for selected compounds 50 The results (μM) are summarized in Table 8 below.

[0376] It has been surprisingly found that certain compounds of the present disclosure exhibit unexpectedly low cardiotoxicity.

[0377] (Table 8) hERG IC 50 Results TIFF0007682097000207.tif21128

[0378] Evaluation of cytochrome P450 inhibition Table 9. Preparation of master solution TIFF0007682097000208.tif44150

[0379] Stock compound solution (1 μL, 2 mM) or DMSO (1 μL) was added to the master solution. The final concentration of test or control compound was 10 μM.

[0380] For CYP1A2 inhibition, 1 μL of specific drug substrate (phenacetin: 8 mM) was added to the master solution at a final concentration of 40 μM.

[0381] For CYP2B6 inhibition, 1 μL of specific drug substrate (bupropion: 10 mM) was added to the master solution at a final concentration of 50 μM.

[0382] For CYP2C9 inhibition, 1 μL of specific drug substrate (tolbutamide: 40 mM) was added to the master solution at a final concentration of 200 μM.

[0383] For CYP2C19 inhibition, 1 μL of specific drug substrate ((s)-Me phenytoin: 10 mM) was added to the master solution at a final concentration of 50 μM.

[0384] For CYP3A4 inhibition, 1 μL of specific drug substrate (midazolam: 1 mM) was added to the master solution at a final concentration of 5 μM.

[0385] For CYP3A4 inhibition, 1 μL of specific drug substrate (testosterone: 10 mM) was added to the master solution at a final concentration of 50 μM.

[0386] The mixture was pre-warmed at 37°C for 5 min. The reaction was initiated by adding 20 μL of 10 mM NADPH solution to a final concentration of 1 mM and carried out at 37°C. The reaction was stopped by adding 400 μL of cold quench solution (methanol containing internal standards (IS: 100 nM alprazolam, 500 nM labetalol, and 2 μM ketoprofen)) at the indicated time points (phenacetin: 20 min; bupropion: 20 min; tolbutamide: 20 min; (s)-Mephenytoin: 20 min; midazolam: 5 min; testosterone: 10 min). The sample was vortexed for 5 min and centrifuged at 3220 g for 40 min at 4°C. 100 μL of the supernatant was then transferred to a new 96-well plate containing 100 μL of water for LC-MS / MS analysis. All experiments were performed in duplicate.

[0387] The percent CYP450 isoform inhibition results (10 μM) for selected compounds are summarized in Table 10 below.

[0388] It has been surprisingly found that certain compounds of the present disclosure exhibit unexpectedly low inhibition of CYP450 enzymes and, therefore, have a low potential for drug-drug interactions.

[0389] Table 10: CYP450 isoform inhibition rate TIFF0007682097000209.tif21131

[0390] Example 4: Rat Pharmacokinetic Studies Rat pharmacokinetic studies of exemplary compounds 03-3, 03-5, and 03-115 were conducted using male SD rats. These rats were typically approximately 6-8 weeks old and weighed 200-300 g. Animals were fasted overnight and allowed free access to food 4 hours after dosing. To prepare for dosing, the required volume of vehicle was added to achieve the target concentrations of the test article and vehicle components. The dosing vehicle was PEG400 or 30% PEG400 in saline for IV administration, or 0.5% methylcellulose in water for PO administration. For IV administration, animals were administered intravenously via the tail vein. For PO administration, animals were administered via oral gavage. After dosing, blood samples (approximately 0.2 mL per time point) were collected via the jugular vein or cardiac puncture. Blood for each sample was transferred to a plastic microcentrifuge tube containing EDTA-K2. The collection tubes containing the blood samples and anticoagulant were inverted multiple times to properly mix the contents of the tubes and then placed on wet ice. The blood samples were centrifuged at 2000 g for 5 minutes at 4°C to obtain plasma, which was stored in a freezer at -75±15°C before analysis. The samples were analyzed using LC-MS / MS. WinNonlin was used for pharmacokinetic calculations.

[0391] For CSF sampling, after anesthesia, the foramen magnum was exposed and CSF was collected using a syringe with an intravenous needle. CSF samples were stored in polypropylene tubes and then stored in a freezer at -75±15°C before analysis.

[0392] For brain sampling, rats were completely exsanguinated using elevated carbon dioxide prior to brain collection. Brain samples were then collected at the appropriate time points, quick-frozen, and maintained at -75±15°C. All brain samples were weighed and homogenized with PBS to a brain weight (g) to PBS volume (mL) ratio of 1:3 prior to analysis. Actual concentrations were determined by multiplying the detected values ​​by the dilution factor.

[0393] Exemplary PK values ​​for IV administration are summarized below in Tables 11-13. Exemplary PK results for PO administration are summarized below in Tables 14-16.

[0394] Exemplary CNS exposure results for IV and SC administration are summarized below in Tables 17-19. Exemplary CNS exposure results for PO administration are summarized below in Table 20.

[0395] PK results in male SD rats are further summarized in Figures 4-5 and 12.

[0396] The compounds of the present disclosure have been surprisingly found to have excellent absorption and systemic exposure profiles. Furthermore, the compounds of the present disclosure have been surprisingly found to exhibit excellent CNS exposure and accumulation.

[0397] Table 11: Rat IV pharmacokinetic results for compound 03-3 TIFF0007682097000210.tif75128

[0398] Table 12: Rat IV pharmacokinetic results for compound 03-5 TIFF0007682097000211.tif75128

[0399] Table 13: Rat IV pharmacokinetic results for compound 03-115 TIFF0007682097000212.tif48128

[0400] Table 14: Rat PO pharmacokinetic results for compound 03-3 TIFF0007682097000213.tif63128

[0401] Table 15: Rat PO pharmacokinetic results for compound 03-5 TIFF0007682097000214.tif63128

[0402] Table 16: Rat PO pharmacokinetic results for compound 03-115 TIFF0007682097000215.tif46128

[0403] Table 17: Rat IV CNS exposure measurements for compound 03-3 TIFF0007682097000216.tif29131

[0404] Table 18: Rat IV CNS exposure measurements for compound 03-5 TIFF0007682097000217.tif29128

[0405] Table 19: Rat SC CNS exposure measurements for compound 03-115 TIFF0007682097000218.tif29128

[0406] Table 20: Rat PO CNS exposure measurements for compound 03-5 TIFF0007682097000219.tif29128

[0407] Example 5: Mouse Pharmacokinetic Studies Mouse pharmacokinetic studies of exemplary compounds 03-3 and 03-5 were conducted substantially similarly to the rat pharmacokinetic studies, except that male C57BL / 6J mice were used instead. These mice were typically approximately 6-8 weeks old and weighed 20-30 g. Animals were allowed free access to food prior to dosing. Sample volume was approximately 0.03 mL per time point, and sampling sites were the dorsal metatarsus or cardiac puncture.

[0408] Exemplary PK results for PO administration are summarized in Tables 21-23 below.

[0409] Exemplary CNS exposure results for PO and SC administration are summarized in Tables 24-26 below.

[0410] PK results in male C57BL / 6J mice are further summarized in Figures 6-7 and 14.

[0411] The compounds of the present disclosure have been surprisingly found to have excellent absorption and systemic exposure profiles. Furthermore, the compounds of the present disclosure have been surprisingly found to exhibit excellent CNS exposure and accumulation.

[0412] Table 21: Mouse POPK results for compound 03-3 TIFF0007682097000220.tif63128

[0413] Table 22: Mouse POPK results for compound 03-5 TIFF0007682097000221.tif63128

[0414] Table 23: Mouse POPK results for compound 03-115 TIFF0007682097000222.tif40128

[0415] Table 24: Mouse PO CNS exposure measurements for compound 03-3 TIFF0007682097000223.tif29128

[0416] Table 25: Mouse PO CNS exposure measurements for compound 03-5 TIFF0007682097000224.tif29128

[0417] Table 26: Mouse SC CNS exposure measurements for compound 03-115 TIFF0007682097000225.tif29128

[0418] Example 6: Dog Pharmacokinetic Study Dog pharmacokinetic studies of exemplary compounds 03-3, 03-5, and 03-115 were conducted substantially similarly to the rat pharmacokinetic studies, but using male beagle dogs instead. Animals for PO studies were fasted overnight before administration and fed approximately 2 hours after administration. Animals for IV studies had free access to food and water. Blood samples were collected via venipuncture of peripheral veins, excluding the administration vein.

[0419] Exemplary PK results for PO administration are summarized in Tables 27-32 below.

[0420] PK results in male beagle dogs are further summarized in Figures 8-9 and 13.

[0421] Table 27: Dog PO PK results for compound 03-3 TIFF0007682097000226.tif40128

[0422] Table 28: Dog PO PK results for compound 03-3 TIFF0007682097000227.tif40128

[0423] Table 29: Dog PO PK results for compound 03-5 TIFF0007682097000228.tif40128

[0424] Table 30: Dog PO PK results for compound 03-5 TIFF0007682097000229.tif40128

[0425] Table 31: Dog PO PK results for compound 03-115 TIFF0007682097000230.tif40128

[0426] Table 32: Dog PO PK results for compound 03-115 TIFF0007682097000231.tif40128

[0427] Example 7: Monkey Pharmacokinetic Studies Monkey pharmacokinetic studies of exemplary compounds 03-3, 03-5, and 03-115 were conducted substantially similarly to the rat pharmacokinetic studies, except that non-naive male cynomolgus monkeys were used instead. Animals for PO studies were fasted overnight before administration and fed approximately 2 hours after administration. Animals for IV studies had free access to food and water. Blood samples were collected via venipuncture of peripheral veins, excluding the administration vein.

[0428] Exemplary PK results for PO administration are summarized in Tables 33-35 below.

[0429] PK results in male cynomolgus monkeys are further summarized in Figures 10-11 and 15.

[0430] The compounds of the present disclosure have been surprisingly found to have excellent absorption and overall exposure profiles. Furthermore, the oral bioavailability of the compounds has been surprisingly found to approach their respective intravenous bioavailability.

[0431] Table 33: Monkey PO PK results for compound 03-3 TIFF0007682097000232.tif63128

[0432] Table 34: Monkey PO PK results for compound 03-5 TIFF0007682097000233.tif63128

[0433] Table 35: Monkey PO PK results for compound 03-115 TIFF0007682097000234.tif40128

[0434] Example 8: Evaluation of additional synthetic adrenergic receptor agonists The potency of the following additional compounds was determined using the methods described in Example 2. Potency data for selected compounds are shown below in Table 36A (EC 50 ) and Table 36B (pEC 50 )

[0435] Table 36A: Pharmacological data for certain additional compounds disclosed herein TIFF0007682097000235.tif51128TIFF0007682097000236.tif230116TIFF000768209700 0237.tif230116TIFF0007682097000238.tif230116TIFF0007682097000239.tif33128EC 50 (nM): A<10nM; B=10~100nM; C=100nM~1μM; D>1μM

[0436] Table 36B: Pharmacological data for certain additional compounds disclosed herein TIFF0007682097000240.tif170137TIFF0007682097000241.tif230137TIFF0007682097000242.tif230137TIFF000768209700 0243.tif230137TIFF0007682097000244.tif230137TIFF0007682097000245.tif230137TIFF0007682097000246.tif216137pEC 50 : A>8; B=8~7; C=<7~6; D<6

[0437] Those skilled in the art will know, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compositions and procedures described herein which equivalents are considered to be within the scope of this disclosure and encompassed by the following claims.

[0438] In addition to the various embodiments described in the specification above, the following additional embodiments are contemplated herein. 1. Compounds according to formula (I) TIFF0007682097000247.tif26128 or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof [In the formula, each A, B, and X is independently nitrogen or carbon; each R1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; m is an integer selected from 0 to 4; R2, R3, and R4 are independently H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; TIFF0007682097000248.tif67150, or R2 and R3 together with the carbons form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring; L is an optionally substituted C1-C5 alkyl linker; each Y, Y, Y, and Y is independently a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; Z is O or S; R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R5 and R6 are cyclically bonded together with Y2 to form an optionally substituted cycloalkyl or heterocycle; each R7 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl; and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino. 2. Compounds according to formula (II) TIFF0007682097000249.tif28128 or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof [In the formula, each A, B, and X is independently nitrogen or carbon; each R1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; m is an integer selected from 0 to 4; R2, R3, and R4 are independently H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; TIFF0007682097000250.tif62151, or R2 and R3 together with the carbons form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring; L is an optionally substituted C1-C5 alkyl linker; each Y, Y, Y, and Y is independently a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; Z is O or S; R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R5 and R6 are cyclically bonded together with Y2 to form an optionally substituted cycloalkyl or heterocycle; each R7 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl; and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino. 3. Compounds according to formula (III) TIFF0007682097000251.tif23128 or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof [In the formula, each R1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; m is an integer selected from 0 to 4; R2, R3, and R4 are independently H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; TIFF0007682097000252.tif61153, or R2 and R3 together with the carbons form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring; L is an optionally substituted C1-C5 alkyl linker; each X1, X2, X3, and X4 independently represents a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; Y is O or S; R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R5 and R6 are cyclically bonded together with Y2 to form an optionally substituted cycloalkyl or heterocycle; each R7 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl; and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino. 4. The compound of embodiment 1 having the following structural formula: TIFF0007682097000253.tif17128 or a pharmaceutically acceptable salt thereof. 5. The compound according to any one of embodiments 1 to 4, which is an agonist, partial agonist or antagonist of an adrenoceptor. 6. The compound of any one of embodiments 1-4, which is a β1-adrenergic receptor agonist, a β2-adrenergic receptor agonist or a non-selective β1 / β2-adrenergic receptor agonist. 7. The compound of any one of embodiments 1-4, which is a β1-adrenergic receptor agonist. 8. The compound of any one of embodiments 1-4, which is a β2-adrenergic receptor agonist. 9. The compound of any one of embodiments 1-4, which is a non-selective β1 / β2-adrenergic agonist. 10. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 9 and a pharmaceutically acceptable excipient. 11. A method of treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-9. 12. A method of treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-9, thereby treating the subject. 13. 10. A method of treating a subject having a disease associated with an adrenoceptor, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-9. 14. The method of any one of embodiments 11 to 13, wherein the disease is a neurodegenerative disease. 15. The diseases include MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; Alcohol-Induced Neuropathy), and the like. 15. The method of embodiment 14, wherein the disease is one or more selected from the group consisting of: Dementia with Lewy Bodies (DLB), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (PD), Dementia with Lewy Bodies (DS), Dementia with Lewy Bodies (DLB ... 16. The method of any one of embodiments 11 to 15, wherein the subject is a human. 17. 17. The method of any one of embodiments 11-16, wherein the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route. 18. Compounds according to formula (XXII'): TIFF0007682097000254.tif25128 or a pharmaceutically acceptable salt thereof [In the formula, R 1’ is a halogen, -R', -CN, or -NO2; Each R' is an optionally substituted C 1~6 is aliphatic; and R 2’ , R 3’ , and R 4’are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring. 19. The compound of embodiment 18, wherein the carbon bonded to the OH group has the (R) configuration. 20. R 1’ 20. The compound of any of embodiments 18-19, wherein is methyl. twenty one. R 2’ But C 1~6 The compound of any one of embodiments 18-20, which is aliphatic. twenty two. R 2’ The compound of any one of embodiments 18-21, wherein is methyl. twenty three. R 3’ But C 1~6 The compound of any one of embodiments 18-22, which is aliphatic. twenty four. R 3’ The compound of any one of embodiments 18-23, wherein is methyl. twenty five. R 4’ But C 1~6 The compound of any one of embodiments 18-22, which is aliphatic. 26. R 4’ The compound of any one of embodiments 18-23, wherein is methyl. 27. Compounds according to formula (XVIII'): TIFF0007682097000255.tif24128 or a pharmaceutically acceptable salt thereof [In the formula, R 1’ is a halogen, -R', -CN, or -NO2; Each R' is an optionally substituted C 1~6 is aliphatic; and R 2’ , R 3’ , and R 4’ are each independently a halogen, —R′, —CN, —NO2, —OR′, or —NR′2; or R 2 ' and R 3 ' together with the carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring. 28. The compound of embodiment 26, wherein the carbon bonded to the OH group has the (S) configuration. 29. R 1’ The compound of any of embodiments 26-27, wherein is cyano. 30. R 2’ But C 1~6 The compound of any one of embodiments 26-28, which is aliphatic. 31. R 2’ The compound of any one of embodiments 26-29, wherein is methyl. 32. R 3’ But C 1~6 The compound of any one of embodiments 26-30, which is aliphatic. 33. R 3’ The compound of any one of embodiments 26-31, wherein is methyl. 34. R 4’ But C 1~6 The compound of any one of embodiments 26-32, which is aliphatic. 35. R 4’ The compound of any one of embodiments 26-33, wherein is methyl.

Claims

1. The structure: (i) ,or (ii) or a pharma- ceutically acceptable salt thereof.

2. The structure: or a pharma- ceutically acceptable salt thereof.

3. The structure:

2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof.

4. The structure:

2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharma- ceutically acceptable excipient.

6. A pharmaceutical composition for use in a method for treating a subject having a disease comprising a compound according to any one of claims 1 to 4, optionally comprising (i) the disease is associated with an adrenergic receptor; (ii) the disease is a neurodegenerative disease, and optionally the disease is selected from the group consisting of MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wake-Keeping Syndrome), and others. one or more selected from the group consisting of Wernicke-Korsakoff syndrome; alcoholic dementia & thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related disease (CJD), depressive disorder, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down's syndrome (DS); (iii) the subject is a human; and / or (iv) the compound is administered to said subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal routes; Pharmaceutical compositions.

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