α1A-adrenergic receptor agonist and method of use

Abstract

The present disclosure relates generally to chemical compounds, and in some embodiments to α1A-adrenergic receptor agonists, and the use of such agonists in the treatment of diseases associated with adrenergic receptors. Disclosed herein is a compound of formula (I), or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof:

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 071,297, filed on 27 August 2020, which is incorporated herein by reference in its entirety.

[0002] Field of Invention This disclosure, as a whole, relates to chemical compounds, and in some embodiments, α 1A - Regarding the use of adrenaline agonists and in the treatment of diseases associated with adrenaline receptors. [Background technology]

[0003] PCT patent application publication number WO2008 / 112773 (Patent Document 1) states that "this application relates to the use of droxidopa, either alone or in combination with one or more additional components, for the treatment of conditions such as neurocardiogenic postural hypotension."

[0004] U.S. Patent No. 5,952,362 (Patent Document 2) describes "Various 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxyphenyl, and aminophenylalkylsulfonamide and urea," and "Alpha in the treatment of various disease conditions such as urinary incontinence, nasal congestion, priapism, depression, anxiety, dementia, aging, Alzheimer's disease, attention deficit and cognitive impairment, and eating disorders such as obesity, bulimia, and anorexia." 1A / 1L The disclosure includes "the use of the above compounds as agonists and compositions containing them." U.S. Patent No. 5,952,362 (Patent Document 2) discloses the compound N-[6-chloro-3-(4,5-dihydro-1H-imidazole-2-ylmethoxy)-2-methylphenyl]methanesulfonamide hydrochloride. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] WO2008 / 112773 [Patent Document 2] U.S. Patent No. 5,952,362 [Overview of the Initiative]

[0006] This disclosure is at least in part based on the identification of compounds that modulate adrenergic receptors and methods of using them to treat diseases associated with adrenergic receptors. This specification discloses compounds of formula (I), or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. TIFF0007873661000001.tif44128

[0007] In some embodiments, R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, deuterium, 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.

[0008] In some embodiments, R1 and R2, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom; R2 and R3, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom; or R3 and R4, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom.

[0009] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen if R1 and R2, together with the C atoms to which they are bonded, do not form an unsubstituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, if R2 and R3, together with the C atoms to which they are bonded, do not form an unsubstituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, and if R3 and R4, together with the C atoms to which they are bonded, do not form an unsubstituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom.

[0010] In this specification, formula (I') A compound having the structure of TIFF0007873661000002.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1, R2, R3, R4, and R5 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 cycloalkoxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heterocycloalkoxy, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or R1 and R2, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom; R2 and R3, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom; or R3 and R4, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom. Here, at least two of R1, R2, R3, R4, and R5 are not hydrogen.

[0011] This specification also discloses compounds having the structure of formula (Ia), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, where R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, deuterium, 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. TIFF0007873661000003.tif48128

[0012] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen.

[0013] Furthermore, the Specified Classification also discloses compounds of formula (Ib), or optically pure stereoisomers thereof, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R1 and R2, together with the C atom to which they are bonded, form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom. TIFF0007873661000004.tif45128

[0014] In some embodiments, R3 and R4 are independently selected from the group consisting of hydrogen, deuterium, 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] Furthermore, this specification also discloses compounds of formula (Ic), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R2 and R3, together with the C atom to which they are bonded, form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom. TIFF0007873661000005.tif48128

[0016] In some embodiments, R1 and R4 are independently selected from the group consisting of hydrogen, deuterium, 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] Furthermore, this specification also discloses compounds of formula (Id), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R3 and R4, together with the C atom to which they are bonded, form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom. TIFF0007873661000006.tif48128

[0018] In some embodiments, R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, 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] This specification also discloses compounds having the structure of formula (II), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF0007873661000007.tif39128

[0020] In some embodiments, R1, R2, and R3 are independently selected from the group consisting of hydrogen, deuterium, 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] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen.

[0022] This specification also discloses compounds having the structure of formula (III), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF0007873661000008.tif38128

[0023] In some embodiments, R1 and R2 are independently selected from the group consisting of deuterium, 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.

[0024] This specification also discloses compounds having the structure of formula (IV), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF0007873661000009.tif38128

[0025] In some embodiments, R1 is independently selected from the group consisting of deuterium, 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.

[0026] In some embodiments, the compounds disclosed herein are adrenergic receptor agonists, partial agonists, or antagonists, and in some embodiments, the compounds are α 1A - An adrenaline receptor agonist, and in some embodiments, the compound is α 1A - It is an adrenaline receptor partial agonist, and in some embodiments, the compound is α 1A - It is an adrenaline receptor antagonist.

[0027] This specification also discloses pharmaceutical compositions comprising compounds disclosed herein, namely compounds having the structure of formula (I), formula (I'), formula (Ia), formula (I-a'), formula (Ib), formula (I-b'), formula (Ic), formula (I-c'), formula (Id), formula (I-d'), formula (I-e'), formula (I-f'), formula (I-g'), formula (I-h'), formula (I-i'), formula (I-j'), formula (II), formula (II'), formula (III), formula (III'), formula (IV), or formula (IV'), and pharmaceutically acceptable excipients.

[0028] Further disclosures describe methods for treating subjects with a disease, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, namely, a compound having the structure of formula (I), formula (I'), formula (Ia), formula (I-a'), formula (Ib), formula (I-b'), formula (Ic), formula (I-c'), formula (Id), formula (I-d'), formula (I-e'), formula (I-f'), formula (I-g'), formula (I-h'), formula (I-i'), formula (I-j'), formula (II), formula (II'), formula (III), formula (III'), formula (IV), or formula (IV'). In some embodiments, the disease is a disease associated with adrenergic receptors. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the subject is a human.

[0029] 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, cerebrovascular disease, epilepsy, Tourette syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia of extension, polymyalgia of the spinal cord, progressive supranuclear phallopsis, dystonia, muscle atrophy, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject orally, enterally, topically, by inhalation, transmucosal, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, supercutaneous, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernosal, intradermal, intrafocal, intraocular, intraosseous, intraperitoneal, subarachnoid, intrauterine, intravaginal, intrabladder, intravitreous, percutaneous, perivascular, buccal, vaginal, sublingual, or via a rectal route.

[0030] In some embodiments, the disease is 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). It is a neurodegenerative disease consisting of one or more conditions selected from the group comprising: syndromes (alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tubular sclerosis complex), prion-related diseases (such as 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). In some embodiments, the disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke's disease). A neurodegenerative disease is one or more selected from the group consisting of Korsakoff syndrome (alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (such as CJD), depressive disorders, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not have Alzheimer's disease (AD). In some embodiments, the subject does not have Down syndrome.

[0031] Also disclosed is a method of treating a subject having a disease with nOH, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, i.e., a compound having the structure of formula (I), formula (I'), formula (I-a), formula (I-a'), formula (I-b), formula (I-b'), formula (I-c), formula (I-c'), formula (I-d), formula (I-d'), formula (I-e'), formula (I-f'), formula (I-g'), formula (I-h'), formula (I-i'), formula (I-j'), formula (II), formula (II'), formula (III), formula (III'), formula (IV), or formula (IV').

[0032] As used herein, the term "partial agonist" means a ligand that acts as an agonist for a receptor but does not reach the maximum response capacity of the system even in complete receptor occupancy, i.e., a partial agonist produces less than maximal activation even when occupying the entire receptor population and thus cannot produce a maximal response regardless of the concentration applied. In some embodiments, the partial agonist has 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 corresponding full agonist (examples of full agonists of the α 1A -adrenergic receptor include norepinephrine and amidafrine) of the same receptor.

[0033] As used herein, the term "α 1A -adrenergic receptor partial agonist" means a ligand that is a partial agonist of the α 1A -adrenergic receptor. In this application, the terms "α 1A -adrenergic receptor partial agonist", "α 1A -ADR partial agonist", "α 1A -AR agonist", and "α 1A partial agonist" can be used interchangeably. In some embodiments, the α 1A -adrenergic partial agonist is an α 1A- The corresponding complete agonist of the adrenaline receptor (α 1A -Examples of complete agonists of the adrenaline receptor include noradrenaline and amidephrine) exhibit maximum potency (or intrinsic activity "IA") of less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, or 15-75%, or 20-65%, or 20-60%, or 20-55%, or 20-50%, or 20-50%, or 20-45%, or 25-60%, or 25-55%, or 25-35%, or 30-40%, or 40-50%, or 45-55%. In some embodiments, α 1A - Adrenaline partial agonists exhibit maximum potency (or intrinsic activity "IA") at concentrations of less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, or less than 85%, but greater than 5%, more than 10%, more than 15%, or more than 20%. Blue et al., BJU International, (2004) 93:162-170 (the whole thereof is incorporated herein by reference) describes partial agonism, in particular, α 1A - Provides compositions and methods that can be used to determine partial agonism of adrenaline receptors, and exemplifies α 1A - Exhibits an adrenaline partial agonist. In certain embodiments, α 1A-ADR partial agonists exhibit intrinsic activity of less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, or 15-75%, less than 20-65%, less than 25-60%, less than 25-55%, less than 25-35%, less than 30-40%, less than 40-50%, or 45-55% of the activity of the full agonist, using the InsPs accumulation assay described by Blue et al. (For example, compared to norepinephrine in the InsPs accumulation assay, RO 115-1240 (dabuzarugron) free base shows an intrinsic activity of 0.31, and RO 115-1240 (dabuzarugron) HCl salt shows an intrinsic activity of 0.27; see Table 1 by Blue et al.). In some embodiments, α 1A -ADR partial agonists have less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, or 15-75%, less than 20-65%, less than 25-60%, less than 25-55%, less than 25-35%, less than 30-40%, less than 40-50%, or 45-55% of the activity of the full agonist, as measured using the FLIPR assay described by Blue et al. (For example, RO 115-1240 (dabuzarugron)HCl salt shows an intrinsic activity of 0.51 compared to norepinephrine in the FLIPR assay; see Table 1 by Blue et al.). In many embodiments, α 1A - ADR partial agonists, compared to full agonists, α 1A - May have similar affinity for adrenaline receptors. α as used herein 1A -The term ADR partial agonist, in some embodiments, refers to any pharmaceutically acceptable salt or prodrug thereof.

[0034] In some embodiments, α 1A -ADR partial agonists are selective alpha 1A-It is an adrenaline partial agonist. When used herein, it is referred to as a "selective α 1A - ADR partial agonist is α 1A - It exhibits partial agonism towards adrenergic receptors, but other α1-adrenergic receptor subtypes (e.g., α 1B -ADR or α 1D It does not show apparent agonism to other receptors such as α-ADR. Blue et al., BJU International, (2004) 93:162-170 (the whole of which is incorporated herein by reference) shows selective agonism (and selective partial agonism), as well as α 1A - Provides compositions and methods that can be used to determine selective agonism (and selective partial agonism) of ADR receptors, α 1A -Demonstrates exemplary selectivity as an ADR partial agonist. In some embodiments, selective α used herein 1A - ADR agonist or selective alpha 1A -ADR partial agonists (for example, using the method described by Blue et al.) 1B -ADR or α 1D -In CHO cells expressing ADR)α 1B -ADR or α 1D -Does not exhibit agonist activity against other receptors, including ADR receptors. In some embodiments, the selective α used herein 1A - ADR agonist or selective alpha 1A - The ADR partial agonist is 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 2.5 to 6, or 3 to 5.5, or 3 to 5.0, or 3 to 5, α 1B -ADR and α 1D - ADR receptor pEC 50 It has. In some embodiments, the selective α used herein 1A - ADR agonist or selective alpha 1A- The ADR partial agonist is defined as having 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 2.5-6, or 3-5.5, or 3-5.0, or 3-5, using the InsPs accumulation assay described by Blue et al. 1B -ADR and α 1D - ADR receptor pEC 50 (For example, α in InsPs accumulation assays) 1B -ADR and α 1D -For ADR receptors, RO 115-1240 (dabzalgron) free base and HCl salts have a pEC of >4.0 50 See Table 1 by Blue et al. for details. In some embodiments, the selective α used herein 1A -AR agonist or selective α 1A - The AR partial agonist is defined as having 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 2.5 to 6, or 3 to 5.5, or 3 to 5.0, or 3 to 5, using the FLIPR assay described by Blue et al. 1B -AR and α 1D - AR receptor pEC 50 (For example, α in the FLIPR accumulation assay) 1B -AR and α 1D -For AR receptors, RO 115-1240 (dabzaligron) free base and HCl salts have a pEC of >5.0 50 See Table 1 by Blue et al. for details. In some embodiments, the selective α used herein 1A -AR agonist or selective α 1A -AR partial agonists are pECs of non-selective agonists such as norepinephrine. 50 α is 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%. 1B -AR and α 1D - AR receptor pEC 50 It has. In some embodiments, the selective α used herein1A -AR agonist or selective α 1A -AR partial agonists were used to test for pEC of non-selective agonists such as norepinephrine using the InsP accumulation assay described by Blue et al. 50 α is 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%. 1B -AR and α 1D - AR receptor pEC 50 It has. In some embodiments, the selective α used herein 1A -AR agonist or selective α 1A -AR partial agonists are less than 85%, less than 80%, less than 75%, less than 65%, less than 60%, less than 55%, or less than 50% when using the FLIPR assay described by Blue et al. 1B -AR and α 1D - AR receptor pEC 50 It has. In some embodiments, the selective α used herein 1A -AR agonist or selective α 1A -AR partial agonists are used at concentrations of 30 μMol / L or less, 50 μMol / L or less, 75 μMol / L or less, or 100 μMol / L or less (for example, using the method described by Blue et al., α 1B -AR or α 1D -In CHO cells expressing AR, α 1B -AR or α 1D - It does not exhibit agonist activity against other receptors, including AR receptors. In some embodiments, selective α 1A -AR agonist or selective α 1A -AR partial agonists are pK (for example, using the method described by Blue et al.) i It does not bind to other receptors that are higher than 5.5, or higher than 6.0, or higher than 6.5, or higher than 7.0, or higher than 7.2, or higher than 7.5, or higher than 7.8, or higher than 8.0, or higher than 9.0. In some embodiments, selective α 1A -AR agonist or selective α 1A-AR partial agonists are pK (for example, using the method described by Blue et al.) i α is higher than 5.0, or higher than 5.5, or higher than 6.0, or higher than 7.0, or higher than 8.0, or higher than 9.0 1B -Also for AR 1D - It does not bind to AR receptors either. [Invention 1001] Equation (I') TIFF0007873661000010.tif48128 A compound of, During the ceremony, R 1 、R 2 、R 3 、R 4 , and R 5 These 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 cycloalkoxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heterocycloalkoxy, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or R 1 and R 2 However, together with the C atoms to which they are bonded, they optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom, or R 2 and R 3 However, together with the C atom to which they are bonded, they optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom, or R 3 and R 4 However, together with the C atoms to which they are bonded, they optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom. Here, R 1 、R 2 、R 3 、R 4 , and R 5 At least two of them are not hydrogen. The aforementioned compound, or a pharmaceutically acceptable salt thereof. [Invention 1002] Equation (I-a') TIFF0007873661000011.tif48128 A compound of, During the ceremony, R 1 、R 2 、R 3 , and R 4 These 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, Here, R 1 、R 2 、R 3 , and R 4 At least two of them are not hydrogen. The aforementioned compound, or a pharmaceutically acceptable salt thereof. [Invention 1003] Formula (I-b') TIFF0007873661000012.tif48128 A compound of, During the ceremony, R 1 and R 2 Together with the C atoms to which they are bonded, they form an unsubstituted or substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, and R 3 and R 4 These 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. The aforementioned compound, or a pharmaceutically acceptable salt thereof. [Invention 1004] Formula (I-c') TIFF0007873661000013.tif48128 A compound of, During the ceremony, R 2 and R 3 Together with the C atoms to which they are bonded, they form an unsubstituted or substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, and R 1 and R 4 These 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. The aforementioned compound, or a pharmaceutically acceptable salt thereof. [Invention 1005] Formula (I-d') TIFF0007873661000014.tif48128 A compound of, During the ceremony, R 3 and R 4 Together with the C atoms to which they are bonded, they form an unsubstituted or substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, and R 1 and R 2 These 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. The aforementioned compound, or a pharmaceutically acceptable salt thereof. [Invention 1006] Equation (I-e') TIFF0007873661000015.tif48128 A compound of, During the ceremony, R 1 、R 2 、R 3 , and R 4 These are, independently, hydrogen, halogen, and C 1~3 Alkyl, C 1~3 Haloalkyl and -OC 1~3 Selected from the group consisting of haloalkyls, Here, R 1 、R 2 、R 3 , and R 4 At least two of them are not hydrogen. The aforementioned compound, or a pharmaceutically acceptable salt thereof. [Invention 1007] Formula (I-f') TIFF0007873661000016.tif48128 A compound of, During the ceremony, R 1 、R 2 、R 3 , and R 4 These are independently hydrogen, chloro, methyl, and -CF 3 , -CH 2 CF 3 -OCHF 2 , and -OCF 3 Selected from the group consisting of, Here, R 1 、R 2 、R 3 , and R 4 At least two of them are not hydrogen. The aforementioned compound, or a pharmaceutically acceptable salt thereof. [Invention 1008] Formula (I-g') TIFF0007873661000017.tif48128 A compound of, During the ceremony, R 1 is halogen, C 1~3 Alkyl, C 1~3 Haloalkyl or -OC 1~3 It is a haloalkyl, R 2 is hydrogen, C 1~3 Haloalkyl or -OC 1~3 It is a haloalkyl, R 3 is hydrogen, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl or -OC 1~3 It is a haloalkyl and R 4 is hydrogen, C 1~3 Haloalkyl or -OC 1~3 It is a haloalkyl, Here, R 2 、R 3 , and R 4 At least one of them is not hydrogen. The aforementioned compound, or a pharmaceutically acceptable salt thereof. [Invention 1009] A compound according to any of the present invention 1001 to 1008, which is an adrenaline receptor agonist, partial agonist, or antagonist. [Invention 1010] A compound according to any of the present invention 1001 to 1008, which is a partial agonist of an adrenaline receptor. [Invention 1011] α 1A -A compound from any of the present invention 1001 to 1008 that is a partial agonist of an adrenaline receptor. [Invention 1012] A pharmaceutical composition comprising any compound according to invention 1001 to 1011 and a pharmaceutically acceptable excipient. [Invention 1013] A method for treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of any compound from 1001 to 1011 of the present invention. [Invention 1014] A method for treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of any compound from 1001 to 1011 of the present invention, thereby treating the subject. [Invention 1015] A method for treating a subject having a disease associated with adrenaline receptors, comprising administering to the subject a therapeutically effective amount of any compound from 1001 to 1011 of the present invention. [Invention 1016] The method of any of the present invention 1013 to 1015, wherein the disease is a neurodegenerative disease. [Invention 1017] 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 method of the present invention 1016, wherein the condition 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 (tubular sclerosis complex), 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). [Invention 1018] Any method of the present invention 1013 to 1015, wherein the disease is nOH. [Invention 1019] Any method 1013 to 1018 of the present invention, wherein the subject is a human. [Invention 1020] Any method of the present invention 1013 to 1019, wherein the compound is administered to the subject orally, enterally, topically, by inhalation, transmucosal, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, supercutaneous, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernosal, intradermal, intrafocal, intraocular, intraosseous, intraperitoneal, subarachnoid, intrauterine, intravaginal, intrabladder, intravitreous, percutaneous, perivascular, buccal, vaginal, sublingual, or via a rectal route. [Modes for carrying out the invention]

[0035] Detailed description of the invention The following detailed description of embodiments of the disclosure includes numerous specific details to provide a complete understanding of the disclosed embodiments. However, it will be obvious to those skilled in the art that embodiments of the disclosure can be carried out without these specific details. In other instances, well-known methods, procedures, components, and circuits are not described in detail so as not to unnecessarily obscure aspects of the embodiments of the disclosure.

[0036] To better describe this disclosure and to guide those skilled in the art in the practice of this disclosure, the following explanations of terms and methods are provided. The singular terms “a,” “an,” and “the” include multiple referents unless the context explicitly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context explicitly states otherwise. The term “comprises” means “includes.” Thus, “comprising A or B” means “including A, B, or A and B” without excluding any additional elements. The term “about” will be understood by those skilled in the art. Whether the term “about” is used expressly or not, all quantities given herein refer to actual given values, and it also means that they refer to approximations to such given values ​​that would be reasonably inferred based on those skilled in the art.

[0037] It should be further understood that all base sizes or amino acid sizes, and all molecular weight or molecular mass values ​​given for nucleic acids or polypeptides are approximations and are provided for illustrative purposes only. Methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and materials are described below.

[0038] Unless otherwise stated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art in which this disclosure pertains. Definitions of common terms in molecular biology can be found in Benjamin Lewin, Genes V, Oxford University Press, 1994 (ISBN 0-19-854287-9), Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9), and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).

[0039] Unless otherwise stated, the nomenclature of substituents not expressly defined herein is reached by naming the terminal portion of the functional group followed by the adjacent functional groups toward the bonding point. Those skilled in the art will recognize that the above definitions are not intended to include unacceptable substitution patterns (e.g., methyl, pentavalent carbon, etc., substituted with five different groups). Such unacceptable substitution patterns are readily recognizable to those skilled in the art. All publications, patent applications, patents, and other references referenced herein are incorporated in their entirety by reference. In case of any conflict, this specification, including the explanation of terms, shall prevail. In addition, materials, methods, and examples are illustrative only and not intended to limit.

[0040] Alkyl groups are monovalent groups derived from alkanes by removing a hydrogen atom from any carbon atom. These include linear and branched chains of 1 to 12 carbon atoms, and typically linear and branched chains having 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 linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl groups. Alkyl groups may be substituted or unsubstituted. Typical substituted alkyl groups are not limited to, but may be single-substituted, disubstituted, or trisubstituted, etc. 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-C6alkyl), -OC(O)-(C1-C6alkyl), -C(O)-NH2, -C(O)-N(H)-C1-C6alkyl, -C(O)-N(C1-C6alkyl)2, -OC(O)-NH2, -C(O)-H, -C(O)-(C1-C6alkyl), -C(S)-(C1-C6alkyl), -NR 70 R 72 And R 70 and R 72 Each of these is independently selected from H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, and C(O)-C1-C6-alkyl, -NR 70 R 72 This includes, but is not limited to, the following. Where used herein, unless otherwise specified, the term alkyl refers to both cyclic and acyclic groups.

[0041] The term "haloalkyl" refers to a linear or branched alkyl group that is substituted with one or more halogen atoms (e.g., -CHF2, -CF3, -CH2CF3, etc.).

[0042] The terms "cyclic alkyl" or "cycloalkyl" refer to monovalent groups derived from cycloalkanes by removing hydrogen atoms from ring carbon atoms. Cycloalkyl groups are saturated or partially saturated non-aromatic structures having monocyclic or polycyclic rings, including isolated, condensed, crosslinked, and spirocyclic systems, having 3 to 14 carbon atoms, or in some embodiments, 3 to 12, 3 to 10, 3 to 8, or 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted. Cycloalkyl groups may be substituted with groups such as those described above for alkyl. Typical substituted cycloalkyl groups are not limited to monosubstituted, disubstituted, or trisubstituted, and may be monosubstituted or multiple substituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of polycyclic ring systems include, but are not limited to, bicyclic [4.4.0]decane, bicyclic [2.2.1]heptane, and spiro[2.2]pentane. (Cycloalkyl)oxy refers to -O-cycloalkyl. (Cycloalkyl)thio refers to -S-cycloalkyl. This term also encompasses sulfur oxidation forms such as -S(O)-cycloalkyl or -S(O)2-cycloalkyl.

[0043] An alkenyl group refers to a linear, branched, or cycloalkyl group as defined above, having one or more double bonds between two carbon atoms. An alkenyl group may have 2 to about 12 carbon atoms, or in some embodiments, 1 to about 10 carbon atoms, or in other embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. An alkenyl group may be substituted or unsubstituted. For alkyl groups, alkenyl groups may be substituted with groups such as those described above. Typical substituted alkenyl groups are, but are not limited to, monosubstituted, disubstituted, or trisubstituted, and may be monosubstituted or multiple substituted. Examples of alkenyl groups include, in particular, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl.

[0044] Alkynyl groups refer to linear, branched, and cycloalkyl groups as defined above, having one or more double bonds between two carbon atoms. Alkynyl groups may have 2 to about 12 carbon atoms, or in some embodiments, 1 to about 10 carbon atoms, or in other embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. Alkynyl groups may be substituted or unsubstituted. Alkynyl groups may be substituted with groups such as those described above for alkyl groups. Typical substituted alkynyl groups are not limited to those described above, but may be monosubstituted, disubstituted, or trisubstituted, and may be monosubstituted or multiple substituted. Exemplary alkynyl groups include, in particular, ethynyl, propargyl, and -C≡C(CH3).

[0045] Aryl groups are cyclic aromatic hydrocarbons, including monocyclic and polycyclic compounds, containing multiple ring compounds with separate and / or condensed aryl groups. Aryl groups may contain 6 to about 18 ring carbons, or in some embodiments, 6 to 14 ring carbons, or in other embodiments, even more than 6 to 10 ring carbons. Aryl groups also include heteroaryl groups, which are aromatic ring compounds containing five or more ring members, where one or more of these ring carbon atoms are replaced by heteroatoms such as N, O, and S, but are not limited to these. Aryl groups may be substituted or unsubstituted. Aryl groups may be substituted with groups such as those described above for alkyl groups. Typical substituted aryl groups are not limited to those described above, but may be monosubstituted, disubstituted, or trisubstituted, and may be monosubstituted or multiple substituted. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, triphenyl, 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 sulfur oxidation forms such as -S(O)-aryl or -S(O)2-aryl. Heteroaryloxy refers to -O-heteroaryl. Heteroarylthio refers to -S-heteroaryl. This term also encompasses sulfur oxidation forms such as -S(O)-heteroaryl or -S(O)2-heteroaryl.

[0046] Preferred heterocyclyl groups include cyclic groups having at least two different elemental atoms as ring members, one or more of which are heteroatoms such as N, O, or S. Heterocyclyl groups may have 3 to about 20 ring members, or in some embodiments, 3 to 18 ring members, or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The cyclic system in a heterocyclyl group can be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups may be substituted or unsubstituted. Heterocyclyl groups may be substituted with groups such as those described above for alkyl groups. Typical substituted heterocyclyl groups are not limited to those that are monosubstituted, disubstituted, or trisubstituted, and may be monosubstituted or multiple substituted. Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranil, piperidyl, morpholinyl, thiomorpholinyl, thioxanil, piperazinyl, azetidinyl, azilidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, furanil, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl Examples include, but are not limited to, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiepanyl, 1,2,3,6-tetrahydropyridyl, indololinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolidinyl, sinnolinyl, phthalazinyl, pteridinyl, and benzothiazolinyl groups. Heterocyclyloxy refers to -O-heterocyclyl. Heterocyclylthio refers to -S-heterocyclyl. This term also encompasses sulfur oxidation forms such as -S(O)-heterocyclyl or -S(O)2-heterocyclyl.

[0047] A polycyclic or polycyclyl group refers to two or more rings in which two or more carbon atoms are common to two adjacent rings, and the rings are "fused rings." If the rings are linked by a single common carbon atom, these are "spiro" ring systems. Rings linked via non-adjacent atoms are "bridged" rings. Polycyclic groups may be substituted or unsubstituted. Polycyclic groups may be substituted with groups such as those mentioned above for alkyl groups. Typical polycyclic groups may be substituted one or more times.

[0048] 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 include structures in which an oxygen atom is directly bonded to two adjacent or non-adjacent carbon atoms in a carbon chain or ring system, which is essentially a cyclic ether structure. Epoxides are cyclic ethers having a triatomic ring.

[0049] An alkoxy group is a substituted or unsubstituted alkyl group as defined above, which is single-bonded to oxygen. The alkoxy group may be substituted or unsubstituted. Typical substituted alkoxy groups may be substituted one or more times. The alkoxy group may be substituted with alkyl groups such as those described above. Examples of 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.

[0050] 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 aSO2-substituted alkyl, -NR a SO2-cycloalkyl, -NR a SO2-substituted cycloalkyl, -NR a SO2-aryl, -NR a SO2-substituted aryl, -NR a SO2-heteroaryl, -NR a SO2-substituted heteroaryl, -NR a SO2-heterocyclyl, -NR a This refers to an SO2-substituted heterocycline, where each R a These are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl.

[0051] Carboxyl refers to -COOH or its salts. Carboxyester refers to -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)β-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclyl, and -C(O)O-substituted heterocyclyl. (Carboxyester)amino refers to -NR a -C(O)O-alkyl, -NR a -C(O)O-substituted alkyl, -NR a -C(O)O-aryl, -NR a -C(O)O-substitution, -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 It is a -C(O)O- substituted heterocycline, where each R aThese are independently as described herein. (Carboxyester)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).

[0052] 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, substituted aminos may include -NH-CO-R. The 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.

[0053] Aminocarbonyl is -C(O)N(R b ) refers to 2, and here each R b Each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. b It may optionally bond with a nitrogen atom to form a heterocycline or substituted heterocycline group, however, both R b The condition is that neither of them is hydrogen. Aminocarbonylalkyl is -alkyl C(O)N(R b ) refers to 2, and here each R b Each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. bIt may optionally bond with a nitrogen atom to form a heterocycline or substituted heterocycline group, however, both R b The condition is that neither of them is hydrogen. Aminocarbonylamino is -NR a C(O)N(R b See 2, where R a and each R b This is defined herein. Aminodicarbonylamino is -NR a C(O)C(O)N(R b )See 2, where R a and each R b This is defined herein. Aminocarbonyloxy is -OC(O)N(R b ) refers to 2, and here each R b These are independently defined as herein. Aminosulfonyl is -SO2N(R b ) refers to 2, and here each R b These are independently defined as described herein.

[0054] The imino is -N=R c This refers to R c This can be selected from hydrogen, aminocarbonylalkyloxy, substituted aminocarbonylalkyloxy, aminocarbonylalkylamino, and substituted aminocarbonylalkylamino.

[0055] The pharmaceutically acceptable salts of the compounds described herein include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isothionic acid. In other cases, the compounds described may contain one or more acidic functional groups, and thus can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can also be prepared in situ in the process of manufacturing the administration vehicle or dosage form, or by separately reacting the purified compound in its free acid form with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Typical alkali or alkaline earth salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine.

[0056] A “prodrug” refers to a derivative of an active drug that requires conversion in the body to release the active drug. In certain embodiments, the conversion reaction is an enzymatic conversion reaction. Prodrugs are often pharmacologically inactive or have low activity until they are converted to the active drug, although this is not always the case. A “promoiety” refers to a form of protecting group that converts an active drug into a prodrug when used to mask functional groups within the active drug. In some cases, the promoiety binds to the drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means. Any convenient prodrug form of the compounds of interest can be prepared according to strategies and methods described, for example, by Rautio et al. ("Prodrugs: design and clinical applications", Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0057] Unless otherwise specifically stated by listing isotopically enriched atoms (e.g., deuterium), the structures shown herein also mean that they include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, substitution of a hydrogen atom with deuterium or tritium, 13 C or 14 Carbon atom substitution by C-enriched carbon atoms, 19 Compounds having this structure, including substitution of fluorine atoms with fluorine-enriched fluorine atoms, are within the scope of this disclosure.

[0058] This specification discloses compounds of formula (I), or optically pure stereoisomers thereof, pharmaceutically acceptable salts, solvates, or prodrugs. TIFF0007873661000018.tif48128

[0059] In some embodiments, R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, deuterium, 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.

[0060] In some embodiments, R1 and R2, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom; R2 and R3, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom; or R3 and R4, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom.

[0061] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen if R1 and R2, together with the C atoms to which they are bonded, do not form an unsubstituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, if R2 and R3, together with the C atoms to which they are bonded, do not form an unsubstituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, and if R3 and R4, together with the C atoms to which they are bonded, do not form an unsubstituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom.

[0062] In some embodiments, R1 and R2, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom; R2 and R3, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom; or R3 and R4, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom.

[0063] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen if R1 and R2, together with the C atoms to which they are bonded, do not form an unsubstituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom, and R2 and R3, together with the C atoms to which they are bonded, do not form an unsubstituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom, and R3 and R4, together with the C atoms to which they are bonded, do not form an unsubstituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-6 membered heterocycle having at least one nitrogen or oxygen atom.

[0064] In this specification, formula (I') A compound having the structure of TIFF0007873661000019.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1, R2, R3, R4, and R5 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 cycloalkoxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heterocycloalkoxy, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or R1 and R2, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom; R2 and R3, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom; or R3 and R4, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom. Here, at least two of R1, R2, R3, R4, and R5 are not hydrogen.

[0065] In some embodiments, R1, R2, R3, R4, and R5 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 cycloalkoxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heterocycloalkoxy, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0066] In some embodiments, R1 and R2, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom; R2 and R3, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom; or R3 and R4, together with the carbon atoms to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom.

[0067] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen if R1 and R2, together with the C atoms to which they are bonded, do not form an unsubstituted 5-9 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-9 membered heterocycle having at least one nitrogen or oxygen atom, and R2 and R3, together with the C atoms to which they are bonded, do not form an unsubstituted 5-9 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-9 membered heterocycle having at least one nitrogen or oxygen atom, and R3 and R4, together with the C atoms to which they are bonded, do not form an unsubstituted 5-9 membered heterocycle having at least one nitrogen or oxygen atom, nor a substituted 5-9 membered heterocycle having at least one nitrogen or oxygen atom.

[0068] This specification also discloses compounds having the structure of formula (Ia), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, where R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, deuterium, 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. TIFF0007873661000020.tif48128

[0069] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen.

[0070] In this specification, equation (I-a') A compound having the structure of TIFF0007873661000021.tif49128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1, R2, R3, and R4 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. Here, at least two of R1, R2, R3, and R4 are not hydrogen.

[0071] Furthermore, the Specified Classification also discloses compounds of formula (Ib), or optically pure stereoisomers thereof, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R1 and R2, together with the C atom to which they are bonded, form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom. TIFF0007873661000022.tif48128

[0072] In some embodiments, R1 and R2, together with the C atom to which they are bonded, form an unsubstituted or substituted five-membered heterocycle having at least one nitrogen or oxygen atom.

[0073] In some embodiments, R3 and R4 are independently selected from the group consisting of hydrogen, deuterium, 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] In this specification, formula (I-b') A compound of TIFF0007873661000023.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1 and R2, together with the C atom to which they are bonded, form an unsubstituted or substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, and R3 and R4 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.

[0075] In some embodiments, R1 and R2, together with the C atom to which they are bonded, form an unsubstituted or substituted five-membered heterocycle having at least one nitrogen or oxygen atom.

[0076] Furthermore, this specification also discloses compounds of formula (Ic), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R2 and R3, together with the C atom to which they are bonded, form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom. TIFF0007873661000024.tif45128

[0077] In some embodiments, R2 and R3, together with the C atom to which they are bonded, form an unsubstituted or substituted five-membered heterocycle having at least one nitrogen or oxygen atom.

[0078] In some embodiments, R1 and R4 are independently selected from the group consisting of hydrogen, deuterium, 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.

[0079] In this specification, formula (I-c') A compound of TIFF0007873661000025.tif45128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R2 and R3, together with the C atom to which they are bonded, form an unsubstituted or substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, and R1 and R4 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.

[0080] In some embodiments, R2 and R3, together with the C atom to which they are bonded, form an unsubstituted or substituted five-membered heterocycle having at least one nitrogen or oxygen atom.

[0081] Furthermore, this specification also discloses compounds of formula (Id), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R3 and R4, together with the C atom to which they are bonded, form an unsubstituted or substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom. TIFF0007873661000026.tif49128

[0082] In some embodiments, R3 and R4, together with the C atom to which they are bonded, form an unsubstituted or substituted five-membered heterocycle having at least one nitrogen or oxygen atom.

[0083] In some embodiments, R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, 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.

[0084] In this specification, we also use the formula (I-d') A compound of TIFF0007873661000027.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R3 and R4, together with the C atom to which they are bonded, form an unsubstituted or substituted 5-8 membered heterocycle having at least one nitrogen or oxygen atom, and 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.

[0085] In some embodiments, R3 and R4, together with the C atom to which they are bonded, form an unsubstituted or substituted five-membered heterocycle having at least one nitrogen or oxygen atom.

[0086] This specification also discloses optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrug compounds thereof. TIFF0007873661000028.tif39128

[0087] In some embodiments, R1, R2, and R3 are independently selected from the group consisting of hydrogen, deuterium, 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.

[0088] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen.

[0089] In this specification, equation (II') A compound of TIFF0007873661000029.tif40128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, 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. Here, at least two of R1, R2, and R3 are not hydrogen.

[0090] This specification also discloses compounds having the structure of formula (III), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF0007873661000030.tif38128

[0091] In some embodiments, R1 and R2 are independently selected from the group consisting of deuterium, 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.

[0092] In this specification, equation (III') A compound having the structure of TIFF0007873661000031.tif38128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1 and R2 are independently selected from the group consisting of halogens, hydroxyls, cyanos, nitros, unsubstituted or substituted sulfonyls, unsubstituted or substituted aminos, unsubstituted or substituted alkyls, unsubstituted or substituted alkoxyls, unsubstituted or substituted alkenyls, unsubstituted or substituted alkynyls, unsubstituted or substituted cycloalkyls, unsubstituted or substituted heterocycloalkyls, unsubstituted or substituted aryls, and unsubstituted or substituted heteroaryls.

[0093] This specification also discloses compounds having the structure of formula (IV), or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. TIFF0007873661000032.tif38128

[0094] In some embodiments, R1 is independently selected from the group consisting of deuterium, 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.

[0095] In this specification, equation (IV') A compound having the structure of TIFF0007873661000033.tif38128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1 is selected from the group consisting of halogens, hydroxyls, cyanos, nitros, unsubstituted or substituted sulfonyls, unsubstituted or substituted aminos, unsubstituted or substituted alkyls, unsubstituted or substituted alkoxyls, unsubstituted or substituted alkenyls, unsubstituted or substituted alkynyls, unsubstituted or substituted cycloalkyls, unsubstituted or substituted heterocycloalkyls, unsubstituted or substituted aryls, and unsubstituted or substituted heteroaryls.

[0096] In this specification, formula (I-e') A compound having the structure of TIFF0007873661000034.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1, R2, R3, and R4 are independently hydrogen, halogen, and C 1~3 Alkyl, C 1~3 Haloalkyl and -OC 1~3 Selected from the group consisting of haloalkyls, Here, at least two of R1, R2, R3, and R4 are not hydrogen.

[0097] In this specification, we also use the formula (I-f') A compound having the structure of TIFF0007873661000035.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, chloro, methyl, -CF3, -CH2CF3, -OCHF2, and -OCF3. Here, at least two of R1, R2, R3, and R4 are not hydrogen.

[0098] In this specification, formula (I-g') A compound having the structure of TIFF0007873661000036.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1 is halogen, C1~3 Alkyl, C 1~3 Haloalkyl, or -OC 1~3 It is a haloalkyl, R2 is hydrogen, C 1~3 Haloalkyl, or -OC 1~3 It is a haloalkyl, R3 is hydrogen, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl, or -OC 1~3 It is a haloalkyl and R4 is hydrogen, C 1~3 Haloalkyl, or -OC 1~3 It is a haloalkyl, Here, at least one of R2, R3, and R4 is not hydrogen.

[0099] In this specification, formula (I-h') A compound having the structure of TIFF0007873661000037.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1 is chloro, methyl, -CHF2, -CF3, -CH2CF3, -OCHF2, or -OCF3. R2 is hydrogen or -CF3. R3 is hydrogen, chloro, methyl, -CHF2, -CF3, -CH2CF3, -OCHF2, or -OCF3, and R4 is hydrogen or -CF3, Here, at least one of R2, R3, and R4 is not hydrogen.

[0100] In this specification, we also use the formula (I-i') A compound having the structure of TIFF0007873661000038.tif48128 or a pharmaceutically acceptable salt thereof is disclosed. During the ceremony, R1 is halogen, C 1~3 Alkyl, C 1~3 Haloalkyl, or -OC 1~3 It is a haloalkyl, R2 is hydrogen, R3 is halogen, C1~3 Haloalkyl, or -OC 1~3 It is a haloalkyl and R4 is hydrogen.

[0101] In this specification, we also use the formula (I-j') Compound with the structure of TIFF0007873661000039.tif48128 Or a pharmaceutically acceptable salt thereof is disclosed, During the ceremony, R1 is chloro, methyl, -CHF2, -CF3, -CH2CF3, -OCHF2, or -OCF3. R2 is hydrogen, R3 is chloro, -CF3, or -OCHF2, and R4 is hydrogen.

[0102] As disclosed above and described herein, in some embodiments, R1, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, deuterium, 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 cycloalkoxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heterocycloalkoxy, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0103] In some embodiments, R1 is hydrogen. In some embodiments, R1 is deuterium. In some embodiments, R1 is a halogen. In some embodiments, R1 is a hydroxyl. In some embodiments, R1 is a cyano. In some embodiments, R1 is a nitro. In some embodiments, R1 is an unsubstituted or substituted sulfonyl. In some embodiments, R1 is an unsubstituted or substituted amino, unsubstituted or substituted alkyl. In some embodiments, R1 is an unsubstituted or substituted alkoxy. In some embodiments, R1 is an unsubstituted or substituted alkenyl. In some embodiments, R1 is an unsubstituted or substituted alkynyl. In some embodiments, R1 is an unsubstituted or substituted cycloalkyl. In some embodiments, R1 is an unsubstituted or substituted cycloalkoxy. In some embodiments, R1 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R1 is an unsubstituted or substituted heterocycloalkoxy. In some embodiments, R1 is an unsubstituted or substituted aryl. In some embodiments, R1 is an unsubstituted or substituted heteroaryl.

[0104] In some embodiments, R1 is chloro. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is t-butyl. In some embodiments, R1 is cyclohexyl. In some embodiments, R1 is phenyl. In some embodiments, R1 is -CFH2. In some embodiments, R1 is -CHF2. In some embodiments, R1 is -CHFCH3. In some embodiments, R1 is -CHOHCH3. In some embodiments, R1 is -CF2CH3. In some embodiments, R1 is -CF2Et. In some embodiments, R1 is -CF2iPr. In some embodiments, R1 is -CF3. In some embodiments, R1 is -CH2CF3. In some embodiments, R1 is -N(CH3)CH2CF3. In some embodiments, R1 is -OMe. In some embodiments, R1 is -OiPr. In some embodiments, R1 is -OCHF2. In some embodiments, R1 is -OCF3. In some embodiments, R1 is -CH2OMe. In some embodiments, R1 is -SO2CF3. In some embodiments, R1 is TIFF0007873661000040.tif13128. In some embodiments, R1 is TIFF0007873661000041.tif14128. In some embodiments, R1 is TIFF0007873661000042.tif14128. In some embodiments, R1 is TIFF0007873661000043.tif14128. In some embodiments, R1 is TIFF0007873661000044.tif13128. In some embodiments, R1 is TIFF0007873661000045.tif is 13128. In some embodiments, R1 is TIFF0007873661000046.tif is 13128. In some embodiments, R1 is TIFF0007873661000047.tif is 13128. In some embodiments, R1 is TIFF0007873661000048.tif is 13128. In some embodiments, R1 is TIFF0007873661000049.tif is 14128. In some embodiments, R1 is TIFF0007873661000050.tif is 13128. In some embodiments, R1 is TIFF0007873661000051.tif is 14128. In some embodiments, R1 is TIFF0007873661000052.tif is 13128. In some embodiments, R1 is TIFF0007873661000053.tif is 13128. In some embodiments, R1 is TIFF0007873661000054.tif is 13128. In some embodiments, R1 is TIFF0007873661000055.tif is 13128. In some embodiments, R1 is TIFF0007873661000056.tif is 14128. In some embodiments, R1 is TIFF0007873661000057.tif is 14128. In some embodiments, R1 is TIFF0007873661000058.tif is 14128. In some embodiments, R1 is TIFF0007873661000059.tif is 14128. In some embodiments, R1 is TIFF0007873661000060.tif is 15128. In some embodiments, R1 is The filename is TIFF0007873661000061.tif14128.

[0105] In some embodiments, R1 is as shown in the compounds in Table 1.

[0106] In some embodiments, R2 is hydrogen. In some embodiments, R2 is deuterium. In some embodiments, R2 is a halogen. In some embodiments, R2 is a hydroxyl. In some embodiments, R2 is a cyano. In some embodiments, R2 is a nitro. In some embodiments, R2 is an unsubstituted or substituted sulfonyl. In some embodiments, R2 is an unsubstituted or substituted amino, unsubstituted or substituted alkyl. In some embodiments, R2 is an unsubstituted or substituted alkoxy. In some embodiments, R2 is an unsubstituted or substituted alkenyl. In some embodiments, R2 is an unsubstituted or substituted alkynyl. In some embodiments, R2 is an unsubstituted or substituted cycloalkyl. In some embodiments, R2 is an unsubstituted or substituted cycloalkoxy. In some embodiments, R2 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R2 is an unsubstituted or substituted heterocycloalkoxy. In some embodiments, R2 is an unsubstituted or substituted aryl. In some embodiments, R2 is an unsubstituted or substituted heteroaryl.

[0107] In some embodiments, R2 is chloro. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is t-butyl. In some embodiments, R2 is cyclohexyl. In some embodiments, R2 is phenyl. In some embodiments, R2 is -CFH2. In some embodiments, R2 is -CHF2. In some embodiments, R2 is -CHFCH3. In some embodiments, R2 is -CHOHCH3. In some embodiments, R2 is -CF2CH3. In some embodiments, R2 is -CF2Et. In some embodiments, R2 is -CF2iPr. In some embodiments, R2 is -CF3. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is -N(CH3)CH2CF3. In some embodiments, R2 is -OMe. In some embodiments, R2 is -OiPr. In some embodiments, R2 is -OCHF2. In some embodiments, R2 is -OCF3. In some embodiments, R2 is -CH2OMe. In some embodiments, R2 is -SO2CF3. In some embodiments, R2 is This is TIFF0007873661000062.tif13128. In some embodiments, R2 is This is TIFF0007873661000063.tif14128. In some embodiments, R2 is This is TIFF0007873661000064.tif14128. In some embodiments, R2 is This is TIFF0007873661000065.tif14128. In some embodiments, R2 is This is TIFF0007873661000066.tif13128. In some embodiments, R2 is This is TIFF0007873661000067.tif13128. In some embodiments, R2 is This is TIFF0007873661000068.tif13128. In some embodiments, R2 is This is TIFF0007873661000069.tif13128. In some embodiments, R2 is This is TIFF0007873661000070.tif13128. In some embodiments, R2 is This is TIFF0007873661000071.tif14128. In some embodiments, R2 is This is TIFF0007873661000072.tif13128. In some embodiments, R2 is This is TIFF0007873661000073.tif14128. In some embodiments, R2 is This is TIFF0007873661000074.tif13128. In some embodiments, R2 is This is TIFF0007873661000075.tif13128. In some embodiments, R2 is This is TIFF0007873661000076.tif13128. In some embodiments, R2 is This is TIFF0007873661000077.tif13128. In some embodiments, R2 is This is TIFF0007873661000078.tif14128. In some embodiments, R2 is This is TIFF0007873661000079.tif14128. In some embodiments, R2 is This is TIFF0007873661000080.tif14128. In some embodiments, R2 is This is TIFF0007873661000081.tif14128. In some embodiments, R2 is This is TIFF0007873661000082.tif15128. In some embodiments, R2 is The filename is TIFF0007873661000083.tif14128.

[0108] In some embodiments, R2 is as shown in the compounds in Table 1.

[0109] In some embodiments, R3 is hydrogen. In some embodiments, R3 is deuterium. In some embodiments, R3 is a halogen. In some embodiments, R3 is a hydroxyl. In some embodiments, R3 is a cyano. In some embodiments, R3 is a nitro. In some embodiments, R3 is an unsubstituted or substituted sulfonyl. In some embodiments, R3 is an unsubstituted or substituted amino, unsubstituted or substituted alkyl. In some embodiments, R3 is an unsubstituted or substituted alkoxy. In some embodiments, R3 is an unsubstituted or substituted alkenyl. In some embodiments, R3 is an unsubstituted or substituted alkynyl. In some embodiments, R3 is an unsubstituted or substituted cycloalkyl. In some embodiments, R3 is an unsubstituted or substituted cycloalkoxy. In some embodiments, R3 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R3 is an unsubstituted or substituted heterocycloalkoxy. In some embodiments, R3 is an unsubstituted or substituted aryl. In some embodiments, R3 is an unsubstituted or substituted heteroaryl.

[0110] In some embodiments, R3 is chloro. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is t-butyl. In some embodiments, R3 is cyclohexyl. In some embodiments, R3 is phenyl. In some embodiments, R3 is -CFH2. In some embodiments, R3 is -CHF2. In some embodiments, R3 is -CHFCH3. In some embodiments, R3 is -CHOHCH3. In some embodiments, R3 is -CF2CH3. In some embodiments, R3 is -CF2Et. In some embodiments, R3 is -CF2iPr. In some embodiments, R3 is -CF3. In some embodiments, R3 is -CH2CF3. In some embodiments, R3 is -N(CH3)CH2CF3. In some embodiments, R3 is -OMe. In some embodiments, R3 is -OiPr. In some embodiments, R3 is -OCHF2. In some embodiments, R3 is -OCF3. In some embodiments, R3 is -CH2OMe. In some embodiments, R3 is -SO2CF3. In some embodiments, R3 is This is TIFF0007873661000084.tif13128. In some embodiments, R3 is This is TIFF0007873661000085.tif14128. In some embodiments, R3 is This is TIFF0007873661000086.tif14128. In some embodiments, R3 is This is TIFF0007873661000087.tif14128. In some embodiments, R3 is This is TIFF0007873661000088.tif13128. In some embodiments, R3 is TIFF0007873661000089.tif is 13128. In some embodiments, R3 is TIFF0007873661000090.tif is 13128. In some embodiments, R3 is TIFF0007873661000091.tif is 13128. In some embodiments, R3 is TIFF0007873661000092.tif is 13128. In some embodiments, R3 is TIFF0007873661000093.tif is 14128. In some embodiments, R3 is TIFF0007873661000094.tif is 13128. In some embodiments, R3 is TIFF0007873661000095.tif is 14128. In some embodiments, R3 is TIFF0007873661000096.tif is 13128. In some embodiments, R3 is TIFF0007873661000097.tif is 13128. In some embodiments, R3 is TIFF0007873661000098.tif is 13128. In some embodiments, R3 is TIFF0007873661000099.tif is 13128. In some embodiments, R3 is TIFF0007873661000100.tif is 14128. In some embodiments, R3 is TIFF0007873661000101.tif is 14128. In some embodiments, R3 is TIFF0007873661000102.tif is 14128. In some embodiments, R3 is TIFF0007873661000103.tif is 14128. In some embodiments, R3 is TIFF0007873661000104.tif is 15128. In some embodiments, R3 is The filename is TIFF0007873661000105.tif14128.

[0111] In some embodiments, R3 is as shown in the compounds in Table 1.

[0112] In some embodiments, R4 is hydrogen. In some embodiments, R4 is deuterium. In some embodiments, R4 is a halogen. In some embodiments, R4 is a hydroxyl. In some embodiments, R4 is a cyano. In some embodiments, R4 is a nitro. In some embodiments, R4 is an unsubstituted or substituted sulfonyl. In some embodiments, R4 is an unsubstituted or substituted amino, unsubstituted or substituted alkyl. In some embodiments, R4 is an unsubstituted or substituted alkoxy. In some embodiments, R4 is an unsubstituted or substituted alkenyl. In some embodiments, R4 is an unsubstituted or substituted alkynyl. In some embodiments, R4 is an unsubstituted or substituted cycloalkyl. In some embodiments, R4 is an unsubstituted or substituted cycloalkoxy. In some embodiments, R4 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R4 is an unsubstituted or substituted heterocycloalkoxy. In some embodiments, R4 is an unsubstituted or substituted aryl. In some embodiments, R4 is an unsubstituted or substituted heteroaryl.

[0113] In some embodiments, R4 is chloro. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is isopropyl. In some embodiments, R4 is cyclopropyl. In some embodiments, R4 is t-butyl. In some embodiments, R4 is cyclohexyl. In some embodiments, R4 is phenyl. In some embodiments, R4 is -CFH2. In some embodiments, R4 is -CHF2. In some embodiments, R4 is -CHFCH3. In some embodiments, R4 is -CHOHCH3. In some embodiments, R4 is -CF2CH3. In some embodiments, R4 is -CF2Et. In some embodiments, R4 is -CF2iPr. In some embodiments, R4 is -CF3. In some embodiments, R4 is -CH2CF3. In some embodiments, R4 is -N(CH3)CH2CF3. In some embodiments, R4 is -OMe. In some embodiments, R4 is -OiPr. In some embodiments, R4 is -OCHF2. In some embodiments, R4 is -OCF3. In some embodiments, R4 is -CH2OMe. In some embodiments, R4 is -SO2CF3. In some embodiments, R4 is This is TIFF0007873661000106.tif13128. In some embodiments, R4 is This is TIFF0007873661000107.tif14128. In some embodiments, R4 is This is TIFF0007873661000108.tif14128. In some embodiments, R4 is This is TIFF0007873661000109.tif14128. In some embodiments, R4 is This is TIFF0007873661000110.tif13128. In some embodiments, R4 is This is TIFF0007873661000111.tif13128. In some embodiments, R4 is This is TIFF0007873661000112.tif13128. In some embodiments, R4 is This is TIFF0007873661000113.tif13128. In some embodiments, R4 is This is TIFF0007873661000114.tif13128. In some embodiments, R4 is This is TIFF0007873661000115.tif14128. In some embodiments, R4 is This is TIFF0007873661000116.tif13128. In some embodiments, R4 is This is TIFF0007873661000117.tif14128. In some embodiments, R4 is This is TIFF0007873661000118.tif13128. In some embodiments, R4 is This is TIFF0007873661000119.tif13128. In some embodiments, R4 is This is TIFF0007873661000120.tif13128. In some embodiments, R4 is This is TIFF0007873661000121.tif14128. In some embodiments, R4 is This is TIFF0007873661000122.tif14128. In some embodiments, R4 is This is TIFF0007873661000123.tif14128. In some embodiments, R4 is This is TIFF0007873661000124.tif14128. In some embodiments, R4 is This is TIFF0007873661000125.tif14128. In some embodiments, R4 is This is TIFF0007873661000126.tif15128. In some embodiments, R4 is The filename is TIFF0007873661000127.tif14128.

[0114] In some embodiments, R4 is as shown in the compounds in Table 1.

[0115] In some embodiments, R5 is hydrogen. In some embodiments, R5 is deuterium. In some embodiments, R5 is a halogen. In some embodiments, R5 is a hydroxyl. In some embodiments, R5 is a cyano. In some embodiments, R5 is a nitro. In some embodiments, R5 is an unsubstituted or substituted sulfonyl. In some embodiments, R5 is an unsubstituted or substituted amino, unsubstituted or substituted alkyl. In some embodiments, R5 is an unsubstituted or substituted alkoxy. In some embodiments, R5 is an unsubstituted or substituted alkenyl. In some embodiments, R5 is an unsubstituted or substituted alkynyl. In some embodiments, R5 is an unsubstituted or substituted cycloalkyl. In some embodiments, R5 is an unsubstituted or substituted cycloalkoxy. In some embodiments, R5 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R5 is an unsubstituted or substituted heterocycloalkoxy. In some embodiments, R5 is an unsubstituted or substituted aryl. In some embodiments, R5 is an unsubstituted or substituted heteroaryl.

[0116] In some embodiments, R5 is chloro. In some embodiments, R5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is isopropyl. In some embodiments, R5 is cyclopropyl. In some embodiments, R5 is t-butyl. In some embodiments, R5 is cyclohexyl. In some embodiments, R5 is phenyl. In some embodiments, R5 is -CFH2. In some embodiments, R5 is -CHF2. In some embodiments, R5 is -CHFCH3. In some embodiments, R5 is -CHOHCH3. In some embodiments, R5 is -CF2CH3. In some embodiments, R5 is -CF2Et. In some embodiments, R5 is -CF2iPr. In some embodiments, R5 is -CF3. In some embodiments, R5 is -CH2CF3. In some embodiments, R5 is -N(CH3)CH2CF3. In some embodiments, R5 is -OMe. In some embodiments, R5 is -OiPr. In some embodiments, R5 is -OCHF2. In some embodiments, R5 is -OCF3. In some embodiments, R5 is -CH2OMe. In some embodiments, R5 is -SO2CF3. In some embodiments, R5 is This is TIFF0007873661000128.tif13128. In some embodiments, R5 is This is TIFF0007873661000129.tif14128. In some embodiments, R5 is This is TIFF0007873661000130.tif14128. In some embodiments, R5 is This is TIFF0007873661000131.tif14128. In some embodiments, R5 is This is TIFF0007873661000132.tif13128. In some embodiments, R5 is This is TIFF0007873661000133.tif13128. In some embodiments, R5 is This is TIFF0007873661000134.tif13128. In some embodiments, R5 is This is TIFF0007873661000135.tif13128. In some embodiments, R5 is This is TIFF0007873661000136.tif13128. In some embodiments, R5 is This is TIFF0007873661000137.tif14128. In some embodiments, R5 is This is TIFF0007873661000138.tif13128. In some embodiments, R5 is This is TIFF0007873661000139.tif14128. In some embodiments, R5 is This is TIFF0007873661000140.tif13128. In some embodiments, R5 is This is TIFF0007873661000141.tif13128. In some embodiments, R5 is This is TIFF0007873661000142.tif13128. In some embodiments, R5 is This is TIFF0007873661000143.tif13128. In some embodiments, R5 is This is TIFF0007873661000144.tif14128. In some embodiments, R5 is This is TIFF0007873661000145.tif14128. In some embodiments, R5 is This is TIFF0007873661000146.tif14128. In some embodiments, R5 is This is TIFF0007873661000147.tif14128. In some embodiments, R5 is This is TIFF0007873661000148.tif15128. In some embodiments, R5 is The filename is TIFF0007873661000149.tif14128.

[0117] In some embodiments, R5 is as shown in the compounds in Table 1.

[0118] In some embodiments, R1 and R2, together with the C atom to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom.

[0119] In some embodiments, R1 and R2 together Forms TIFF0007873661000150.tif16128. In some embodiments, R1 and R2 together form Forms TIFF0007873661000151.tif16128. In some embodiments, R1 and R2 together form Forms TIFF0007873661000152.tif18128. In some embodiments, R1 and R2 together form Forms TIFF0007873661000153.tif18128. In some embodiments, R1 and R2 together form Forms TIFF0007873661000154.tif20128. In some embodiments, R1 and R2 together Forms TIFF0007873661000155.tif18128. In some embodiments, R1 and R2 together form Forms TIFF0007873661000156.tif18128. In some embodiments, R1 and R2 together form Forms TIFF0007873661000157.tif18128.

[0120] In some embodiments, R1 and R2 are combined as shown in the compounds in Table 1.

[0121] In some embodiments, R2 and R3, together with the C atom to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom.

[0122] In some embodiments, R2 and R3 together Forms TIFF0007873661000158.tif16128. In some embodiments, R2 and R3 together form Forms TIFF0007873661000159.tif16128. In some embodiments, R2 and R3 together form Forms TIFF0007873661000160.tif18128. In some embodiments, R2 and R3 together form Forms TIFF0007873661000161.tif18128. In some embodiments, R2 and R3 together form Forms TIFF0007873661000162.tif20128. In some embodiments, R2 and R3 together form Forms TIFF0007873661000163.tif18128. In some embodiments, R2 and R3 together form Forms TIFF0007873661000164.tif18128. In some embodiments, R2 and R3 together form Forms TIFF0007873661000165.tif18128.

[0123] In some embodiments, R2 and R3 are combined as shown in the compounds in Table 1.

[0124] In some embodiments, R3 and R4, together with the C atom to which they are bonded, optionally form an unsubstituted or substituted 5- to 9-membered heterocycle having at least one nitrogen or oxygen atom.

[0125] In some embodiments, R3 and R4 together Forms TIFF0007873661000166.tif16128. In some embodiments, R3 and R4 together form Forms TIFF0007873661000167.tif16128. In some embodiments, R3 and R4 together form Forms TIFF0007873661000168.tif18128. In some embodiments, R3 and R4 together form Forms TIFF0007873661000169.tif18128. In some embodiments, R3 and R4 together form Forms TIFF0007873661000170.tif20128. In some embodiments, R3 and R4 together Forms TIFF0007873661000171.tif18128. In some embodiments, R3 and R4 together form Forms TIFF0007873661000172.tif18128. In some embodiments, R3 and R4 together form Forms TIFF0007873661000173.tif18128.

[0126] In some embodiments, R3 and R4 are combined as shown in the compounds in Table 1.

[0127] In some embodiments, at least two of R1, R2, R3, and R4 are not hydrogen if R1 and R2, together with the C atom to which they are bonded, do not form an unsubstituted 5- to 8-membered heterocycle or a substituted 5- to 8-membered heterocycle having at least one nitrogen or oxygen atom.

[0128] As disclosed above and described herein, in some embodiments, R1, R2, R3, and R4 are independently hydrogen, halogen, and C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl, or -OC 1~3These are haloalkyl groups (e.g., fluoro, chloro, methyl, -CHF2, -CF3, -CH2CF3, -OCHF2, -OCF3, etc.).

[0129] In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halogen. In some embodiments, R1 is C 1~3 It is alkyl. In some embodiments, R1 is C 1~3 It is a haloalkyl. In some embodiments, R1 is -OC 1~3 It is alkyl. In some embodiments, R1 is -OC 1~3 It is a haloalkyl group. In some embodiments, R1 is fluoro. In some embodiments, R1 is chloro. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is -CHF2. In some embodiments, R1 is -CF3. In some embodiments, R1 is -CH2CF3. In some embodiments, R1 is -OCHF2. In some embodiments, R1 is -OCF3.

[0130] In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogen. In some embodiments, R2 is C 1~3 It is alkyl. In some embodiments, R2 is C 1~3 It is a haloalkyl. In some embodiments, R2 is -OC 1~3 It is alkyl. In some embodiments, R2 is -OC 1~3 It is a haloalkyl group. In some embodiments, R2 is fluoro. In some embodiments, R2 is chloro. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is -CHF2. In some embodiments, R2 is -CF3. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is -OCHF2. In some embodiments, R2 is -OCF3.

[0131] In some embodiments, R3 is hydrogen. In some embodiments, R3 is a halogen. In some embodiments, R3 is C 1~3 It is alkyl. In some embodiments, R3 is C 1~3 It is a haloalkyl. In some embodiments, R3 is -OC 1~3 It is alkyl. In some embodiments, R3 is -OC 1~3 It is a haloalkyl group. In some embodiments, R3 is fluoro. In some embodiments, R3 is chloro. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is -CHF2. In some embodiments, R3 is -CF3. In some embodiments, R3 is -CH2CF3. In some embodiments, R3 is -OCHF2. In some embodiments, R3 is -OCF3.

[0132] In some embodiments, R4 is hydrogen. In some embodiments, R4 is a halogen. In some embodiments, R4 is C 1~3 It is alkyl. In some embodiments, R4 is C 1~3 It is a haloalkyl. In some embodiments, R4 is -OC 1~3 It is alkyl. In some embodiments, R4 is -OC 1~3 It is a haloalkyl group. In some embodiments, R4 is fluoro. In some embodiments, R4 is chloro. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is -CHF2. In some embodiments, R4 is -CF3. In some embodiments, R4 is -CH2CF3. In some embodiments, R4 is -OCHF2. In some embodiments, R4 is -OCF3.

[0133] In some embodiments, R1, R2, R3, and R4 are combined as shown in the compounds in Table 1.

[0134] In some embodiments, the compounds disclosed herein are adrenergic receptor agonists, partial agonists, or antagonists, and in some embodiments, the compounds are α 1A - An adrenaline receptor agonist, and in some embodiments, the compound is α 1A - It is an adrenaline receptor partial agonist, and in some embodiments, the compound is α 1A - It is an adrenaline receptor antagonist.

[0135] Further disclosures describe methods for treating subjects with a disease, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, namely, a compound having the structure of formula (I), formula (I'), formula (Ia), formula (I-a'), formula (Ib), formula (I-b'), formula (Ic), formula (I-c'), formula (Id), formula (I-d'), formula (I-e'), formula (I-f'), formula (I-g'), formula (I-h'), formula (I-i'), formula (I-j'), formula (II), formula (II'), formula (III), formula (III'), formula (IV), or formula (IV'). In some embodiments, the disease is a disease associated with adrenergic receptors. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the subject is a human.

[0136] 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, cerebrovascular disease, epilepsy, Tourette syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia of extension, polymyalgia of the spinal cord, progressive supranuclear phallopsis, dystonia, muscle atrophy, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject orally, enterally, topically, by inhalation, transmucosal, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, supercutaneous, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernosal, intradermal, intrafocal, intraocular, intraosseous, intraperitoneal, subarachnoid, intrauterine, intravaginal, intrabladder, intravitreous, percutaneous, perivascular, buccal, vaginal, sublingual, or via a rectal route.

[0137] In some embodiments, the disease is 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). It is a neurodegenerative disease consisting of one or more conditions selected from the group comprising: syndromes (alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tubular sclerosis complex), prion-related diseases (such as 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). In some embodiments, the disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke's disease). A neurodegenerative disease is one or more selected from the group consisting of Korsakoff syndrome (alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (such as CJD), depressive disorders, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not have Alzheimer's disease (AD). In some embodiments, the subject does not have Down syndrome.

[0138] The term “treatment” is used herein interchangeably with the term “treatment method” and refers to both 1) the cure, delay, reduction of symptoms, and / or cessation of progression of a diagnosed pathological condition, disease, or disorder, and 2) and preventive / preventive measures. Persons requiring treatment may include individuals who already have a particular medical disease or disorder, as well as those who may ultimately acquire a disorder (i.e., those at risk or requiring preventive measures).

[0139] As used herein, the term “subject” refers to any individual or patient on whom the method of the subject is performed. Generally, the subject is human, as will be understood by those skilled in the art, but the subject may also be an animal.

[0140] Terms such as "therapeutic effective dose," "effective dose," "therapeutic effective dose," and "effective dose" refer to the amount of the compound in question that, upon administration, elicits a desired biological or medical response in a tissue, system, animal, or human. Generally, the response is either an improvement in the patient's symptoms or a desired biological outcome. In some embodiments, such an amount should be sufficient to modulate adrenergic receptors.

[0141] In some embodiments, an effective amount of the adrenaline receptor modulating compound is approximately 50 ng / ml to 50 pg / ml (for example, approximately 50 ng / ml to 40 pg / ml, approximately 30 ng / ml to 20 pg / ml, approximately 50 ng / ml to 10 μg / ml, approximately 50 ng / ml to 1 μg / ml, approximately 50 ng / ml to 800 ng / ml, approximately 50 ng / ml to 700 ng / ml, approximately 50 ng / ml to 600 ng / ml, approximately 50 ng / ml to 500 ng / ml, approximately 50 ng / ml to 400 ng / ml, approximately 60 ng / ml to 4 This refers to amounts within the range of 00 ng / ml, approximately 70 ng / ml to 300 ng / ml, approximately 60 ng / ml to 100 ng / ml, approximately 65 ng / ml to 85 ng / ml, approximately 70 ng / ml to 90 ng / ml, approximately 200 ng / ml to 900 ng / ml, approximately 200 ng / ml to 800 ng / ml, approximately 200 ng / ml to 700 ng / ml, approximately 200 ng / ml to 600 ng / ml, approximately 200 ng / ml to 500 ng / ml, approximately 200 ng / ml to 400 ng / ml, or approximately 200 ng / ml to approximately ng / ml.

[0142] In some embodiments, an effective amount of the adrenaline receptor modulating compound is approximately 10 pg to 100 mg, for example, approximately 10 pg to 50 pg, approximately 50 pg to 150 pg, approximately 150 pg to 250 pg, approximately 250 pg to 500 pg, approximately 500 pg to 750 pg, approximately 750 pg to 1 ng, approximately 1 ng to 10 ng, approximately 10 ng to 50 ng, approximately 50 ng to 150 ng, and approximately 150 ng to 250 mg. The dosage ranges from approximately 250 ng to 500 ng, approximately 500 ng to 750 ng, approximately 750 ng to 1 mg, approximately 1 pg to 10 pg, approximately 10 pg to 50 pg, approximately 50 pg to 150 pg, approximately 150 pg to 250 pg, approximately 250 pg to 500 pg, approximately 500 pg to 750 pg, approximately 750 pg to 1 mg, approximately 1 mg to 50 mg, approximately 1 mg to 100 mg, or approximately 50 mg to 100 mg. This dosage may be a single dose or the total daily dose. The total daily dose may be in the range of approximately 10 pg to 100 mg, approximately 100 mg to 500 mg, or approximately 500 mg to 1000 mg.

[0143] This specification also discloses pharmaceutical compositions comprising compounds disclosed herein, namely compounds having the structure of formula (I), formula (I'), formula (Ia), formula (I-a'), formula (Ib), formula (I-b'), formula (Ic), formula (I-c'), formula (Id), formula (I-d'), formula (I-e'), formula (I-f'), formula (I-g'), formula (I-h'), formula (I-i'), formula (I-j'), formula (II), formula (II'), formula (III), formula (III'), formula (IV), or formula (IV'), and pharmaceutically acceptable excipients.

[0144] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be administered to a patient together with the compounds of this disclosure and does not impair their pharmacological activity. Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, water, salts or partial glyceride mixtures of electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0145] In pharmaceutical compositions comprising only the compounds described herein as active ingredients, a method of administering these compositions may further include a step of administering additional drugs or therapeutic agents. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological drugs, drugs that modulate cardiovascular function, drugs that modulate 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 include any other drugs or biologics found in any drug class. For example, other drug classes may include allergy / cold / ENT therapy, analgesics, anesthetics, anti-inflammatory drugs, antibacterial agents, antiviral agents, asthma / pulmonary therapy, cardiovascular therapy, dermatological therapy, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunotherapy, neurotherapy, ophthalmic therapy, psychiatric therapy, or rheumatic therapy. Other examples of agents or therapies that may be administered in conjunction with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-angiogenic compounds.

[0146] As used herein, the term “therapeutic dose” means the amount of an active compound or drug that elicits a biological or pharmaceutical response in a tissue, system, animal, individual, or human, as determined by researchers, veterinarians, physicians, or other clinicians, and includes one or more of the following: (1) preventing disease, e.g., preventing disease, condition, or disorder in an individual that is susceptible to disease, condition, or disorder but has not yet experienced or exhibited the pathology or symptomatology of that disease; (2) inhibiting disease, e.g., inhibiting disease, condition, or disorder in an individual that has experienced or exhibited the pathology or symptomatology of that disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomatology); and (3) improving disease, e.g., improving disease, condition, or disorder in an individual that has experienced or exhibited the pathology or symptomatology of that disease, condition, or disorder (i.e., reversing the pathology and / or symptomatology).

[0147] In some embodiments, the compounds disclosed herein may be adrenergic receptor modulators (e.g., adrenergic receptor agonists, partial agonists, or antagonists). In some embodiments, the adrenergic receptor modulators of this disclosure may be useful for modulating the activity of a target adrenergic receptor in vitro or in vivo. An aspect of the method described herein involves contacting a sample with an effective amount of an adrenergic receptor modulator (e.g., as described herein) to determine whether the desired activity is present.

[0148] Adrenergic receptors (ADRs) are G protein-binding receptors (GPCRs) that are widely expressed throughout the body and play a crucial role in regulating multiple physiological processes, including cognition, stress-related behavior, inflammation, and smooth muscle contraction / dilation, myocardial contraction, airway responsiveness, and cognition. Adrenergic receptors mediate the central and peripheral effects of noradrenaline (NA) and adrenaline. Multiple subtypes of ADRs exist, including α-adrenergic receptors and β-adrenergic receptors. Each subtype is expressed in a different pattern and is involved in different physiological processes. Therefore, ligands that selectively target one subtype are highly useful both as research tools for identifying the roles of different ADR subtypes and as therapeutic agents for multiple diseases associated with NA and adrenergic system dysfunction.

[0149] α-Adrenergic receptors are α 1A - Adrenergic receptor (α 1A -ADR), α 1B - Adrenergic receptor (α 1B -ADR), and α 1D - Adrenergic receptor (α 1D The α-adrenergic receptor (α-ADR) further includes three subtypes. Because these subtypes are expressed in different patterns and are involved in different physiological processes, ligands that can selectively target one subtype have therapeutic potential for multiple diseases. However, the discovery of subtype-selective ligands is difficult due to the high level of sequence homology shared by these subtypes. Many existing agonists for the α-adrenergic receptor also exhibit poor blood-brain barrier (BBB) ​​permeability. However, effective therapies for most central nervous system (CNS) indications often require good drug BBB permeability.

[0150] As a class of G protein-binding receptors, adrenaline receptors transmit signals via G protein-dependent and arrestin-dependent pathways. G protein or arrestin signaling can mediate different physiological responses. Recently, it has become clear that agonists can exhibit biased activation of signaling pathways. The ability of a ligand to activate a receptor and produce a pathway-dependent response has been called "signaling bias" or "functional selectivity." Because G proteins and arrestins mediate different physiological processes, biased agonists can offer improved therapeutic selectivity with reduced side effects. Therefore, this disclosure aims to provide adrenaline receptor subtype-selective agonists with improved blood-brain barrier (BBB) ​​penetration.

[0151] Adrenergic receptor modulators can be agonists of target adrenergic receptors. In some cases, an effective dose of an adrenergic receptor modulator is sufficient to activate intracellular adrenergic receptor-related activity by 10% or more, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or even more, compared to a control, e.g., a control cell exhibiting a known level of receptor activity.

[0152] Adrenergic receptor modulators may be partial agonists of the target adrenergic receptor. In some cases, the effective amount of the adrenergic receptor modulator is sufficient to achieve partial agonism of the intracellular adrenergic receptor, for example, the compound in question achieving 10% or more activation of the receptor compared to a control, e.g., a fully activated receptor, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% activation. Partial agonism can be evaluated using any convenient method, such as a cell-based assay using a known fully activated agonist as a 100% activation control, and the relative maximum activation of the receptor can be measured relative to the fully activated agonist.

[0153] Adrenergic receptor modulators may be antagonists of target adrenergic receptors. In some cases, an effective amount of an adrenergic receptor modulator is sufficient to inhibit or reduce the activity of the target adrenergic receptor in a sample by 10% or more, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even more, compared to a control, e.g., a sample not exposed to the compound of interest.

[0154] In some embodiments of this method, the target adrenergic receptor is α 1A - These are adrenaline receptors.

[0155] Target adrenergic receptors may be responsible for mediating intracellular signaling or pathways in cells. In some embodiments, the sample comprises cells, and modulation of adrenergic receptors modulates cellular physiological processes. Any desirable physiological process can be targeted for intracellular modulation using the methods of this study. In some embodiments, the physiological process is involved in cardiac function, and in certain cases, the physiological process is involved in cognitive function. In certain cases, the physiological process is involved in inflammatory pathways or pathological conditions. The methods of this study can provide mediation of intracellular concentrations of intracellular signaling molecules, such as cAMP. The methods of this study can provide partial or complete blockade of target adrenergic receptors, resulting in modulation (e.g., activation) of cAMP in the sample. In some embodiments, the methods do not modulate the cellular β-arrestin pathway. In some cases, the cells are inflammatory cells, and cellular function is regulated. The methods of this study can provide inhibition of inflammatory pathways in cells. In some cases, TNF-α is inhibited intracellularly, and for example, TNF-α concentration or production is reduced by performing the methods of this study. In certain embodiments of this method, the cells are neurons. In some embodiments, the modulation of adrenaline receptors enhances neurogenesis.

[0156] The compounds disclosed herein may be used in a conventional manner to control, prevent or treat 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, cerebrovascular disease, epilepsy, Tourette syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, ataxia Friedrich's syndrome, ataxia distensibility, polymyalgia spinosa, progressive supranuclear phallopsis, dystonia, muscle atrophy, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis, autosomal dominant cerebral arteriovenous disease (CADASIL) with subcortical infarction and leukoencephalopathy, and diabetic retinopathy. Such treatment methods, their dosage levels, and requirements can be selected by those skilled in the art from available methods and techniques.

[0157] Some aspects and embodiments of this disclosure involve at least in part relatively low doses of α 1A - α by AR partial agonist 1A - This is based on the discovery that partial agonism of AR receptors can increase cardiac output resulting from improved venous return and myocardial contractility without the simultaneous increase in arteriolar vascular resistance, thus leading to increased blood flow to various parts of the body, including the brain. Therefore, it is necessary to identify patients with nOH, or low cerebral blood flow (CBF) and / or diseases or disorders associated with fluctuations in CBF, and to apply α to these patients. 1A Compositions and methods comprising administering an AR partial agonist are provided herein.

[0158] In this regard, I do not wish to be bound to any one particular theory, but α 1A -AR receptors are preferentially found on venous vascular branches and ventricular myocytes. α 1AActivation of α1-AR receptors activates smooth muscle within venous vascular branches, reduces venous capacitance, promotes blood return to the heart, and also activates cardiomyocytes, increasing pumping action. This makes it a cardiotonic agent with physiological inotropic effects. With increased venous return, preload is increased, thus increasing the amount of cardiac filling, and the inotropic effect enhances ejection function. Both combine to deliver further output to the arteries. However, unlike the indirect sympathomimetic droxidopa / Northera or the non-selective α1-AR agonist midodrine, α 1A -AR partial agonists, in certain embodiments, arteriole smooth muscle (mainly α 1B -AR and α 1D -AR function is preserved, and therefore peripheral vascular resistance will not increase significantly (there is no increase in "afterload"). Consequently, the increase in blood pressure will not be very strong (especially in the supine position), and the increase in cardiac output will easily perfuse organs, including the brain.

[0159] Accordingly, the present disclosure includes methods and compositions for treating diseases, disorders, or conditions associated with, or caused by, an impairment (or relative reduction) in either or both of (a) cardiac output and / or venous return.

[0160] In certain embodiments and aspects of this disclosure, compositions and methods result in improved cognitive function, increased cerebral metabolic activity, and / or improved inflammation control in patients. In some embodiments, the methods described herein result in cognitive improvements, as demonstrated by improvements in cognitive tests or models such as patient memory tests, diagnostic indices of mental state, brain function, mental condition, and contextual learning tests. Such cognitive tests, diagnoses, and models are well known in the art. In various embodiments and aspects, any of the many acceptable contextual learning tests for animals or humans may be used to assess baseline cognitive function and / or measure or quantify improvements in cognitive function. In some embodiments, the compositions and methods described herein may result in improvements in one or more tests, diagnoses, and models such as: Similarly, increased cerebral metabolic activity and improved inflammation control may, in certain embodiments, be imaged via FDG-PET and cerebrospinal fluid (CSF) sampling, enabling the measurement of inflammatory cytokines and markers of glial cell activation.

[0161] 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 three minutes of changing posture from a supine to an upright position (Neurology 1996;46:1470). OH can produce a wide variety of symptoms, including dizziness, lightheadedness, fainting and (syncope), and discomfort in the upper chest and shoulder area ("coat hanger" pain). These symptoms often inhibit, or even interfere with, everyday activities that require standing and walking. In addition, OH is associated with increased morbidity and mortality. For example, see 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.

[0162] The underlying causes of orthostatic hypotension (OH) can be broadly classified into neurogenic and non-neurogenic categories. Neurogenic orthostatic hypotension (nOH) is a form of OH caused by peripheral or central nervous system disorders, such as OH involving the nervous system, e.g., primary autonomic dysfunction (including pure autonomic dysfunction, multiple system atrophy, and Parkinson's disease), and autonomic neuropathy (including autonomic dysfunction) (including diabetes and non-diabetic autonomic neuropathy) (Arbique et al., JAMDA 15(2014)234-239). Such disorders can lead to a deficiency or dysregulation of norepinephrine, the main neurotransmitter that regulates blood pressure in response to changes in posture (Loavenbruck et al, Curr. Med. Res. Opin., 2015;31:2095-2104). As a result, the autonomic nervous system is unable to properly regulate blood pressure during changes in posture, and patients experience a significant drop in blood pressure that can lead to symptoms such as dizziness, lightheadedness, or fainting.

[0163] Therefore, managing the nOH state fundamentally requires increasing cerebral blood flow (CBF) in relation to the otherwise pathological decrease in blood pressure during the patient's supine to standing posture change. Various aspects and embodiments of the compositions and methods provided herein include: α1A -AR partial agonists are administered to patients with nOH, and the action of the partial agonists reduces the frequency and severity of signs and symptoms associated with nOH (including dizziness / vertigo, pre-fainting symptoms, fainting / loss of consciousness, and "coat hanger pain"). By maintaining better CBF, in some embodiments, patients will also maintain improved cognitive function, particularly the "fluctuating" cognitive function commonly seen in "synuclein disease" conditions, which are typically often associated with nOH. Descriptions of symptoms / tests / screenings and some treatments for nOH can be found in Eschlbock et al, J Neural Tansm, (2017) 124:1567-1605 and Gibbons et al, J Neurol, (2017) 264:1567-1582.

[0164] Where used herein, “combined,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to this disclosure. For example, the compounds described may be administered simultaneously with another therapeutic agent, sequentially in separate unit dosage forms, or together in a single unit dosage form. Accordingly, this disclosure provides a single unit dosage form comprising the compounds described, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered “combined” if a patient or individual is simultaneously exposed to both agents. In many embodiments, two or more agents are considered to be administered “combined” if a patient or individual simultaneously exhibits therapeutically appropriate levels of the agents in a particular target tissue or sample (e.g., in the brain, in serum, etc.).

[0165] When the compounds of this disclosure are administered in combination with other agents, they may be administered to the patient sequentially or concurrently. Alternatively, the pharmaceutical or prophylactic compositions of this disclosure include ivermectin, or any other compound described herein, and combinations with other therapeutic or prophylactic agents. Additional therapeutic agents that are typically administered to treat a particular disease or condition may be referred to as “agents appropriate for the disease or condition being treated.”

[0166] In some embodiments, the methods described herein include administering one or more additional activators in a therapeutically effective amount. Combination therapy means that an adrenergic receptor-modulating compound can be used in combination with another therapeutic agent to treat a single disease or condition. In certain embodiments, the compounds of the disclosure are administered concurrently with the administration of another therapeutic agent, which may be administered as a component of a composition containing the compounds of the disclosure or as a component of a different composition.

[0167] The compound in question can be administered in combination with other therapeutic agents in a variety of therapeutic applications. Target therapeutic applications for combination therapy include those where the activity of a target adrenergic receptor is a causative or contributing factor in disease progression. Therefore, the compound in question finds use in combination therapies where inhibition of the target adrenergic receptor is desired. Examples of diseases and conditions that can be treated with combination therapies including the compound in question include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental disorders, respiratory disorders, asthma, memory impairment, depression, inflammatory diseases, stroke, ischemic brain or tissue injury, and cancer. Target agents that can be used in combination with the adrenergic receptor modulator in question include, but are not limited to, antidepressants, antipsychotics, beta-blockers, vasoconstrictors, hypotensives, palliatives, chemotherapeutic agents, drugs used in Alzheimer's disease, and anti-inflammatory agents.

[0168] The adrenergic receptor modulators described herein can be used in conjunction with any drug useful for treating cardiac conditions such as cardiac shock, hypertension, congestive heart failure, coronary heart disease, arrhythmias, myocardial infarction, or ischemic heart disease. Drugs that can be used in combination with these adrenergic receptor modulators include, but are not limited to, denopamine, dobutamine, xamoterol, acebutol, atenolol, betaxolol, bisoprolol, pindolol, esmolol, metoprolol, nebibolol, vortioxetine, carvedilol, labetalol, phentolamine, prazosin, silazolin, methoxamine, synephrine, etilephrine, metalaminol, midrin, and coumarin.

[0169] The adrenergic receptor modulators described herein can be used in combination with any agent useful for treating neurodegenerative or neurodevelopmental disorders such as Alzheimer's disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue injury, Down syndrome, or autism. Target agents that can be used in combination with the adrenergic receptor modulators described herein include, but are not limited to, acepromazine. In some embodiments, the adrenergic receptor modulators described herein can be used in combination with cholinesterase inhibitors or NMDA receptor modulators to treat diseases such as neurodegenerative or neurodevelopmental disorders. Target agents include, but are not limited to, donepezil, aricept, galantamine, razadyne, memantine, namenda, rivastigmine, exelon, tacrine, and cognex. Other drugs for specific purposes that can be used in combination with the adrenergic receptor modulators of this study include 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadorumidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mibazerol, rilmenidine, romifidine, talipexol, thiamenidine, tizanidine, tronidine, This includes, but is not limited to, xylazine, xylometazoline, aripiprazole, asenapine, atipamezole, silazolin, clozapine, efaloxane, idazoxane, lurasidone, merperone, mianlin, mirtazapine, napitan, olanzapine, paliperidone, phenoxybenzamine, phentolamine, pyribezil, rauwolsine, risperidone, rotigonin, quetiapine, norquetiapine, setiptiline, trazoline, yohimbine, ziprasidone, and zotepine.Other agents for specific purposes that may be used in conjunction with the adrenergic receptor modulators of this study include, but are not limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levosalbutamol or revalbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol, salbutamol or albuterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, milbeterol, orodaterol, vilanterol, fenoterol, hexoprenaline, isoxussupreline, ritodrine, salbutamol or albuterol, terbutaline, zilpeterol, ICI-118,551, and butoxamine.

[0170] Compounds used in the compositions and methods of this disclosure may also be modified by adding appropriate functional groups to enhance their selective biological properties. Such modifications are known in the art and include those that increase biopenetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), enhance oral availability, increase solubility to enable administration by injection, alter metabolism, and / or alter excretion rate.

[0171] According to preferred embodiments, the compositions of this disclosure are formulated for pharmaceutically administered to a subject or patient, for example, a mammal, preferably a human. Such pharmaceutically administered compositions are used to improve, treat or prevent any of the diseases described herein in a subject.

[0172] The agents of this disclosure are often administered as active therapeutic agents, i.e., pharmaceutical compositions containing various other pharmaceutically acceptable components. 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 use. The composition may also include, depending on the desired formulation, pharmaceutically acceptable non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluents are selected so as not to affect the combined biological activity. Examples of such diluents include distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers.

[0173] In some embodiments, this disclosure provides pharmaceutically acceptable compositions comprising one or more therapeutically effective amounts of the compounds described herein, formulated with one or more pharmaceutically acceptable carriers (excipients) and / or diluents for use in treating diseases described herein, including but not limited to stroke, ischemia, Alzheimer's disease, ankylosing spondylitis, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthmatic atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, systemic lupus erythematous, nephritis, ulcerative colitis, and Parkinson's disease. While the compounds described may be administered alone, it is preferable to administer the compounds as part of the pharmaceutical formulations (compositions) described herein. The compounds described may be formulated for administration in any convenient manner for use in human or veterinary medicine due to their similarity to other pharmaceuticals.

[0174] As described in detail, the pharmaceutical compositions of this disclosure may be specifically formulated for administration in solid or liquid form, including, for example, oral administration, e.g., drenches (aqueous or nonaqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and systemically absorbed tablets for application to the tongue, boluses, powders, granules, pastes; parenteral administration, e.g., sterile solutions or suspensions, or by subcutaneous, intramuscular, intravenous, or epidural injection as sustained-release formulations; topical application, e.g., as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or oral cavity; intravaginal or rectal administration, e.g., as pessaries, creams, or foams; sublingual; intraocular; transdermal; or adapted for administration to the nasal, lung, and other mucosal surfaces.

[0175] Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants may also be present in the composition.

[0176] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metasulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0177] Formulations for use in accordance with this disclosure include formulations suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. Formulations may be conveniently presented as unit dosage forms and may be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single-dose formulation varies depending on the host being treated and the specific mode of administration. Generally, the amount of active ingredient that can be combined with a carrier material to produce a single-dose formulation is the amount of the compound that produces the therapeutic effect. Generally, this amount will be in the range of about 1% to about 99% of the active ingredient. In some embodiments, this amount will be in the range of about 5% to about 70%, about 10% to about 50%, or about 20% to about 40%.

[0178] In certain embodiments, the formulations described herein comprise a compound of the Disclosure and an excipient selected from the group consisting of cyclodextrin, liposomes, micellar-forming agents, such as bile acids, and polymer carriers, such as polyesters and polyanhydrides. In certain embodiments, the aforementioned formulations make the compounds described herein orally bioavailable.

[0179] A method for preparing a formulation or composition containing the compounds described herein includes the step of associating the compounds of the disclosure with a carrier and optionally one or more minor components. Generally, formulations may be prepared by homogeneously and closely associating the compounds of the disclosure with a liquid carrier, or a micronized solid carrier, or both, and then shaping the product as necessary.

[0180] The pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oily suspension. This suspension may be formulated according to techniques known in the art using a suitable dispersant or wetting agent (e.g., Tween 80) and a suspending agent. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixative oils have been conventionally used as solvents or suspension media. For this purpose, any smooth fixative oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, particularly their polyoxyethylated versions, are useful in the preparation of injectable preparations, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as those described in the Swiss Pharmacopoeia (Pharmacopeia Helvetica), or similar alcohols. For formulation purposes, other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used.

[0181] In some cases, it may be desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a crystalline or amorphous liquid suspension that is poorly water-soluble. The absorption rate of the drug then depends on its dissolution rate, which in turn may depend on the size and shape of the crystals. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oily vehicle.

[0182] Injectable depot formulations are prepared by forming a microcapsule matrix of the described compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Depot injection formulations are also prepared by capturing the drug in liposomes or microemulsions that are compatible with body tissues.

[0183] The pharmaceutical compositions of this disclosure may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administering aqueous suspensions and solutions, and propylene glycol orally, the active ingredient is combined with emulsifiers and suspending agents. Specific sweeteners and / or flavorings and / or colorings may be added as needed.

[0184] Preparations described herein that are suitable for oral administration may each contain a predetermined amount of the compound disclosed herein as an active ingredient, and may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes. The compounds described herein may also be administered as boluses, electuaries, or pastes.

[0185] In solid dosage forms for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), the active ingredient is contained in one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; and wetting agents, e.g., glycerol. Mixed with humectants; disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and solution retarders such as sodium carbonate; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents, such as kaolin and bentonoth clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include buffers. Similar types of solid compositions may also be used as fillers in soft-shell and hard-shell gelatin capsules, using excipients such as lactose and high molecular weight polyethylene glycol.

[0186] Tablets can be prepared by compression or molding with one or more adjuncts as optional. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium glycolate starch or cross-linked carboxymethylcellulose sodium), a surfactant, or a dispersant. Molded tablets can be prepared using a suitable machine that moistens a mixture of powder compounds with an inert liquid diluent. When a solid carrier is used, the preparation may be in tablet form, or in powder or pellet form placed in a hard gelatin capsule, or in the form of a troche or lozenge. The amount of solid carrier may vary, for example, from about 25 to 800 mg, preferably from about 25 mg to 400 mg. When a liquid carrier is used, the preparation may be in the form of a sterile injectable solution such as a syrup, emulsion, soft gelatin capsule, ampoule, or non-aqueous liquid suspension. When the composition is in capsule form, any conventional encapsulation is preferred, for example, using the aforementioned carrier in a hard gelatin capsule shell.

[0187] Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally or additionally be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a desired release profile. They may be formulated for rapid release, for example, lyophilization. They may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. These compositions may also optionally contain an opacifying agent and may optionally be compositions that release only or preferentially the active ingredient in a delayed manner in a specific part of the gastrointestinal tract. Examples of embedding compositions that may be used include polymer materials and waxes. The active ingredient may, where appropriate, be in the form of microencapsulated material containing one or more of the above-mentioned excipients.

[0188] Liquid dosage forms for oral administration of the compounds of this disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage forms may contain, for example, inert diluents, solubilizers, and emulsifiers commonly used in the art, such as water or other solvents, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly 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, as well as mixtures thereof.

[0189] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives.

[0190] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0191] The pharmaceutical compositions of this disclosure may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of this disclosure with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the active ingredient. Examples of such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0192] Topical administration of the pharmaceutical compositions of this disclosure is particularly useful when the desired treatment involves an area or organ that is easily accessible by topical application. For topical application to the skin, the pharmaceutical compositions should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Suitable carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical compositions may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this disclosure may be applied topically to the lower intestinal tract by rectal suppository formulations or in suitable enema formulations. Topically administered transdermal patches are also included in this disclosure.

[0193] The pharmaceutical compositions of this disclosure may be administered by nasal aerosol or inhalation. Such compositions may be prepared in accordance with well-known techniques in the field of pharmaceutical formulations and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other solubilizers or dispersants known in the art.

[0194] For ophthalmic use, the pharmaceutical composition may be formulated as a microparticle suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment such as petrolatum.

[0195] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of this disclosure to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flow of the compounds across the skin. The rate of such flow can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0196] Suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using a coating material such as lecithin, maintaining the required particle size in the case of a dispersion, and using a surfactant.

[0197] Such compositions may contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. In certain embodiments, encapsulation of one or more antibacterial and / or antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid, may be desirable. The inclusion of isotonic agents such as sugars and sodium chloride in the composition may be alternatively or additionally desirable. In addition, the inclusion of absorption-delaying agents such as aluminum monostearate and gelatin may result in longer absorption of the injectable pharmaceutical form.

[0198] In certain embodiments, the compound or pharmaceutical preparation described is administered orally. In other embodiments, the compound or pharmaceutical preparation described is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0199] When the compounds described herein are administered to humans and animals as pharmaceuticals, they may be given either by themselves or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0200] The preparations described herein may be administered orally, parenterally, topically, or rectally. They may, of course, be administered in a form suitable for the relevant route of administration. For example, they may be administered 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 suppository). Oral administration is preferred.

[0201] Such compounds may be administered to humans and other animals for therapeutic purposes by any preferred route of administration, including orally and nasally, for example, by spray, rectally, vaginally, parenterally, intravesically, and topically (in powder, ointment, or drops, including buccal and sublingual).

[0202] Regardless of the selected route of administration, the compounds described herein and / or the pharmaceutically acceptable compositions of this disclosure, which can be used in a preferred hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0203] The actual dose levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0204] Kits containing the disclosed adrenaline receptor modulators are also provided. The systems of this disclosure include, for example, a collection of active agents assembled by a healthcare professional for administration to a subject such as a patient. Such systems may include the adrenaline receptor modulators disclosed herein and one or more additional activators. Kits containing adrenaline receptor modulators are provided, which may include one or more doses of the adrenaline receptor modulator and optionally one or more doses of additional activators. Conveniently, the formulations may be provided in unit dosage forms. Such kits may include, in addition to the formulation, for example, a container containing a unit dose, an informational leaflet describing the use of the formulation in a manner as disclosed herein, for example, instructions for using a unit dose of the formulation to treat a cytoproliferative disorder. These instructions may be present in various forms in the systems and kits of the subject, and one or more of these forms may be present in the kit. One possible form in which these instructions may be present is as information printed on a preferred medium or substrate, for example, one or more sheets of paper on which the information is printed, the kit packaging, or an accompanying leaflet. Another means is a computer-readable medium on which the information is recorded, such as a diskette or CD. Furthermore, another possible means is a website address that can be used to access the information from the retrieved site via the internet. Any convenient means may be present in the kit.

[0205] The following examples are provided to further illustrate the advantages and features of the Disclosure, but are not intended to limit the scope of the Disclosure. The examples are typical of what may be used, but other procedures, methods, or techniques known to those skilled in the art may be used instead. Table 1 below shows exemplary synthesized compounds of the Disclosure.

[0206] (Table 1) Exemplary Compounds TIFF0007873661000174.tif190128TIFF0007873661000175.tif196115TIFF00078736610 00176.tif204115TIFF0007873661000177.tif202115TIFF0007873661000178.tif202115 TIFF0007873661000179.tif197115TIFF0007873661000180.tif202115TIFF00078736610 00181.tif204115TIFF0007873661000182.tif225126TIFF0007873661000183.tif217126 TIFF0007873661000184.tif222126TIFF0007873661000185.tif216126TIFF00078736610 00186.tif211126TIFF0007873661000187.tif221126TIFF0007873661000188.tif230126 TIFF0007873661000189.tif225126TIFF0007873661000190.tif236126TIFF00078736610 00191.tif230126TIFF0007873661000192.tif215126TIFF0007873661000193.tif214126

[0207] In some embodiments, the present disclosure provides compounds from Table 1 or pharmaceutically acceptable salts thereof. [Examples]

[0208] Example I Scheme 1: Preparation of Compound 22 TIFF0007873661000194.tif58144 A solution of ester A-1 (6g, 26.19 mmol) in DMA (72 mL) with pyrazole (8.92 g, 130.96 mol), N 1 ,N 2 -Dimethylethane-1,2-diamine (692.68 mg, 7.86 mmol), CuI (1.5 g, 7.86 mmol), and K2CO3 (10.86 g, 78.58 mol) were added. The mixture was stirred under N2 at 120°C for 12 hours. TLC (petroleum ether / SiO2 3:1, R f A reaction strength of 0.5) indicated that approximately 70% of the starting material remained, and 30% of the desired product was detected. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic matter was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain ester A-2 (0.6 g, yield 10%) as a colorless oil. 1 H NMR(400MHz,CDCl3-d)δ 7.90-7.97(m,1H),7.75(d,J=1.4Hz,1H),7.58(d,J=2.3Hz,1H),7.47-7.53(m ,1H),7.35(t,J=7.8Hz,1H),6.47(t,J=2.0Hz,1H),3.93(s,3H),2.34(s,3H).

[0209] To a solution of ester A-2 (470 mg, 2.17 mmol) in toluene (5 ml), DIBAL-H (6.52 ml, 1 M) was added at -78°C. The mixture was stirred at -78°C for 3 hours. TLC (petroleum ether / SiO2 2:1) showed that the starting material was consumed and a new major spot was formed. The mixture was quenched with aqueous HCl (1 N, 30 ml) and extracted with SiO2 (3 × 10 ml). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain alcohol A-3 (340 mg, 85% purity, 71% yield) as a white solid. 1H NMR(400MHz,CDCl3-d)δ 7.79(d,J=1.5Hz,1H),7.61(d,J=2.2Hz,1H),7.55(d,J=7.2Hz,1H),7.25-7.34(m,2H),6.51(t,J=2.0Hz,1H),4.63(s,2H),3.08(br s,1H),2.02(s,3H).

[0210] To a solution of alcohol A-3 (340 mg, 1.81 mmol) in DCM (5 mL), SOCl2 (429.8 mg, 3.61 mmol) and a catalytic amount of DMF were added. The mixture was stirred at 20°C for 2 hours. TLC (petroleum ether / siRNA 2:1) showed that N-4 was consumed and a new major spot was formed. The mixture was neutralized with aqueous NaHCO3 (20 mL), the organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain benzyl chloride A-4 (340 mg, purity 90%, yield 82%) as a yellow solid. 1 H NMR(400MHz,CDCl3-d)δ 7.70(d,J=1.3Hz,1H);7.56(d,J=2.3Hz,1H),7.39(dd,J=7.1,1.59Hz,1H),7.27(br s, 2H), 6.43 (t, J=2.0Hz, 1H), 4.64 (s, 2H), 2.20 (s, 2H), 2.14-2.25 (m, 1H).

[0211] NaCN (137.53 mg, 2.81 mmol) was added to a solution of benzyl A-4 chloride (290 mg, 1.40 mmol) in DMSO (6 mL). The mixture was stirred at 40°C for 2 hours. TLC showed that all of the starting material was consumed and a new major spot was formed. The mixture was diluted with siRNA (30 ml), the combined organic matter was washed with water (3 × 10 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / siRNA 2:1) to obtain nitrile A-5 (210 mg, 90% purity, 68% yield) as a yellow solid. 1H NMR(400MHz,CDCl3-d)δ 7.74(d,J=1.7Hz,1H);7.59(d,J=2.4Hz,1H),7.48(t,J=4.5Hz,1H),7.30-7. 38(m,2H),6.47(t,J=2.1Hz,1H),3.76(s,2H),2.15(s,3H);LCMS(ESI+):m / z 197.9(M+1).

[0212] To a solution of nitrile A-5 (210 mg, 1.06 mmol) in ethane-1,2-diamine (2 mL), CS2 (8.11 mg, 0.106 mmol) was added. The mixture was stirred at 110 °C for 2 hours. LC-MS showed that the starting material consumed 97% of the product with the desired mass. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 μm column, mobile phase: A: HCl / H2O = 0.040% v / v; B: ACN) to obtain compound 22 (42.8 mg, purity 99%, yield 17%) as a yellow solid. 1 H NMR(400MHz,CD3OD-d4)δ 7.91(dd,J=18.4,2.4Hz,1H),7.50(dd,J=7.2,2.4Hz,1H),7.49-7.30(m,1H),6.64(t,J=2.4 Hz),4.07(s,2H),3.96(s,4H),2.06(s,3H);LCMS(ESI+):m / z 241.1(M+1).

[0213] Example 2: Scheme 2: Preparation of Compound 27 TIFF0007873661000195.tif85144 Sodium borohydride (2.72 g, 71.77 mmol) was added at 0°C to a solution of 2-bromo-4-chlorobenzaldehyde (15 g, 68.35 mmol) in methanol (250 mL). After 30 minutes, TLC (3:1 petroleum ether / siRNA) showed that the starting material had been consumed and new spots were detected. The mixture was quenched with water (120 mL), concentrated, and extracted with ethyl acetate (2 × 150 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain alcohol B-2 (15 g, 100% yield) as a white solid. 1 H NMR(400MHz, CDCl3-d)δ 7.57(d,J=1.9Hz,1H),7.44(d,J=8.2Hz,1H),7.33(dd,J=8.2,1.91Hz,1H),4.73(s,2H),2.23-2.39(m,1H),2.15(br s,1H).

[0214] A solution of alcohol B-2 (15 g, 67.73 mmol) in SOCl2 (90 mL) was heated to 80°C. After 3 hours, TLC (3:1 petroleum ether / siRNA) showed that the starting material had been consumed and new spots were detected. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash chromatography (silica gel, gradient 50 / 1 to 10 / 1 petroleum ether / siRNA) to obtain benzyl B-3 chloride (10.3 g, yield 63%) as a colorless oil. 1 H NMR (400MHz, CDCl3-d) δ 7.63(d,J=1.2Hz,1H),7.44(d,J=8.2Hz,1H),7.33(dd,J=8.3,1.13Hz,1H),4.68(s,2H).

[0215] To a solution of benzyl chloride, B-3 (22.3 g, 92.95 mmol) in 150 mL of DMSO, NaCN (7.29 g, 148.71 mmol) was added. The mixture was heated to 45°C. After 3 hours, TLC (10:1 petroleum ether / siRNA) showed that all the starting material had been consumed and major spots had formed. The mixture was cooled, diluted with 100 mL of water, and extracted with siRNA (2 × 100 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. This was purified by flash chromatography (eluting silica gel, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to obtain nitrile B-4 (18 g, 87% yield) as a white solid. 1 H NMR (400MHz, CDCl3-d) δ 7.63 (d, J = 2.1 Hz, 1H), 7.44-7.50 (m, 1H), 7.37 (dd, J = 8.3, 2.1 Hz, 1H), 3.82 (s, 2H).

[0216] To a solution of nitrile B-4 (6 g, 26.03 mmol) in anhydrous dioxane (200 mL), B2Pin2 (7.93 g, 31.24 mmol), KOAc (7.66 g, 78.09 mmol), and Pd(dppf)Cl2 (180 mg) were added at 20°C. The reaction mixture was degassed with N2 for 2 minutes and then heated at 90°C for 12 hours. TLC (5:1 petroleum ether / siRNA) showed that the starting material had been consumed and new spots had formed. The reaction mixture was diluted with water (500 mL) and extracted with siRNA (3 × 200 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, gradient 100 / 1 to 20 / 1 petroleum ether / siRNA) yielded the product pinacol boronate B-5 (4 g, 55% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.65 (d, J = 2.4 Hz, 1H), 7.62-7.58 (m, 1H), 7.50-7.45 (m, 1H), 4.13 (s, 2H), 1.32 (s, 12H).

[0217] To a solution of pinacol boronate B-5 (300 mg, 1.08 mmol) in 10 mL of 4:1 dioxane / H2O, Na2CO3 (229.12 mg, 2.16 mmol), 2-chloropyrazine (185.69 mg, 1.62 mmol), and PdCl2(PPh3)2 (75.87 mg, 108.09 μmol) were added. The mixture was stirred at 80°C. After 30 minutes, LC-MS showed that the starting material had been consumed and 43% of the product with the desired mass was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with siRNA (50 mL x 3). The combined organic matter was washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with 100 / 1 to 20 / 1 petroleum ether / siRNA) to obtain the product pyrazine B-6 (yield 120 mg, 48%) as a white solid. 1 H NMR(400MHz, CDCl3-d)δ 8.83(d,J=1.1Hz,1H),8.70-8.61(m,2H),7.60-7.53(m,2H),7.53-7.47(m,1H),4.04(s,2H);LCMS(ESI+):m / z 230.1(M+1).

[0218] To a solution of F-1 (100 mg, 435.42 μmol) in ethane-1,2-diamine (3 mL), CS2 (3.32 mg, 43.54 μmol) was added. The mixture was stirred at 110°C. After 2 hours, LC-MS showed that the starting material had been consumed and 49% of the product with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: A: HCl / H2O = 0.040% v / v; B: ACN) to obtain compound 27 (44.6 mg, yield 38%, HCl salt) as an off-white solid. 1H NMR(400MHz,D2O)δ 8.79(s,1H),8.76(d,J=2.6Hz,1H),8.69(d,J=2.7Hz,1H),7.67(s,1H),7.64- 7.58(m,1H),7.50(d,J=8.3Hz,1H),3.97(s,2H),3.73(s,4H);LCMS(ESI+):m / z 273.1(M+1).

[0219] Example 3: Scheme 3: Preparation of Compound 40 TIFF0007873661000196.tif18142 To a solution of PPh3 (1.23 g, 4.69 mmol) in dry DCM (20 mL), CBr4 (777.59 mg, 2.34 mmol) was added under nitrogen at 0°C. After 30 minutes, a solution of 2-methoxy-4-chlorobenzaldehyde C-1 (200 mg, 1.17 mmol) in DCM (2 mL) was added to the mixture. After 2 hours, TLC (3:1 petroleum ether / siRNA) showed that all the starting material had been consumed and a new product had been formed. The mixture was diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic matter was washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The solution was purified by flash chromatography (silica gel, gradient 50:1-20:1 petroleum ether / siRNA) to obtain bromide C-2 (0.25 g, yield 65%) as a yellow oil. 1 H NMR(400MHz, CDCl3-d)δ 7.63(d,J=8.2Hz,1H),7.52(s,1H),6.96(dd,J=8.2,1.91Hz,1H),6.86(d,J=2.0Hz,1H),3.84(s,3H).

[0220] A solution of dibromide C-2 (250 mg, 0.765 mmol) in ethyleneamine (2 mL) was stirred at 20°C. After 12 hours, LC-MS showed that all of the starting material had been consumed and 40% of the product with the desired mass had been produced. The mixture was concentrated to obtain the residue. The residue was purified by pre-TLC (MeOH) and further purified by preparative HPLC (mobile phase: A: HCl / H2O = 0.040% v / v; B: CH3CN, column: Welch Xtimate C18 150 × 25 mm × 5 μm) to obtain compound 40 (16 mg, yield 10%) as a white solid. 1 H NMR(400MHz,CD3OD-d4)δ 7.29(d,J=7.95Hz,1H),7.11(d,J=1.8Hz,1H),7.03(dd,J=8.1,2.0Hz,1H),3.92(s,4H),3.91(s,3H),3.84(s,2H);LCMS(ESI+):RT=1.627min,m / z 225.0(M+1).

[0221] Example 4: Scheme 4: Preparation of Compound 42 A solution of phenol D-1 (2 g, 11.10 mmol, 1 equivalent) in CF3CH2OH (10 mL) was heated at 110°C for 30 minutes. TiCl4 (2.11 g, 11.10 mmol) was added over 10 minutes. After 30 minutes, a solution of 3-chlorobutan-2-one (1.42 g, 16.65 mmol, 1.2 equivalents) in CF3CH2OH (10 mL) was added dropwise over 10 minutes. After 12 hours, TLC (PET ether / SiO3:1) showed that most of the starting material had been consumed and the desired product had been produced. The reaction mixture was poured into saturated NH4Cl (50 ml) and extracted with petroleum ether / SiO4 (30 ml x 3). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to obtain ester D-2 (0.2 g, yield 8%) as a yellow oil. 1H NMR(400MHz, CDCl3-d)δ 7.30-7.35(m,2H),7.11(dd,J=8.4,2.0Hz,1H),4.49(q,J=8.8,2H),3.81(s,2H),2.38(s,3H),2.14(s,3H).

[0222] Ethane-1,2-diamine (77.62 mg, 1.29 mmol, 1.5 equivalents) was added at 0°C to a solution of AlMe3 (1.29 ml, 1.5 equivalents) in toluene (5 ml). After 30 minutes, a solution of ester D-2 (0.2 g, 0.861 mmol, 1 equivalent) in toluene (3 mL) was added at 0°C. The mixture was stirred at 110°C for 15 hours to obtain a yellow mixture. TLC (3:1 PET ether / siRNA) indicated that the starting material had been consumed and the desired product had been produced. The mixture was cooled to room temperature and quenched with MeOH (4 ml) and DCM (10 ml). The resulting mixture was filtered and concentrated. The residue was purified by preparative TLC (MeOH) and isolated by lyophilization to obtain compound 42 (27 mg, yield 14%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3-d)δ 7.30-7.25(m,2H),7.10(d,J=6.3Hz,1H),3.72(s,2H),3.59(s,4H),2.38(s,3H),2.10(s,3H);LCMS(ESI+):RT=1.837min,m / z 229.1(M+1).

[0223] Example 5: Evaluation of synthetic adrenergic receptor agonists Calcium flux experimental design: α-1 adrenergic receptor (α1-AR) is G q It binds to proteins, which leads to the downstream activation of phospholipase C and the release of calcium from intracellular storage. The increase in intracellular calcium upon α1-AR activation can be detected by calcium-6 dye.

[0224] Cell preparation: Cells expressing α1-AR were washed in warmed phosphate-buffered saline to remove the culture medium and collected using Versene (Caisson Labs, catalog number EDL01). The cells were centrifuged at 250 × g for 5 minutes, resuspended in growth medium, counted with a hemocytometer, seeded, and cultured overnight in a tissue culture incubator in a 384-well plate with a black clear bottom (Corning, catalog number 3764) at a rate of 10,000 cells per well in 30-50 μL of growth medium.

[0225] One vial of calcium-6 dye (Molecular Devices catalog no. R8190) was reconstituted in 10 mL of Hank's equilibrium salt solution (HBSS, Corning catalog no. 45000-462) containing 20 mM HEPES (Caisson Labs catalog no. HOL06) and stored at -20°C. On the day of the assay, the reconstituted calcium-6 was diluted 1:8 with HBSS / HEPES (VWR catalog no. E506) containing 2 mM CaCl2 and 2 mM sodium probenecid salt (AAT Bioquest catalog no. 20061) to prepare a cell dye solution. The medium was removed from the cells by tapping the plate upside down on an absorption wipe, followed by centrifugation at 50 × g while upside down for 15 seconds, and then removed again on an absorption wipe. Using a reagent dispenser (Integra viaFILL), 12 μL of cell dye solution was added to the cells, and the cells were incubated at 37°C and 5% CO2 for 90 minutes.

[0226] Compound Preparation: Candidate α-adrenergic compounds dissolved in 10 mM DMSO were diluted in assay buffer (HBSS / HEPES containing 2 mM CaCl2 and 2 mM probenecid sodium salt). Serial dilutions of the compounds (10 concentrations, 5-fold increments) were prepared in assay buffer using a 96-well plate (Corning 3365). All assay plates included vehicle (DMSO) and positive control (10 μM epinephrine) conditions (as well as dose-response curves for epinephrine). The completed 96-well compound plates were stamped onto a 384-well compound source plate (Corning 3657) at 50 μL per well using a viaFLO384 or viaFLO96 electronic pipette (Integra Biosciences), creating four technically replicated wells per dose. A 384-well compound plate was briefly centrifuged at 250xg, sealed (Axygen PCR-SP), and incubated at 37°C until 90 minutes of cell dye incubation was complete.

[0227] Stimulation and calcium flux quantification: A Flexstation 3 controlled by Softmax Pro software v7.0.3 (Molecular Devices) was pre-loaded with a FLIPR Tetra pipette tip (Molecular Devices catalog number 9000-0763) and set to 37°C at least 1 hour before 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 before starting the assay.

[0228] Calcium-6 fluorescence was detected by excitation at 485 nm, with a cutoff of 515 nm, and emission measured at 525 nm. For each assay well, baseline calcium-6 fluorescence was detected for 18 seconds, after which 12 μL of the compound was added at a rate of 12 μL per second. Changes in calcium-6 fluorescence were detected for a further 22 seconds (total reading time of 40 seconds). All detections were performed with moderate gain sensitivity and bottom readings, using 6 flashes per reading.

[0229] Data Analysis: For calcium flux, Softmax Pro was used to measure the maximum change from baseline over a 40-second reading time, and the data was exported as a raw text file. Efficacy estimates (EC) were then calculated. 50 The efficacy was derived from dose-response curves (maximum change from baseline versus logarithmic concentration of the test compound) fitted using Graphpad Prism via four-parameter nonlinear regression. Efficacy was determined by comparing the signal window size of the test compound (maximum-minimum of the fitted curve) with that of epinephrine, a full agonist control. All dose-response curves on a given plate were analyzed simultaneously to define a single shared baseline value and the Hill slope was constrained to >0 to avoid misfitting from inactive compounds. All experiments were repeated at least three times, and average (mean) potency and maximum effect were reported against a full agonist dose-response comparator in the plate.

[0230] Table 2 below shows the efficacy data.

[0231] (Table 2)α 1A - AR assay data TIFF0007873661000198.tif77128TIFF0007873661000199.tif23274TIFF0007873661000200.tif23274TIF F0007873661000201.tif23274TIFF0007873661000202.tif23274TIFF0007873661000203.tif148128 Average pEC 50 A > 8.01; B = 8.00 ~ 6.01; C ≤ 6.00 Average Emax:A>61%;B=21~60%;C≦20%

[0232] Those skilled in the art will be able to identify or confirm numerous equivalents to the specific compositions and procedures described herein by routine experimentation alone. Such equivalents are considered to be within the scope of this disclosure and are covered by the following claims.

Claims

1. Formula (I-j'): (In the formula, R1 is chloro, methyl, -CHF2, -CF3, -CH2CF3, -OCHF2, or -OCF3. R2 is hydrogen, R 3 is -CF 3 or -OCHF 2, and R4 is hydrogen. A compound of or a pharmaceutically acceptable salt thereof.

2. The aforementioned compound, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. The following formula: A compound of or a pharmaceutically acceptable salt thereof.

4. The following formula: A compound of or a pharmaceutically acceptable salt thereof.

5. The aforementioned compound, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.

7. A pharmaceutical composition for treating a subject having a disease, comprising a compound according to any one of claims 1 to 5.

8. The pharmaceutical composition according to claim 7, wherein the disease is a disease related to adrenaline receptors.

9. The pharmaceutical composition according to claim 7 or 8, wherein the disease is a neurodegenerative disease.

10. 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 cholangiopathic disease). The pharmaceutical composition according to claim 9, which is one or more selected from the group consisting of amine deficiency, normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), 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).

11. The pharmaceutical composition according to claim 7, wherein the disease is neurogenic orthostatic hypotension (nOH).

12. The pharmaceutical composition according to any one of claims 8 to 11, wherein the subject is a human.

13. A pharmaceutical composition according to any one of claims 8 to 12, administered to the subject via oral, enteral, topical, inhalation, transmucosal, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, supercutaneous, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernosal, intradermal, intrafocal, intraocular, intraosseous, intraperitoneal, subarachnoid, intrauterine, intravaginal, intrabladder, intravitreous, percutaneous, perivascular, buccal, vaginal, sublingual, or rectal route.

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