Alpha 1A-adrenergic receptor agonists and methods of use thereof

Abstract

The present disclosure is based, at least in part, on the identification of compounds that modulate adrenergic receptors and methods of using the compounds to treat diseases associated with adrenergic receptors. For example, disclosed herein is a compound of formula (I) or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof: TIFF2025512777000057.tif48128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 323,421, filed March 24, 2022. The disclosure of said prior application is deemed to be part of the disclosure of this application and is incorporated by reference in its entirety into this application.

[0002] FIELD OF THEINVENTION The present disclosure relates generally to chemical compounds, in some embodiments, 1A - Adrenergic receptor agonists and their use in the treatment of diseases associated with adrenergic receptors. [Background technology]

[0003] background PCT Patent Application Publication WO2008112773 (Patent Document 1) claims that "This application relates to the use of droxidopa, alone or in combination with one or more additional ingredients, for the treatment of conditions such as neurally mediated orthostatic hypotension."

[0004] U.S. Patent No. 5,952,362 describes "various 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxyphenyl, and aminophenyl, as well as alkylsulfonamides and ureas" and "alpha-amyloides in the treatment of various conditions, such as urinary incontinence, nasal congestion, priapism, depression, anxiety, dementia, senility, Alzheimer's disease, attention and cognition deficits, and eating disorders, such as obesity, bulimia, and anorexia." 1A / 1L The '362 patent discloses that "the use of the above compounds and compositions containing them as agonists in the treatment of rheumatoid arthritis and rheumatoid arthritis." The '362 patent discloses the compound N-[6-chloro-3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-2-methylphenyl]methanesulfonamide hydrochloride. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] PCT Patent Application Publication WO2008112773 [Patent Document 2] U.S. Patent No. 5,952,362 Summary of the Invention

[0006] overview The present disclosure is based, at least in part, on the identification of compounds that modulate adrenergic receptors and methods of using the compounds to treat diseases associated with the adrenergic receptors. Disclosed herein is a compound of formula (I) or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof: TIFF2025512777000002.tif48128

[0007] For some embodiments, A, W, and G are independently nitrogen, CR3, CR4, or CR5.

[0008] For some embodiments, Y is N or CR1.

[0009] For some embodiments, R1, R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0010] Also disclosed herein are compounds of formula (II) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000003.tif56128

[0011] For some embodiments, Y is N or CR1.

[0012] For some embodiments, R1, R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0013] Also disclosed herein are compounds of formula (II) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000004.tif44128

[0014] For some embodiments, R1 and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0015] Also disclosed herein is a compound of formula (IV) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000005.tif53128

[0016] For some embodiments, R1 and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0017] Also disclosed herein are compounds of formula (V) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000006.tif43128

[0018] For some embodiments, R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0019] Also disclosed herein is a compound of formula (VI) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000007.tif33128

[0020] For some embodiments, R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0021] Also disclosed herein is a compound of formula (VII) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000008.tif39128

[0022] For some embodiments, R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0023] Also disclosed herein is a compound of formula (VIII) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000009.tif43128

[0024] For some embodiments, R1 and R2 are selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0025] Also disclosed herein are compounds of formula (IX) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000010.tif28128

[0026] For some embodiments, R1 and R3 are selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0027] For certain embodiments, R2 is selected from the group consisting of hydrogen and halogen.

[0028] Also disclosed herein are compounds of formula (X) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000011.tif42128

[0029] For some embodiments, R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0030] In some embodiments, the compounds described herein are agonists, partial agonists, or antagonists of the adrenoceptor. 1A In some embodiments, the compound is an α-adrenergic receptor agonist. 1A In some embodiments, the compound is an α-adrenergic receptor partial agonist. 1A -It is an adrenergic receptor antagonist.

[0031] Also disclosed herein are pharmaceutical compositions comprising a compound described herein, i.e., a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula IX), or Formula (X), and a pharma- ceutically acceptable excipient.

[0032] Further disclosed herein is a method of treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound described herein, i.e., a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula IX), or Formula (X). In some embodiments, the disease is an adrenergic receptor-associated disease. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the subject is a human.

[0033] In some embodiments, the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedreich's ataxia, ataxia-telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject by 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.

[0034] In some embodiments, the disease is 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-Corsa syndrome), and Cough syndrome, alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (CJD, etc.), 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). In some embodiments, the disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia, Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (well-established dementia), or a combination of these. The neurodegenerative disease is one or more selected from the group consisting of: Nicke-Korsakoff syndrome, alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not suffer from Alzheimer's disease (AD). In some embodiments, the subject does not suffer from Down's syndrome.

[0035] Also disclosed herein is a method of treating a subject having nOH, comprising administering to the subject a therapeutically effective amount of a compound described herein, i.e., a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula IX), or Formula (X), and a pharma- ceutically acceptable excipient.

[0036] The term "partial agonist" as used herein refers to a ligand that acts as an agonist at a receptor but does not reach the maximal response capacity of the system even with full receptor occupancy, i.e., a partial agonist results in submaximal activation even when occupying the total receptor population and therefore fails to produce a maximal response regardless of the concentration applied. In some embodiments, a partial agonist exhibits a maximal efficacy that is less than 1%, or 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85% of the efficacy of a corresponding full agonist at the same receptor (α 1A -Examples of full agonists of adrenergic receptors include noradrenaline and amidephrine.

[0037] As used herein, the term "α 1A -adrenergic receptor partial agonist" is an α 1A In the present application, the term "α 1A -adrenergic receptor partial agonist," "α 1A -ADR partial agonist," "α 1A -AR agonist" and "α 1A The terms "partial agonist" and "partial agonist" may be used interchangeably. 1A -Adrenergic partial agonists are α 1A- exhibiting a maximal efficacy (or intrinsic activity, "IA") of less than 10%, or less than 15%, or less than 20%, or less than 25%, or less than 30%, or less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or between 15-75%, or between 20-65%, or between 20-60%, or between 20-55%, or between 20-50%, or between 20-45%, or between 25-60%, or between 25-55%, or between 25-35%, or between 30-40%, or between 40-50%, or between 45-55% (α 1A - Examples of full agonists of the adrenoceptor include noradrenaline and amidephrine. In some embodiments, the α 1A -Adrenergic partial agonists exhibit less than 30%, or less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85% but greater than 5%, or less than 10%, or less than 15%, or less than 20% of maximum efficacy (or intrinsic activity, "IA"). Blue et al., BJU International, (2004) 93:162-170 (incorporated herein by reference in its entirety) describes partial agonism, particularly alpha 1A The present invention provides compositions and methods that can be used to determine partial agonism of α-adrenergic receptors, and 1A In certain embodiments, α 1AAn -ADR partial agonist has less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or 15-75%, or 20-65%, or 25-60%, or 25-55%, or 25-35%, or 30-40%, or 40-50%, or 45-55% of the activity of a full agonist according to the InsPs accumulation assay described in Blue et al. (See, e.g., Table 1 in Blue et al., which shows an intrinsic activity of 0.31 for RO 115-1240 (dabzalgulone) free base and 0.27 for RO 115-1240 (dabzalgulone) HCl salt compared to noradrenaline in the InsPs accumulation assay). In some embodiments, an α 1A An -ADR partial agonist has less than 35%, or less than 40%, or less than 45%, or less than 50%, or less than 55%, or less than 60%, or less than 65%, or less than 70%, or less than 75%, or less than 80%, or less than 85%, or 15-75%, or 20-65%, or 25-60%, or 25-55%, or 25-35%, or 30-40%, or 40-50%, or 45-55% of the activity of a full agonist according to the FLIPR assay described in Blue et al. (See, e.g., Table 1 of Blue et al., which shows an intrinsic activity of 0.51 for RO 115-1240 (dabzalgurone) HCl salt compared to noradrenaline in the FLIPR assay). In many embodiments, an α 1A -ADR partial agonists have a higher α 1A -adrenergic receptors. 1A -ADR partial agonist, in some embodiments, contemplates any pharma- ceutically acceptable salt or prodrug thereof.

[0038] In some embodiments, α 1A -ADR partial agonists are selective α 1A - adrenergic partial agonists. As used herein, a "selective alpha 1A-ADR partial agonist" is an α 1A - Shows partial agonism at α1-adrenergic receptors, but not at other α1-adrenergic receptor subtypes (e.g., α 1B -ADR or α 1D Blue et al., BJU International, (2004) 93:162-170 (hereby incorporated by reference in its entirety) discusses selective agonism (and selective partial agonism), particularly α 1A The present invention provides compositions and methods that can be used to determine selective agonism (and selective partial agonism) of the -ADR receptor, 1A In some embodiments, the selective α-ADR partial agonists used herein demonstrate exemplary selectivity as α-ADR partial agonists. 1A -ADR agonist or selective α 1A -ADR partial agonists are (e.g., α-ADR partial agonists according to the method described in Blue et al. 1B -ADR or α 1D -ADR-expressing CHO cells)α 1B -ADR or α 1D In some embodiments, the selective α 1A -ADR agonist or selective α 1A -ADR partial agonists have an α of less than 8.0, or less than 7.5, or less than 7.0, or less than 6.5, or less than 6.0, or less than 5.5, or less than 5, or less than 4.5, or less than 4, or less than 3.5, or between 2.5 and 6, or between 3 and 5.5, or between 3 and 5.0, or between 3 and 5. 1B -ADR and α 1D -pEC against ADR receptors 50 In some embodiments, the selective α 1A -ADR agonist or selective α 1A -ADR partial agonists have an α of less than 7.0, or less than 6.5, or less than 6.0, or less than 5.5, or less than 5, or less than 4.5, or less than 4, or less than 3.5, or between 2.5 and 6, or between 3 and 5.5, or between 3 and 5.0, or between 3 and 5.1B -ADR and α 1D -ADR receptor, pEC by InsPs accumulation assay as described by Blue et al. 50 (e.g., in the InsPs accumulation assay, 1B -ADR and α 1D -ADR receptors, pEC > 4.0 for RO 115-1240 (dabzalgurone) free base and HCl salt 50 (See Table 1 of Blue et al., which shows the structure of the selective α 1A -AR agonist or selective α 1A -AR partial agonists have an α of less than 7.0, or less than 6.5, or less than 6.0, or less than 5.5, or less than 5, or less than 4.5, or less than 4, or less than 3.5, or between 2.5 and 6, or between 3 and 5.5, or between 3 and 5.0, or between 3 and 5. 1B -AR and α 1D pECs by FLIPR assay as described by Blue et al. against the -AR receptor 50 (e.g., α in FLIPR accumulation assays) 1B -AR and α 1D pEC >5.0 for RO 115-1240 (dabzalgurone) free base and HCl salt against the -AR receptor 50 (See Table 1 of Blue et al., which shows the structure of the selective α 1A -AR agonist or selective α 1A -AR partial agonists have less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of the α-AR activity of nonselective agonists such as noradrenaline. 1B -AR and α 1D -pEC against AR receptors 50 In some embodiments, the selective α 1A -AR agonist or selective α 1A-AR partial agonists have less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of the α-AR activity of nonselective agonists such as noradrenaline. 1B -AR and α 1D pECs by the InsPs accumulation assay described by Blue et al. against the -AR receptor 50 In some embodiments, the selective α 1A -AR agonist or selective α 1A -AR partial agonists have less than 85%, or less than 80%, or less than 75%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of the α-AR activity of nonselective agonists such as noradrenaline. 1B -AR and α 1D pECs by FLIPR assay as described by Blue et al. against the -AR receptor 50 In some embodiments, the selective α 1A -AR agonist or selective α 1A The -AR partial agonist may be administered at a concentration of 30 μMol / L or less, 50 μMol / L or less, 75 μMol / L or less, or 100 μMol / L or less (e.g., α-AR partial agonist according to the method described in Blue et al. 1B -AR or α 1D In CHO cells expressing α-AR 1B -AR or α 1D In some embodiments, the selective α 1A -AR agonist or selective α 1A -AR partial agonists have a pK greater than 5.5, or greater than 6.0, or greater than 6.5, or greater than 7.0, or greater than 7.2, or greater than 7.5, or greater than 7.8, or greater than 8.0, or greater than 9.0 (e.g., according to the methodology described in Blue et al.). i In some embodiments, the selective α 1A -AR agonist or selective α 1A-AR partial agonists have a pK greater than 5.0, or greater than 5.5, or greater than 6.0, or greater than 7.0, or greater than 8.0, or greater than 9.0 (e.g., according to the methodology described in Blue et al. i With α 1B -AR or α 1D -Does not bind to AR receptors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Detailed Description In the following detailed description of the embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of the disclosed embodiments. 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.

[0040] The following interpretations of terms and methods are provided to better explain the present disclosure and guide those skilled in the art in practicing 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, "including A or B" means "including A, B, or A and B" without excluding additional elements. The term "about" will be understood by those skilled in the art. Regardless of whether the term "about" is explicitly used, all quantities given herein refer to the actual given value, and also refer to approximations to such given values ​​that are reasonably estimated based on the skilled artisan.

[0041] Further, it should be understood that all base or amino acid sizes, and all molecular weight or molecular mass values ​​given for nucleic acids or polypeptides are approximate and are provided for illustration purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, the preferred methods and materials are described below.

[0042] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.For definitions of common terms in molecular biology, refer to 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).

[0043] Unless otherwise stated, the nomenclature of substituents not expressly defined herein is obtained by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. Those skilled in the art will recognize that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with five different groups, pentavalent carbon, etc.). Such impermissible substitution patterns are readily recognized by those skilled in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated in their entirety. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are merely illustrative and not limiting.

[0044] Alkyl groups refer to monovalent groups derived from an alkane by removing a hydrogen atom from any carbon atom, and include straight and branched chains having 1 to 12 carbon atoms, typically 1 to about 10 carbon atoms, or in some embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl groups. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be mono-substituted or may be multiply substituted, such as, but not limited to, mono-, di-, or tri-substituted. Such substituents include C2-C6-alkenyl, C2-C6-alkynyl, halo, I, Br, Cl, F, -OH, -COOH, sulfhydryl, (C1-C6-alkyl)S-, C1-C6-alkylsulfinyl, nitro, cyano, trifluoromethyl, -NH2, =O, =S, =N-CN, =N-OH, -OCH2F, -OCHF2, -OCF3, -SCF3, -S O2-NH2, C1-C6-alkoxy, -C(O)O-(C1-C6 alkyl), -OC(O)-(C1-C6 alkyl), -C(O)-NH2, -C(O)-N(H)-C1-C6 alkyl, -C(O)-N(C1-C6 alkyl)2, -OC(O)-NH2, -C(O)-H, -C(O)-(C1-C6 alkyl), -C(S)-(C1-C6 alkyl), -NR 70 R 72 Including, but not limited to, R 70 and R 72 are each independently selected from H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, and C(O)-C1-C6-alkyl. As used herein, the term alkyl refers to both cyclic and non-cyclic groups, unless otherwise specified.

[0045] The term "cyclic alkyl" or "cycloalkyl" refers to a monovalent group derived from a cycloalkane by removing a hydrogen from a ring carbon atom. Cycloalkyl groups are saturated or partially saturated non-aromatic structures having single or multiple rings, including isolated, fused, bridged, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments, 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted. Cycloalkyl groups can be substituted with groups such as those described above for alkyl. Representative substituted cycloalkyl groups can be mono-substituted or multiply substituted, such as mono-, di-, or tri-substituted, but are not limited thereto. 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, and the like. (Cycloalkyl)oxy refers to -O-cycloalkyl. (Cycloalkyl)thio refers to -S-cycloalkyl. This term also encompasses oxidized forms of sulfur, such as -S(O)-cycloalkyl or -S(O)2-cycloalkyl.

[0046] Alkenyl groups refer to straight and branched chain and cycloalkyl groups as defined above, having one or more double bonds between two carbon atoms. Alkenyl groups can have from 2 to about 12 carbon atoms, or in some embodiments from 1 to about 10 carbon atoms, or in other embodiments from 1 to about 6 carbon atoms, or in other embodiments from 1, 2, 3, or 4 carbon atoms. Alkenyl groups can be substituted or unsubstituted. Alkenyl groups can be substituted with groups such as those described above for alkyl. Representative substituted alkenyl groups can be mono-substituted or multiply substituted, such as mono-, di-, or tri-substituted, but are not limited thereto. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl.

[0047] Alkynyl groups refer to straight and branched chain and cycloalkyl groups as defined above, having one or more triple bonds between two carbon atoms. Alkynyl groups can have from 2 to about 12 carbon atoms, or in some embodiments from 1 to about 10 carbon atoms, or in other embodiments from 1 to about 6 carbon atoms, or in other embodiments from 1, 2, 3, or 4 carbon atoms. Alkynyl groups can be substituted or unsubstituted. Alkynyl groups can be substituted with groups such as those described above for alkyl. Representative alkynyl groups can be mono-substituted or multiply substituted, such as mono-, di-, or tri-substituted, but are not limited thereto. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, -C≡C(CH3), and the like.

[0048] Aryl groups are cyclic aromatic hydrocarbons including single and multiple ring compounds, including multiple ring compounds containing separate and / or fused aryl groups. Aryl groups may contain 6 to about 18 ring carbons, or in some embodiments 6 to 14 ring carbons, or even in other embodiments 6 to 10 ring carbons. Aryl groups also include heteroaryl groups, which are aromatic ring compounds containing 5 or more ring members in which one or more ring carbon atoms are replaced with heteroatoms, including but not limited to N, O, and S. Aryl groups may be substituted or unsubstituted. Aryl groups may be substituted with groups such as those described above for alkyl. Representative substituted aryl groups may be mono-substituted or may be substituted multiple times, such as mono-, di-, or tri-substituted, but are not limited to these. Aryl groups include, but are not limited to, phenyl, biphenylenyl, triphenylenyl, naphthyl, anthryl, and pyrenyl groups. Aryloxy refers to -O-aryl. Arylthio refers to -S-aryl, where aryl is as defined herein. This term also encompasses oxidized forms of sulfur, such as -S(O)-aryl or -S(O)2-aryl. Heteroaryloxy refers to -O-heteroaryl. Heteroarylthio refers to -S-heteroaryl. This term also encompasses oxidized forms of sulfur, such as -S(O)-heteroaryl or -S(O)2-heteroaryl.

[0049] Suitable heterocyclyl groups include cyclic groups having atoms of at least two different elements as members of its ring, one or more of which is a heteroatom, including but not limited to N, O, or S. Heterocyclyl groups can 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 a heterocyclyl group can be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups can be substituted or unsubstituted. Heterocyclyl groups can be substituted with groups such as those described above for alkyl. Representative substituted heterocyclyl groups can be mono-substituted or multiply substituted, such as, but not limited to, mono-, di-, or tri-substituted. Exemplary heterocyclyl groups are 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, Heterocyclyloxy refers to -O-heterocyclyl. Heterocyclylthio refers to -S-heterocyclyl. The term also encompasses oxidized forms of sulfur, such as -S(O)-heterocyclyl or -S(O)2-heterocyclyl.

[0050] A polycyclic or polycyclyl group refers to two or more rings in which two or more carbons are common to two adjacent rings, where the rings are "fused rings" and when the rings are joined by one common carbon atom, a "spiro" ring system. Rings that are joined by non-adjacent atoms are "bridged" rings. Polycyclic groups can be substituted or unsubstituted. Polycyclic groups can be substituted with groups such as those described above for alkyl. Representative polycyclic groups can be substituted one or more times.

[0051] Halogen groups include F, Cl, Br, and I, nitro groups refer to -NO2, cyano groups refer to -CN, isocyano groups refer to -N≡C, and epoxy groups encompass structures in which an oxygen atom is directly attached to two adjacent or non-adjacent carbon atoms of a carbon chain or ring system, which is essentially a cyclic ether structure. Epoxides are cyclic ethers with a three atom ring.

[0052] An alkoxy group is a substituted or unsubstituted alkyl group, as defined above, single-bonded to oxygen. An alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times. An alkoxy group may be substituted with groups as described above for alkyl. 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.

[0053] Thiol refers to -SH. Thiocarbonyl refers to (=S). Sulfonyl refers to -SO2-halogen, -SO2-alkyl, -SO2-substituted alkyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclyl, and -SO2-substituted heterocyclyl. Sulfonylamino refers to -NR a SO2-alkyl, -NR a SO2-substituted alkyl, -NRa SO2-Cycloalkyl, -NR a SO2-substituted cycloalkyl, -NR a SO2-aryl, -NR a SO2-substituted aryl, -NR a SO2-Heteroaryl, -NR a SO2-substituted heteroaryl, -NR a SO2-heterocyclyl, -NR a SO2-substituted heterocyclyl, where each R a is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl.

[0054] Carboxyl refers to -COOH or a salt thereof. Carboxy ester refers to -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)β-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclyl, and -C(O)O-substituted heterocyclyl. (Carboxy ester)amino refers to -NR a -C(O)O-alkyl, -NR a -C(O)O-substituted alkyl, -NR a -C(O)O-aryl, -NR a -C(O)O-substituted aryl, -NR a -C(O)β-cycloalkyl, --NR a -C(O)O-substituted cycloalkyl, -NR a -C(O)O-heteroaryl, --NR a -C(O)O-substituted heteroaryl, -NR a -C(O)O-heterocyclyl and -NR a -C(O)O-substituted heterocyclyl, where R ais as described herein. (Carboxy ester)oxy refers to -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclyl, and -OC(O)O-substituted heterocyclyl. Oxo refers to (=O).

[0055] The terms "amine" and "amino" refer to derivatives of ammonia in which one or more hydrogen atoms are replaced by substituents including, but not limited to, alkyl, alkenyl, aryl, and heterocyclyl groups. In some embodiments, a substituted amino can include -NH-CO-R. A carbamate group refers to -O(C=O)NR1R2, where R1 and R2 are independently hydrogen, an aliphatic group, an aryl group, or a heterocyclyl group.

[0056] Aminocarbonyl is -C(O)N(R b )2, where each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. b Both R b may optionally be taken together with the nitrogen attached thereto to form a heterocyclyl or substituted heterocyclyl group, provided that both are not hydrogen. Aminocarbonylalkyl refers to -alkylC(O)N(R b )2, where each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. b Both R bmay optionally be taken together with the nitrogen attached thereto to form a heterocyclyl or substituted heterocyclyl group, provided that both are not hydrogen. a C(O)N(R b )2, except that R a and each R b is as defined herein. Aminodicarbonylamino means -NR a C(O)C(O)N(R b )2, except that R a and each R b is as defined herein. Aminocarbonyloxy refers to -OC(O)N(R b )2, where each R b are independently as defined herein. Aminosulfonyl refers to -SON(R b )2, where each R b are independently as defined herein.

[0057] Imino is -N=R c However, R c may be selected from hydrogen, aminocarbonylalkyloxy, substituted aminocarbonylalkyloxy, aminocarbonylalkylamino, and substituted aminocarbonylalkylamino.

[0058] Pharmaceutically acceptable salts of the compounds described herein include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like. In other cases, the compounds described may contain one or more acidic functional groups, and thus can form pharma- ceutically acceptable salts with pharma-ceutically acceptable bases. These salts may likewise be prepared in situ during the administration vehicle or dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharma- ceutically acceptable metal cation, ammonia, or a pharma-ceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0059] "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 an enzymatic conversion. Prodrugs are often, but not necessarily, pharmacologically inactive or less active until converted to the active agent. "Promoiety" refers to a form of protecting group that, when used to mask a functional group in an active agent, converts the active agent into a prodrug. In some cases, the promoiety is 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 compound of interest can be prepared according to the strategies and methods described, for example, by Rautio et al. ("Prodrugs: design and clinical applications", Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0060] Unless an isotopically enriched atom (e.g., deuterium) is specifically recited, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, those in which a hydrogen atom is replaced by deuterium or tritium, 13 C- or 14 C-enriched carbon atoms are substituted, fluorine atoms are 19 Compounds having the present structures, including those replaced with F-enriched fluorine atoms, are within the scope of this disclosure.

[0061] Disclosed herein are compounds of formula (I) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof: TIFF2025512777000012.tif56128

[0062] For some embodiments, A, W, and G are independently nitrogen, CR3, CR4, or CR5.

[0063] For some embodiments, Y is N or CR1.

[0064] For some embodiments, R1, R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0065] Also disclosed herein are compounds of formula (II) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000013.tif56128

[0066] For some embodiments, Y is N or CR1.

[0067] For some embodiments, R1, R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0068] Also disclosed herein are compounds of formula (II) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000014.tif44128

[0069] For some embodiments, R1 and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0070] Also disclosed herein is a compound of formula (IV) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000015.tif53128

[0071] For some embodiments, R1 and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0072] Also disclosed herein are compounds of formula (V) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000016.tif43128

[0073] For some embodiments, R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0074] Also disclosed herein is a compound of formula (VI) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000017.tif33128

[0075] For some embodiments, R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0076] Also disclosed herein is a compound of formula (VII) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000018.tif39128

[0077] For some embodiments, R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0078] Also disclosed herein is a compound of formula (VIII) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000019.tif43128

[0079] For some embodiments, R1 and R2 are selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0080] Also disclosed herein are compounds of formula (IX) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000020.tif28128

[0081] For some embodiments, R1 and R3 are selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0082] For certain embodiments, R2 is selected from hydrogen and halogen.

[0083] Also disclosed herein are compounds of formula (X) or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF2025512777000021.tif37128

[0084] For some embodiments, R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0085] In some embodiments, the compounds described herein are agonists, partial agonists, or antagonists of the adrenoceptor. 1A In some embodiments, the compound is an α-adrenergic receptor agonist. 1A In some embodiments, the compound is an α-adrenergic receptor partial agonist. 1A -It is an adrenergic receptor antagonist.

[0086] Further disclosed herein is a method of treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound described herein, i.e., a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula IX), or Formula (X). In some embodiments, the disease is an adrenergic receptor-associated disease. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the subject is a human.

[0087] In some embodiments, the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedreich's ataxia, ataxia-telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject by 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.

[0088] In some embodiments, the disease is 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-Corsa syndrome), and Cough syndrome, alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (CJD, etc.), 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). In some embodiments, the disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia, Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (well-established dementia), or a combination of these. The neurodegenerative disease is one or more selected from the group consisting of: Nicke-Korsakoff syndrome, alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not suffer from Alzheimer's disease (AD). In some embodiments, the subject does not suffer from Down's syndrome.

[0089] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both 1) therapeutic procedures or measures that cure, delay, alleviate symptoms, and / or halt the progression of a diagnosed condition, disease, or disorder, and 2) prophylactic / preventative measures. Those in need of treatment can include individuals who already have a particular illness or medical disorder as well as those who may eventually suffer from the disorder (i.e., those at risk or in need of preventative measures).

[0090] As used herein, the term "subject" refers to any individual or patient upon whom the subject method is performed. Generally, the subject is a human, but as will be appreciated by those of skill in the art, the subject may also be an animal.

[0091] The terms "therapeutically effective amount", "effective dose", "therapeutically effective dose", or "effective amount", and the like, refer to an amount of a compound of interest that induces a desired biological or medical response in a tissue, system, animal, or human by administration of the compound. Generally, the response is either an improvement in a patient's condition or a desired biological outcome. In some embodiments, such an amount should be sufficient to modulate adrenergic receptors.

[0092] In some embodiments, an effective amount of an adrenergic receptor modulating compound is from about 50 ng / ml to 50 pg / ml (e.g., from about 50 ng / ml to 40 pg / ml, from about 30 ng / ml to 20 pg / ml, from about 50 ng / ml to 10 μg / ml, from about 50 ng / ml to 1 μg / ml, from about 50 ng / ml to 800 ng / ml, from about 50 ng / ml to 700 ng / ml, from about 50 ng / ml to 600 ng / ml, from about 50 ng / ml to 500 ng / ml, from about 50 ng / ml to 400 ng / ml, from about 60 ng / ml to 400ng / ml, about 70ng / ml to 300ng / ml, about 60ng / ml to 100ng / ml, about 65ng / ml to 85ng / ml, about 70ng / ml to 90ng / ml, about 200ng / ml to 900ng / ml, about 200ng / ml to 800ng / ml, about 200ng / ml to 700ng / ml, about 200ng / ml to 600ng / ml, about 200ng / ml to 500ng / ml, about 200ng / ml to 400ng / ml, or about 200ng / ml to about 70ng / ml).

[0093] In some embodiments, an effective amount of an adrenergic receptor modulating compound is from about 10 pg to 100 mg, e.g., from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1 ng, from about 1 ng to 10 ng, from about 10 ng to 50 ng, from about 50 ng to 150 ng, from about 150 ng to 250 ng, about 250ng to 500ng, about 500ng to 750ng, about 750ng to 1mg, about 1pg to 10pg, about 10pg to 50pg, about 50pg to 150pg, about 150pg to 250pg, about 250pg to 500pg, about 500pg to 750pg, about 750pg to 1mg, about 1mg to 50mg, about 1mg to 100mg, or about 50mg to 100mg. The amount may be a single dose or a total amount per day. The total amount per day may be in the range of about 10pg to 100mg, about 100mg to 500mg, or about 500mg to 1000mg.

[0094] Also disclosed herein are pharmaceutical compositions comprising a compound described herein, i.e., a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula IX), or Formula (X), and a pharma- ceutically acceptable excipient.

[0095] The term "pharmaceutical acceptable carrier" refers to a non-toxic carrier that can be administered to a patient together with the compound of this disclosure and does not destroy its pharmacological activity. Pharmaceutically acceptable carriers that can be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0096] In pharmaceutical compositions containing only the compounds described herein as active ingredients, the method for administering these compositions may further include administering additional agents or additional therapies to the subject. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production, hormones and antagonists, drugs that affect gastrointestinal function, chemotherapy for microbial diseases, and / or chemotherapy for neoplastic diseases. Other pharmacological therapies may include any other drug or biologic found in any drug class. For example, other drug classes may include allergy / cold / ENT therapy, painkillers, anesthetics, anti-inflammatory agents, antibacterial agents, antiviral agents, asthma / pulmonary therapy, cardiovascular therapy, dermatology therapy, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunotherapy, neurotherapy, ophthalmology therapy, psychiatric therapy, or rheumatology therapy. Other examples of agents or therapies that can be administered with the compounds described herein include matrix metalloprotease inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

[0097] The term "therapeutically effective amount" as used herein refers to an amount of an active compound or pharmaceutical agent that elicits a biological or pharmacological response in a tissue, system, animal, individual or human that is desired by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of: (1) preventing a disease, e.g., preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but has not yet experienced or exhibited the pathology or symptomology of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, condition or disorder (i.e., halting further development of the pathology and / or symptomology); and (3) ameliorating a disease, e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomology).

[0098] In some embodiments, the compounds described herein can be adrenergic receptor modulating compounds (e.g., adrenergic receptor agonists, partial agonists, or antagonists). The adrenergic receptor modulating compounds of the present disclosure can be useful in some embodiments for modulating the activity of a target adrenergic receptor in vitro or in vivo. Aspects of the subject methods include contacting a sample with an effective amount of an adrenergic receptor modulating compound (e.g., as described herein) to determine whether a desired activity is present.

[0099] Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the body and play an important role in the control of multiple physiological processes, including cognition, stress-related behavior, inflammation, smooth muscle contraction / dilation, myocardial contraction, airway reactivity, and cognition. Adrenergic receptors mediate the central and peripheral effects of noradrenaline (NA) and adrenaline. There are multiple subtypes of ADRs, including α-adrenergic receptors and β-adrenergic receptors. Each subtype is expressed in a different pattern and is involved in different physiological processes. Thus, ligands that selectively target one of the subtypes are highly useful both as research tools to identify the role of different ADR subtypes and as therapeutic agents for multiple diseases associated with dysfunction of NA and the adrenergic system.

[0100] α-adrenergic receptors are 1A -Adrenergic receptors (α 1A -ADR), α 1B -Adrenergic receptors (α 1B -ADR), and α 1D -Adrenergic receptors (α 1DThe α-adrenergic receptor further comprises three subtypes: α-adrenergic receptor (ALR), ...

[0101] As a class of G protein-coupled receptors, adrenergic receptors transmit signals through G protein and arrestin-dependent pathways. G protein or arrestin signaling can mediate different physiological responses. Recently, it has been found 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 called "signaling bias" or "functional selectivity." Because G proteins and arrestins mediate different physiological processes, biased agonists can provide improved therapeutic selectivity with reduced side effects. Thus, the present disclosure relates to adrenergic receptor subtype-selective agonists with improved blood-brain barrier (BBB) ​​permeability.

[0102] The adrenergic receptor modulating compound can be an agonist of the target adrenergic receptor. In some cases, an effective amount of an adrenergic receptor modulating compound is an amount sufficient to activate the activity associated with the adrenergic receptor in a cell by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, or 200% or more, compared to a control, e.g., a control cell exhibiting a known level of activity of the receptor.

[0103] Adrenergic receptor modulating compound can be a partial agonist of target adrenergic receptor.In some cases, the effective amount of adrenergic receptor modulating compound is sufficient to achieve partial agonism of adrenergic receptor in cell, for example, the compound of interest achieves 10% or more activation of receptor, for example 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more activation compared to control, for example, fully activated receptor.Partial agonism can be evaluated by any convenient method, such as cell-based assay using a known full agonist as a control of 100% activation, where the relative maximum activation of receptor can be measured compared to full agonist.

[0104] The adrenergic receptor modulating compound can be an antagonist of the target adrenergic receptor. In some cases, an effective amount of an 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 more, compared to a control, e.g., a sample not contacted with the compound of interest.

[0105] In some embodiments of the method, the target adrenergic receptor is α 1A -Adrenergic receptors.

[0106] The target adrenergic receptor may be one responsible for mediating an intracellular signal or pathway in the cell. In some embodiments, the sample comprises a cell, and modulation of the adrenergic receptor modulates a physiological process in the cell. Any convenient physiological process may be targeted for modulation in the cell using the methods of interest. In some embodiments, the physiological process is a process involved in cardiac function, and in certain cases, the physiological process is a process involved in cognitive function. In certain cases, the physiological process is a process involved in an inflammatory pathway or condition. The methods of interest may provide for mediation of intracellular concentrations of signaling molecules, such as cAMP, in the cell. The methods of interest may provide partial or complete blocking of the target adrenergic receptor to result in modulation (e.g., activation) of cAMP in the sample. In some embodiments, the methods do not modulate the β-arrestin pathway of the cell. In some cases, the cell is an inflammatory cell, and the function of the cell is controlled. The methods of interest may provide for inhibition of an inflammatory pathway in the cell. In some cases, TNF-α is inhibited in the cell, for example, the concentration or production of TNF-α is reduced by performing the methods of interest. In certain embodiments of the method, the cell is a neuron. In some embodiments, modulation of adrenergic receptors enhances neurogenesis.

[0107] The compounds of this disclosure may be used in a conventional manner to control, prevent, or treat the diseases described herein, including but not limited to myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedreich's ataxia, ataxia telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis, cerebral autosomal dominant arteriopathy with subcortical infarction (CADASIL), and diabetic retinopathy. Such treatment methods, their dosage levels and requirements can be selected by one skilled in the art from available methods and techniques.

[0108] Some aspects and embodiments of the present disclosure provide a method for treating rheumatoid arthritis using relatively low doses of α 1A -AR partial agonist α 1A Based at least in part on the discovery that partial agonism of the -AR receptor can increase cardiac output by improving venous return and myocardial contractility without increasing arteriolar vascular resistance, thereby increasing blood flow to various parts of the body, including the brain. Accordingly, the present invention provides a method for identifying a patient with nOH, or a disease or disorder associated with low cerebral blood flow (CBF) and / or CBF fluctuations, and administering to the patient an α-AR receptor agonist. 1A and administering an -AR partial agonist to the subject.

[0109] While not wishing to be bound by any particular theory in this regard, 1A α-AR receptors are found primarily on venous vascular branches and ventricular myocytes. 1AActivation of the α1-AR receptor activates the smooth muscle of the venous vasculature branches, reducing venous volume and promoting the return of blood to supply the heart, and also activates the myocardial cells, increasing pumping action, making it a cardiac agent with a physiological inotropic effect. With an increase in venous return, the preload increases, so the filling volume of the heart rises, and the inotropic effect enhances the ejection function, and both combine to increase the volume of the stroke into the arteries. However, unlike the indirect sympathomimetic droxidopa / norterra, or the nonselective α1-AR agonist midodrine, it does not have a physiological inotropic effect. 1A In certain embodiments, the -AR partial agonist inhibits the activation of arteriolar smooth muscle (mainly α 1B -AR and α 1D -AR function) is preserved, and therefore peripheral vascular resistance is not significantly increased (no increase in "afterload"). Therefore, the increase in BP (especially in the supine position) is not very strong, and the increased cardiac output allows organs, including the brain, to be easily perfused.

[0110] Accordingly, the present disclosure includes methods and compositions for treating diseases, disorders or conditions associated with or caused by impairment (or relative reduction) of one or both of (a) cardiac output and (b) venous return.

[0111] In certain aspects and embodiments of the present disclosure, the compositions and methods result in improved cognition, increased brain metabolic activity, and / or improved inflammation control in patients. In some embodiments, the methods described herein result in improved cognition in patients, as demonstrated, for example, by improvements in cognitive tests or models, memory tests, mental status, brain function, diagnostic indicators of psychiatric symptoms, contextual learning tests, and the like. Such cognitive tests, diagnoses, and models are well known in the art. In various aspects and embodiments, any of a number of accepted contextual learning tests for animals or humans can be used to assess baseline cognitive function and / or measure or quantify improvement in cognitive function. In some embodiments, the compositions and methods described herein can result in improvements in one or more of the following tests, diagnoses, and models. Similarly, for increased brain metabolic activity and improved inflammation control, these can be imaged in certain embodiments by FDG-PET and sampling of cerebrospinal fluid (CSF), which allows for the measurement of markers of inflammatory cytokines and glial cell activation.

[0112] Orthostatic hypotension (OH), also known as postural hypotension, is a form of low blood pressure that occurs when a person stands up. In medical terms, OH is defined as a drop in systolic blood pressure of at least 20 or 30 mmHg, or diastolic blood pressure of at least 10 mmHg, within 3 minutes of changing posture from supine to upright (Neurology 1996; 46:1470). OH can produce a variety of symptoms, including dizziness, lightheadedness and fainting (syncope), as well as discomfort in the upper chest and shoulder area ("coat hanger" pain). Due to these symptoms, OH often inhibits and thus interferes with daily activities that require standing or walking. In addition, OH is associated with increased morbidity and mortality. See, e.g., Jones et al, Expert Review of Cardiovascular Therapy, 2015; 13:11, 1263-1276; Kuritzky et al., Postgrad. Med. 2015; 127(7):702-715; and Low et al, J. Clin. Neurol., 2015; 11(3):220-226.

[0113] The underlying causes of OH can be broadly divided into neurogenic and non-neurogenic categories. Neurogenic orthostatic hypotension (nOH) is a form of OH involving the nervous system, e.g., OH induced by peripheral or central nervous disorders such as primary autonomic failure (pure autonomic failure, multiple system atrophy, and Parkinson's disease) and autonomic neuropathy (dysautonomia) (including diabetes and non-diabetic autonomic neuropathy) (Arbique et al., JAMDA 15 (2014) 234-239). Such disorders can cause a deficiency or dysregulation of norepinephrine, the main neurotransmitter that regulates blood pressure in response to postural changes (Loavenbruck et al, Curr. Med. Res. Opin., 2015; 31:2095-2104). As a result, the autonomic nervous system is unable to adequately regulate blood pressure during postural changes and the patient experiences a significant drop in blood pressure resulting in, for example, dizziness, lightheadedness, or fainting.

[0114] Thus, management of nOH symptoms most fundamentally requires increasing cerebral blood flow (CBF) in conjunction with a reduction in otherwise pathological blood pressure during a patient's supine to standing posture change. In various aspects and embodiments of the compositions and methods provided herein, an α1A-AR partial agonist is administered to a patient with nOH, and the action of the partial agonist reduces the frequency and severity of associated signs and symptoms of nOH, including lightheadedness / dizziness, prefainting symptoms, fainting / loss of consciousness, and "coat hanger pain." By maintaining better CBF, in some embodiments, improved cognitive function is also maintained, especially in patients prone to the "fluctuations" common in synucleinopathic symptoms often typically associated with nOH. For a description of symptoms / tests / screening and some treatments for nOH, see Eschlbock et al, J Neural Tansm,(2017) 124:1567-1605 and Gibbons et al, J Neurol,(2017) 264:1567-1582.

[0115] As used herein, the terms "co-administration," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the described compounds may be administered simultaneously or sequentially with another therapeutic agent, in separate unit dosage forms or in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form that includes the described compounds, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "in combination" when a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "in combination" when a patient or individual simultaneously exhibits therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in the brain, in serum, etc.).

[0116] When the compounds of this disclosure are administered in combination therapy with other agents, they may be administered sequentially or simultaneously to a patient. Alternatively, a pharmaceutical or prophylactic composition according to this disclosure includes a combination of ivermectin, or any other compound described herein, with another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0117] In some embodiments, the subject method comprises administering a therapeutically effective amount of one or more additional active agents.By combination therapy, it is meant that the adrenergic receptor modulating compound can be used in combination with another therapeutic agent to treat a single disease or condition.In certain embodiments, the compound of the present disclosure is administered simultaneously with the administration of another therapeutic agent, which can be administered as a component of a composition that includes the compound of the present disclosure or as a component of a different composition.

[0118] The compounds of interest may be administered in combination with other therapeutic agents in a variety of therapeutic applications. Therapeutic applications of interest for combination therapy include those in which the activity of the target adrenergic receptor is a cause or exacerbator of disease progression. Thus, the compounds of interest are useful in combination therapy in which inhibition of the target adrenergic receptor in a subject is desirable. Examples of conditions that may be treated by combination therapy with the compounds of interest include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental diseases, respiratory disorders, asthma, memory disorders, depression, inflammatory diseases, stroke, ischemic brain or tissue damage, and cancer. Agents of interest that may be used with the compounds of interest that modulate the adrenergic receptor 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.

[0119] The subject adrenergic receptor modulating compounds can be used with any agent that is useful in treating cardiac conditions such as cardiogenic shock, hypertension, congestive heart failure, coronary heart disease, arrhythmias, myocardial infarction or ischemic heart disease, etc. Agents of interest that can be used with the subject adrenergic receptor modulating compounds include, but are not limited to, denopamine, dobutamine, xamoterol, acebutolol, atenolol, betaxolol, bisoprolol, pindolol, esmolol, metoprolol, nebivolol, vortioxetine, carvedilol, labetalol, phentolamine, prazosin, cirazoline, methoxamine, synephrine, etilefrine, metaraminol, midrine, and coumarin.

[0120] The adrenoceptor modulating compound of interest can be used with any agent that is useful for treating neurodegenerative or neurodevelopmental diseases, such as Alzheimer's disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue injury, Down's syndrome, or autism. Agents of interest that can be used with the adrenoceptor modulating compound of interest include, but are not limited to, acepromazine. In some embodiments, the adrenoceptor modulating compound of interest can be used in combination with a cholinesterase inhibitor or an NMDA receptor modulating agent to treat diseases, such as neurodegenerative or neurodevelopmental diseases. Agents of interest include, but are not limited to, donepezil, aricept, galantamine, razadyne, memantine, namenda, rivastigmine, exelon, tacrine, and cognex. Other agents of interest that may be used in conjunction with the adrenergic receptor modulating compounds of interest include 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tiamenidine, tizanidine, tolonidine, and xylanidine. These include, but are not limited to, azithromycin, xylometazoline, aripiprazole, asenapine, atipamezole, cirazoline, clozapine, efaroxan, idazoxan, lurasidone, melperone, mianserin, mirtazapine, napitan, olanzapine, paliperidone, phenoxybenzamine, phentolamine, piribedil, rauwolscine, risperidone, rotigotine, quetiapine, norquetiapine, setiptiline, tolazoline, yohimbine, ziprasidone and zotepine.Other agents of interest that may be used in conjunction with the subject adrenergic receptor modulating compounds include, but are not limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levosalbutamol or levalbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol, salbutamol or albuterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, mirveterol, olodaterol, vilanterol, fenoterol, hexoprenaline, isoxsuprine, ritodrine, salbutamol or albuterol, terbutaline, zilpaterol, ICI-118, 551, and butoxamine.

[0121] The compounds utilized in the compositions and methods of the present disclosure may be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include those that enhance biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), enhance oral availability, enhance solubility to allow administration by injection, alter metabolism, and / or alter excretion rate.

[0122] 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 being. Such pharmaceutical compositions are used to ameliorate, treat or prevent any of the diseases described herein in the subject.

[0123] The agents of the present disclosure are often administered as pharmaceutical compositions containing an active therapeutic agent and various other pharma- ceutically acceptable ingredients. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application. Depending on the desired formulation, the composition may contain pharma- ceutically acceptable non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, and the like.

[0124] In some embodiments, the present disclosure provides pharma- ceutically acceptable compositions comprising a therapeutically effective amount of one or more of the described compounds formulated with one or more pharma- ceutically acceptable carriers (additives) and / or diluents for use in the treatment of diseases described herein, including but not limited to stroke, ischemia, Alzheimer's disease, ankylosing spondylitis, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, systemic lupus erythematosus, nephritis, ulcerative colitis, and Parkinson's disease. Although it is possible to administer the described compounds alone, it is preferred to administer the described compounds as a pharmaceutical formulation (composition) as described herein. The described compounds may be formulated for administration in any convenient manner for use in human or veterinary medicine, by analogy with other pharmaceuticals.

[0125] As described in detail, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid forms, including forms adapted for oral administration, such as, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue, etc., for buccal, sublingual and systemic absorption; parenteral administration, for example, by sterile solutions or suspensions, or subcutaneous, intramuscular, intravenous or epidural injection as sustained release formulations; topical application, for example, as creams, ointments, or controlled release patches or sprays applied to the skin, lungs, or oral cavity; vaginal or rectal administration, for example, as pessaries, creams or foams; sublingual administration; ocular administration; transdermal administration; or administration to the nasal, pulmonary, and other mucosal surfaces.

[0126] Wetting agents, emulsifying agents, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0127] Examples of pharma- ceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0128] Formulations for use according to the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient. In some embodiments, this amount will range from about 5% to about 70%, about 10% to about 50%, or about 20% to about 40%.

[0129] In certain embodiments, the formulations described herein comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides, and a compound of the present disclosure. In certain embodiments, the formulations render the compounds of the present disclosure orally bioavailable.

[0130] The method of preparing a formulation or composition containing the described compound includes the step of bringing the disclosed compound into association with the carrier and, optionally, one or more accessory ingredients. In general, the formulations can be prepared by uniformly and intimately bringing the disclosed compound into association with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0131] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may be, for example, a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any smooth fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may contain long chain alcohol diluents or dispersants, such as those described in the Pharmacopeia Helvetica, or similar alcohols. For formulation purposes, other commonly used surfactants may also be used, such as Tweens, Spans and other emulsifiers or bioavailability enhancers that are commonly used in the manufacture of pharma- ceutically acceptable solid, liquid, or other dosage forms.

[0132] In some cases, it may be desirable to delay the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous substances that are poorly water-soluble.The absorption rate of drugs then depends on their dissolution rate, which in turn depends on the size and crystalline system of the crystals.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drugs in oil vehicles.

[0133] Injectable depot forms are made by forming microencapsule matrices of the compounds of the present disclosure in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0134] The pharmaceutical composition of the present disclosure may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. For oral administration of aqueous suspensions and solutions, and propylene glycol, the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweetening and / or flavoring and / or coloring agents may be added.

[0135] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc. The compounds described herein may also be administered as a bolus, electuary, or paste.

[0136] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be mixed with sodium citrate or dicalcium phosphate and / or with fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid, binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, wetting agents, such as glycerol, disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, humectants, such as glycerol, disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, gelatin, polyvinylpyrrolidone, sucrose, gelatin, polyvinylpyrrolidone, sucrose, gelatin, polyvinylpyrrolidone, alginates ... Mix with one or more pharma- ceutically acceptable carriers, such as any of the following: glyceryl stearate, certain silicates, and sodium carbonate, solution retarders, such as paraffin, absorption enhancers, such as quaternary ammonium compounds, wetting agents, such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, absorbents, such as kaolin and bentonite clay, lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and coloring agents.In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents.Similar types of solid compositions may also be used as fillers in soft and hard shell gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0137] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made in a suitable machine by moistening a mixture of powdered compounds with an inert liquid diluent. When a solid carrier is used, the preparation can be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier varies, for example, from about 25 to 800 mg, preferably from about 25 mg to 400 mg. When a liquid carrier is used, the preparation can be in the form of a sterile injectable liquid, such as, for example, a syrup, emulsion, soft gelatin capsule, ampoule, or non-aqueous liquid suspension. When the composition is in the form of a capsule, any of the usual encapsulation methods are suitable, for example, by using the aforementioned carriers in a hard gelatin capsule shell.

[0138] Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They can alternatively or additionally be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various percentages of hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres to provide the desired release profile. They can be formulated for rapid release, for example, lyophilized. They can be sterilized, for example, by filtration through a bacterial retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or any other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can optionally be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0139] The liquid dosage form for oral administration of the compounds of the present disclosure includes pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0140] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0141] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and the like, and mixtures thereof.

[0142] The pharmaceutical composition of the present disclosure may also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present disclosure with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0143] Topical administration of the pharmaceutical composition of the present disclosure is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated into a suitable ointment containing the active component suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present disclosure may also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present disclosure.

[0144] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0145] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0146] Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present disclosure to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0147] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0148] 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, phenol sorbic acid, and the like. Alternatively or additionally, it may be desirable to include isotonic agents in the composition, such as sugars, sodium chloride, and the like. In addition, prolonged absorption of the injectable pharmaceutical form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0149] In certain embodiments, the described compounds or pharmaceutical preparations are administered orally. In other embodiments, the described compounds or pharmaceutical preparations are administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0150] When the compounds described herein are administered to humans and animals as pharmaceuticals, they may be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0151] The preparations described herein may be given orally, parenterally, topically, or rectally. They are, of course, given in a form suitable for the relevant route of administration. For example, they are given in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc. (administration by injection, infusion or inhalation, topical administration by lotion or ointment, and rectal administration by suppositories). Oral administration is preferred.

[0152] Such compounds may be administered to humans and other animals for treatment by any suitable route of administration, including, for example, orally by spray, nasally, rectally by powders, ointments, or drops, intravaginally, parenterally, intracisternally, and topically (including buccal and sublingual).

[0153] Regardless of the route of administration selected, the compounds described herein, which may be used in a suitable hydrated form, and / or pharmaceutical compositions of the disclosure, are formulated into pharma- ceutical acceptable dosage forms by conventional methods known to those of skill in the art.

[0154] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0155] Kits are also provided that include the disclosed adrenergic receptor modulating compounds. The disclosed systems include a collection of active agents assembled for administration to a subject, such as a patient, for example, by a medical professional. Such systems may include the adrenergic receptor modulating compounds disclosed herein and one or more additional active agents. Kits are provided that include the adrenergic receptor modulating compounds, which may include one or more doses of the adrenergic receptor modulating compounds, and optionally one or more doses of one or more additional active agents. Conveniently, the formulations may be provided in unit dosage form. In such kits, in addition to the container containing the formulation(s), e.g., the unit dose, there is an information package insert that describes the use of the subject formulation in the methods as disclosed herein, e.g., instructions for using the subject unit dose to treat a cell proliferative condition. These instructions may be present in the subject systems and kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is as information printed on a suitable medium or substrate, such as a sheet or sheets of paper upon which the information is printed, kit packaging, a package insert, etc. Another means is a computer readable medium on which the information has been recorded, such as a diskette, CD, etc. Yet another means that may be present is a website address that may be used to access the information at a remote site via the Internet. Any convenient means may be present in the kit.

[0156] The following examples are provided to further illustrate the advantages and features of the present disclosure, but are not intended to limit the scope of the present disclosure. The examples are representative of those that may be used, but other procedures, methodologies, or techniques known to those skilled in the art may be used instead. Table 1 below shows exemplary compounds of the present disclosure that have been synthesized.

[0157] Table 1: Exemplary compounds TIFF2025512777000022.tif185128TIFF2025512777000023.tif179128TIFF2025512 777000024.tif179128TIFF2025512777000025.tif179128TIFF2025512777000026.t if179128TIFF2025512777000027.tif179128TIFF2025512777000028.tif179128TIF F2025512777000029.tif179128TIFF2025512777000030.tif179128TIFF20255127770 00031.tif179128TIFF2025512777000032.tif179128TIFF2025512777000033.tif17 9128TIFF2025512777000034.tif179128TIFF2025512777000035.tif179128TIFF202 5512777000036.tif179128TIFF2025512777000037.tif179128TIFF20255127770000 38.tif179128TIFF2025512777000039.tif179128TIFF2025512777000040.tif224117 EXAMPLES

[0158] Example 1 Scheme 1: Preparation of Compound 2 Example I TIFF2025512777000041.tif61135

[0159] To a solution of 3-bromo-2-chloronitrobenzene (A-1) (20 g, 104.5 mmol) in THF (1000 mL) was added vinylmagnesium bromide (418 mL, 418 mmol, 1 M in THF) at -40 °C, and the mixture was stirred at -40 °C for 1 h. TLC (petroleum ether / ethyl acetate = 3 / 1) showed that the starting material was consumed and three new spots were generated. The mixture was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (2 × 300 mL). The combined organics were dried over Na2SO4, filtered, and evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (eluted with petroleum ether / ethyl acetate = 50 / 1) to give indole A-2 (3.6 g, 15% yield) as a light brown solid. 1 H NMR (400MHz, CDCl3-d) δ8.50(br s, 1H), 7.33(t, J=2.76Hz, 1H), 7.24(d, J=8.2Hz, 1H), 7.08(d, J=8.2Hz, 1H), 6.65(t, J=2.8Hz, 1H).

[0160] To a solution of indole A-2 (1 g, 4.34 mmol) and HO (5 mL) in dioxane (20 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.1 g, 6.51 mmol), Pd(PPh3)4 (0.50 g, 0.043 mmol), Na2CO3 (0.9 g, 8.68 g), and the mixture was stirred at 100 °C under N2 atmosphere for 3 h. TLC showed that the starting material was consumed and a new spot was formed. After cooling to 20 °C, the reaction mixture was eluted with EtOAc (100 mL), washed with saturated brine (50 mL), the EtOAc layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (silica, eluted with petroleum ether / ethyl acetate=50 / 1 to 10 / 1) to give isopropenylindole A-3 (0.6 g, 72% yield) as a pale red oil. 1H NMR (400MHz, CDCl3-d) δ8.42(br s, 1H), 7.24-7.29(m, 1H), 7.18(d, J=7.9Hz, 1H), 7.03(d, J=7.9Hz, 1H), 6.78( dd, J=3.1, 2.2Hz, 1H), 5.39(s, 1H), 5.32(d, J=1.32Hz, 1H), 2.21-2.31(m, 3H).

[0161] A mixture of isopropenylindole A-3 (500 mg, 2.61 mmol) and Rh / Al2O3 (500 mg) in MeOH (30 mL) was stirred under H2 atmosphere (15 psi) at 25 °C. After 12 h, TLC (petroleum ether / EtOAc = 6 / 1) showed that the starting material was consumed and a new spot was detected. The reaction mixture was filtered and concentrated under reduced pressure to give isopropylindole A-4 (400 mg, 79% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ8.38(br s, 1H), 7.27(s, 1H), 7.16(d, J=7.9Hz, 1H), 6.94(d, J=7.9Hz, 1H), 6.68(t, J=2.7Hz, 1H), 3.27-3.41(m, 1H), 1.38(d, J=6.8Hz, 6H).

[0162] To a solution of isopropyl indole A-4 (0.5 g, 2.6 mmol) in DMF (10 mL) at 0 °C was added t-BuOK (440 mg, 3.9 mmol). After 20 min, a solution of 2-bromoacetonitrile (630 mg, 5.2 mol) in DMF (2 mL) was added and the reaction mixture was warmed to 20 °C. After 2 h, TLC (petroleum ether / ethyl acetate = 5 / 1) showed that the starting material was consumed. The reaction was quenched with H2O (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. Purification by flash chromatography (silica, eluting with petroleum ether / ethyl acetate = 30 / 1 to 5 / 1) gave nitrile A-5 (0.4 g, 66% yield) as a pale yellow solid. 1H NMR (400MHz, CDCl3-d) δ7.19(d, J=7.9Hz, 1H), 7.08(d, J=3.3Hz, 1H), 6.97(d, J=7.9Hz, 1H), 6.69(d, J=3.5Hz, 1H), 5.49(s, 2H), 3.32(spt, J=7.0Hz, 1H), 1.35(d, J=6.8Hz, 6H).

[0163] To a solution of nitrile A-5 (200 mg, 0.86 mmol) in ethane-1,2-diamine (4 mL) was added CS2 (3.3 mg, 0.04 mmol) at 20° C., and then the reaction mixture was stirred at 120° C. for 2 h. TLC (petroleum ether / ethyl acetate=3 / 1) showed that the starting material was consumed. The reaction mixture was cooled at 20° C. and concentrated under reduced pressure, and then the residue was purified by Prep-HPLC (HCl buffer) and lyophilized to give compound 2 (63 mg, HCl salt, 24% yield) as a white solid. 1 H NMR (400MHz, MeOH-d4) δ7.29(d, J=3.3Hz, 1H), 7.16(d, J=7.9Hz, 1H), 6.97(d, J=8.0Hz, 1H), 6.76 (d, J=3.3Hz, 1H), 3.96(s, 4H), 5.67(s, 2H), 3.32-3.41(m, 1H), 1.34(d, J=6.9Hz, 6H), M+H=276.1.

[0164] Example 2 Scheme 2: Preparation of compound 17 TIFF2025512777000042.tif56138

[0165] To a solution of 7-chlorindole (B-1) (0.2 g, 1.3 mmol) in DMF (5 mL, 64.7 mmol) was added POCl3 (243 mg, 1.58 mmol) dropwise at 0 °C. The solution was stirred at 45 °C. After 2 h, TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.3) showed that the starting material was consumed and a new spot was detected. The solution was poured into aqueous NaOH solution (2 M, 5 mL), extracted with EtOAc (2 × 5 mL), saturated brine (2 × 5 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue. Purification by silica gel flash chromatography (petroleum ether / ethyl acetate = 5 / 1) gave indole B-2 (0.2 g, 84% yield) as a yellow liquid. 1 H NMR (400MHz, CDCl3-d) δ10.07(s, 1H), 8.99(br s, 1H), 8.22(dd, J=7.9, 0.9Hz, 1H), 7.90(s, 1H), 7.31-7.35(m, 1H), 7.23-7.26(m, 1H).

[0166] To a solution of indole B-2 (0.5 g, 2.78 mmol) in THF (10 mL) was added LiAlH4 (159 mg, 4.18 mmol) portionwise at 0 °C. The mixture was warmed to 20 °C. After 12 h, TLC (petroleum ether / ethyl acetate = 5 / 1, Rf = 0.4) showed that the starting material was consumed and a new spot was detected. The mixture was cooled to 0 °C and quenched by adding 1N HCl (10 mL). The mixture was extracted with EtOAc (3 × 10 mL). The combined organics were subsequently washed with saturated brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The same scale experiment was performed. Both batches were combined and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give indole B-3 (0.50 g, 54% yield) as a white solid. 1 H NMR (400MHz, CDCl3-d) δ8.11(br s, 1H), 7.49(d, J=7.9Hz, 1H), 7.20(d, J=7.5Hz, 1H), 7.01-7.10(m, 2H), 2.34(d, J=1.0Hz, 3H).

[0167] To a solution of indole B-3 (100.0 mg, 603.79 μmol) in DMF (1 mL) was added sodium hydride (48.30 mg, 1.21 mmol, 60% wt). The mixture was then stirred at 20 °C for 1 h. Bromoacetonitrile was added (144.85 mg, 1.21 mmol) and the mixture was stirred at 20 °C. After 12 h, TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.25) showed that most of the starting material had been consumed and a new spot was detected. Four equal-scale reactions were set up and run as described above. These reaction mixtures were combined, diluted with water (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organics were washed with saturated brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. Purification by flash chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1) gave nitrile B-4 (200 mg, 32% yield) as a white solid. 1 H NMR (400MHz, CDCl3-d) δ7.47(dd, J=7.9, 0.92Hz, 1H), 7.23(dd, J=7.6, 0.61Hz, 1H), 7.05-7.13(m, 1H), 6.85(d, J=0.9Hz, 1H), 5.42(s, 2H), 2.30(s, 3H).

[0168] To a solution of nitrile B-4 (100 mg, 488.6 μmol) in ethylenediamine (3 mL) was added one drop of carbon disulfide. The mixture was warmed to 60° C. After 2 h, LC-MS showed that the starting material was consumed and 90% product with the desired Ms (Rt=0.221) was detected. The reaction mixture was diluted with MeOH (3 mL) and filtered to obtain the residue. The same scale experiment was performed. Both batches were combined and the residue was purified by Prep-HPLC (HCl buffer) to give compound 17 (59.5 mg, 25% yield, HCl salt) as a white solid. 1H NMR (400MHz, MeOH-d4) δ7.51(d, J=7.87Hz, 1H), 7.19(d, J=7.51Hz, 1H), 7.05-7.11(m, 2H), 5.62(s, 2H), 3.96(s, 4H), 2.31(s, 3H)M+H=248.0.

[0169] Example 3 Scheme 3: Preparation of compound 21 TIFF2025512777000043.tif52128

[0170] 2-Chloro-6-fluorobenzaldehyde (C-1) was added to a 100 ml 3-neck RBF equipped with a stir bar and low temperature thermometer. The flask was flushed with nitrogen. After 5 min, 10 ml of THF was added, stirring was started, and the mixture was cooled in an ice / H2O bath. After 10 min, EtMgBr (1.0 M in THF) was added dropwise while maintaining the internal temperature at ≦10° C. The mixture was stirred for 30 min and then allowed to warm to room temperature over 1 h. The reaction mixture was cooled in an ice / H2O bath and then quenched by the addition of 25 ml of saturated NH4Cl and 50 ml of H2O. The mixture was extracted with 3×50 ml of EtOAc. The combined organics were washed with 50 ml of H2O followed by 50 ml of saturated brine. The solution was dried over Na2SO4, filtered, concentrated and purified by flash chromatography (silica, gradient: 1% to 10% EtOAc in hexanes) to give alcohol C-2 (1.181 g, 51%) as a clear oil. 1 H NMR (300MHz, CDCl3-d) δ7.22-7.12(m, 2H), 7.02-6.92(m, 1H), 5.11(dd, J=16.2, 6 .9Hz, 1H), 2.45(dd, J=9.8, 5.0Hz, 1H), 2.10-1.80(m, 2H), 0.97(t, J=7.7Hz, 3H).

[0171] A 100 ml 3-neck RBF equipped with a stir bar was capped with a septum and flushed with nitrogen. The flask was charged with 30 ml DCM followed by oxalyl chloride. The mixture was cooled to -78 °C in an acetone / dry ice bath. DMSO was added dropwise with gas evolution. After 10 min, a solution of alcohol C-2 in 10 ml DCM was added dropwise and the solution was stirred for 1 h. TEA was added and the reaction mixture was allowed to warm to room temperature for 1 h. TLC showed the reaction was complete (95:5 Hex / EtOAc). The reaction mixture was quenched by adding 50 ml H2O and extracted with 3 x 50 ml DCM. The combined organics were washed with 50 ml H2O followed by 50 ml saturated brine. The solution was dried over Na2SO4, filtered and concentrated to give 0.163 g of a crude oil. Purification by flash chromatography (silica, gradient: 1% to 5% EtOAc in hexanes over 10 column volumes) afforded ketone C-3 (0.830 g, 84% yield) as a clear oil. 1 H NMR (300MHz, CDCl3-d) δ7.30 (dd, J=8.4, 5.8, 1H), 7.21 (d, J=8.4Hz, 1H), 7.03 (dd, J=8.4Hz, 1H), 2.06 (q, J=7.8Hz, 2H), 1.21 (t, J=7.8Hz, 3H).

[0172] Ketone C-3 was added to a 50 ml RBF with a stir bar. The flask was flushed with nitrogen and equipped with a reflux condenser. The flask was charged with 8 ml DME, stirring was started, and 8 ml hydrazine hydrate was added dropwise. The stirred mixture was heated to reflux overnight. TLC shows a new spot (9:1 Hex / EtOAc). The reaction mixture was cooled and concentrated. 50 ml H2O was added and the mixture was extracted with 3 x 50 ml EtOAc. The combined organics were washed with 50 ml H2O followed by a saturated brine wash. The solution was dried over Na2SO4, filtered, and concentrated to give 1.094 g of crude oil. Purification by flash chromatography (silica, gradient: 4% to 40% EtOAc in hexanes over 10 column volumes) gave indazole C-4 (0.333 g, 41% yield) as a white solid. 1H NMR (300MHz, CDCl3-d) δ10.21(bs, 1H), 7.32(d, J=7.8Hz, 1H), 7.24(dd, J=8.1, 6.9 Hz, 1H), 7.10 (dd, J=8.1, 1.2Hz, 1H), 3.23 (q, J=7.8Hz, 2H), 1.42 (t, J=7.8Hz, 3H).

[0173] NaH (60% dispersion) was added to a 100 mL 2-neck flask equipped with a thermometer and stir bar. The flask was flushed with nitrogen for 10 min and 5 mL of DMF was added. Stirring was started and the mixture was cooled to 0 °C in an ice / H2O bath. Indazole C-4 was dissolved in 5 mL of DMF and added dropwise with evolution of H2. After 30 min, bromoacetonitrile was added dropwise. The internal temperature was maintained at ≦10 °C. The reaction mixture was allowed to warm to room temperature for 1 h. TLC showed a new spot (9:1 Hex / EtOAc). The reaction mixture was quenched by the addition of 50 mL of H2O. The mixture was extracted with 3×30 mL of 1:1 toluene / EtOAc. The combined organics were washed with 50 mL of H2O followed by 50 mL of saturated brine. The solution was dried over NaSO4, filtered, and concentrated to give 0.477 g of compound 20 as a pale orange solid. Purification by flash chromatography (silica, 1% to 10% EtOAc in hexanes) afforded nitrile C-5 (0.167 g, 66% yield) as a white solid. 1 H NMR (300MHz, CDCl3-d) δ7.37 (dd, J=7.2, 1.2Hz, 1H), 7.231 (t, J=7.2Hz, 1H), 7.18 (dd, J=6.9, 1.2Hz, 1H), 5.22(s, 2H), 3.19(q, J=7.5Hz, 2H), 1.40(t, J=7.5Hz, 3H).

[0174] A 100 mL round bottom flask equipped with a reflux condenser and equipped with a stir bar was charged with indazole C-5 and 3 mL of ethylenediamine. The flask was purged with nitrogen for 5 min, then one drop of carbon disulfide was carefully added. The mixture was warmed to 120° C. After 90 min, TLC showed the reaction was complete (60% 90 / 10 / 1 DCM / MeOH / NH4OH). The mixture was cooled, quenched with 50 mL of H2O, and extracted with 3×25 mL of EtOAc. The combined organics were washed with 50 mL of H2O and 50 mL of saturated brine. The solution was dried over Na2SO4, filtered, and concentrated to give an orange solid. Purification by flash chromatography (silica, gradient: 15 to 100% 90 / 10 / 1 DCM / MeOH / NH4OH in DCM over 10 CV, then 100 in 10 CV) gave 0.122 g of compound 21 (56% yield) as a white solid. 1 H NMR (300MHz, CDCl3-d) 7.33(dd, J=8.4, 1.2Hz), 7.26(t, overlap, J=6.9Hz, 1H), 7.12(dd, J=6.9, 1.2Hz, 1H ), 5.10(s, 2H), 3.58(s, 4H), 3.19q, J=7.8Hz, 2H), 1.3(t, J=7.8Hz, 3H); M+H=263.05.

[0175] Example 4 Evaluation of synthetic adrenergic receptor agonists

[0176] Calcium flux experimental design: α-1 adrenergic receptor (α1-AR) is a G q It binds to proteins that result in downstream activation of phospholipase C and release of calcium from intracellular stores. The increase in intracellular calcium upon α1-AR activation can be detected by calcium 6 dye.

[0177] Cell preparation: Cells expressing α1-AR were washed with warm phosphate-buffered saline to remove media and collected in Barthen's solution (Caisson Labs, catalog no. EDL01). Cells were centrifuged at 250xg for 5 min, resuspended in growth media, counted with a hemocytometer, and seeded into black clear-bottom 384-well plates (Corning, catalog no. 3764) at 10,000 cells per well in 30-50 μL of growth media and cultured overnight in a tissue culture incubator.

[0178] One vial of calcium 6 dye (Molecular Devices, Cat. No. R8190) was reconstituted in 10 mL of Hank's Balanced Salt Solution (HBSS, Corning, Cat. No. 45000-462) containing 20 mM HEPES (Caisson Labs, Cat. No. HOL06) according to the manufacturer's instructions and stored at -20°C. On the day of the assay, the reconstituted calcium 6 was diluted 1:8 with HBSS / HEPES containing 2 mM CaCl2 (VWR, Cat. No. E506) and 2 mM sodium salt of probenecid (AAT Bioquest, Cat. No. 20061) to make the cell dye solution. Media was removed from the cells by tapping the plate upside down on an absorbent wipe, then centrifuged again upside down on an absorbent wipe at 50xg for 15 seconds. 12 μL of cell dye solution was added to the cells by a reagent dispenser (Integra viaFILL) and the cells were incubated at 37° C., 5% CO 2 for 90 min.

[0179] Compound preparation: Candidate α-adrenergic compounds dissolved at 10 mM in DMSO were diluted in assay buffer (HBSS / HEPES containing 2 mM CaCl2 and 2 mM sodium salt of probenecid). Compound serial dilutions (10 concentrations, serially diluted in 5-fold increments) were prepared in assay buffer in 96-well plates (Corning 3365). Vehicle (DMSO) and positive control (10 μM epinephrine) conditions were included on every assay plate, as well as a dose-response curve for epinephrine. Completed 96-well compound plates were stamped into 384-well compound source plates (Corning 3657) at 50 μL per well with a viaFLO 384 or viaFLO 96 electronic pipette (Integra Biosciences) to create 4 technical replicate wells per dose. The 384-well compound plate was centrifuged briefly at 250xg, sealed (Axygen PCR-SP) and incubated at 37°C until the 90 minute cell dye incubation was completed.

[0180] Stimulation and quantification of calcium flux: A Flexstation 3 controlled by Softmax Pro software v7.0.3 (Molecular Devices) pre-loaded with FLIPR Tetra Pipette Tips (Molecular Devices, Cat. No. 9000-0763) was set to 37° C. for at least 1 hour prior to the assay. Calcium 6 stained cells and a 384-well compound plate were loaded into the Flexstation and incubated on the machine for 5 minutes prior to the start of the assay.

[0181] Calcium 6 fluorescence was detected with excitation at 485 nm and emission measurement at 525 nm with a cutoff of 515 nm. For each assay well, baseline calcium 6 fluorescence was detected for 18 seconds before addition of 12 μL of compound at 12 μL / sec. Calcium 6 fluorescence was detected for an additional 22 seconds, for a total read time of 40 seconds. All detections were performed with medium gain sensitivity, bottom read, 6 flashes per read.

[0182] Data Analysis: For calcium flux, the maximum change from baseline over a 40 second reading period was determined by Softmax Pro and data were exported as raw text files. Potency estimates (EC 50 ) were derived from dose-response curves (maximum change from baseline vs. log concentration of test compound) fitted by 4-parameter nonlinear regression with Graphpad Prism. Potency was determined by comparing the magnitude of the signal window (max-min of fitted curve) of the test compound to that of the full agonist control, epinephrine. All dose-response curves on a given plate were analyzed simultaneously to define a single common baseline value, and Hill slopes were constrained to >0 to avoid erroneous curve fitting from inactive compounds. All experiments were repeated a minimum of three times, and mean potency and maximum effect compared to the dose-response comparator of the full agonist within the plate were reported.

[0183] Efficacy data is presented in Table 2 below.

[0184] (Table 2)α 1A -AR efficacy data TIFF2025512777000044.tif20572TIFF2025512777000045.tif22072TIFF2025512777000046.tif76128 Average pEC 50 :A>8.01, B=8.00~6.01, C≦6.00 Average Emax: A>61%, B=21~60%, C≦20%

[0185] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compositions and procedures described herein which are considered to be within the scope of this disclosure and encompassed by the appended claims.

[0186] Although the invention has been described with reference to the presently preferred embodiments, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the scope of the appended claims.

Claims

1. Equation (I) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: During the ceremony, A, W, and G are independently nitrogen, CR ３ CR ４ , or CR ５ And, Y is N or CR １ and R １ , R ２ , R ３ , R ４ , R ５ , and R ６ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

2. Formula (II) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: During the ceremony, Y is N or CR １ and R １ , R ２ , R ３ , R ４ , R ５ , and R ６ The following are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

3. Formula (III) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: In the formula, R １ and R ２ The following are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

4. Formula (IV) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: In the formula, R １ and R ２ The following are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

5. Formula (V) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: In the formula, R １ , R ２ , and R ３ The following are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

6. Equation (VI) Compounds or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs of: In the formula, R １ This is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

7. Formula (VII) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: In the formula, R １ This is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

8. Formula (VIII) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: In the formula, R １ and R ２ This is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

9. Formula (IX) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: During the ceremony, R １ and R ３ This is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R2 is selected from the group consisting of hydrogen, deuterium, and halogens.

10. Formula (X) Compounds of or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: In the formula, R １ This is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted sulfonyl, 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 heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

11. A compound according to any one of claims 1 to 10, which is an adrenaline receptor agonist, partial agonist, or antagonist.

12. α １Ａ - A compound according to any one of claims 1 to 10, which is a partial agonist of an adrenaline receptor.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition for treating a subject having a disease, comprising a therapeutically effective amount of the compound according to any one of claims 1 to 10.

15. The pharmaceutical composition according to claim 14, wherein the subject has a disease related to adrenaline receptors.

16. The pharmaceutical composition according to claim 14, wherein the disease is a neurodegenerative disease.

17. The aforementioned diseases include MCI (mild cognitive impairment), aMCI (amnesic 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, and The pharmaceutical composition according to claim 16, which is one or more selected from the group consisting of thiamine deficiency, normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as Creutzfeldt-Jakob disease (CJD)), depressive disorders, 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).

18. The pharmaceutical composition according to claim 14, wherein the disease is nOH.

19. The pharmaceutical composition according to claim 14, wherein the subject is a human.

20. The pharmaceutical composition according to claim 14, administered to the subject by oral, enteral, topical, inhalation, transmucosal, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, supercutaneous, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernosal, intradermal, intrafocal, intraocular, intraosseous, intraperitoneal, intramedullary, intrauterine, intravaginal, intrabladder, intravitreous, percutaneous, perivascular, buccal, vagina, sublingual, or rectal route.

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