Beta adrenergic agonist and methods of using the same

Abstract

To provide a compound useful in the treatment of diseases associated with an adrenergic receptor, and a method for treating a subject having a disease associated with an adrenergic receptor.SOLUTION: For example, a compound of formula (I') or a pharmaceutically acceptable salt thereof is disclosed. One embodiment of methods for treating a subject includes administering to the subject the compound and a peripherally acting P-blocker (PABRA).SELECTED DRAWING: Figure 1

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 Mar. 27, 2019, and U.S. Provisional Patent Application No. 62 / 934,482, filed Nov. 12, 2019, each of which is incorporated herein by reference in its entirety.

[0002] Field The present disclosure generally relates to compounds and, in some embodiments, to their use in the treatment of diseases associated with beta - adrenergic agonists and adrenergic receptors.

Background Art

[0003] Background The PCT application publication number WO2017 / 197324 (Patent Document 1) discloses "a method of treating a subject for a disease or condition associated with an adrenergic receptor, comprising administering a therapeutically effective amount of an adrenergic receptor - modulating 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 a learning or memory or both impairment due to a neurodegenerative disorder, comprising administering to the mammal an effective amount of at least one compound or a salt thereof that is a β1 - adrenergic receptor agonist, partial agonist or receptor ligand."

[0005] U.S. Patent Application Publication No. 2014 / 0235726 (Patent Document 3) discloses "a method of improving cognition in a patient having Down syndrome, comprising administering to the patient one or more β2 - adrenergic receptor agonists in an amount and frequency effective to improve the patient's cognition as measured by a context learning test."

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

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

[0008] Summary The present disclosure is based, at least in part, on the identification of compounds that modulate adrenergic receptors and methods of using them to treat diseases associated with adrenergic receptors. Compounds of formula (I) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof are disclosed herein. TIFF2025087743000002.tif29128

[0009] In some embodiments, each A, B, and X is independently nitrogen or carbon. In some embodiments, each R 1Each independently is selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorothiol, 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, R 2 , R 3 , and R 4 Each independently is 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, selected from the group consisting of TIFF2025087743000003.tif60156, or R 2 and R 3 together with carbon 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, and each Y 1 , Y 2 , Y 3 , and Y 4 Each independently is 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, R 5 and R 6 Each independently is selected from hydrogen, unsubstituted or substituted alkyl, or R5 and R 6 is, Y 2 which is cyclically bonded together with Y to form an optionally substituted cycloalkyl or heterocyclic ring, and each R 7 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, and R 8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R 9 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 of formula (II) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF2025087743000004.tif30128

[0015] In some embodiments, each A, B, and X is independently nitrogen or carbon. In some embodiments, each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorothio, 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, R 2 , R 3 , and R 4 are each independently selected from the group consisting of 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, TIFF2025087743000005.tif60156, or R 2 and R 3 together with carbon 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, and each Y 1 , Y 2 , Y 3 , and Y 4 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, R 5 and R 6 are each independently selected from hydrogen, unsubstituted or substituted alkyl, or R 5 and R 6 are cyclically bonded together with Y 2 to form an optionally substituted cycloalkyl or heterocycle, and each R 7 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, and R 8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R 9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino.

[0020] Furthermore, the compound according to formula (III) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs are disclosed herein. TIFF2025087743000006.tif26128

[0021] In some embodiments, each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorothio, 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, R 2 , R 3 , and R 4 are independently selected from the group consisting of 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, TIFF2025087743000007.tif60156 or R 2 and R3 forms, together with carbon, 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, and each X 1 , X 2 , X 3 , and X 4 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, R 5 and R 6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R 5 and R 6 are cyclically bonded together with Y 2 to form an optionally substituted cycloalkyl or heterocycle, and each R 7 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, R 8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R 9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino.

[0026] Furthermore, the compound according to formula (I’): TIFF2025087743000008.tif32128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, A’, B’, and X’ are each independently nitrogen or carbon; each R 1’ is independently halogen, -R’, -CN, -NO 2 , -SF 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R’, -C(O)R’, -C(O)NR’ 2 ; each R’ is independently hydrogen or a group optionally selected from C 1~6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 is independently a group optionally selected from C 1~6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 halogen, -R’, -CN, -NO 2 , -OR’, -NR’ 2, TIFF2025087743000009.tif60161 or R 2 ’ and R 3 ’ together with carbon may 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; L’ is optionally substituted C 1~5 alkylene; Y 1’ , Y 2’ , Y 3’ , and Y 4’ are each independently a covalent bond, carbon, oxygen, or nitrogen substituted with hydrogen, optionally substituted C 1~6 alkyl, or optionally substituted nitrogen substituted with 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’ are cyclically bonded together with Y 2’ 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’ is independently -R’, halogen, -CN, -NO 2 , -NR’ 2 , or -OR’; n’ is an integer selected from 0 to 4; R 8’ is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring; and each R 9’ is independently hydrogen, halogen, -CN, -OR x , -NR’ 2 , or optionally substituted alkyl; and R 10’ and R 11’ are each independently hydrogen or optionally substituted C 1~2 is aliphatic].

[0027] Furthermore, a compound according to formula (I’’): TIFF2025087743000010.tif32128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, A’, B’, and X’ are each independently nitrogen or carbon; each R 1’ is independently halogen, -R’, -CN, -NO 2 , -SF 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R’, -C(O)R’, -C(O)NR’ 2 , -NR’C(O)R’, -NR’CO 2 R’, or -CO 2 R’; each R’ is independently hydrogen, or C 1~6An optionally substituted group selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 is independently C 1~6 An optionally substituted group selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 halogen, -R', -CN, -NO 2 、-OR', -NR' 2 、 TIFF2025087743000011.tif60162, or R 2 ' and R 3 ' together with 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 an optionally substituted C1~5 is an alkylene; Y 1’ , Y 2’ , Y 3’ , and Y 4’ are each independently a covalent bond, carbon, oxygen, or nitrogen substituted with hydrogen, optionally substituted C 1~6 alkyl, or nitrogen optionally substituted with a 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’ are, together with Y 2’ cyclically bonded 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’ is independently -R’, halogen, -CN, -NO 2 , -NR’ 2 , or -OR’; n’ is an integer selected from 0 to 4; R 8’ is hydrogen, -CN, optionally substituted alkyl, or an optionally substituted aryl ring; and each R 9’ is independently hydrogen, halogen, -CN, -OR x , -NR’ 2 , or optionally substituted alkyl; and R 10’ and R 11’ are each independently hydrogen or optionally substituted C 1~2 is aliphatic].

[0028] Furthermore, a compound having the following structural formula: TIFF2025087743000012.tif17128 or a pharmaceutically acceptable salt thereof is disclosed herein.

[0029] Furthermore, a compound having the following structural formula: TIFF2025087743000013.tif16128 or a pharmaceutically acceptable salt thereof is disclosed herein.

[0030] Furthermore, a compound having the following structural formula: TIFF2025087743000014.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 the 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 additive.

[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 non - selective β1 / β2 - adrenergic agonists.

[0033] Further disclosed is a method of treating a subject having a disease, the method 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 a disease associated with adrenergic receptors. 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, Garlic disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedreich's ataxia, ataxia telangiectasia, spinal muscular atrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to a subject orally, enterally, topically, by inhalation, transmucosally, intravenously, intramuscularly, intraperitoneally, subcutaneously, intranasally, epidurally, intracranially, intraventricularly, topically on the skin, extra-amniotically, intra-arterially, intra-articularly, intracardially, intracorporally, intradermally, intralesionally, intraocularly, intraosseously, intraperitoneally, intrathecally, intrauterinely, intravaginally, intravesically, intravitreally, transdermally, perivascularly, buccally, vaginally, sublingually, or via the rectal route.

[0035] In some embodiments, the disease is one or more neurodegenerative diseases selected from the group consisting of 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; 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 disorder, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down syndrome (DS). In some embodiments, the disease is one or more neurodegenerative diseases selected from the group consisting of MCI, aMCI, 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; 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 disorder, DLB (Lewy body dementia), 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 syndrome.

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

[0037] As used herein, the term "peripherally acting β-blocker (PABRA)" means a β-adrenergic receptor antagonist or simply a β1-, β2- or non-selective β-blocker. In certain embodiments, examples of selective peripherally acting β-blockers (PABRAs) that can be used in the methods disclosed herein include nadolol, atenolol, sotalol and labetalol. In certain embodiments, the β-blocker that can be used in the methods herein is one or more selected from the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol and nebivolol; in other embodiments, the method does not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol or nebivolol as the β-blocker.

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

[0039] In certain embodiments of the compositions and methods provided herein, one or more peripherally acting β-blockers (PABRAs) are administered before or simultaneously with the compound of the present disclosure to inhibit or eliminate agonism of the peripheral β1 and / or β2 adrenergic receptors by the compound of the present disclosure. In various embodiments, it is preferred to block the peripheral β1 and / or β2 adrenergic receptors according to the compositions and methods of the present disclosure to eliminate or at least minimize any adverse peripheral cardiac, metabolic or muscular effects in the human being being treated.

[0040] In some embodiments of the methods provided herein, in addition to the compounds described herein, a β1 agonist and / or a β2 agonist, or a non-selective β1 / β2 agonist is administered to a patient.

[0041] As used herein, the term "β1 agonist" is used to mean a β1-adrenergic receptor agonist or a β1-ADR agonist. In certain embodiments, it is understood that the term "β1 agonist" includes compounds that are primarily β1 agonists but may also exhibit some peripheral agonism for 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" clearly encompasses both selective and partial agonists, as well as biased and unbiased agonists. Examples of β1 adrenergic agonists include, for example, xamoterol, noreadrenaline, isoprenaline, dopamine, pindolol and dobutamine and pharmaceutically acceptable salts of any of the foregoing. Partial agonists and ligands of β1-ADR are known. Further, using the methodology of Kolb et al, but instead for β1-ADR, one of ordinary skill in the art will be able to 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" is used to mean a β2 - adrenergic receptor agonist or a β2 - ADR agonist. In certain embodiments, the term "β2 agonist" is understood to include compounds that are primarily β2 agonists but may also exhibit some peripheral agonism with respect to other adrenergic receptors, such as the β1 - adrenergic receptor. In this 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" clearly encompasses both selective and partial agonists. The β2 agonists that can be used in accordance with 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 are salbutamol, levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, oritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and isoetharine. Examples of long - acting β2 agonists that can be used are 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 unexpectedly been found that the compounds of the present disclosure exhibit unexpectedly advantageous properties. For example, the compounds of the present disclosure have unexpectedly been found to act as low nM (<10 nM) partial agonists of the β2 adrenergic receptor. Furthermore, the compounds of the present disclosure exhibit an unexpectedly high ability to cross the blood - brain barrier and accumulate in the cerebrospinal fluid. In addition, the compounds of the present disclosure exhibit excellent oral bioavailability and stability while at the same time showing low toxicity and a low potential for drug - drug interactions. [Invention 1001] A compound of formula (I') or a pharmaceutically acceptable salt thereof: TIFF2025087743000015.tif32128In formula, 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 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 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 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 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 halogen, -R', -CN, -NO 2, -OR’, -NR’ 2 , TIFF2025087743000016.tif60162 or R 2 ’ and R 3 ’ together with carbon may 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; L’ is an optionally substituted C 1~5 alkylene; Y 1’ , Y 2’ , Y 3’ , and Y 4’ are each independently a covalent bond, carbon, oxygen, or nitrogen substituted with hydrogen, optionally substituted C 1~6 alkyl, or optionally substituted nitrogen substituted with 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’ are cyclically bonded together with Y 2’ 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’ is independently -R’, halogen, -CN, -NO 2 , -NR’ 2、or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring; and each R 9’ is independently hydrogen, halogen, -CN, -OR x , -NR' 2 , or optionally substituted alkyl; and R 10’ and R 11’ are each independently hydrogen or optionally substituted C 1~2 is aliphatic. [Invention 1002] A compound according to formula (II') or a pharmaceutically acceptable salt thereof: TIFF2025087743000017.tif30128 wherein A', B', and X' are each independently nitrogen or carbon; each R 1’ is independently halogen, -R', -CN, -NO 2 , -SF 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R', -C(O)R', --C(O)NR' 2 ; each R' is independently hydrogen, or a group optionally selected from C 1~6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 is independently C 1~6An optionally substituted group selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 halogen, -R’, -CN, -NO 2 , -OR’, -NR’ 2 , TIFF2025087743000018.tif60162, or R 2 ’ and R 3 ’ together with 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 alkylene; Y 1’ Y 2’ Y 3’ and Y 4’ are each independently a covalent bond, carbon, oxygen, or nitrogen substituted with hydrogen, optionally substituted C 1~6 alkyl, or 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 joined in a ring together with Y 2’ 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’ is independently -R', halogen, -CN, -NO 2 , -NR' 2 , or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring; and Each R 9’ is independently hydrogen, halogen, -CN, -OR x , -NR' 2 , or optionally substituted alkyl. [Invention 1003] A compound according to formula (III') or a pharmaceutically acceptable salt thereof: TIFF2025087743000019.tif26128 wherein A', B', and X' are each independently nitrogen or carbon; Each R 1’ is independently halogen, -R', -CN, -NO 2 , -SF 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R', -C(O)R', --C(O)NR' 2 ; Each R' is independently hydrogen, or C 1~6An optionally substituted group selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 is independently, C 1~6 An optionally substituted group selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 halogen, -R', -CN, -NO 2 、-OR', -NR' 2 、 TIFF2025087743000020.tif60162, or R 2 ' and R 3 ' together with 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; 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 an optionally substituted C1~5 is an alkylene; Y 1’ , Y 2’ , Y 3’ , and Y 4’ are each independently a covalent bond, carbon, oxygen, or nitrogen substituted with hydrogen, optionally substituted C 1~6 alkyl, or nitrogen optionally substituted with a 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’ are, together with Y 2’ cyclically bonded 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’ is independently -R’, halogen, -CN, -NO 2 , -NR’ 2 , or -OR’; n’ is an integer selected from 0 to 4; R 8’ is hydrogen, -CN, optionally substituted alkyl, or an optionally substituted aryl ring; and each R 9’ is independently hydrogen, halogen, -CN, -OR x , -NR’ 2 , or optionally substituted alkyl. [Invention 1004] A compound according to formula (XVIII’) or a pharmaceutically acceptable salt thereof: TIFF2025087743000021.tif24128 wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; each R’ is optionally substituted C 1~6 aliphatic; and R 2’ , R 3’ and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 ; or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring. [Inventive Concept 1005] A compound according to formula (XXII’) or a pharmaceutically acceptable salt thereof: TIFF2025087743000022.tif25128 wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; each R’ is optionally substituted C 1~6 aliphatic; and R 2’ , R 3’ and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 ; or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring. [Inventive Concept 1006] R 1’ is halogen, -CN, or optionally substituted C 1~6 aliphatic, a compound according to any one of Inventive Concepts 1001 to 1005. [Inventive Concept 1007] R 1’The compound of the present invention 1006, wherein it is -CN. [The present invention 1008] R 1’ wherein R is optionally substituted C 1~6 The compound of the present invention 1006, wherein it is aliphatic. [The present invention 1009] R 1’ The compound of the present invention 1008, wherein R is methyl. [The present invention 1010] R 1’ wherein R is -CF 3 The compound of the present invention 1008, wherein it is -CF. [The present invention 1011] R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring, and any compound of the present inventions 1001 to 1010. [The present invention 1012] R 2’ wherein R is optionally substituted C 1~6 The compound of any one of the present inventions 1001 to 1010, wherein it is aliphatic. [The present invention 1013] R 2’ The compound of the present invention 1012, wherein R is methyl. [The present invention 1014] R 3’ wherein R is optionally substituted C 1~6 The compound of any one of the present inventions 1001 to 1010, wherein it is aliphatic. [The present invention 1015] R 3’ The compound of the present invention 1014, wherein R is methyl. [The present invention 1016] R 4’ wherein R is optionally substituted C 1~6 The compound of any one of the present inventions 1001 to 1010, wherein it is aliphatic. [The present invention 1017] R 4’ The compound of the present invention 1016, wherein R is methyl. [The present invention 1018] The following structural formula: The compound of the present invention 1001 or a pharmaceutically acceptable salt thereof having TIFF2025087743000023.tif16128. [The present invention 1019] The following structural formula: The compound of the present invention 1001 or a pharmaceutically acceptable salt thereof having TIFF2025087743000024.tif17128. [The present invention 1020] The following structural formula: The compound of the present invention 1001 or a pharmaceutically acceptable salt thereof having TIFF2025087743000025.tif16128. [The present invention 1021] A compound of any one of the present inventions 1001 to 1020, which is an agonist, partial agonist or antagonist of an adrenergic receptor. [The present invention 1022] A compound of any one of the present inventions 1001 to 1020, which is a β1 - adrenergic receptor agonist, β2 - adrenergic receptor agonist or non - selective β1 / β2 - adrenergic receptor agonist. [The present invention 1023] A compound of any one of the present inventions 1001 to 1020, which is a β1 - adrenergic receptor agonist. [The present invention 1024] A compound of any one of the present inventions 1001 to 1020, which is a β2 - adrenergic receptor agonist. [The present invention 1025] A compound of any one of the present inventions 1001 to 1020, which is a non - selective β1 / β2 - adrenergic agonist. [The present invention 1026] A pharmaceutical composition comprising a compound of any one of the present inventions 1001 to 1020 and a pharmaceutically acceptable additive. [The present invention 1027] A method for treating a subject having a disease, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of any one of the present inventions 1001 to 1020. [The present invention 1028] A method of treating a subject having a disease, the method comprising administering to the subject a therapeutically effective amount of any one of Compounds 1001 to 1020 of the present invention, thereby treating the subject. [Compound 1029 of the present invention] A method of 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 one of Compounds 1001 to 1020 of the present invention. [Compound 1030 of the present invention] Any one of Methods 1027 to 1029 of the present invention, wherein the disease is a neurodegenerative disease. [Compound 1031 of the present invention] The method of Compound 1030 of the present invention, wherein the disease is one or more 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 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; 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 disorder, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down syndrome (DS). [Compound 1032 of the present invention] Any one of Methods 1027 to 1031 of the present invention, wherein the subject is human. [Compound 1033 of the present invention] Administering the compound to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, on the skin, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernous, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal routes, the method according to any one of claims 1027 to 1032 of the present invention.

Brief Description of the Drawings

[0044]

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Mode for Carrying Out 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 the embodiments of the present disclosure. However, it will be apparent to those skilled in the art that the 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 so as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0046] The following explanation of terms and methods is provided to better describe the present disclosure and to guide those skilled in the art in the practice of the present 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 "includes." Thus, "comprising A or B" means "including A, B, or both A and B" without excluding additional elements. The term "about" will be understood by those skilled in the art. Whether or not the term "about" is explicitly used, all quantities set forth in this specification refer to the actual given value shown and also mean approximations to such shown values that would be reasonably inferred based on ordinary skill in the art.

[0047] Furthermore, it is to be understood that all base sizes or amino acid sizes, and all molecular weights or molecular mass values shown for nucleic acids or polypeptides are approximate values and are presented for illustrative purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0048] Unless otherwise defined, 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, published by Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).

[0049] Unless otherwise indicated, the nomenclature of substituents not explicitly defined herein is obtained by naming the terminal portion of the functional group towards the point of attachment, followed by naming the adjacent functional groups. One of ordinary skill in the art will understand that the above definitions are not intended to include unacceptable substitution patterns (e.g., methyl substituted with five different groups, pentavalent carbon, etc.). Such unacceptable substitution patterns will be readily recognized by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Since they were available on August 11, 2011, all sequences shown in the Genbank accession numbers of the disclosure are incorporated by reference herein. In case of conflict, this specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and 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-chain and branched-chain groups having 1 to 12 carbon atoms, typically 1 to about 10 carbons, 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. The alkyl group may be substituted or unsubstituted. Representative substituted alkyl groups may 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 "cycloalkyl" or "cyclic alkyl" refers to a monovalent group derived from 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. The cycloalkyl group may be substituted or unsubstituted. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, for example, but not limited to, may be 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, bicyclo[4.4.0]decane, bicyclo[2.2.1]heptane, spiro[2.2]pentane, etc. (Cycloalkyl)oxy refers to -O-cycloalkyl. (Cycloalkyl)thio refers to -S-cycloalkyl. This term also encompasses oxidized forms of sulfur, for example, -S(O)-cycloalkyl, or -S(O 2 -cycloalkyl.

[0052] An alkenyl group refers to a straight-chain, branched-chain, and cycloalkyl group as defined above, having one or more double bonds between two carbon atoms. An alkenyl group may have 2 to about 12 carbon atoms, or in some embodiments, 1 to about 10 carbons, or in other embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. The alkenyl group may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, for example, but not limited to, may be mono-, di-, or tri-substituted. Examples of alkenyl groups include, but are not limited to, especially vinyl, allyl, -CH=CH(CH 3 ), -CH=C(CH 3 ) 2 , -C(CH3 )=CH 2 , cycloalkenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl are included.

[0053] An alkynyl group refers to a straight-chain, branched-chain, and cycloalkyl group as defined above having one or more triple bonds between two carbon atoms. The alkynyl group may have 2 to about 12 carbon atoms, or in some embodiments, 1 to about 10 carbons or in other embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. The alkynyl group may be substituted or unsubstituted. Representative substituted alkynyl groups may 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, especially ethynyl, propargyl, and -C≡C(CH 3 ) is included.

[0054] An aryl group is a cyclic aromatic hydrocarbon that includes single and multiple ring compounds, including separate and / or fused aryl groups. The aryl group may include 6 to about 18 ring carbons, or in some embodiments, 6 to 14 ring carbons or in other embodiments, further 6 to 10 ring carbons. The aryl group also includes a heteroaryl group which is an aromatic ring compound containing 5 or more ring members in which one or more of the ring carbon atoms are substituted with heteroatoms such as, but not limited to, N, O, and S. The aryl group may be substituted or unsubstituted. Representative substituted aryl groups may be mono-substituted or substituted more than once, for example, but not limited to, may be mono-, di-, or tri-substituted. The aryl group includes, but is not limited to, phenyl, biphenylyl, triphenylyl, naphthyl, anthryl, and pyrenyl groups. Aryloxy refers to -O-aryl. Arylthio refers to -S-aryl, where aryl is as defined herein. This term also includes oxidized forms of sulfur, for example, --S(O)-aryl, or -S(O) 2 -aryl. Heteroaryloxy refers to -O-heteroaryl. Heteroarylthio refers to -S-heteroaryl. This term also includes oxidized forms of sulfur, for example, -S(O)-heteroaryl, or -S(O) 2 -heteroaryl.

[0055] Suitable heterocyclyl groups include cyclic groups having at least two different elemental atoms as ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, or S. The heterocyclyl group may contain from 3 to about 20 ring members, or in some embodiments from 3 to 18, or from about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring system in the heterocyclyl group may be unsaturated, partially saturated, and / or saturated. The heterocyclyl group may be substituted or unsubstituted. Representative substituted heterocyclyl groups may 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, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxaazepinyl, diazepinyl, thiaazepinyl, 1,2,3,6-tetrahydropyridyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolidinyl, 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 is included.

[0056] A polycyclic or polycyclic group refers to two or more rings in which two or more carbons are common to two adjacent rings, where those rings are "fused rings"; if those rings are joined by a single common carbon atom, these are "spiro" ring systems. Rings joined through non-adjacent atoms are "bridged" rings. The polycyclic group may be substituted or unsubstituted. Representative polycyclic groups may be substituted one or more times.

[0057] Halogen groups include F, Cl, Br, and I; the nitro group refers to -NO 2 and refers to -CN; the isocyano group refers to -N≡C; the epoxy group includes a structure in which an oxygen atom is directly bonded to two adjacent or non-adjacent carbon atoms of a carbon chain or ring system, which is essentially a cyclic ether structure. An epoxide is a cyclic ether containing a three-atom ring.

[0058] An alkoxy group is a substituted or unsubstituted alkyl group as defined above, singly bonded to oxygen. The alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more 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, the compounds of the present disclosure may include "optionally substituted" moieties. In general, the term "substituted (substituting)" means that one or more hydrogens of the specified moiety are replaced with a suitable substituent, whether or not preceded by the term "optionally". Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from the specified groups, the substituents may be the same or different at any position. Combinations of substituents contemplated by the present disclosure preferably result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that do not substantially change when subjected to the conditions for their generation, 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 2 ) 0~4 R 〇 ; -(CH 2 ) 0~4 OR 〇 ; -O(CH 2 ) 0~4 R o , -O-(CH 2 ) 0~4 C(O)OR 〇 ; -(CH 2 ) 0~4 CH(OR 〇 ) 2 ; -(CH 2 ) 0~4 SR 〇 ; R 〇 Optionally substituted -(CH 2 ) 0~4 Ph; R 〇 Optionally substituted -(CH 2 ) 0~4 O(CH 2 ) 0~1 Ph; R〇 -CH=CHPh which may be substituted; R 〇 -(CH 2 ) 0~4 O(CH 2 ) 0~1 -pyridyl; -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0~4 N(R 〇 ) 2 ; -(CH 2 ) 0~4 N(R 〇 )C(O)R 〇 ; -N(R 〇 )C(S)R 〇 ; -(CH 2 ) 0~4 N(R 〇 )C(O)NR 〇 2 ; -N(R 〇 )C(S)NR 〇 2 ; -(CH 2 ) 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 ; -(CH 2 ) 0~4 C(O)R 〇 ; -C(S)R 〇 ; -(CH 2 ) 0~4 C(O)OR 〇 ; -(CH 2 ) 0~4 C(O)SR 〇 ; -(CH 2 ) 0~4 C(O)OSiR 〇 3 ; -(CH 2 ) 0~4 OC(O)R 〇 ; -OC(O)(CH2 ) 0~4 SR o ;SC(S)SR 〇 ;-(CH 2 ) 0~4 SC(O)R 〇 ;-(CH 2 ) 0~4 C(O)NR 〇 2 ;-C(S)NR 〇 2 ;-C(S)SR 〇 ;-SC(S)SR 〇 ;-(CH 2 ) 0~4 OC(O)NR 〇 2 ;-C(O)N(OR 〇 )R 〇 ;-C(O)C(O)R 〇 ;-C(O)CH 2 C(O)R 〇 ;-C(NOR 〇 )R 〇 ;-(CH 2 ) 0~4 SSR 〇 ;-(CH 2 ) 0~4 S(O) 2 R 〇 ;-(CH 2 ) 0~4 S(O) 2 OR 〇 ;-(CH 2 ) 0~4 OS(O) 2 R 〇 ;-S(O) 2 NR 〇 2 ;-S(O)(NR 〇 )R 〇 ;-S(O) 2 N=C(NR 〇 2 ) 2 ;-(CH 2 ) 0~4 S(O)R 〇 ;-N(R 〇 )S(O) 2 NR 〇 2 ;-N(R 〇 )S(O) 2 R〇 ;-N(OR 〇 )R 〇 ;-C(NH)NR 〇 2 ;-P(O) 2 R 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)O-N(R 〇 ) 2 ; or -(C 1~4 linear or branched alkylene)C(O)O-N(R 〇 ) 2 wherein each R 〇 may be substituted as defined below and is independently hydrogen, C 1~6 aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent occurrences of R 〇 together with their intervening atom(s), if any, 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 a ring formed by two independent occurrences of R 〇 together with their intervening atoms) suitable monovalent substituents thereon are independently halogen, -(CH 2 ) 0~2 R ● ;-(haloR ● );-(CH 2 ) 0~2 OH;-(CH 2 ) 0~2OR ● ;-(CH 2 ) 0~2 CH(OR ● ) 2 ;-O(halo R ● );-CN;-N 3 ;-(CH 2 ) 0~2 C(O)R ● ;-(CH 2 ) 0~2 C(O)OH;-(CH 2 ) 0~2 C(O)OR ● ;-(CH 2 ) 0~2 SR ● ;-(CH 2 ) 0~2 SH;-(CH 2 ) 0~2 NH 2 ;-(CH 2 ) 0~2 NHR ● ;-(CH 2 ) 0~2 NR ● 2 ;-NO 2 、-SiR ● 3 ;-OSiR ● 3 ;-C(O)SR ● ;-(C 1~4 linear or branched alkylene)C(O)OR ● ; or -SSR ● and wherein each R ● is unsubstituted or, when preceded by "halo", substituted only with one or more halogens and is independently selected from C 1~4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R 〇 include =O and =S.

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

[0063] R * Suitable substituents on the aliphatic group of R include halogen, -R ● ; -(haloR ● ); -OH, -OR ● ; -O(haloR ● ); -CN; -C(O)OH; -C(O)OR ● ; -NH 2 ; -NHR ● ; -NR ● 2 ; or -NO 2 is included, where each R ●is unsubstituted or, when "halo" precedes, substituted with only one or more halogens and is independently, C 1~4 aliphatic, -CH 2 Ph; -O(CH 2 ) 0~1 Ph; or a 5- to 6-membered saturated; partially unsaturated; or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

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

[0065] R † Suitable substituents on the aliphatic group of are independently halogen, -R ● ; -(haloR● ); -OH; -OR ● ; -O(haloR ● ); -CN; -C(O)OH; -C(O)OR ● ; -NH 2 ; -NHR ● ; -NR ● 2 ; or -NO 2 and wherein each R ● is unsubstituted or, when preceded by "halo", substituted only with one or more halogens and is independently C 1~4 aliphatic, -CH 2 Ph; -O(CH 2 ) 0~1 Ph; or a 5- to 6-membered saturated; partially unsaturated; or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0066] Thiol refers to -SH. Thiocarbonyl refers to (=S). Sulfonyl refers to -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclyl, and -SO 2 -substituted heterocyclyl. Sulfonylamino refers to -NR a SO 2 alkyl, -NR a SO 2 -substituted alkyl, -NR a SO 2 cycloalkyl, --NR a SO 2 substituted cycloalkyl, -NR a SO 2 aryl, -NR a SO 2 substituted aryl, --NR a SO 2 heteroaryl, -NRa SO 2 substituted heteroaryl, -NR a SO 2 heterocyclyl, -NR a SO 2 refers to substituted heterocyclyl, wherein each R a is as defined herein.

[0067] Carboxyl refers to -COOH or a salt thereof. Carboxyester 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. (Carboxyester)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, wherein R a is as recited herein. (Carboxyester)oxy refers to -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)β-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclyl, and -O-C(O)O-substituted heterocyclyl. Oxo refers to (=O).

[0068] The terms "amine" and "amino" refer to derivatives of ammonia, wherein one or more hydrogen atoms are replaced by substituents including, but not limited to, alkyl, alkenyl, aryl, and heterocyclyl groups. In some embodiments, substituted amino may include -NH-CO-R. A carbamate group refers to -O(C=O)NR 1 R 2 wherein R 1 and R 2 are independently hydrogen, an aliphatic group, an aryl group, or a heterocyclyl group.

[0069] Aminocarbonyl refers to -C(O)N(R b ) 2 wherein each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. Also, each R b may optionally combine with the nitrogen to which it is attached to form a heterocyclyl or substituted heterocyclyl group, provided that both R b are not both hydrogen. Aminocarbonylalkyl refers to -alkylC(O)N(R b ) 2 wherein each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. Also, each R b may optionally combine with the nitrogen to which it is attached to form a heterocyclyl or substituted heterocyclyl group, provided that both R b are not both hydrogen. Aminocarbonylamino refers to -NR a C(O)N(R b ) 2 wherein R a and each R b are as defined herein. Aminodicarbonylamino refers to -NRa C(O)C(O)N(R b ) 2 refers to, where R a and each R b are as defined herein. Aminocarbonyl oxy refers to -O-C(O)N(R b ) 2 where each R b is independently as defined herein. Aminosulfonyl refers to -SO 2 N(R b ) 2 where each R b is independently as defined herein.

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

[0071] In addition, unless otherwise stated, the structural formulas shown herein are intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, replacement of hydrogen by deuterium (e.g., D or H 2 ) or tritium (e.g., T or H 3 ), or replacement of carbon by 13 C- or 14 C-enriched carbon, compounds having such structural formulas are included within and are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as 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 of the compounds from non-toxic organic or inorganic acids or quaternary ammonium salts. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloride, hydrobromide, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and 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, isothionic acid and other salts prepared from organic acids. In other cases, the above 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 in the administration vehicle or dosage form manufacturing process, or by reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or 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. 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 agent that requires conversion in the body to release the active agent. In certain embodiments, the conversion is enzymatic conversion. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active agent. The "pro moiety" refers to a form of a protecting group that is used to mask a functional group within the active agent to convert the active agent into a prodrug. In some cases, the pro moiety will be attached to the drug via a bond (s) that is cleaved by enzymatic or non-enzymatic means in vivo. Any convenient prodrug form of the present compounds can be prepared, for example, by the strategies and methods described in Rautio et al. ("Prodrugs: design and clinical applications", Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0074] Disclosed herein are compounds of formula (I) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF2025087743000026.tif29128

[0075] Each A, B, and X may independently be nitrogen or carbon. Each R 1 is independently hydrogen, halogen, cyano, nitro, pentafluorothio, 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] R 2 、R 3 、and R4 is 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, may be TIFF2025087743000027.tif67150, or R 2 and R 3 together with carbon may form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0077] L may be an optionally substituted C1-C5 alkyl linker, and each Y 1 , Y 2 , Y 3 , and Y 4 is independently a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Z may be O or S.

[0078] R 5 and R 6 are independently hydrogen, unsubstituted or substituted alkyl, or R 5 and R 6 are cyclically bonded together with Y 2 to form an optionally substituted cycloalkyl or heterocycle, and each R 7 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 may be an integer selected from 0 to 4, R 8may be hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R 9 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 of formula (II) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF2025087743000028.tif31128

[0081] Each A, B, and X may independently be nitrogen or carbon. Each R 1 may be hydrogen, halogen, cyano, nitro, pentafluorothio, 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] R 2 、R 3 、and R 4 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, TIFF2025087743000029.tif62150, or R 2 and R 3It may form, together with carbon, an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0083] L may be an optionally substituted C1-C5 alkyl linker, and each Y 1 , Y 2 , Y 3 , and Y 4 may independently be a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Z may be O or S.

[0084] R 5 and R 6 may independently be hydrogen, unsubstituted or substituted alkyl, or R 5 and R 6 may be cyclically bonded together with Y 2 to form an optionally substituted cycloalkyl or heterocycle, and each R 7 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 may be an integer selected from 0 to 4, R 8 may be hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R 9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, or unsubstituted or substituted amino.

[0086] Furthermore, the compounds of formula (III) or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs are disclosed herein. TIFF2025087743000030.tif27128

[0087] Each R 1 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.

[0088] R 2 、R 3 、and R 4 may independently be 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, TIFF2025087743000031.tif62150, or R 2 and R 3 may together with carbon form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

[0089] L may be an optionally substituted C1-C5 alkyl linker, and each X 1 、X 2 、X 3 、and X 4 may independently be a covalent bond, carbon, oxygen, or nitrogen substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Y may be O or S.

[0090] R 5 and R 6is independently hydrogen, unsubstituted or substituted alkyl, or R 5 and R 6 is, with Y 2 joined together cyclically to form an optionally substituted cycloalkyl or heterocycle, and each R 7 is independently 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 may be an integer selected from 0 to 4, and R 8 is hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl, and R 9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, or unsubstituted or substituted amino.

[0092] Furthermore, a compound according to formula (I’): TIFF2025087743000032.tif32128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, A’, B’, and X’ are each independently nitrogen or carbon; each R 1’ is independently halogen, -R’, -CN, -NO 2 , -SF 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R’, -C(O)R’, -C(O)NR’ 2 ; each R’ is independently hydrogen, or C 1~6An optionally substituted group selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 is independently C 1~6 An optionally substituted group selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 halogen, -R', -CN, -NO 2 、-OR', -NR' 2 、 TIFF2025087743000033.tif61150, or R 2 ' and R 3 ' together with 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 an optionally substituted C1~5 is an alkylene; Y 1’ Y, 2’ Y, 3’ and Y 4’ are each independently a covalent bond, carbon, oxygen, or nitrogen substituted with hydrogen, optionally substituted C 1~6 alkyl, or nitrogen optionally substituted with a 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’ are, together with Y 2’ cyclically bonded 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’ is independently -R’, halogen, -CN, -NO 2 2, -NR’ 2 2, or -OR’; n’ is an integer selected from 0 to 4; R 8’ is hydrogen, -CN, optionally substituted alkyl, or an optionally substituted aryl ring; each R 9’ is independently hydrogen, halogen, -CN, -OR x , -NR’ 2 2, or optionally substituted alkyl; and R 10’ and R 11’ are each independently hydrogen or optionally substituted C 1~2 aliphatic].

[0093] Furthermore, a compound according to formula (I''): TIFF2025087743000034.tif32128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, A', B', and X' are each independently nitrogen or carbon; each R 1’ is independently halogen, -R', -CN, -NO 2 , -SF 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R', -C(O)R', -C(O)NR' 2 , -NR'C(O)R', -NR'CO 2 R', or -CO 2 R'; each R' is independently hydrogen or a substitutable group selected independently from C 1~6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 is independently C 1~6An optionally substituted group selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 halogen, -R’, -CN, -NO 2 、-OR’, -NR’ 2 、 TIFF2025087743000035.tif60162 or R 2 ’ and R 3 ’ together with 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 alkylene; Y 1’ 、Y 2’ 、Y 3’ 、and Y 4’ are each independently a covalent bond, carbon, oxygen, or nitrogen substituted with hydrogen, optionally substituted C 1~6 alkyl, or 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’ together with Y 2’ are cyclically bonded 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’ is independently -R', halogen, -CN, -NO 2 , -NR' 2 , or -OR'; n' is an integer selected from 0 to 4; R 8’ is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring; Each R 9’ is independently hydrogen, halogen, -CN, -OR x , -NR' 2 , or optionally substituted alkyl; and R 10’ and R 11’ are each independently hydrogen or optionally substituted C 1~2 is aliphatic].

[0094] As defined above and as 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 as 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 as 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’ is independently halogen, -R’, -CN, -NO 2 , -SF 5 , -OR x , -NR x 2 , -NHR x , -SO 2 R’, -C(O)R’, -C(O)NR’ 2 , -NR’C(O)R’, -NR’CO 2 R’, or -CO 2 R’.

[0101] In some embodiments, R 1’ is hydrogen. In some embodiments, R 1’ is halogen. In some embodiments, R 1’ is -R’. In some embodiments, R 1’ is cyano. In some embodiments, R 1’ is -NO 2 . In some embodiments, R 1’ is -SF 5 . In some embodiments, R 1’ is -OR x . In some embodiments, R 1’ is -NR x2 is. In some embodiments, R 1’ is -NHR x is. In some embodiments, R 1’ is -SO 2 R’. In some embodiments, R 1’ is -C(O)R’. In some embodiments, R 1’ is -C(O)NR’ 2 is. In some embodiments, R 1’ is -NR’C(O)R’. In some embodiments, R 1’ is -NR’CO 2 R’. In some embodiments, R 1’ is -CO 2 R’.

[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 -CH 3 is. In some embodiments, R 1’ is -CH 2 CH 3 is. In some embodiments, R 1’ is -CH(CH 3 ) 2 is.

[0104] In some embodiments, R 1’ is -CF 3 is. In some embodiments, R 1’ is -CF 2 H. In some embodiments, R 1’ is -CFH 2 is. In some embodiments, R 1’ is -CF 2 CH 3 is. In some embodiments, R 1’ is -CH 2 CF 3 is. In some embodiments, R1’ is -C≡CCH. In some embodiments, R 1’ is vinyl. In some embodiments, R 1’ is -C≡CCF 3 In some embodiments, R 1’ is -CO 2 H.

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

[0106] In some embodiments, R 1’ is -OCH 3 In some embodiments, R 1’ is -OCH 2 CH 3 In some embodiments, R 1’ is -OCH(CH 3 ) 2 In some embodiments, R 1’ is -OCF 3 In some embodiments, R 1’ is -NHCH 3 In some embodiments, R 1’ is -NHCD 3 In some embodiments, R 1’ is -N(CD 3 )CO 2 tBu. In some embodiments, R 1’ is -NHCH 2 CH 3 In some embodiments, R 1’ is -NHCH 2 (CH 3 ) 2 In some embodiments, R 1’ is -NHCH 2 CF 3 In some embodiments, R 1’ is -NHPh. In some embodiments, R 1’ is -NHAc. In some embodiments, R 1’ is -N(CH 3 ) 2 In some embodiments, R1’ is TIFF2025087743000036.tif11128. In some embodiments, R 1’ is TIFF2025087743000037.tif14128. In some embodiments, R 1’ is TIFF2025087743000038.tif6128. In some embodiments, R 1’ is TIFF2025087743000039.tif8128. In some embodiments, R 1’ is TIFF2025087743000040.tif9128. In some embodiments, R 1’ is TIFF2025087743000041.tif9128. In some embodiments, R 1’ is TIFF2025087743000042.tif12128. In some embodiments, R 1’ is TIFF2025087743000043.tif13128. In some embodiments, R 1’ is TIFF2025087743000044.tif9128. In some embodiments, R 1’ is TIFF2025087743000045.tif11128. In some embodiments, R 1’ is TIFF2025087743000046.tif9128. In some embodiments, R 1’ is TIFF2025087743000047.tif11128. In some embodiments, R 1’ is TIFF2025087743000048.tif9128. In some embodiments, R 1’ is TIFF2025087743000049.tif14128. In some embodiments, R1’ is TIFF2025087743000050.tif9128. In some embodiments, R 1’ is TIFF2025087743000051.tif10128. In some embodiments, R 1’ is TIFF2025087743000052.tif9128. In some embodiments, R 1’ is TIFF2025087743000053.tif10128. In some embodiments, R 1’ is TIFF2025087743000054.tif9128. In some embodiments, R 1’ is TIFF2025087743000055.tif11128. In some embodiments, R 1’ is TIFF2025087743000056.tif10128. In some embodiments, R 1’ is TIFF2025087743000057.tif13128. In some embodiments, R 1’ is TIFF2025087743000058.tif17128. In some embodiments, R 1’ is TIFF2025087743000059.tif12128. In some embodiments, R 1’ is TIFF2025087743000060.tif7128. In some embodiments, R 1’ is TIFF2025087743000061.tif11128. In some embodiments, R 1’ is TIFF2025087743000062.tif10128. In some embodiments, R 1’ is TIFF2025087743000063.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 a C 1~6 group which is optionally substituted and is independently selected from aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocyclic ring, nitrogen, oxygen, or sulfur, 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 aliphatic. For example, in some embodiments, R' is -CF 3 , -CF 2 H, or -CFH 2 .

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

[0112] In some embodiments, R' is an optionally substituted 3- to 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- to 10-membered bicyclic partially unsaturated carbocyclic ring.

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

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

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

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

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

[0120] In some embodiments, R’ is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 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 is independently C 1~6A group which may be substituted and is selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, 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 is optionally substituted C 1~6 and is aliphatic. For example, in some embodiments, R x is -CF 3 -, -CF 2 H, or -CFH 2 . In some embodiments, R x is C 1~6 alkyl.

[0124] As defined above, m' is an integer selected from 0 to 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 halogen, -R', -CN, -OH, -OR', -NR' 2 , -NHR', -NH 2 , TIFF2025087743000064.tif60162, or R 2’ and R 3’Together with carbon, it forms 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 halogen. In some embodiments, R 2’ is -R'. In some embodiments, R 2’ is -CN. In some embodiments, R 2’ is -NO 2 In some embodiments, R 2’ is -OH. In some embodiments, R 2’ is -OR'. In some embodiments, R 2’ is -NR' 2 In some embodiments, R 2’ is -NHR'. In some embodiments, R 2’ is -NH 2 In some embodiments, R

[0128] In some embodiments, R 2’ is TIFF2025087743000065.tif16128. In some embodiments, R 2’ is TIFF2025087743000066.tif14128. In some embodiments, R 2’ is TIFF2025087743000067.tif20128. In some embodiments, R 2’ is TIFF2025087743000068.tif19128. In some embodiments, R 2’ is TIFF2025087743000069.tif15128. In some embodiments, R 2’is TIFF2025087743000070.tif12128. In some embodiments, R 2’ is TIFF2025087743000071.tif13128. In some embodiments, R 2’ is TIFF2025087743000072.tif15128. In some embodiments, R 2’ is TIFF2025087743000073.tif15128. In some embodiments, R 2’ is TIFF2025087743000074.tif14128. In some embodiments, R 2’ is TIFF2025087743000075.tif16128.

[0129] In some embodiments, R 2’ is hydrogen. In some embodiments, R 2’ is deuterium. In some embodiments, R 2’ is -CH 3 . In some embodiments, R 2’ is -CD 3 . In some embodiments, R 2’ is TIFF2025087743000076.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 2 . In some embodiments, R 3’ is -OH. In some embodiments, R 3’ is -OR'. In some embodiments, R 3’ is -NR'2 is. In some embodiments, R 3’ is -NHR'. In some embodiments, R 3’ is -NH 2 .

[0131] In some embodiments, R 3’ is TIFF2025087743000077.tif16128. In some embodiments, R 3’ is TIFF2025087743000078.tif14128. In some embodiments, R 3’ is TIFF2025087743000079.tif20128. In some embodiments, R 3’ is TIFF2025087743000080.tif19128. In some embodiments, R 3’ is TIFF2025087743000081.tif15128. In some embodiments, R 3’ is TIFF2025087743000082.tif12128. In some embodiments, R 3’ is TIFF2025087743000083.tif13128. In some embodiments, R 3’ is TIFF2025087743000084.tif15128. In some embodiments, R 3’ is TIFF2025087743000085.tif15128. In some embodiments, R 3’ is TIFF2025087743000086.tif14128. In some embodiments, R 3’ is TIFF2025087743000087.tif16128.

[0132] In some embodiments, R 3’is hydrogen. In some embodiments, R 3’ is deuterium. In some embodiments, R 3’ is -CH 3 In some embodiments, R 3’ is -CD 3 In some embodiments, R 3’ is TIFF2025087743000088.tif12128.

[0133] In some embodiments, R 2’ and R 3’ together with 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 carbon form an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0135] In some embodiments, R 2’ and R 3’ together with 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 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 TIFF2025087743000089.tif forms 11128. In some embodiments, R 2’ and R 3’ together with carbon, TIFF2025087743000090.tif forms 13128. In some embodiments, R 2’ and R 3’ together with carbon, TIFF2025087743000091.tif forms 17128. In some embodiments, R 2’ and R 3’ together with carbon, TIFF2025087743000092.tif forms 22128.

[0138] In some embodiments, R 4’ is hydrogen. In some embodiments, R 4’ is halogen. In some embodiments, R 4’ is -R'. In some embodiments, R 4’ is -CN. In some embodiments, R 4’ is -NO 2 . In some embodiments, R 4’ is -OH. In some embodiments, R 4’ is -OR'. In some embodiments, R 4’ is -NR' 2 . In some embodiments, R 4’ is -NHR'. In some embodiments, R 4’ is -NH 2 . In some embodiments, R 4’ is -CF 3 .

[0139] In some embodiments, R 4’ is TIFF2025087743000093.tif 16128. In some embodiments, R 4’ is TIFF2025087743000094.tif 14128. In some embodiments, R 4’ is TIFF2025087743000095.tif is 20128. In some embodiments, R 4’ is TIFF2025087743000096.tif is 19128. In some embodiments, R 4’ is TIFF2025087743000097.tif is 15128. In some embodiments, R 4’ is TIFF2025087743000098.tif is 12128. In some embodiments, R 4’ is TIFF2025087743000099.tif is 13128. In some embodiments, R 4’ is TIFF2025087743000100.tif is 15128. In some embodiments, R 4’ is TIFF2025087743000101.tif is 15128. In some embodiments, R 4’ is TIFF2025087743000102.tif is 14128. In some embodiments, R 4’ is TIFF2025087743000103.tif is 16128.

[0140] In some embodiments, R 4’ is hydrogen. In some embodiments, R 4’ is deuterium. In some embodiments, R 4’ is -CH 3 . In some embodiments, R 4’ is -CD 3 . In some embodiments, R 4’ is TIFF2025087743000104.tif is 12128.

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

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

[0143] In some embodiments, L’ is -CH 2 -.

[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’ are each independently a covalent bond, carbon, oxygen; or nitrogen substituted with hydrogen, optionally substituted C 1~6 alkyl, or optionally substituted nitrogen substituted with an optionally substituted 3- to 7-membered saturated carbocyclic ring.

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

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

[0148] In some embodiments, Y3’ is a covalent bond. In some embodiments, Y 3’ is carbon. In some embodiments, Y 3’ is oxygen. In some embodiments, Y 3’ is hydrogen, optionally substituted C 1~6 alkyl, or nitrogen optionally substituted with an optionally substituted 3- to 7-membered saturated carbocyclic ring.

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

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

[0151] In some embodiments, Y 4’ is a covalent bond. In some embodiments, Y 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] As defined above, Z' is O or S.

[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’ are joined cyclically with Y 2’ 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’ is optionally substituted C 1~6 alkyl.

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

[0159] In some embodiments, R 5’ and R 6’ are joined cyclically with Y 2’ to form an optionally substituted 3- to 7-membered saturated carbocyclic ring.

[0160] In some embodiments, R 5’ and R 6’ are joined cyclically with Y 2’ 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’ are cyclically bonded together with Y 2’ 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’ are cyclically bonded together with Y 2’ 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 ’ are each selected from those shown in Table 1 below.

[0164] As defined above, each R 7 ’ is independently -R’, halogen, -CN, -NO 2 , -OH, -NR’ 2 , -NHR’, -NH 2 , or -OR’.

[0165] In some embodiments, R 7’ is hydrogen. In some embodiments, R 7’ is halogen. In some embodiments, R 7’ is -CN. In some embodiments, R 7’ is -NO 2 . In some embodiments, R 7’ is -OH. In some embodiments, R 7’ is -NR’ 2 . In some embodiments, R 7’ is -NHR’. In some embodiments, R 7’ is -NH 2 . In some embodiments, R 7’ is -OR’.

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

[0167] As defined above, n’ is an integer selected from 0 to 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, optionally substituted alkyl, or optionally substituted aryl ring.

[0170] In some embodiments, R 8’ is hydrogen. In some embodiments, R 8’ is -CN. In some embodiments, R 8’ is optionally substituted C 1~6 alkyl. In some embodiments, R 8’ is 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’ is 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 halogen. In some embodiments, R 9’ is -CN. In some embodiments, R 9’ is -OR xis. In some embodiments, R 9’ is -NR’ 2 is. In some embodiments, R 9’ is -NHR’. In some embodiments, R 9’ is -NH 2 is. In some embodiments, R 9’ is optionally substituted C 1~6 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’ are each independently hydrogen or optionally substituted C 1~2 aliphatic. 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 optionally substituted C 1 aliphatic. In some embodiments, R 10’ is methyl. In some embodiments, R 10’ is optionally substituted C 2 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 optionally substituted C 1 aliphatic. In some embodiments, R 11’ is methyl. In some embodiments, R 11’is an optionally substituted C 2 that is aliphatic. In some embodiments, R 11’ is ethyl.

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

[0180] Furthermore, a compound according to formula (II’): TIFF2025087743000105.tif28128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein each of A’, B’, X’, R 1’ , R 2’ , R 3’ , R 4’ , and m’ is as defined above, both alone and in combination, and as described in the embodiments provided herein].

[0181] Furthermore, a compound according to formula (III’): TIFF2025087743000106.tif25128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein R 1’ , R 2’ , R 3’ , R 4’ , and m’ are as defined above, both alone and in combination, and as described in the embodiments provided herein].

[0182] Furthermore, a compound according to formula (IV’): TIFF2025087743000107.tif25128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein each of R 1’ , R 2’ , R 3’ , and R 4’ is as defined above, both alone and in combination, and as described in the embodiments provided herein]. In some such embodiments, R1’ is -CF 3 is. In some such embodiments, R 1’ is -CF 2 H. In some such embodiments, R 1’ is -OCF 3 is. In some such embodiments, R 1’ is -CN. In some such embodiments, R 1’ is -C(O)NR’ 2 is. 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’ is -Br. In some such embodiments, R 1’ is -CH 3 is.

[0183] Furthermore, a compound according to formula (V’): TIFF2025087743000108.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein each of R 1’ and m’ is, both alone and in combination, as defined above and as described in the embodiments provided herein].

[0184] Furthermore, a compound according to formula (VI’): TIFF2025087743000109.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein R 1’ is, both alone and in combination, as defined above and as described in the embodiments provided herein].

[0185] Furthermore, a compound according to formula (VII’): TIFF2025087743000110.tif 24128 or a pharmaceutically acceptable salt thereof is disclosed herein [Wherein, R 1’ , R 2’ , R 3’ , R 4’ , and each of m' is, both alone and in combination, as defined above and as described in the embodiments provided herein].

[0186] Furthermore, a compound according to formula (VIII'): TIFF2025087743000111.tif 25128 or a pharmaceutically acceptable salt thereof is disclosed herein [Wherein, R 1’ , R 2’ , R 3’ , R 4’ , and each of m' is, both alone and in combination, as defined above and as described in the embodiments provided herein].

[0187] Furthermore, a compound according to formula (IX'): TIFF2025087743000112.tif 24128 or a pharmaceutically acceptable salt thereof is disclosed herein [Wherein, R 1’ , R 2’ , R 3’ , R 4’ , and each of m' is, both alone and in combination, as defined above and as described in the embodiments provided herein].

[0188] Furthermore, a compound according to formula (X'): TIFF2025087743000113.tif 24128 or a pharmaceutically acceptable salt thereof is disclosed herein [Wherein, R 1’ is halogen, -R x , -CN, -NO 2 , -SF 5 , -OR x, -SO 2 R', or -C(O)R'; R 2’ 、R 3’ 、and R 4’ are each independently halogen, -R', -CN, -NO 2 、-OR', or -NR' 2 or R 2’ and R 3’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring; and R' and R x are, both alone and in combination, as defined above and as described in the embodiments provided herein. In some such embodiments, R 1’ is -CF 3 . In some such embodiments, R 1’ is -CF 2 H. In some such embodiments, R 1’ is -OCF 3 . In some such embodiments, R 1’ is -CN. 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’ is -Br. In some such embodiments, R 1’ is -CH 3 .

[0189] Furthermore, a compound according to formula (XI'): TIFF2025087743000114.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, R 1’ is halogen, -R', -CN, -NO2 、 -SF 5 、 -OR x 、 -SO 2 R’, or -C(O)R’; R 2’ 、R 3’ 、 and R 4’ are each independently halogen, -R’, -CN, -NO 2 、 -OR’, or -NR’ 2 or R 2’ and R 3’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring; and R’ and R x are, both alone and in combination, as defined above and as described in the embodiments provided herein.

[0190] Furthermore, a compound according to formula (XII’): TIFF2025087743000115.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, R 1’ is halogen, -R’, -CN, -NO 2 、 -SF 5 、 -OR x 、 -SO 2 R’, or -C(O)R’; and R’ and R x are, both alone and in combination, as defined above and as described in the embodiments provided herein.

[0191] Furthermore, a compound according to formula (XIII’): TIFF2025087743000116.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, R 1’ is halogen, -R’, -CN, -NO 2 、 -SF 5 、 -OR x 、 -SO2 is -R’ or -C(O)R’; and R’ and R x are, both alone and in combination, as defined above and as described in the embodiments provided herein.]

[0192] Furthermore, a compound according to formula (XIV’): TIFF2025087743000117.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; R 2’ , R 3’ and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3 - to 7 - membered cycloalkyl or heterocyclic ring; and R’ is, both alone and in combination, as defined above and as described in the embodiments provided herein.]

[0193] Furthermore, a compound according to formula (XV’): TIFF2025087743000118.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; R 2’ , R 3’ and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 or R 2’ and R 3 ’ together with carbon forms an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring; and R’ is, both alone and in combination, as defined above and as described in the embodiments provided herein].

[0194] Furthermore, a compound according to formula (XVI’): TIFF2025087743000119.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; and R’ is, both alone and in combination, as defined above and as described in the embodiments provided herein].

[0195] Furthermore, a compound according to formula (XVII’): TIFF2025087743000120.tif24128 or a pharmaceutically acceptable salt thereof is disclosed herein [wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; each R’ is an optionally substituted C 1~6 aliphatic; and R 2’ , R 3’ and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 ; or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring].

[0196] Furthermore, a compound according to formula (XVIII’): TIFF2025087743000121.tif 24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [Wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; each R’ is an optionally substituted C 1~6 aliphatic; and R 2’ , R 3’ , and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 , or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring].

[0197] Furthermore, a compound according to formula (XIX’): TIFF2025087743000122.tif 24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [Wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; and R’ is an optionally substituted C 1~6 aliphatic].

[0198] Furthermore, a compound according to formula (XX’): TIFF2025087743000123.tif 24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [Wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; and R’ is an optionally substituted C 1~6 aliphatic].

[0199] Furthermore, a compound according to formula (XXI’): TIFF2025087743000124.tif 24128 or a pharmaceutically acceptable salt thereof is disclosed herein. [wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; each R’ is optionally substituted C 1~6 aliphatic; and R 2’ , R 3’ , and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 , or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring].

[0200] Furthermore, a compound according to formula (XXII’): TIFF2025087743000125.tif 25128 or a pharmaceutically acceptable salt thereof is disclosed herein. [wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; each R’ is optionally substituted C 1~6 aliphatic; and R 2’ , R 3’ , and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 , or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring].

[0201] Furthermore, a compound according to formula (XXIII’): TIFF2025087743000126.tif 24128 or a pharmaceutically acceptable salt thereof is disclosed herein [Wherein, R 1’ is halogen, -R’, -CN, or -NO 2 and; R’ is optionally substituted C 1~6 aliphatic].

[0202] Furthermore, a compound according to formula (XXIV’): TIFF2025087743000127.tif 25128 or a pharmaceutically acceptable salt thereof is disclosed herein [Wherein, R 1’ is halogen, -R’, -CN, or -NO 2 and; R’ is optionally substituted C 1~6 aliphatic].

[0203] Furthermore, a compound according to formula (XXV’): TIFF2025087743000128.tif 29128 or a pharmaceutically acceptable salt thereof is disclosed herein [Wherein A’, B’, X’, R 1’ , R 2’ , R 3’ , R 4’ , and m’ are each, both alone and in combination, as defined above and as described in the embodiments provided herein].

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

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

[0206] Terms such as "therapeutically effective amount", "effective dose", "therapeutically effective dose", "effective amount", etc. refer to the amount of the compound that, upon administration of the compound, will induce a biological or medical response in the desired tissue, system, animal or human. Generally, the response is either remission of symptoms in a patient or a desired biological outcome. In some embodiments, such amount should be sufficient to modulate the adrenergic receptor.

[0207] In some embodiments, the effective amount of the adrenergic receptor modulating compound is an amount in the range of about 50 ng / ml to 50 pg / ml (e.g., about 50 ng / ml to 40 pg / ml, about 30 ng / ml to 20 pg / ml, about 50 ng / ml to 10 μg / ml, about 50 ng / ml to 1 μg / ml, about 50 ng / ml to 800 ng / ml, about 50 ng / ml to 700 ng / ml, about 50 ng / ml to 600 ng / ml, about 50 ng / ml to 500 ng / ml, about 50 ng / ml to 400 ng / ml, about 60 ng / ml to 400 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 ng / ml).

[0208] In some embodiments, the effective amount of the adrenergic receptor modulating compound is an amount in the range of about 10 pg to 100 mg, e.g., 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 ng, about 1 ng to 10 ng, about 10 ng to 50 ng, about 50 ng to 150 ng, about 150 ng to 250 ng, 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 amount may be a single dose or may be the total daily dose. The total daily dose may be in the range of about 10 pg to 100 mg, or may be in the range of about 100 mg to 500 mg, or may be in the range of about 500 mg to 1000 mg.

[0209] Also, for example, the present disclosure discloses a pharmaceutical composition comprising a compound described herein 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'). The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be administered to a patient together with the compounds of the present disclosure and without destroying their 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, buffering 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 carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0210] In pharmaceutical compositions containing only the compounds described herein as active ingredients, methods for administering these compositions may additionally include the step of administering to the subject an additional agent or treatment. Such treatments include, but are not limited to, anemia treatment, diabetes treatment, hypertension treatment, cholesterol treatment, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production; hormones and antagonists, drugs that affect gastrointestinal function, chemotherapeutic drugs for microbial diseases, and / or chemotherapeutic drugs for neoplastic diseases. Other pharmacological treatments may include any other drug or biological substance found in any drug class. For example, other drug classes may include allergy / cold / ENT treatments, analgesics, anesthetics, anti-inflammatory drugs, antimicrobials, antivirals, asthma / lung treatments, cardiovascular treatments, dermatological treatments, endocrine / metabolic therapies, gastrointestinal treatments, cancer treatments, immunotherapies, neurological treatments, eye treatments, psychiatric treatments or rheumatology treatments. Other examples of agents or treatments that can be administered with the compounds described herein include matrix metalloprotease inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressive drugs, cytokines, growth factors, immunomodulatory drugs, prostaglandins or anti-angiogenic compounds.

[0211] As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical that elicits a biological or medical response in a tissue, system, animal, individual, or human as required 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 a disease, condition, or disorder but has not yet experienced or manifested the pathology or overall symptoms of the disease; e.g., preventing a disease, condition, or disorder; (2) inhibiting a disease in an individual who is experiencing or manifesting the pathology or overall symptoms of a disease, condition, or disorder; e.g., inhibiting a disease, condition, or disorder (i.e., arresting further development of the pathology and / or overall symptoms); and (3) alleviating a disease; e.g., alleviating a disease, condition, or disorder in an individual who is experiencing or manifesting the pathology or overall symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or overall symptoms).

[0212] In some embodiments, the compounds described herein can be adrenergic receptor modulating compounds (e.g., agonists, partial agonists, or antagonists of adrenergic receptors). The adrenergic receptor modulating compounds of the disclosure can be used, in some embodiments, to modulate the activity of target adrenergic receptors 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] The adrenergic receptor (ADR) is a G protein-coupled receptor (GPCR) that is widely expressed throughout the body and plays an important role in the regulation of multiple physiological processes, including cognition, stress-related behaviors, inflammation, and smooth muscle contraction / relaxation, myocardial contraction, airway reactivity, and cognition. The adrenergic receptor mediates the central and peripheral actions of norepinephrine (NA) and epinephrine. There are multiple subtypes of ADR, including α-adrenergic receptors 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 NA and adrenergic system dysfunction.

[0214] The β-adrenergic receptor further includes three subtypes, namely, the β1-adrenergic receptor (β1-ADR), the β2-adrenergic receptor (β2-ADR), and the β3-adrenergic receptor (β3-ADR). Since 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 because these subtypes have a high level of sequence homology. Many existing agonists for the β-adrenergic receptor also exhibit poor blood-brain barrier (BBB) penetration, which requires efforts in drug discovery for central nervous system (CNS) applications.

[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 been revealed that agonists can exhibit biased activation of signaling pathways. The ability of a ligand to activate a receptor and generate a response in a pathway-dependent manner is referred to as "signaling bias" or "functional selectivity". Since G proteins and β-arrestin mediate distinct physiological processes, biased agonists can bring about improved therapeutic selectivity along with a reduction in adverse effects. Accordingly, the present disclosure is directed to β-adrenergic receptor subtype-selective agonists having improved blood-brain barrier (BBB) permeability.

[0216] An adrenergic receptor modulating compound can be an agonist of a target adrenergic receptor. In some cases, an effective amount of the adrenergic receptor modulating compound is an amount sufficient to activate the activity associated with the adrenergic receptor in a cell by 10% or more, such as 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, control cells showing a known activity level of the receptor.

[0217] The above-mentioned adrenergic receptor modulating compound can be a partial agonist of the target adrenergic receptor. In some cases, an effective amount of the adrenergic receptor modulating compound is an amount sufficient to achieve partial agonism of the adrenergic receptor in a cell. For example, in such cases, the compound achieves 10% or more activation of the receptor, such as 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 activation of the receptor compared to a control, such as a fully activated receptor. Partial agonism can be evaluated using any convenient method, such as a cell-based assay using a full agonist known as a 100% activation control, in which the relative maximal activation of the receptor can be measured compared to the full agonist.

[0218] The above-mentioned 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, such as 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, such as a sample not contacted with the compound of interest.

[0219] In some embodiments, the compounds of the present disclosure act as low nM partial agonists of the β2 adrenergic receptor. For example, in some embodiments, the 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 50It has. In some embodiments, the compounds of the present disclosure act as low nM partial agonists of the β2 - adrenergic receptor 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, the compounds of the present disclosure act as low μM partial agonists of the β2 - adrenergic receptor. For example, in some embodiments, the 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, the compounds of the present disclosure act as low μM partial agonists of the β2 - adrenergic receptor 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, about 0.1 μM to about 1.0 μM 50 It has.

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

[0223] The target adrenergic receptor can be one that mediates an intracellular signal or pathway in a cell. In some embodiments, the sample contains cells, and the regulation of the adrenergic receptor regulates a physiological process in the cell. Using this method, any convenient physiological process can be targeted for regulation in a cell. 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. This method can provide mediation of the intracellular concentration of an intracellular signaling molecule, such as cAMP. This method can provide partial or complete blockade of the target adrenergic receptor, resulting in the regulation (e.g., activation) of cAMP in the sample. In some embodiments, the above method does not regulate the β - arrestin pathway of the cell. In some cases, the cell is an inflammatory cell and the function of that cell is controlled. This method can result in the inhibition of an inflammatory pathway in the cell. In some cases, TNF - alpha is inhibited in the cell, for example, by performing this method, the concentration or production of TNF - alpha decreases. In certain embodiments of the above method, the cell is a neuron. In some embodiments, enhancing neurogenesis by regulating the adrenergic receptor.

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

[0225] As used herein, the terms "combination" and "combined", and related terms, refer to the simultaneous or sequential administration of the therapeutic agents according to the present disclosure. For example, the above compounds can be administered together with another therapeutic agent simultaneously or sequentially, in separate unit dosage forms or in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form comprising the above compounds, additional therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or vehicles. When a patient or individual is simultaneously exposed to both drugs, the two or more drugs are typically determined to have been administered "in combination". In many embodiments, when a patient or individual simultaneously exhibits therapeutic-related levels of the drugs in a particular target tissue or sample (e.g., in the brain, in serum, etc.), the two or more drugs are determined to have been administered "in combination".

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

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

[0228] The present compounds can be administered in combination with other therapeutic agents in a variety of therapeutic applications. Therapeutic applications for the purpose of combination therapy include applications where the activity of the target adrenergic receptor is a cause or exacerbating factor in disease progression. Thus, the present compounds can be used in combination therapies where inhibition of the target adrenergic receptor in a subject is desired. Examples of disease states that can be treated by combination therapy comprising the present compounds include, but are not limited to, heart conditions or diseases, neurodegenerative or neurodevelopmental diseases, respiratory disorders, asthma, memory disorders, depression, inflammatory diseases, stroke, ischemic brain or tissue damage, and cancer. Agents that can be used in combination with the present adrenergic receptor modulating compounds include, but are not limited to, antidepressants, antipsychotics, beta blockers, vasoconstrictors, antihypertensives, decongestants, chemotherapeutic agents, agents used in Alzheimer's disease, and anti-inflammatory agents.

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

[0230] This adrenergic receptor modulating compound can be used in combination with any agent useful in the treatment of neurodegenerative or neurodevelopmental disorders such as Alzheimer's disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue damage, Down syndrome or autism. Agents for the purpose that can be used in combination with this adrenergic receptor modulating compound include, but are not limited to, acepromazine. In some embodiments, this adrenergic receptor modulating compound can be used in combination with a cholinesterase inhibitor or an NMDA receptor modulator in the treatment of a disease, such as a neurodegenerative or neurodevelopmental disorder. Agents for the purpose include, but are not limited to, donepezil, Aricept, galantamine, Razadyne, memantine, Namenda, rivastigmine, Exelon, tacrine and Cognex. Other agents for the purpose that can be used in combination with this adrenergic receptor modulating compound include, but are not limited to, 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, cannabidiol, clonidine, detomidine, dexmedetomidine, fadomidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mibefradil, rilmenidine, romifidine, talipexole, tiamenidine, tizanidine, taurinidine, xylazine, xylometazoline, aripiprazole, asenapine, atipamezole, silazoline, clozapine, efaroxan, idazoxan, lurasidone, melperone, mianserin, mirtazapine, napitane, olanzapine, paliperidone, phenoxybenzamine, phentolamine, piribedil, rauolscine, risperidone, rotigotine, quetiapine, norquetiapine, setiptiline, terazoline, yohimbine, diprasidone and zotepine.Other agents that can be used in combination with the adrenergic receptor modulating compound include, but are not limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levalbuterol or levulbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol, salbutamol or albuterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, milbeterol, 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 adding suitable functional groups to enhance their 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 enable administration by injection, alter metabolism, and / or alter the rate of excretion.

[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. Such pharmaceutical compositions are used to alleviate, treat, or prevent any of the diseases described herein in a subject.

[0233] The agents of the present disclosure are often administered as a pharmaceutical composition comprising 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. The above composition may include a pharmaceutically acceptable non-toxic carrier or diluent, which is defined as a vehicle commonly used to formulate a pharmaceutical composition for animal or human administration, depending on the desired formulation. 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 above pharmaceutical composition or formulation may include other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0234] In some embodiments, the present disclosure provides a pharmaceutically acceptable composition 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 the 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 it is possible to administer the above compounds alone, it is preferred to administer the above compounds as a pharmaceutical formulation as described herein. By analogy with other pharmaceuticals, the above compounds can be formulated for administration in any convenient manner for use in human or veterinary medicine.

[0235] As described in detail, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including oral administration, such as drinking medicine (aqueous or non-aqueous solutions or suspensions), tablets, such as those targeted for buccal, sublingual, and systemic absorption, bolus agents, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, for example, as sterile solutions or suspensions, or sustained release formulations; topical administration, such as creams, ointments, or controlled release patches or sprays applied to the skin, lung, or oral cavity; vaginal or rectal administration, such as by vaginal suppositories, creams, or foams; sublingual; ocular; transdermal; or nasal, pulmonary, and other mucosal surfaces adapted thereto.

[0236] Wetting agents, emulsifying agents, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, and fragrances, preservatives, and antioxidants may also be present in the above compositions.

[0237] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[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. The above formulations can be conveniently provided in unit dosage form and can be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with a carrier substance to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier substance to produce a single dosage form is generally the amount of the compound that 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, the formulations as described herein include an additive selected from the group consisting of cyclodextrin, liposome, micelle-forming agent such as bile acid, and polymeric carrier such as polyester and polyanhydride; and a compound of the present disclosure. In certain embodiments, the above formulations make the above compounds of the present disclosure biologically available orally.

[0240] A method of preparing a formulation or composition comprising the above compound includes associating a compound of the present disclosure with a carrier and, optionally, one or more accessory ingredients. Generally, a formulation can be prepared by uniformly and intimately associating a compound of the present disclosure with a liquid carrier, or a finely divided solid carrier, or both, and then shaping the product if necessary.

[0241] The pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile aqueous or oily suspension. This suspension can be formulated by techniques known in the art using suitable dispersing or wetting agents (such as 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, as 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. In addition, sterile non - volatile oils have been conventionally used as solvents or suspending media. For this purpose, any non - irritating non - volatile oil containing synthetic mono - or diglycerides can be used. Natural pharmaceutically acceptable oils, for example, fatty acids such as oleic acid and its glyceride derivatives, such as olive oil or castor oil, especially in their polyoxyethylated versions, are useful in the preparation of injectables. These oily solutions or suspensions may also contain long - chain alcohol diluents or dispersing agents, such as those described in the Swiss Pharmacopoeia, or similar alcohols. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers generally used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for the purposes of the formulation.

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

[0243] The injectable depot form is prepared by forming microencapsule matrices of the above compound in a biodegradable polymer such as polylactide - polyglycolide. Depending on the ratio of the drug to the polymer and the nature of the specific polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). The depot injectable formulation can also be prepared by entrapping the above drug in liposomes or microemulsions that are compatible with body tissues.

[0244] The pharmaceutical compositions of the present disclosure can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, generally 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. When administering aqueous suspensions and solutions and propylene glycol orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents can be added.

[0245] The formulations described herein suitable for oral administration can be in the form of capsules, cachets, pills, tablets, lozenges (base with added flavor, usually using sucrose and gum arabic or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non - aqueous liquids, or as water - in - oil or oil - in - water liquid emulsions, or as elixirs or syrups, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and gum arabic), and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present disclosure as the active ingredient. The compounds described herein can also be administered as boluses, linctuses or pastes.

[0246] In the case of solid dosage forms for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is combined with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic, etc.; humectants, such as glycerol; disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; dissolution retardants, such as paraffin; absorption promoters, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, etc.; 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 mixed with coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may contain a buffering agent. Solid compositions of the same type can also be used as fillers in soft and hard shell gelatin capsules using additives such as lactose or milk sugar, and even high molecular weight polyethylene glycol.

[0247] Tablets can be prepared by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or sodium cross-linked carboxymethylcellulose), a surfactant or a dispersing agent. Molded tablets can be prepared using a suitable machine that humidifies a mixture of the powdered compound with an inert liquid diluent. When using a solid carrier, the formulation may be in tablet form, may be enclosed in hard gelatin capsules in powder or pellet form, or may be in the form of a troche or lozenge. The amount of the solid carrier varies, for example, from about 25 to 800 mg, preferably from about 25 mg to 400 mg. When using a liquid carrier, the formulation may be, for example, in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile injectable solution, for example, an ampoule or a non-aqueous liquid suspension. When the composition is in the form of a capsule, any routine encapsulation using, for example, the above carriers in a hard gelatin capsule shell is suitable.

[0248] For tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, it is possible to optionally make score lines or prepare them using coatings and shells, such as enteric coatings and other coatings well-known in the pharmaceutical formulation field. Alternatively or additionally, they can be formulated using, for example, various ratios of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to obtain a desired release profile and achieve delayed or controlled release of the active ingredient(s) therein. They can be formulated for rapid release, for example, by freeze-drying. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in 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 an opacifying agent and may optionally be compositions that release the active ingredient(s) only or preferentially in a specific part of the digestive tract using a delayed technique. Examples of embedding compositions that can be used include polymer substances and waxes. The active ingredient(s) may, where appropriate, be in microencapsulated form containing one or more of the above additives.

[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, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, 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, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof, etc.

[0250] In addition to the inert diluent, the oral composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfumes and preservatives.

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

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

[0253] When the desired treatment relates to an area or organ that is readily accessible by topical application, topical administration of the pharmaceutical compositions of the present disclosure is particularly useful. For topical application to the skin, the pharmaceutical composition should be formulated into 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 petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated into 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present disclosure can also be topically applied to the lower intestinal tract by rectal suppository formulations or by suitable enema formulations. Transdermal patches for topical administration are also included in the present disclosure.

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

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

[0256] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the above compounds in a suitable medium. Absorption promoters can also be used to increase the flux of the above compounds through the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or by dispersing the above compounds in a polymeric 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. For example, by using coating substances such as lecithin, by maintaining the required particle size in the case of dispersants, and by using surfactants, proper fluidity can be maintained.

[0258] Such compositions may contain adjuvants 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, phenolsorbic acid, etc. Alternatively or in addition, it may be desirable to include in the composition isotonic agents such as sugars, sodium chloride, etc. In addition, by including agents that delay absorption such as aluminum monostearate and gelatin, prolonged absorption of injectable pharmaceutical forms can be achieved.

[0259] In certain embodiments, the above compounds or pharmaceutical formulations are administered orally. In other embodiments, the above compounds or pharmaceutical formulations are administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

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

[0261] The formulations described herein can be administered orally, parenterally, topically, or rectally. They are of course administered in a form suitable for the relevant route of administration. For example, they are administered orally 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 treatment by any suitable route of administration, including orally, such as by nasal spray, rectally, intravaginally, parenterally, intravesically, as well as topically, such as by powders, ointments, or drops, including sublingual and buccal.

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

[0264] To obtain the amount of the active ingredient that is effective in achieving the desired therapeutic response in a particular patient, composition, and mode of administration without being toxic to the patient, the actual dosage level of the active ingredient in the pharmaceutical compositions of the present disclosure can vary.

[0265] Also provided are kits containing the disclosed adrenergic receptor modulating compounds. The systems of the present disclosure include, for example, a collection of active agents assembled 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 kits containing the disclosed 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 above formulations may be provided in unit dosage form. Such kits include, in addition to the formulation(s), e.g., a container containing a unit dose, an information 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 state. These instructions may exist in various forms in the systems and kits, and one or more of them may be present within the kit. One form in which these instructions may exist is information printed on a suitable medium or substrate within the packaging of the kit, e.g., as an insert on a piece of paper on which the information is printed, etc. Another means may be a computer-readable medium on which the information is recorded, e.g., a floppy disk, CD, etc. Another means that may exist 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 within the kit.

[0266] The compounds synthesized and characterized in the present disclosure are illustrated in Table 1 below. Table 1 also illustrates representative compounds contemplated by the present disclosure. (Table 1) Compounds of the present disclosure TIFF2025087743000129.tif 184143 TIFF2025087743000130.tif 221143 TIFF2025087743000131.tif 226143 TIFF2025087743000132.tif 227143 TIFF2025087743000133.tif 231143 TIFF2025087743000134.tif 229143 TIFF2025087743000135.tif 208143 TIFF2025087743000136.tif 211143 TIFF2025087743000137.tif 218143 TIFF2025087743000138.tif 232143 TIFF2025087743000139.tif 220143 TIFF2025087743000140.tif 207143 TIFF2025087743000141.tif 231143 TIFF2025087743000142.tif 222143 TIFF2025087743000143.tif 231143 TIFF2025087743000144.tif 197143 TIFF2025087743000145.tif 200143 TIFF2025087743000146.tif 232143 TIFF2025087743000147.tif 221143 TIFF2025087743000148.tif 224143 TIFF2025087743000149.tif 226143 TIFF2025087743000150.tif 225143 TIFF2025087743000151.tif 227143 TIFF2025087743000152.tif 202143 TIFF2025087743000153.tif 221143 TIFF2025087743000154.tif 220143 TIFF2025087743000155.tif 224143 TIFF2025087743000156.tif 208143 TIFF2025087743000157.tif 221143 TIFF2025087743000158.tif 180143 TIFF2025087743000159.tif 225143 TIFF2025087743000160.tif 223143 TIFF2025087743000161.tif219143TIFF2025087743000162.tif224143TIFF2025087743000163.tif213143TIFF2025087743000164.tif231143TIFF2025087743000165.tif219143TIFF2025087743000166.tif213143TIFF2025087743000167.tif228143TIFF2025087743000168.tif222143TIFF2025087743000169.tif208143TIFF2025087743000170.tif228143TIFF2025087743000171.tif200143TIFF2025087743000172.tif186143TIFF2025087743000173.tif194143TIFF2025087743000174.tif229143TIFF2025087743000175.tif226143TIFF2025087743000176.tif230143TIFF2025087743000177.tif61143.

[0267] In some embodiments, the present 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 the 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 additive. Further disclosed is a method of treating a subject having a disease associated with an adrenergic receptor, the method comprising administering to the subject a therapeutically effective amount of a compound having the 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') thereby treating the subject. In some embodiments, the disease is a neurodegenerative disease and the subject is human.

[0269] In some embodiments, the disease is selected from the group consisting of myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Garlic disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedreich's ataxia, ataxia telangiectasia, spinal muscular atrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the above compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, cutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernous, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal routes. In one embodiment, the above 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 the methods described in detail 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. TIFF2025087743000178.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. TIFF2025087743000179.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. TIFF2025087743000180.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. TIFF2025087743000181.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. TIFF2025087743000182.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. TIFF2025087743000183.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. TIFF2025087743000184.tif17142

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

Examples

[0278] Example 1: Compound Synthesis Scheme 1. Synthesis of Compound 03-1. TIFF2025087743000185.tif56151

[0279] In Scheme 1, the synthesis of compound 03-1 is exemplified.

[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(PPh 3 ) 4 (1.01 g, 0.88 mmol, 0.05 equiv). The resulting mixture was purged with N 2 (3×), and then heated at 120 °C for 6 h. After cooling, 1.5 N aqueous HCl was introduced into the flask and stirring was continued overnight at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO 3 (30 mL), and then extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 30 / 1 - 5 / 1) to afford 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 3 (100 mL). Subsequently, the reaction mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over Na 2 SO4 It was dried, 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, 1 N in THF) at -35 °C. The resulting mixture was stirred at -35 °C for 30 minutes. Then, borane-THF (2 mL, 1 N in THF) was added dropwise. The resulting solution was stirred at -15 °C for 2 hours and then quenched with saturated NaHCO 3 aqueous solution (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM / CH 3 OH (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 h and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated NaHCO 3 aqueous solution and brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by HPLC [C18, MeCN / H 2 O (0.1% formic acid), (1% - 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%). TIFF2025087743000186.tif26150

[0284] TIFF2025087743000187.tif23128

[0285] Compound 03-2. TIFF2025087743000188.tif18151

[0286] Scheme 2. Synthesis of compound 03-3. TIFF2025087743000189.tif53152

[0287] Scheme 2 illustrates the synthesis of compound 03-3. TIFF2025087743000190.tif26150

[0288] Scheme 3. Synthesis of compound 03-4. TIFF2025087743000191.tif60153

[0289] Scheme 3 illustrates the synthesis of compound 03-4. TIFF2025087743000192.tif25150

[0290] Scheme 4. Synthesis of Compounds 03-5 and 03-48. TIFF2025087743000193.tif50149

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

[0292] Step 1: Synthesis of 2-Cyano-6-vinylpyridine To a stirred mixture of 2-chloro-6-cyanopyridine (8.0 g, 69.3 mmol), 1-vinyltri-n-butylstannane (21.97 g, 69.29 mmol, 20.34 mL), and Pd(PPh 3 ) 4 (3.34 g, 3.61 mmol) in anhydrous toluene (150 mL) was bubbled with N 2 for 5 minutes, and then heated at 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 phases were washed with brine, dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 95 / 5 - 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 slowly added mCPBA (61.56 g, 249.72 mmol) portionwise at 0 °C over 30 minutes, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was cooled to 5 °C and saturated NaHCO 3An aqueous solution was added, and the mixture was extracted with DCM (200 mL × 2). The organic layers were combined, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / EtOAc (silica, 90 / 10 - 80 / 20) to afford 6-(oxiran-2-yl)picolinitrile 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)picolinitrile and (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinitrile To a stirred solution of 6-(oxiran-2-yl)picolinitrile (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 h, 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 afford the desired product as a racemic mixture. The racemic mixture was separated by SFC (Chiralpak AS-H (30*250) mm, 5 μ column, CO 2 :80% modifier:20% (0.2% isopropylamine in IPA) as the eluent) to afford Compound 03-5, (S)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinitrile (1.05 g, 26.3%) and Compound 03-48, (R)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinitrile (0.98 g, 24.5%) as white solids. TIFF2025087743000194.tif33162

[0295] Scheme 5. Synthesis of Compound 03-247 TIFF2025087743000195.tif53149

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

[0297] Step 1: Synthesis of 3-methyl-4-vinylpyridine Dioxane / H 2 To a solution of 4-bromo-3-methylpyridine (1.0 g, 4.80 mmol) in O (15 mL / 1.5 mL), Cs 2 CO 3 (4.69 g, 14.39 mmol), potassium vinyltrifluoroborate (0.96 g, 7.19 mmol) and Pd(PPh 3 ) 2 Cl 2 (0.20 g, 0.27 mmol) were added. The mixture was stirred at 85 °C for 15 h under N 2 atmosphere. Then the resulting mixture was filtered and washed with EtOAc (2×20 mL). The filtrate was dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with hexane / EtOAc (silica, 90 / 10~75 / 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 CH 2 Cl 2 To a solution of (R)-1-(3-methylpyridin-4-yl)ethane-1,2-diol (0.125 g, 0.82 mmol) in CH 3 Cl 3 (4 mL), MeC(OCH 2 Cl 2(4 mL) was redissolved, and then TMSBr (0.26 g, 1.71 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue in anhydrous CH 3 OH (4 mL) was added to K 2 CO 3 (0.33 g, 2.40 mmol), 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 obtain 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 EtOH / H 2 O (2 mL / 1 mL) solution of (R)-3-methyl-4-(oxiran-2-yl)pyridine (0.08 g, 0.60 mmol) was added to tert-BuNH 2 (0.24 g, 3.30 mmol). The resulting mixture was stirred at 60 °C for 15 hours and concentrated under reduced pressure. The residue was purified by HPLC [C18, MeCN / H 2 O (0.1% trifluoroacetic acid), (1% - 100%)] to obtain compound 03-247, (R)-2-(tert-butylamino)-1-(3-methylpyridin-4-yl)ethan-1-ol, which was then converted to its 2HCl salt as a white solid (0.044 g, 26%). TIFF2025087743000196.tif18150

[0300] Those skilled in the art will appreciate that the above synthetic scheme is representative of a method for making the compounds of the present disclosure and that numerous other compounds can be synthesized using similar such methods.

[0301] Example 2: Evaluation of the synthesized adrenergic receptor agonists cAMP homogeneous time-resolved fluorescence (HTRF). Compound efficacy was determined using the cAMP Gs dynamic HTRF assay (Cisbio, catalog number 62AM4PEC) mainly following the manufacturer's instructions detailed below.

[0302] Compound preparation. Beta - adrenergic compound candidates dissolved at 10 mM in DMSO were diluted in 1× Stimulation Buffer 1 (Cisbio Part number 64SB1FDD) containing 1 mM 3 - isobutyl - 1 - methylxanthine (IBMX; Cayman Chemical Company, catalog number 13347). Serial dilutions were performed in a 96 - well V - bottom polypropylene compound microplate (Corning, catalog number 3363) in Stimulation Buffer containing 1 mM IBMX up to twice the final desired concentration. The standard serial dilution curve was a 10 - point, 5 - fold dilution starting from a maximum 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). 5 μL from the 2× compound plate was stamped into a white 384 - well low - volume HiBase assay plate (Greiner Bio - One; catalog number 784075) to obtain 4 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 dose to compensate for the addition of cells.

[0303] Cell preparation. 1× stimulation buffer, PBS for washing (Dulbecco's phosphate buffered saline, -Mg-Ca; Caisson Labs, catalog number PBL01), PBS for assay (Dulbecco's phosphate buffered saline, +Mg, +Ca; Caisson Labs, catalog number PBL02), and Versene (0.02% sodium EDTA solution in PBS without calcium or magnesium; Caisson Labs, catalog number EDL01) were pre-warmed to 37°C. Cells expressing beta-adrenergic receptor were washed in PBS for washing to remove the growth medium, and then detached from the surface by incubating with Versene at 37°C for 5 - 10 minutes. Cells were collected using assay PBS, counted manually with a hemocytometer or by an automated cell counter, pelleted by centrifugation (200×g, 5 minutes), and resuspended in 1× stimulation buffer at 37°C to a final density of 1.5×10 6 cells / mL. 5 μL of the suspended cell solution (a total of 7500 cells) was added to all wells of a 384-well assay plate, and the assay plate was covered with an Axygen® plate seal (Corning PCR-SP), and incubated for 30 minutes in a humidified 37°C environment supplemented with 5% CO 2 2.

[0304] HTRF reagent addition, reading, and data analysis. 30 minutes after cell stimulation with the test compound, the assay plate was centrifuged at 500×g for 10 seconds, and the incubation was stopped by the addition of 5 μL of cAMP-D2 receptor diluted 1:21 in detection and lysis buffer 2 (Cisbio 62CL2FDF), which was 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 centrifuged again at 500×g for 10 seconds, and HTRF was measured using a Tecan Spark plate reader at 50 flashes per well. The HTRF ratio (665 nm / 620 nm × 10,000) was determined and plotted in GraphPad Prism to generate a concentration-response curve. The potency estimate (EC 50 ) was obtained from a four-parameter non-linear regression of the concentration-response curve, and the estimate of relative efficacy was determined by comparing the magnitude of the test compound HTRF signal window (minimum - maximum dose) to the signal window of the full agonist control isoproterenol.

[0305] The potency data for the selected compounds are summarized in Table 2 below.

[0306] (Table 2) Pharmacological data of the compounds disclosed herein TIFF2025087743000197.tif39128EC 50 (nM): A < 10 nM; B = 10 - 100 nM; C = 100 nM - 1 μM; D > 1 μM

[0307] Certain compounds of the present disclosure were unexpectedly found to be partial agonists of the β2 - adrenergic receptor, particularly in human glioblastoma cells (e.g., 1321N1). The inhibition curves for the selected compounds are further summarized in Figures 1, 2, and 3. The potency data for further 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 good properties. For example, as described above, the compounds of the present disclosure have unexpectedly been found to act as low nM (<10 nM) partial agonists of the β2 - adrenergic receptor. Further, as demonstrated by the following examples, the compounds of the present disclosure exhibit an unexpectedly high ability to cross 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 showing low toxicity and a low potential for drug - drug interactions. The following examples illustrate some of the unanticipated results achieved with the compounds of the present disclosure.

[0309] Plasma Protein and Brain Tissue Binding Brain Tissue Binding Measurement Thawing of frozen brain tissue homogenate (stored at - 80 °C). The frozen brain tissue homogenate was thawed immediately in a room - temperature bath. Note: Only use brain tissue homogenates that have been thawed within one time.

[0310] Preparation of working solutions. Working solutions of the test compound and the control compound propranolol were prepared in DMSO at a concentration of 200 μM. Then, 4 μL of the working solution was taken out 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 samples were vortexed thoroughly.

[0311] Preparation of dialysis membranes. The dialysis membranes were 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 the brain tissue homogenate sample and dialyzed against an equal volume of dialysis buffer (PBS). The assay was performed in duplicate. The dialysis plate was sealed and incubated at 37 °C, 5% CO 2It was incubated at approximately 100 rpm for 6 hours. At the end of dialysis, the seal was removed and 50 μL of the sample was transferred to separate tubes in the plate from both the buffer and the brain tissue homogenate chamber.

[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 sample. 400 μL of a quenching solution at room temperature (acetonitrile containing internal standards (IS, 100 nM alprazolam, 500 nM labetalol and 2 μM ketoprofen)) was added to precipitate the protein. 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. From the peak area ratio, the concentrations of the test compound and the control compound in the buffer and the brain tissue homogenate chamber were determined. The percentage of the bound test compound and the control compound 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 Un-diluted fu = ((1 / Fu 平均 ) - 1) + 1 / D Bound % = (1 - un-diluted fu) × 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 homogenate D = dilution factor of brain tissue Bound % = brain tissue binding %

[0315] Measurement of plasma protein binding Preparation of 100 mM sodium phosphate and 150 mM NaCl buffer (PBS). Na2 HPO 4 When a basic solution was prepared by dissolving 14.2 g / L of NaH 2 PO 4 12.0 g / L and 8.77 g / L of NaCl in deionized water, the solution could be stored at 4 °C for up to 7 days. The basic solution was titrated with the acidic solution to pH 7.4, 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 standard of 7.4 ± 0.1.

[0316] Thawing of frozen plasma (stored at -80 °C). The 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). Use only plasma that has been thawed within 2 times since arrival. b). Use only plasma within the pH range of 7 to 8.

[0317] Preparation of working solutions. Working solutions of the test compound and the control compound ketoconazole were prepared in DMSO at a concentration of 200 μM. Then, 3 μL of the working solution was taken out 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 membranes. The dialysis membranes were immersed in ultrapure water for 60 minutes to separate the strips, then in 20% ethanol for 20 minutes, and finally in the dialysis buffer for 20 minutes.

[0319] Procedure for equilibrium dialysis. The dialysis device was assembled according to the manufacturer's instructions. Each cell was filled with 120 μL of the spiked plasma sample and dialyzed against an equal volume of dialysis buffer (PBS). The assay was performed in duplicate. The dialysis plate was sealed and incubated at 37 °C, 5% CO 2It was then incubated at 100 rpm for 6 hours. At the end of the incubation, the seal was removed and 50 μL of the sample was transferred from both the buffer and plasma chambers to the 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 sample. 300 μL of room temperature quench solution (acetonitrile containing internal standards (IS, 100 nM alprazolam, 500 nM labetalol and 2 μM ketoprofen)) was added to precipitate the 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 the 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 ) × 100 Bound% = 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 means the concentration of the starting sample before incubation.

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

[0324] Certain compounds of the present disclosure have been found to exhibit the property of binding and accumulating in the central nervous system.

[0325] (Table 3) Percent of unbound fraction of PPB and brain tissue binding TIFF2025087743000198.tif28128

[0326] MDCK-MDR1 permeability assay Preparation of MDCK-MDR1 cells. Cell culture medium was added to each well (50 μL) and reservoir (25 mL) of the Transwell insert. Then, the HTS Transwell plate was incubated at 37 °C, 5% CO 2 for 1 hour, after which the cells were seeded. MDCK-MDR1 cells were diluted with the culture medium to 1.56×10 6 cells / mL, and 50 μL of the cell suspension was dispensed into the filter wells of a 96-well HTS Transwell plate. The cells were cultured in a cell culture incubator at 37 °C, CO 2 5%, relative humidity 95% for 4 to 8 days. The cell culture medium was replaced every other day starting within 24 hours after the first plating.

[0327] Preparation of stock solutions. A 10 mM stock solution of the test compound was prepared in DMSO. Stock solutions of the positive controls were prepared in DMSO at a concentration of 10 mM. Metoprolol, prazosin, and imatinib were used as control compounds in this assay.

[0328] Evaluation 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). After the measurement, the plate was returned to the incubator. The TEER value should be higher than 42 ohm·cm2, which indicates a high-quality MDCK-MDR1 monolayer. The TEER value was calculated according to the following formula. TEER measurement value (ohm) × membrane area (cm 2 ) = TEER value (ohm·cm 2 )

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

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

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

[0332] To determine the 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. The Lucifer Yellow solution (100 μL) was added to each transwell insert (apical compartment), and then the well in the receiver plate (basolateral compartment) was filled with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plate was incubated at 37 °C for 30 minutes, and then 80 μL of the sample was directly taken out from the apical and basolateral wells (using the basolateral access hole) and transferred to the wells of a new 96-well plate. The Lucifer Yellow fluorescence (for monitoring monolayer integrity) signal was measured with a fluorescence 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 equation: Papp =(V A ×[Drug] 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), Area is the surface area of the membrane (0.143 cm 2 for a Transwell 96-well permeable support), and Time is the total transport time in seconds.

[0335] The efflux ratio was determined using the following equation: Efflux ratio = P app(B-A) / P app(A-B)

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

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

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

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

[0340] To show a high-quality MDCK-MDR1 monolayer, <1% LY leakage is acceptable.

[0341] Summarize the efflux rates and ratios with the selected compounds in Table 4 below.

[0342] (Table 4) MDCK-MDR1 Efflux Rates and Ratios TIFF2025087743000199.tif32128

[0343] Microsomal and Hepatocyte Stability Microsomal Stability Protocol: The master solution was prepared as follows. TIFF2025087743000200.tif29158

[0344] Two separate experiments were performed as follows: In the case of using NADPH: 10 μL of 20 mg / mL liver microsomes and 40 μL of 10 mM NADPH were added to the incubation. The final concentrations of microsomes and NADPH were 0.5 mg / mL and 1 mM, respectively. In the case of not using 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] 4 μL of 3, 10, 30, and 100 μM test compound solutions or control compound solutions were added at final concentrations of 0.03, 0.1, 0.3, and 1 μM to initiate the reaction, which was carried out at 37 °C.

[0346] 50 μL aliquots 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. 100 μL aliquots of the supernatant were 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 the extracted ion chromatograms. The gradient value, k, was determined by linear regression of the natural logarithm of the parent drug residual rate against the incubation time curve.

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

[0350] In vitro t 1 / 2 (minutes) to in vitro intrinsic clearance (in vitro CL int , μL / min / protein mg) was performed using the following equation (average of duplicate determinations): TIFF2025087743000201.tif11128

[0351] In vitro t 1 / 2 (minutes) to scaled-up unbound intrinsic clearance (scaled-up CL int , mL / min / kg) was performed using the following equation (average of duplicate determinations): TIFF2025087743000202.tif11140

[0352] Scaling factors for predicting intrinsic clearance in liver microsomes TIFF2025087743000203.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] The results of microsomal stability in the selected compounds (μL / minute / mg of protein) are summarized in Table 5 below.

[0354] (Table 5) Results of Microsomal Stability TIFF2025087743000204.tif21128

[0355] Hepatocyte Stability Protocol: Preparation of Working Solutions 10 mM and 100 μM stock solutions of the test compound(s) and positive control were prepared in a suitable solvent (DMSO). In separate conical tubes, 10 mM test compounds and positive controls 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 compounds and positive controls 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 compounds and positive controls 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 compounds and positive controls 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 Incubation medium (William's 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. Next, vials of cryopreserved hepatocytes were removed from storage, taking care to maintain the vials at cryogenic temperatures until the thawing process occurred. The vials were placed in a 37 °C water bath and the cells were thawed by gently shaking the vials for 2 minutes. After thawing was complete, the vials were sprayed with 70% ethanol and transferred to a biosafety cabinet.

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

[0358] Cells were counted using AOPI staining solution to determine the viable cell density. Cells with insufficient viability (viability < 75%) are not permitted for use. The cells were then diluted in incubation medium to a working cell density of 0.5×10 6 cells / mL. As a representative of the negative control, little or no substrate turnover should be observed before adding to the plate, so to eliminate enzyme activity, a portion of the hepatocytes at 0.5×10 6 cells / mL was boiled for 5 minutes.

[0359] Procedure for determining stability 198 μL of hepatocytes were pipetted into each well of a 96-well non-coated plate. The plate was placed on an orbital shaker in an incubator and the hepatocytes were warmed for 10 minutes. 2 μL of the test compounds at 3, 10, 30, and 100 μM or the positive control were pipetted into each well of the 96-well non-coated plate to initiate the reaction. The final concentrations of the test compounds or control compounds were 0.03, 0.1, 0.3, and 1 μM. The plate was returned to the incubator and placed on an orbital shaker. 25 μL aliquots of the well contents were removed at 0, 15, 30, 60, 90, and 120 minutes. The aliquots were then mixed with 6 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 plate was centrifuged at 3,220 g for 20 minutes. 100 μL aliquots of the supernatant were mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis. All incubations were performed in duplicate. The results of hepatocyte stability with the selected compounds (μL / min / cell 10 6 ) are summarized in Table 6 below.

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

[0361] The in vitro half-life (in vitro t 1 / 2 ) was determined from the slope value: in vitro t 1 / 2 = 0.693 / k as determined from.

[0362] The conversion of the in vitro half-life (in minutes) to the scaled-up intrinsic clearance (scaled-up CL 1 / 2 , mL / min / kg) was performed using the following equation (average of duplicate determinations): int as follows: Scaling up CL int = kV / N × scaling factor; V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1×10 6 cells).

[0363] The scaling factors for predicting in vivo intrinsic clearance using hepatocytes of different species are listed below. TIFF2025087743000205.tif57152

[0364] (Table 6) Results of hepatocyte stability TIFF2025087743000206.tif28144

[0365] hERG cardiotoxicity (Table 7) Substances and instrumentation TIFF2025087743000207.tif149150

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

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

[0368] Preparation of the working solution for the test compound. The test compound was first prepared in DMSO at a final stock solution concentration of 10 or 30 mM. Subsequently, the stock solution of the test compound was 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, the working solution was prepared by diluting the 30, 10, 3.33, 1.11 and 0.37 mM intermediate solutions 1000-fold using the extracellular solution. Thus, the final concentrations of the working solution were 30, 10, 3.33, 1.11 and 0.37 μM. The final DMSO concentration of the working solution was 0.1 - 0.3% (v / v). IC 50 For determination, the human ERG current in the presence of 5 doses was tested.

[0369] Experimental procedure. The cover slip was removed from the cell culture dish and placed on the microscope stage of the bath chamber. Using a 10x objective lens, the desired cells were positioned. The tip of the electrode was positioned by focusing on the cell surface under the microscope using a 10x objective lens. Once the tip was in focus, the lower electrode was advanced towards the cell using the path control of the manipulator, while simultaneously moving the objective lens to keep the focus on the tip. Then, using the fine adjustment of the manipulator, it was brought closer to the cell little by little. Gentle suction was applied through the side part of the electrode holder to form a gigohm seal. C fast was used to remove the current volume corresponding to the voltage step. A whole-cell configuration was obtained by applying repeated short, strong suctions until the membrane patch ruptured. Then, the membrane potential was set to -60 mV to ensure that the hERG channel was not open. Then, with the amplifier C slow was used to cancel the spikes of the current volume. The holding potential was set to -90 mV for 500 ms, the current was recorded at 50 kHz and filtered at 10 kHz. The leakage was examined at -80 mV for 500 ms.

[0370] The hERG current was induced by polarizing at +30 mV for 4.8 seconds, and then the voltage was returned to -50 mV for 5.2 seconds to remove inactivation, and the non-inactivated tail current was observed. The hERG current amplitude was determined using the maximum amount of the tail current size. The current was recorded for 120 seconds to evaluate the current stability. Only the stable cells with parameters exceeding the threshold were applied for drug administration.

[0371] A vehicle control was administered to the cells to establish a baseline. When it was found that the hERG current was stabilized for 3 minutes, the test compound was applied. The hERG current in the presence of the test compound was recorded for approximately 5 minutes until a steady state was reached, and then five sweeps were captured. For the dose-response test, five doses of the compound were applied to the cells incrementally from low concentration to high concentration. To ensure good processing ability of the cultured cells and operations, five dose concentrations of the positive control, dofetilide, were also used to examine the same batch of cells.

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

[0373] The data satisfying the above criteria for hERG current characteristics were further analyzed. The hERG current inhibition rate was calculated using the following formula. Peak current inhibition = (1 - ) × 100 Peak tail current media

[0374] Using Graphpad Prism 6.0, the dose-response curves of the test compounds were plotted together with the percentage of hERG current inhibition against the concentration of the test compounds and fitted to a sigmoid 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 the selected compounds 50 Results (μM) are summarized in Table 8 below.

[0376] Certain compounds of the present disclosure have unexpectedly been found to exhibit unexpectedly low cardiotoxicity.

[0377] (Table 8) hERG IC 50 results TIFF2025087743000208.tif21128

[0378] Evaluation of Cytochrome P450 Inhibition (Table 9) Preparation of Master Solution TIFF2025087743000209.tif44150

[0379] Stock compound solution (1 μL, 2 mM) or DMSO (1 μL) was added to the master solution. The final concentration of the test compound 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 minutes. The reaction was initiated by adding 20 μL of a 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 designated time points (phenacetin: 20 minutes; bupropion: 20 minutes; tolbutamide: 20 minutes; (s)-Me phenytoin: 20 minutes; midazolam: 5 minutes; testosterone: 10 minutes). The samples were vortexed for 5 minutes and centrifuged at 3220 g for 40 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. All experiments were performed in duplicate.

[0387] The results of the CYP450 isoform inhibition rates (10 μM) with the selected compounds are summarized in Table 10 below.

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

[0389] (Table 10) CYP450 isoform inhibition rates TIFF2025087743000210.tif21131

[0390] Example 4: Rat pharmacokinetic study The pharmacokinetic studies of the exemplary compounds 03-3, 03-5, and 03-115 were conducted using male Sprague-Dawley rats. These rats were typically about 6-8 weeks old and weighed 200 g to 300 g. The animals were fasted overnight and allowed free access to food 4 hours after dosing. To prepare the dosing, the necessary volume of vehicle was added to achieve the target concentrations of the test article and vehicle components. The dosing vehicle was PEG400 in IV or 30% PEG400 in physiological saline, or 0.5% methylcellulose in water in PO. In IV administration, the animals were administered intravenously via the tail vein. In PO administration, the animals were administered via forced oral gavage. After dosing, blood samples were collected via jugular vein or cardiac puncture (about 0.2 mL per time point). The blood of 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 at -75 ± 15 °C in a freezer before analysis. The samples were analyzed using LC-MS / MS. WinNonlin was used for the calculation of pharmacokinetics.

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

[0392] For brain sample collection, before brain collection, the rats were completely exsanguinated using an increase in carbon dioxide. Then, brain samples were collected at the time points employed, quickly frozen, and maintained at -75 ± 15 °C. All brain samples were weighed and homogenized with PBS until the ratio of brain weight (g) to PBS volume (mL) was 1:3 before analysis. The actual concentration is the detected value multiplied by the dilution factor.

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

[0394] The results of exemplary CNS exposures in IV and SC administrations are summarized in Tables 17 - 19 below. The results of exemplary CNS exposures in PO administration are summarized in Table 20 below.

[0395] The PK results in male Sprague - Dawley rats are further summarized in Figures 4 - 5, and 12.

[0396] It has been unexpectedly found that the compounds of the present disclosure have excellent absorption and overall exposure characteristics. Furthermore, it has been unexpectedly found that the compounds of the present disclosure exhibit excellent CNS exposure and accumulation.

[0397] (Table 11) Results of rat IV pharmacokinetics for Compound 03 - 3 TIFF2025087743000211.tif75128

[0398] (Table 12) Results of rat IV pharmacokinetics for Compound 03 - 5 TIFF2025087743000212.tif75128

[0399] (Table 13) Results of rat IV pharmacokinetics for Compound 03 - 115 TIFF2025087743000213.tif48128

[0400] (Table 14) Results of rat PO pharmacokinetics for Compound 03 - 3 TIFF2025087743000214.tif63128

[0401] (Table 15) Results of rat PO pharmacokinetics for Compound 03 - 5 TIFF2025087743000215.tif63128

[0402] (Table 16) Results of rat PO pharmacokinetics for Compound 03 - 115 TIFF2025087743000216.tif46128

[0403] (Table 17) Rat IV CNS Exposure Measurement for Compound 03 - 3 TIFF2025087743000217.tif29131

[0404] (Table 18) Rat IV CNS Exposure Measurement with Compound 03-5 TIFF2025087743000218.tif29128

[0405] (Table 19) Rat SC CNS Exposure Measurement with Compound 03-115 TIFF2025087743000219.tif29128

[0406] (Table 20) Rat PO CNS Exposure Measurement with Compound 03-5 TIFF2025087743000220.tif29128

[0407] Example 5: Mouse Pharmacokinetics Study The mouse pharmacokinetics studies of exemplary compounds 03-3 and 03-5 were conducted in substantially the same manner as the rat pharmacokinetics studies, using male C57BL / 6J mice instead. These mice were typically about 6 - 8 weeks old and weighed 20 g - 30 g. The animals were allowed free access to food prior to dosing. The sample volume was approximately 0.03 mL per time point, and the sample collection site was the dorsal midfoot or cardiac puncture.

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

[0409] Results of exemplary CNS exposure 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] It has been unexpectedly found that the compounds of the present disclosure have excellent absorption and overall exposure characteristics. Furthermore, it has been unexpectedly found that the compounds of the present disclosure exhibit excellent CNS exposure and accumulation.

[0412] (Table 21) Results of Mouse PO PK with Compound 03-3 TIFF2025087743000221.tif63128

[0413] (Table 22) Results of Mouse PO PK with Compound 03-5 TIFF2025087743000222.tif63128

[0414] (Table 23) Results of Mouse PO PK with Compound 03-115 TIFF2025087743000223.tif40128

[0415] (Table 24) Mouse PO CNS Exposure Measurement with Compound 03-3 TIFF2025087743000224.tif29128

[0416] (Table 25) Mouse PO CNS Exposure Measurement with Compound 03-5 TIFF2025087743000225.tif29128

[0417] (Table 26) Mouse SC CNS Exposure Measurement with Compound 03-115 TIFF2025087743000226.tif29128

[0418] Example 6: Canine Pharmacokinetics Study The canine pharmacokinetics studies of the exemplary compounds 03-3, 03-5, and 03-115 were conducted in substantially the same manner as the rat pharmacokinetics studies, using male beagle dogs instead. Animals for the PO study were fasted overnight before dosing and fed approximately 2 hours after dosing. Animals for the IV study had free access to food and water. Blood samples were collected via venipuncture of peripheral veins other than the dosing 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) Results of Canine PO PK with Compound 03-3 TIFF2025087743000227.tif40128

[0422] (Table 28) Results of Canine PO PK with Compound 03-3 TIFF2025087743000228.tif40128

[0423] (Table 29) Results of Canine PO PK with Compound 03-5 TIFF2025087743000229.tif40128

[0424] (Table 30) Results of Canine PO PK with Compound 03-5 TIFF2025087743000230.tif40128

[0425] (Table 31) Results of Canine PO PK with Compound 03-115 TIFF2025087743000231.tif40128

[0426] (Table 32) Results of Canine PO PK with Compound 03-115 TIFF2025087743000232.tif40128

[0427] Example 7: Primate Pharmacokinetics Study The primate pharmacokinetics studies of the exemplary compounds 03-3, 03-5, and 03-115 were conducted in substantially the same manner as the rat pharmacokinetics studies, using male cynomolgus monkeys instead. Animals for PO studies were fasted overnight before dosing and fed approximately 2 hours after dosing. Animals for IV studies had free access to food and water. Blood samples were collected via venipuncture of peripheral veins other than the dosing 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 unexpectedly been found to have excellent absorption and overall exposure characteristics. Further, the oral bioavailability of the compounds has unexpectedly been found to be close to their respective intravenous bioavailabilities.

[0431] (Table 33) Results of monkey PO PK with compound 03-3 TIFF2025087743000233.tif63128

[0432] (Table 34) Results of monkey PO PK with compound 03-5 TIFF2025087743000234.tif63128

[0433] (Table 35) Results of monkey PO PK with compound 03-115 TIFF2025087743000235.tif40128

[0434] Example 8: Evaluation of Additional Synthesized Adrenergic Receptor Agonists The potencies of the following additional compounds were measured using the method described in Example 2. Potency data for the selected compounds are summarized in Table 36A (EC 50 ) and Table 36B (pEC 50 ) below.

[0435] (Table 36A) Pharmacological Data for Certain Specific Additional Compounds Disclosed herein TIFF2025087743000236.tif51128TIFF2025087743000237.tif230116TIFF2025087743000238.tif230116TIFF2025087743000239.tif230116TIFF2025087743000240.tif33128EC 50 (nM): A < 10 nM; B = 10 - 100 nM; C = 100 nM - 1 μM; D > 1 μM

[0436] (Table 36B) Pharmacological Data for Certain Specific Additional Compounds Disclosed herein TIFF2025087743000241.tif170137TIFF2025087743000242.tif230137TIFF2025087743000243.tif230137TIFF2025087743000244.tif230137TIFF2025087743000245.tif230137TIFF2025087743000246.tif230137TIFF2025087743000247.tif216137pEC 50 : A > 8; B = 8 to 7; C = <7 to 6; D < 6

[0437] One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific compositions and procedures described herein. Such equivalents are considered to be within the scope of this disclosure and are included in the following claims.

[0438] In addition to the various embodiments described above in the specification, the following additional embodiments are contemplated herein. 1. A compound according to formula (I) TIFF2025087743000248.tif26128 or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof [Wherein, each A, B, and X is independently nitrogen or carbon; each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorothio, 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; R 2 、R 3 、and R 4 is independently selected from the group consisting of 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, TIFF2025087743000249.tif67150, or R 2 and R 3 together with carbon, form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring; L is an optionally substituted C1-C5 alkyl linker; Each Y 1 、Y 2 、Y 3 、and Y 4 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; R 5 and R 6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R 5 and R 6 are cyclically bonded together with Y 2 to form an optionally substituted cycloalkyl or heterocycle; Each R 7 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; R 8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl; and R 9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino. 2. The compound according to formula (II) TIFF2025087743000250.tif28128 or its optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug [wherein, each A, B, and X is independently nitrogen or carbon; each R 1 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; R 2 、R 3 、and R 4 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, TIFF2025087743000251.tif62151 or are selected from the group consisting of, or R 2 and R 3 together with carbon form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring; L is an optionally substituted C1-C5 alkyl linker; each Y 1 、Y2 , Y 3 , and Y 4 is independently nitrogen which may be substituted by a covalent bond, carbon, oxygen, or hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; Z is O or S; R 5 and R 6 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R 5 and R 6 are cyclically bonded together with Y 2 to form an optionally substituted cycloalkyl or heterocycle; Each R 7 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; R 8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl; and R 9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino]. 3. The compound according to formula (III) TIFF2025087743000252.tif23128 or its optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug [wherein, Each R 1is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, pentafluorothiol, 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; R 2 R 3 and R 4 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, TIFF2025087743000253.tif61153, or R 2 and R 3 together with carbon form an unsubstituted or substituted 3- to 7-membered cycloalkyl or heterocyclic ring; L is an optionally substituted C1-C5 alkyl linker; Each X 1 X 2 X 3 and X 4 is independently 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; R 5 and R 6 are independently selected from hydrogen and unsubstituted or substituted alkyl, or R 5 and R 6 are Y 2Combined annularly together to form an optionally substituted cycloalkyl or heterocycle; Each R 7 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; R 8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted aryl; and R 9 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 according to Embodiment 1 having the following structural formula TIFF2025087743000254.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 adrenergic receptor. 6. The compound according to any one of Embodiments 1 to 4, which is a β1 - adrenergic receptor agonist, β2 - adrenergic receptor agonist or non - selective β1 / β2 - adrenergic receptor agonist. 7. The compound according to any one of Embodiments 1 to 4, which is a β1 - adrenergic receptor agonist. 8. The compound according to any one of Embodiments 1 to 4, which is a β2 - adrenergic receptor agonist. 9. The compound according to any one of Embodiments 1 to 4, which is a non - selective β1 / β2 - adrenergic agonist. 10. A pharmaceutical composition comprising the compound according to any one of Embodiments 1 to 9 and a pharmaceutically acceptable additive. 11. A method for treating a subject having a disease, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of Embodiments 1 to 9. 12. A method for treating a subject having a disease, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of Embodiments 1 to 9, thereby treating the subject. 13. A method for treating a subject having a disease associated with an adrenergic receptor, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of Embodiments 1 to 9. 14. The method according to any one of Embodiments 11 to 13, wherein the disease is a neurodegenerative disease. 15. The method according to Embodiment 14, wherein the disease is one or more 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 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 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 disorder, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down syndrome (DS). 16. The method according to any one of Embodiments 11 to 15, wherein the subject is a human. 17. The method according to any one of embodiments 11 to 16, wherein the compound is administered to the subject via an oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, topical on the skin, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernous, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route. 18. Compound according to formula (XXII’): TIFF2025087743000255.tif25128 or a pharmaceutically acceptable salt thereof [wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; each R’ is an optionally substituted C 1~6 aliphatic; and R 2’ R 3’ and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring]. 19. The compound according to embodiment 18, wherein the carbon bonded to the OH group has the (R) configuration. 20. R 1’ is methyl, the compound according to any one of embodiments 18 to 19. 21. R 2’ is C 1~6 aliphatic, the compound according to any one of embodiments 18 to 20. 22. R 2’ is methyl, the compound according to any one of embodiments 18 to 21. 23. R 3’ is C 1~6The compound according to any one of Embodiments 18 to 22, which is aliphatic. 24. R 3’ The compound according to any one of Embodiments 18 to 23, wherein R is methyl. 25. R 4’ is C 1~6 The compound according to any one of Embodiments 18 to 22, which is aliphatic. 26. R 4’ The compound according to any one of Embodiments 18 to 23, wherein R is methyl. 27. Compound according to formula (XVIII’): TIFF2025087743000256.tif24128 or a pharmaceutically acceptable salt thereof [wherein, R 1’ is halogen, -R’, -CN, or -NO 2 ; each R’ is optionally substituted C 1~6 aliphatic; and R 2’ , R 3’ , and R 4’ are each independently halogen, -R’, -CN, -NO 2 , -OR’, or -NR’ 2 , or R 2 ’ and R 3 ’ together with carbon form an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring]. 28. The compound according to Embodiment 26, wherein the carbon bonded to the OH group has the (S) configuration. 29. R 1’ is cyano, the compound according to any one of Embodiments 26 to 27. 30. R 2’ is C 1~6 aliphatic, the compound according to any one of Embodiments 26 to 28. 31. R2’ The compound according to any one of Embodiments 26 to 29, wherein it is methyl. 32. R 3’ is 1~6 aliphatic, the compound according to any one of Embodiments 26 to 30. 33. R 3’ is methyl, the compound according to any one of Embodiments 26 to 31. 34. R 4’ is 1~6 aliphatic, the compound according to any one of Embodiments 26 to 32. 35. R 4’ is methyl, the compound according to any one of Embodiments 26 to 33.

Claims

1. A compound according to formula (I') or a pharma- ceutically acceptable salt thereof: During the ceremony, A', B', and X' are each independently nitrogen or carbon; Each R １’ are independently halogen, —R′, —CN, —NO ２ , -SF 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 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 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 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R ２’ , R ３’ , and R ４’ each independently represents a halogen, —R′, —CN, or —NO ２ , -OR', -NR' ２ , 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; 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 an optionally substituted C １～５ is alkylene; Y １’ , Y ２’ , Y ３’ , and Y ４’ Each independently represents a covalent bond, carbon, oxygen, 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; R ５’ and R ６’ Y ２’ and are joined 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; 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.

2. A compound according to formula (II') or a pharma- ceutically acceptable salt thereof: During the ceremony, A', B', and X' are each independently nitrogen or carbon; Each R １’ are independently halogen, —R′, —CN, —NO ２ , -SF 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 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 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 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R ２’ , R ３’ , and R ４’ each independently represents a halogen, —R′, —CN, or —NO ２ , -OR', -NR' ２ , 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; 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 an optionally substituted C １～５ is alkylene; Y １’ , Y ２’ , Y ３’ , and Y ４’ Each independently represents a covalent bond, carbon, oxygen, 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; R ５’ and R ６’ Y ２’ and are joined 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; 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.

3. A compound according to formula (III') or a pharma- ceutically acceptable salt thereof: During the ceremony, A', B', and X' are each independently nitrogen or carbon; Each R １’ are independently halogen, —R′, —CN, —NO ２ , -SF 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 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 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 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m' is an integer selected from 0 to 4; R ２’ , R ３’ , and R ４’ each independently represents a halogen, —R′, —CN, or —NO ２ , -OR', -NR' ２ , 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; 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 an optionally substituted C １～５ is alkylene; Y １’ , Y ２’ , Y ３’ , and Y ４’ Each independently represents a covalent bond, carbon, oxygen, 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; R ５’ and R ６’ Y ２’ and are joined 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; 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.

4. A compound according to formula (XVIII') or a pharma- ceutically acceptable salt thereof: During the ceremony, R １’ is 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’ each independently represents 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.

5. A compound according to formula (XXII') or a pharma- ceutically acceptable salt thereof: During the ceremony, R １’ is 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’ each independently represents 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.

6. R １’ is halogen, —CN, or optionally substituted C １～６ The compound according to any one of claims 1 to 5, which is aliphatic.

7. R １’ The compound according to claim 6, wherein is -CN.

8. R １’ is optionally substituted C １～６ The compound of claim 6 which is aliphatic.

9. R １’ The compound of claim 8 , wherein is methyl.

10. R １’ But -CF ３ 9. The compound of claim 8, wherein

11. R ２ ' and R ３ 11. The compound of any one of claims 1 to 10, wherein together with the carbon, ' forms an optionally substituted 3- to 7-membered cycloalkyl or heterocyclic ring.

12. R ２’ is optionally substituted C １～６ The compound according to any one of claims 1 to 10, which is aliphatic.

13. R ２’ The compound of claim 12, wherein is methyl.

14. R ３’ is optionally substituted C １～６ The compound according to any one of claims 1 to 10, which is aliphatic.

15. R ３’ The compound of claim 14 , wherein is methyl.

16. R ４’ is optionally substituted C １～６ The compound according to any one of claims 1 to 10, which is aliphatic.

17. R ４’ The compound of claim 16, wherein is methyl.

18. The following structural formula:

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

19. The following structural formula:

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

20. The following structural formula:

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

21. A compound according to any one of claims 1 to 20 which is an agonist, partial agonist or antagonist of an adrenergic receptor.

22. The compound according to any one of claims 1 to 20, which is a β1-adrenergic receptor agonist, a β2-adrenergic receptor agonist or a non-selective β1 / β2-adrenergic receptor agonist.

23. The compound according to any one of claims 1 to 20, which is a β1-adrenergic receptor agonist.

24. The compound according to any one of claims 1 to 20, which is a β2-adrenergic receptor agonist.

25. The compound according to any one of claims 1 to 20, which is a non-selective β1 / β2-adrenergic agonist.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharma- ceutically acceptable excipient.

27. A method of treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 20.

28. 23. A method of treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 20, thereby treating the subject.

29. 21. 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 according to any one of claims 1 to 20.

30. The method according to any one of claims 27 to 29, wherein the disease is a neurodegenerative disease.

31. The disease may be 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 (Wernicke-Korsakoff syndrome; 31. The method of claim 30, wherein the condition is one or more selected from the group consisting of 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), ADHD (Attention Deficit Hyperactivity Disorder), Alzheimer's Disease (AD), Early AD, and Down's Syndrome (DS).

32. The method of any one of claims 27 to 31, wherein the subject is a human.

33. 33. The method of any one of claims 27-32, 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.

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