Compositions and methods for improving neurological diseases and disorders

Abstract

In various aspects and embodiments, compositions and methods for identifying patients in need of improved cognition and / or treatment of neurodegenerative diseases in patients and treating such patients are provided. More specifically, in some embodiments, the present disclosure comprises administering a beta-AR agonist (such as a beta agent) and a peripherally acting beta blocker (PABRA) to a patient in need thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 212,077, filed June 17, 2021, and U.S. Provisional Patent Application No. 63 / 073,353, filed September 1, 2020, which are incorporated herein by reference in their entirety.

[0003] This disclosure generally relates to compositions and methods for improving a patient's cognition and / or treating a patient's neurodegenerative disease. Background Technology Technical Field

[0005] U.S. Patent Application Publication No. 20130096126 discloses "a method for enhancing the learning or memory of mammals suffering from neurodegenerative diseases with impaired learning or memory or both, the method involving the step of administering at least one compound or a salt thereof, said compound or salt thereof being an effective amount of β1-AR energy receptor agonist, partial agonist or receptor ligand for improving the learning or memory or both of said mammals".

[0006] U.S. Patent Application Publication No. 20140235726 discloses "a method for improving cognition in a patient with Down syndrome, the method involving administering one or more β2-adrenergic receptor agonists to the patient in an amount and frequency that effectively improves the patient's cognition, as measured by a situational learning test."

[0007] U.S. Patent Application Publication No. 20160184241 discloses "a method for improving cognition in a patient with Down syndrome, the method involving administering one or more β2-AR agonists or a pharmaceutically acceptable salt of either or both to the patient intranasally in an amount and frequency that effectively improves the patient's cognition, as measured by a situational learning test."

[0008] PCT application publication number WO2017115873 discloses "a combination of two or more compounds selected from the group consisting of compounds represented by compounds 1-130, for the prevention or treatment of Alzheimer's disease (AD)" and states that "in an attempt to achieve the aforementioned objective, the inventors screened an existing drug library of 1280 drug compounds approved by the U.S. Food and Drug Administration (FDA) by using nerve cells induced to differentiate from iPS cells derived from AD patients, and extracted 129 compounds (including one concomitant drug) that improve Aβ pathology in nerve cells as candidate therapeutic agents for AD."

[0009] PCT application publication number WO2006108424 states that "[the present invention] also relates to dermatological compositions that do not have skin sensitizing properties, and said dermatological compositions contain enantiomers of β2-adrenergic receptor agonists that are enantiomerically pure."

[0010] PCT application publication number WO2018195473 discloses "a method for treating a subject with a synucleinosis (e.g., Parkinson's disease), the method comprising administering to the subject requiring such treatment a therapeutically effective amount of a β2-adrenergic receptor agonist and at least one therapeutic agent".

[0011] PCT application WO2019 / 241736 (Ford) discloses "compositions and methods for improving a patient's cognition and / or treating a patient's neurodegenerative disease," and that many of the methods "...comprise identifying a patient who needs or desires to improve cognitive function and / or treat a neurodegenerative disease, and administering a beta agonist and optionally a peripherally acting beta blocker (PABRA) to the patient." Ford further discloses that "examples of selective peripherally acting beta blockers (PABRAs) that can be used in some embodiments in the methods disclosed herein include nadolol, atenolol, sotalol, and labetalol."

[0012] PCT application WO / 2018 / 195473 (Sherzer) discloses "[a] method of treating a subject with synucleinosis, the method comprising: administering to the subject requiring such treatment a therapeutically effective amount of a β2-adrenergic receptor agonist and at least one therapeutic agent selected from the group consisting of: synucleinosis therapeutic agents, β2-adrenergic receptor antagonists and health supplements, ... thereby treating the subject with Parkinson's disease, wherein the β2-adrenergic receptor antagonist is selected from the group consisting of: carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol, sotalol, timolol, oxprenolol, and butaxamine." Summary of the Invention

[0013] In one aspect, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering to a patient a therapeutically effective amount of a β-AR agonist (such as a β-agent) and a subtherapeutic dose of a peripherally acting β-blocker (PABRA). In one embodiment, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering to a patient a therapeutically effective amount of a β-AR agonist (such as a β-agent) and a subtherapeutic dose of a peripherally acting β-blocker (PABRA). In another embodiment, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering to a patient a therapeutically effective amount of a β-AR agonist (such as a β-agent) and a subtherapeutic dose of a peripherally acting β-blocker (PABRA).

[0014] As used herein, the term “β-drug” means a compound having a structure of formula (I), (I”), (II), (III), (I’), (II’), (III’), (IV’), (V’), (VI’), (VII’), (VIII’), (IX’), (X’), (XI’), (XII’), (XIII’), (XIV’), (XV’), (XVI’), (XVII’), (XVIII’), (XIX’), (XX’), (XXI’), (XXII’), (XXIII’), (XXIV’), or (XXV’); or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. In various embodiments, the β-agent is a compound provided in Table 1 herein. In some embodiments, the β-agent is compound 03-5, or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug. In some embodiments, the β-agent disclosed herein is an agonist, partial agonist, or antagonist of an adrenergic receptor; in some embodiments, the β-agent is a β-AR agonist; in some embodiments, the β-agent is a β1-adrenergic receptor agonist, a β2-adrenergic receptor agonist, or a nonselective β1 / β2-adrenergic receptor agonist; in some embodiments, the β-agent is a β1-adrenergic receptor agonist; in some embodiments, the β-agent is a β2-adrenergic receptor agonist; in some embodiments, the β-agent is a nonselective β1 / β2-adrenergic agonist.

[0015] In some embodiments, the β agent is a compound of formula (I) or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug.

[0016]

[0017] In some embodiments, A, B, and X are each independently nitrogen or carbon. In some embodiments, each R1 is independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, pentafluorosulfonyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. In some embodiments, m is an integer selected from 0 to 4.

[0018] In some embodiments, R2, R3, and R4 are independently selected from the group consisting of: H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl.

[0019]

[0020]

[0021] Alternatively, R2 and R3 together with carbon can form unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0022] In some embodiments, L is an optionally substituted C1-C5 alkyl linker, Y1, Y2, Y3 and Y4 are each independently covalent, carbon, oxygen or nitrogen, optionally substituted with hydrogen, an unsubstituted or substituted alkyl group, or an unsubstituted or substituted cycloalkyl group, and Z is O or S.

[0023] In some embodiments, R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl groups, or R5 and R6 are cyclically linked and together with Y2 to form optionally substituted cycloalkyl or heterocyclic groups, and each R7 is independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0024] In some embodiments, n is an integer selected from 0 to 4, R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl and unsubstituted or substituted aryl, and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy and unsubstituted or substituted amino.

[0025] This article also discloses β-agents, which are compounds of formula (II) or optically pure stereoisomers thereof, pharmaceutically acceptable salts, solvates, or prodrugs.

[0026]

[0027] In some embodiments, A, B, and X are each independently nitrogen or carbon. In some embodiments, each R1 is independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, pentafluorosulfonyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. In some embodiments, m is an integer selected from 0 to 4.

[0028] In some embodiments, R2, R3, and R4 are independently selected from the group consisting of: H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl.

[0029]

[0030] Alternatively, R2 and R3 together with carbon can form unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0031] In some embodiments, L is an optionally substituted C1-C5 alkyl linker, Y1, Y2, Y3 and Y4 are each independently covalent, carbon, oxygen or nitrogen, optionally substituted with hydrogen, an unsubstituted or substituted alkyl group, or an unsubstituted or substituted cycloalkyl group, and Z is O or S.

[0032] In some embodiments, R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl groups, or R5 and R6 are cyclically linked and together with Y2 to form optionally substituted cycloalkyl or heterocyclic groups, and each R7 is independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0033] In some embodiments, n is an integer selected from 0 to 4, R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl and unsubstituted or substituted aryl, and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy and unsubstituted or substituted amino.

[0034] In another embodiment, the β agent is a compound of formula (III) or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug.

[0035]

[0036] In some embodiments, each R1 is independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, pentafluorothioalkyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. m is an integer selected from 0 to 4.

[0037] In some embodiments, R2, R3, and R4 are independently selected from the group consisting of: H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl.

[0038]

[0039] Alternatively, R2 and R3 together with carbon can form unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0040] In some embodiments, L is an optionally substituted C1-C5 alkyl linker, X1, X2, X3 and X4 are each independently covalent, carbon, oxygen or nitrogen, optionally substituted with hydrogen, an unsubstituted or substituted alkyl group, or an unsubstituted or substituted cycloalkyl group, and Y is O or S.

[0041] In some embodiments, R5 and R6 are independently selected from hydrogen, unsubstituted or substituted alkyl groups, or R5 and R6 are cyclically linked and together with Y2 to form optionally substituted cycloalkyl or heterocyclic groups, and each R7 is independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0042] In some embodiments, n is an integer selected from 0 to 4, R8 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl and unsubstituted or substituted aryl, and R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy and unsubstituted or substituted amino.

[0043] This article further discloses a compound according to formula (I'):

[0044]

[0045] Or its pharmaceutically acceptable salt.

[0046] in:

[0047] A', B', and X' are each independently nitrogen or carbon;

[0048] Each R 1' Independently, it is halogen, -R', -CN, -NO2, -SF5, -OR x -NR x 2. -NHR x , -SO2R', -C(O)R', -C(O)NR'2;

[0049] Each R' is independently hydrogen or a optionally substituted group selected from the following: C 1-6Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic partially unsaturated or aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 member bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0050] Each R x Independently, it is a optionally substituted group selected from the following: C 1-6 Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic partially unsaturated or aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 member bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0051] m' is an integer selected from 0 to 4;

[0052] R 2' R 3' and R 4' Each of these can be independently a halogen, -R', -CN, -NO2, -OR', -NR'2,

[0053] or

[0054] R 2' and R 3' It forms, together with carbon, an optionally substituted 3-7 membered saturated carbon ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0055] L' is C that has been optionally substituted. 1-5 Alkylene;

[0056] Y 1' Y 2' Y 3' and Y 4' Each is independently a covalent bond, carbon, oxygen, or nitrogen, optionally with hydrogen, optionally with substituted C. 1-6 Alkyl groups or optionally substituted 3-7 membered saturated carbon rings;

[0057] Z' is either O or S;

[0058] R 5 'and R 6 Each is independently hydrogen or optionally substituted alkyl; or

[0059] R 5 'and R 6 ' is a ring connection, and is related to Y 2' Together they form optionally substituted 3-7 membered saturated carbon rings; optionally substituted 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycles having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0060] Each R 7 Independently, it can be -R, halogen, -CN, -NO2, -NR'2, or -OR';

[0061] n' is an integer selected from 0 to 4;

[0062] R 8 'is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring; and

[0063] Each R 9 Independently, it is hydrogen, halogen, -CN, -OR x -NR'2 or optionally substituted alkyl groups; and

[0064] R 10 'and R 11' Each is independently hydrogen or optionally substituted C 1-2 Aliphatic.

[0065] This article further discloses a compound according to formula (I”):

[0066]

[0067] Or its pharmaceutically acceptable salt.

[0068] in:

[0069] A', B', and X' are each independently nitrogen or carbon;

[0070] Each R 1' Independently, it is halogen, -R', -CN, -NO2, -SF5, -OR x -NR x 2. -NHR x, -SO2R', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'CO2R' or -CO2R';

[0071] Each R' is independently hydrogen or a optionally substituted group selected from the following: C 1-6 Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic partially unsaturated or aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 member bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0072] Each R x Independently, it is a optionally substituted group selected from the following: C 1-6 Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic partially unsaturated or aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 member bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0073] m' is an integer selected from 0 to 4;

[0074] R 2' R 3' and R 4' Each of these can be independently a halogen, -R', -CN, -NO2, -OR', -NR'2,

[0075] or

[0076] R 2' and R 3' It forms, together with carbon, an optionally substituted 3-7 membered saturated carbon ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0077] L' is C that has been optionally substituted. 1-5 Alkylene;

[0078] Y 1' Y 2' Y 3'and Y 4' Each is independently a covalent bond, carbon, oxygen, or nitrogen, optionally with hydrogen, optionally with substituted C. 1-6 Alkyl groups or optionally substituted 3-7 membered saturated carbon rings;

[0079] Z' is either O or S;

[0080] R 5 'and R 6 Each is independently hydrogen or optionally substituted alkyl; or

[0081] R 5 'and R 6 ' is a ring connection, and is related to Y 2' Together they form optionally substituted 3-7 membered saturated carbon rings; optionally substituted 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycles having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0082] Each R 7 Independently, it can be -R, halogen, -CN, -NO2, -NR'2, or -OR';

[0083] n' is an integer selected from 0 to 4;

[0084] R 8 'is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring; and

[0085] Each R 9 Independently, it is hydrogen, halogen, -CN, -OR x -NR'2 or optionally substituted alkyl groups; and

[0086] R 10 'and R 11' Each is independently hydrogen or optionally substituted C 1-2 Aliphatic.

[0087] In some embodiments, the β agent is a compound having the following structure:

[0088]

[0089] Or its pharmaceutically acceptable salt.

[0090] In some embodiments, the β agent is a compound having the following structure:

[0091]

[0092] Or its pharmaceutically acceptable salt.

[0093] In some embodiments, the β agent is a compound having the following structure:

[0094]

[0095] Or its pharmaceutically acceptable salt.

[0096] In one aspect, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering to a patient a therapeutically effective amount of compound 03-5 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug, and a subtherapeutic dose of a peripherally acting beta-blocker (PABRA). In one embodiment, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering to a patient a therapeutically effective amount of compound 03-5 and a subtherapeutic dose of a peripherally acting beta-blocker (PABRA). In another embodiment, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering to a patient a therapeutically effective amount of compound 03-5 and a subtherapeutic dose of a peripherally acting beta-blocker (PABRA).

[0097] As used herein, the term "patient" is used interchangeably with "subject" and refers to an individual who receives a composition or treatment as disclosed herein or undergoes a method of the disclosure. In some embodiments, the patient or subject may have been diagnosed with a condition, disease, or symptom and is receiving / applying a composition or method of the disclosure for treatment of the condition, disease, or symptom. In some embodiments, the patient or subject is any individual receiving a composition or method of the disclosure and is not necessarily diagnosed with any particular condition, disease, or symptom. In some embodiments, the patient or subject is any individual who desires to improve cognition or cognitive function. In various embodiments, the patient or subject may be a human or any other animal (canine, feline, etc.).

[0098] In some embodiments of the methods and compositions provided herein, the purpose of PABRA is not to directly treat a specific disease indication or symptom, but rather to counteract undesirable peripheral side effects of a β-AR agonist (such as a beta agent). For example, PABRA may be administered to reduce, limit, or counteract any side effects of a β-AR agonist (such as a beta agent), such as cardiac effects or performance-enhancing effects, thus reducing the likelihood of abuse. Therefore, in some embodiments, the PABRA dose may be lower than the dose typically used in previously approved treatment situations and indications where the PABRA is intended to directly treat a specific disease. As used herein, the term "subtherapeutic dose" means a dose of a drug that is less than the minimum dose independently effective for treating a specific disease indication. In some embodiments, the subtherapeutic dose is less than the lowest dose of a drug independently approved by a regulatory authority for treating any specific disease indication. In some embodiments, the subtherapeutic dose is less than the lowest dose of a drug approved by the U.S. FDA for treating any specific disease indication. In some embodiments, the subtherapeutic dose is less than the lowest dose of a drug approved by a regulatory authority (such as the US FDA) for treating any specific disease indication. In some embodiments, a subtherapeutic dose of PABRA is sufficient to counteract or antagonize one or more undesirable side effects of a β-AR agonist (such as a beta agent), but the dose is lower than that typically administered to treat a disease or condition independently. For example, in some embodiments, the subtherapeutic dose may be 90% or less; or 85% or less; or 80% or less; or 75% or less; or 70% or less; or 65% or less; or 60% or less; or 55% or less; or 50% or less; or 45% or less; or 40% or less; or 35% or less; or 30% or less; or 25% or less; or 20% or less; or 15% or less; or 10% or less; or 5% or less; or 4% or less; or 3% or less; or 2.5% or less; or 2% or less; or 1.5% or less; or 1% or less; or 0.5% or less compared to the dose at which the agent is effective for a specific disease indication or is approved for the treatment of a specific disease indication. In some embodiments, the subtherapeutic dose of PABRA may be about 90%; or about 85%; or about 80%; or about 75%; or about 70%; or about 5%; or about 60%; or about 55%; or about 50%; or about 45%; or about 40%; or about 35%; or about 30%; or about 25%; or about 20%; or about 15%; or about 10% or less; or about 5%; or about 4%; or about 3%; or about 2.5%; or about 2%; or about 1.5% or less; or about 1%; or about 0.5%.For example, in the United States, a 40 mg once-daily dose of PABRA naldolol is approved for the treatment of hypertension and angina. Therefore, in some embodiments, a subtherapeutic dose of naldolol would be less than a 40 mg daily dose; for example, a subtherapeutic dose of naldolol compared to a 40 mg daily dose could be 90% or less; or 85% or less; or 80% or less; or 75% or less; or 70% or less; or 65% or less; or 60% or less; or 55% or less; or 50% or less; or 45% or less; or 40% or less; or 35% or less; or 30% or less; or 25% or less; or 20% or less; or 15% or less; or 10% or less; or 5 % or less; or 4% or less; or 3% or less; or 2.5% or less; or 2% or less; or 1.5% or less; or 1% or less; or 0.5% or less; or in some embodiments, the subtherapeutic dose of naldolol may be about 90% of the 40 mg daily dose; or about 85%; or about 80%; or about 75%; or about 70%; or about 65%; or about 60%; or about 55%; or about 50%; or about 45%; or about 40%; or about 35%; or about 30%; or 25%; or about 20%; or about 15%; or about 10% or less; or about 5%; or about 4%; or about 3%; or about 2.5%; or about 2%; or about 1.5% or less; or about 1%; or about 0.5%. In some embodiments, the peripherally acting beta-blocker (PABRA) is naldolol and is administered at a total daily dose of about 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, the aforementioned dose of naldolol is a weekly dose or a twice-weekly dose. Another example of a PABRA that can be used in the methods described herein is atenolol. Atenolol is approved for a variety of indications including hypertension, angina prevention, angina pectoris, and myocardial infarction, at a dose range of 25-200 mg once daily.Therefore, in some embodiments, the subtherapeutic dose of atenolol will be less than 25 mg daily; for example, the subtherapeutic dose of atenolol compared to a daily dose of 25 mg may be 90% or less; or 85% or less; or 80% or less; or 75% or less; or 70% or less; or 65% or less; or 60% or less; or 55% or less; or 50% or less; or 45% or less; or 40% or less; or 35% or less; or 30% or less; or 25% or less; or 20% or less; or 15% or less; or 10% or less; or 5% or less; or 4% or less; or 3% or less; or 2 0.5% or less; or 2% or less; or 1.5% or less; or 1% or less; or 0.5% or less; or in some embodiments, a subtherapeutic dose of atenolol may be about 90%; or about 85%; or about 80%; or about 75%; or about 70%; or about 65%; or about 60%; or about 55%; or about 50%; or about 45%; or about 40%; or about 35%; or about 30%; or 25%; or about 20%; or about 15%; or about 10% or less; or about 5%; or about 4%; or about 3%; or about 2.5%; or about 2%; or about 1.5% or less; or about 1%; or about 0.5%. In some embodiments, the peripherally acting beta-blocker (PABRA) is atenolol, and is administered in doses of about 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, the aforementioned dose of atenolol is a weekly dose or a twice-weekly dose.

[0099] In some embodiments, PABRA, as used herein, may have relatively limited CNS (blood-brain barrier) penetration and is therefore preferentially active in the periphery.

[0100] In some embodiments of the methods and compositions disclosed herein, a β-AR agonist (such as a β-agent) is administered at a therapeutically effective dose for improving a patient's cognition and / or treating a patient's neurodegenerative disease. In some embodiments, the β-AR agonist (such as a β-agent) can be administered at a dose of about 0.01 to 100 mg. In some embodiments, the β-AR agonist (such as a β-agent) can be administered at a dose of about 30 to 160 μg. In some embodiments, the β-AR agonist (such as a β-agent) can be administered at a dose of about 50 to 160 μg. For some embodiments, β-AR agonists (such as β-agents) can be administered at doses of approximately 1 to 300 μg, 5 to 200 μg, 10 to 180 μg, 10 to 40 μg, 20 to 50 μg, 40 to 80 μg, 50 to 100 μg, 100 to 200 μg, 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 150 to 170 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 μg, etc. Administered at doses of up to 120 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, about 10 μg, about 20 μg, about 25 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 125 μg, about 130 μg, about 140 μg, about 150 μg, or about 160 μg, about 170 μg, about 175 μg, about 180 μg, about 190 μg, or about 200 μg. In some embodiments, a β-AR agonist (such as a β-agent) can be administered at a dose of 150 μg to 1 mg; or 200 μg to 500 μg; or about 250 μg; or about 300 μg; or about 400 μg; or about 500 μg. In some embodiments, a β-AR agonist (such as a β-agent) can be administered at a dose of 0.5-50 mg; or 1-25 mg; or 1-10 mg; or 10-20 mg; or 25-50 mg; or 2 mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 15 mg; or about 20 mg; or about 25 mg; or about 30 mg; or about 40 mg; or about 50 mg.In some embodiments of the aspects or examples provided herein, a β-AR agonist (such as a β-agent) is administered at a dose of 0.5-20 mg; or 1-10 mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg. In some embodiments, the above doses are daily doses, twice-daily doses, weekly doses, or twice-weekly doses.

[0101] In some embodiments of any of the methods or compositions provided herein, the β-AR agonist (such as a β-agent) is administered in the morning. As used herein, the term “morning” means before 1 PM; or before noon; or before 11:30 AM; or before 11 AM; or before 10:30 AM; or before 10 AM; or before 9:30 AM; or before 9 AM; or before 8:30 AM; or before 8 AM; or within 30 minutes of the subject waking up; or within 45 minutes of the subject waking up; or within 60 minutes of the subject waking up; or within 90 minutes of the subject waking up; or within 2 hours of the subject waking up; or within 2.5 hours of the subject waking up; or within 3 hours of the subject waking up; or within 3.5 hours of the subject waking up; or within 4 hours of the subject waking up; or within 5 hours of the subject waking up; or within the time limit for the subject to wake up. Within 6 hours after the subject wakes up; or within 30 minutes after the subject wakes up; or within 45 minutes after the subject wakes up; or within 60 minutes after the subject wakes up; or within 90 minutes after the subject wakes up; or within 2 hours after the subject wakes up; or within 2.5 hours after the subject wakes up; or within 3 hours after the subject wakes up; or within 3.5 hours after the subject wakes up; or within 4 hours after the subject wakes up; or within 5 hours after the subject wakes up; or within 6 hours after the subject wakes up; or before the subject eats after waking up; or at least 15 minutes before the subject eats after waking up; or at least 30 minutes before the subject eats after waking up; or at least 45 minutes before the subject eats after waking up; or at least 1 hour before the subject eats after waking up.

[0102] In some embodiments of the methods and compositions disclosed herein, the β agent is compound 03-5, or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug, and is administered at a dose effective in improving a patient's cognition and / or treating a patient's neurodegenerative disease. In some embodiments, compound 03-5 can be administered at a dose of about 0.01 to 100 mg. In some embodiments, compound 03-5 can be administered at a dose of about 30 to 160 μg. In some embodiments, compound 03-5 can be administered at a dose of about 50 to 160 μg. For some embodiments, compound 03-5 can be expressed in doses of about 1 to 300 μg, 5 to 200 μg, 10 to 180 μg, 10 to 40 μg, 20 to 50 μg, 40 to 80 μg, 50 to 100 μg, 100 to 200 μg, 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 150 to 170 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 1 Administered at doses of 20 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, about 10 μg, about 20 μg, about 25 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 125 μg, about 130 μg, about 140 μg, about 150 μg, or about 160 μg, about 170 μg, about 175 μg, about 180 μg, about 190 μg, or about 200 μg. In some embodiments, compound 03-5 can be administered at a dose of 150 μg to 1 mg; or 200 μg to 500 μg; or about 250 μg; or about 300 μg; or about 400 μg; or about 500 μg. In some embodiments, compound 03-05 can be administered at a dose of 0.5-50 mg; or 1-25 mg; or 3-20 mg; or 1-20 mg; or 1-10 mg; or 10-20 mg; or 25-50 mg; or mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 11 mg; or about 12 mg; or about 13 mg; or about 14 mg; or about 15 mg; or about 20 mg; or about 25 mg; or about 30 mg; or about 40 mg; or about 50 mg.In some embodiments of the aspects or examples provided herein, compound 03-5 is administered at a dose of 0.5-20 mg; or 1-10 mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg. In some embodiments, the above doses are daily doses, twice-daily doses, weekly doses, or twice-weekly doses.

[0103] In some embodiments, the dosage of any agent provided herein may be a total daily dose. In some embodiments, the total daily dose as provided herein is achieved by administering once daily; in some embodiments, the total daily dose is achieved by administering twice daily; and in still other embodiments, the total daily dose is achieved by administering more than twice daily. In some embodiments, the dosage of any agent provided herein may be a dose administered once weekly or twice weekly. In some embodiments, a therapeutically effective amount of a beta agent and a subtherapeutic dose of a peripherally acting beta blocker (PABRA) are administered for a period of several weeks or longer; or for a period of three weeks or longer; or for a period of five weeks or longer; or for a period of ten weeks or longer; or for a period of twenty weeks or longer; or for a period of one year or longer.

[0104] In one aspect, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering to a patient a therapeutically effective amount of a β-AR agonist (such as a β agent) and a peripherally acting β-blocker (PABRA), wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In some embodiments, a peripherally acting beta-blocker (PABRA, such as naldolol or atenolol) is administered at doses of about 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. For some embodiments without different instructions, the above doses are the total daily doses. For others, the above doses are the total weekly doses. For some embodiments, the therapeutically effective dose of a β-AR agonist (such as a beta agent) and a peripherally acting beta blocker (PABRA) is administered for several weeks or longer.

[0105] In one aspect, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering to a patient a therapeutically effective amount of compound 03-5, or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug, and a peripherally acting beta-blocker (PABRA), wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. In some embodiments, a peripherally acting beta-blocker (PABRA, such as naldolol or atenolol) is administered at doses of about 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. For some embodiments without different instructions, the above doses are the total daily doses. For others, the above doses are the total weekly doses. For some embodiments, the therapeutically effective dose of a β-AR agonist (such as a beta agent) and a peripherally acting beta blocker (PABRA) is administered for several weeks or longer.

[0106] The methods provided herein may further include brain imaging of a patient to determine local metabolic activation and / or cerebral perfusion in the cerebral cortex, forebrain, midbrain, and brainstem, and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases. In some embodiments, brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET) used alone or in combination with other imaging methods such as magnetic resonance imaging (MRI) and CT. In some embodiments, brain imaging is, or may include, magnetic resonance imaging-arterial spin labeling (MRI-ASL) or magnetic resonance imaging-oxygen level-dependent computed tomography (MRI-BOLD). In some embodiments, brain imaging may include MRI-ASL for monitoring cerebral blood flow, including, for example, cerebral blood flow to the hippocampus or thalamus. In some embodiments of the aspects and examples disclosed herein, “improving cognition and / or treating neurodegenerative diseases” in a patient may include improving cognitive and executive function, improving the inflammatory state in a brain or cerebrospinal fluid (CSF) sample, reducing the burden of proteinopathy (e.g., based on imaging or CSF sampling), and / or improving the patient’s local brain metabolic state (reversing metabolic decline) or perfusion. In some embodiments of the methods and compositions disclosed herein, a β-AR agonist (such as a β agent) is administered at a therapeutically effective dose for improving the patient’s cognition and / or treating the patient’s neurodegenerative disease. Therefore, in some embodiments, “identifying patients who need or desire to improve cognitive function and / or treat neurodegenerative diseases” may include identifying patients who need or desire to improve cognitive and executive function, improve the inflammatory state in a brain or CSF sample, reduce the burden of proteinopathy (e.g., based on imaging or CSF sampling), and / or improve the local brain metabolic / perfusion state (reversing metabolic decline or inadequate perfusion). In another aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic activation or perfusion in the cerebral cortex, forebrain, midbrain, and brainstem regions and / or identifying whether the patient needs or desires improved cognitive function and / or treatment of neurodegenerative diseases, and administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative diseases, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In a similar aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic or perfusion activation in the cerebral cortex, forebrain, midbrain, and brainstem regions and / or identifying whether the patient needs or desires improved cognitive function and / or treatment of neurodegenerative diseases, and administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative diseases, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose.

[0107] The method may further include subsequently performing brain imaging on the patient again to determine local metabolic activation, cognitive function, and / or any improvement in treatment of the neurodegenerative disease in the cerebral cortex, forebrain, midbrain, and brainstem. In some embodiments, brain imaging is FDG-PET used alone or in combination with other imaging methods such as MRI and CT. In some embodiments, brain imaging is, or may include, MRI-ASL or MRI-BOLD.

[0108] In another aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions, and administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In a related aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions, and administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise subsequently performing brain imaging on the patient again to determine local metabolic or perfusion activation in the cerebral cortex, limbic system, forebrain, midbrain, and brainstem regions, and any improvement in cognitive function. In some embodiments, brain imaging is FDG-PET used alone or in combination with other imaging methods such as MRI and CT. In some embodiments, brain imaging is, or may include, MRI-ASL or MRI-BOLD. In some embodiments, brain imaging may include MRI-ASL for monitoring cerebral blood flow, including, for example, cerebral blood flow to the hippocampus; and in a subsequent MRI-ASL, improvement in cerebral blood flow (e.g. to the hippocampus) indicates the effective effect of a β-AR agonist (such as a β agent) and / or improved cognition in the patient.

[0109] In some embodiments, detectable markers are provided that can generate spatial patterns in brain imaging results. In some embodiments, 2-[ 18 F]Fluoro-2-deoxy-D-glucose ( 18 FDG can be used for FDG-PET, which can provide characteristic spatial patterns of brain metabolism and help clinicians make reasonable and accurate early diagnoses for appropriate management or prognosis.

[0110] In some embodiments, detectable markers on blood water molecules are generated by magnetic radiofrequency (RF) processing of neck blood, which can produce spatial patterns of brain perfusion as an imaging result. In some such embodiments, MRI-ASL is used, which can provide characteristic spatial patterns of brain perfusion and help clinicians make reasonable and accurate early diagnoses for appropriate management or prognosis.

[0111] In some aspects, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In some related aspects, a method for improving cognitive function and / or treating neurodegenerative diseases is provided, wherein the method comprises administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose.

[0112] In some embodiments, the method may further include performing brain imaging on the patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions, and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases. In some embodiments, brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET) used alone or in combination with other imaging methods such as magnetic resonance imaging (MRI) and CT. In some embodiments, brain imaging is, or may include, MRI-ASL or MRI-BOLD. In some embodiments of the aspects and embodiments disclosed herein, “improved cognition and / or treatment for neurodegenerative diseases” in a patient may include improved cognitive and executive function, improved inflammatory status in brain or cerebrospinal fluid (CSF) samples, reduction of proteinopathy burden (e.g., based on imaging or CSF sampling), and / or improvement of the patient’s local brain metabolic status (reversal of metabolic decline). Similarly, in some embodiments, “identifying patients who need or expect to improve cognitive function and / or treat neurodegenerative diseases” may include identifying patients who need or expect to improve cognitive and executive function, improve inflammatory status in brain or CSF samples, reduce proteinopathy burden (e.g., based on imaging or CSF sampling), and / or improve local brain metabolic status (reversing metabolic decline). In another aspect, a method is provided in which the method includes performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions and / or identifying whether the patient needs or expects to improve cognitive function and / or treat neurodegenerative diseases, and administering a β-AR agonist (e.g., a β-agent) and a peripherally acting β-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative diseases, wherein the peripherally acting β-blocker (PABRA) is administered at a dose of about 15 mg or less. In a related aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions and / or identifying whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative diseases, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. In some embodiments, the administration of the peripherally acting β-blocker (PABRA) is to reduce, limit, or counteract any side effects of the β-AR agonist (such as a β-agent), such as performance enhancement effects, and to reduce the likelihood of abuse.In a similar aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions and / or identifying whether the patient needs or desires improved cognitive function and / or treatment of neurodegenerative diseases, and administering to the patient compound 03-5, or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, and a peripherally acting beta-blocker (PABRA) to improve the patient's cognition and / or treat the patient's neurodegenerative diseases, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. In another aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions and / or identifying whether the patient needs or desires improved cognitive function and / or treatment of neurodegenerative diseases, and administering to the patient compound 03-5, or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, and a peripherally acting beta-blocker (PABRA) to improve the patient's cognition and / or treat the patient's neurodegenerative diseases, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. In some embodiments, administration of the peripherally acting beta-blocker (PABRA) is intended to reduce, limit, or counteract any side effects of beta-AR agonists (such as beta agents), such as performance enhancement effects, and to reduce the likelihood of abuse.

[0113] The method may further include subsequently performing brain imaging again on the patient to determine local metabolic or perfusion activation in the cerebral cortex, forebrain, midbrain, and brainstem regions, cognitive function, and / or any improvement in treatment of the neurodegenerative disease. In some embodiments, the brain imaging is FDG-PET used alone or in combination with other imaging methods such as MRI and CT. In some embodiments, the brain imaging is, or may include, MRI-ASL or MRI-BOLD. In another aspect, a method is provided in which the method includes performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions, administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient; and subsequently performing brain imaging again on the patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions, any improvement in cognitive function. In some embodiments, the brain imaging is FDG-PET used alone or in combination with other imaging methods such as MRI and CT. In some embodiments, the brain imaging is, or may include MRI-ASL or MRI-BOLD. In some embodiments, the patient does not have Alzheimer's disease. In some embodiments, the patient does not have Down syndrome. In some embodiments, the patient does not have Parkinson's disease. In some embodiments, the patient does not have Lewy body dementia.

[0114] In any aspect of this document and in some embodiments of the examples, a β-AR agonist (such as a β-agent) can be administered at a dose of about 0.01 to 100 mg. In some embodiments, a β-AR agonist (such as a β-agent) can be administered at a dose of about 30 to 160 μg. In some embodiments, a β-AR agonist (such as a β-agent) can be administered at a dose of about 50 to 160 μg. For some embodiments, β-AR agonists (such as β-agents) can be administered at doses of approximately 1 to 300 μg, 5 to 200 μg, 10 to 180 μg, 10 to 40 μg, 20 to 50 μg, 40 to 80 μg, 50 to 100 μg, 100 to 200 μg, 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 150 to 170 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 μg, etc. Administered at doses of up to 120 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, about 10 μg, about 20 μg, about 25 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 125 μg, about 130 μg, about 140 μg, about 150 μg, or about 160 μg, about 170 μg, about 175 μg, about 180 μg, about 190 μg, or about 200 μg. In some embodiments, a β-AR agonist (such as a β agent) can be administered at a dose of 150 μg to 1 mg; or 200 μg to 500 μg; or about 250 μg; or about 300 μg; or about 400 μg; or about 500 μg. In some embodiments, a β-AR agonist (such as a β-agent) can be administered at a dose of 0.5-50 mg; or 1-25 mg; or 1-10 mg; or 10-20 mg; or 25-50 mg; or 2 mg; or 2-8 mg; or about 0.25 mg; or about 0.5 mg; or about 0.75 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 11 mg; or about 12 mg; or about 13 mg; or about 14 mg; or about 15 mg; or about 20 mg; or about 25 mg; or about 30 mg; or about 40 mg; or about 50 mg.In some embodiments of the aspects or examples provided herein, a β-AR agonist (such as a β-agent) is administered at a dose of 0.5-20 mg; or 1-10 mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 11 mg; or about 12 mg; or about 13 mg; or about 15 mg. In some embodiments, the above doses are daily, twice-daily, weekly, or twice-weekly. In some embodiments, the doses of the β-AR agonist (such as a β-agent) and the peripherally acting β-blocker (PABRA) are administered weekly for several weeks or longer.

[0115] In some embodiments, naldolol is a mixture of four diastereomers. In some embodiments, the applied naldolol is a specific enantiomer-pure isomer.

[0116] In some embodiments, brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET) used alone or in combination with other imaging methods such as magnetic resonance imaging (MRI) and CT. In some embodiments, brain imaging is, or may include, MRI-ASL or MRI-BOLD. In some embodiments of the aspects and embodiments disclosed herein, “improving cognition and / or treating neurodegenerative diseases” for a patient may include improving cognitive and executive function, improving the inflammatory state in brain or cerebrospinal fluid (CSF) samples, reducing the burden of proteinopathy (e.g., based on imaging or CSF sampling), and / or improving the patient’s local brain metabolic state (reversing metabolic decline). Similarly, in some embodiments, “identifying patients who need or expect to improve cognitive function and / or treat neurodegenerative diseases” may include identifying patients who need or expect to improve cognitive and executive function, improve the inflammatory state in brain or CSF samples, reduce the burden of proteinopathy (e.g., based on imaging or CSF sampling), and / or improve the local brain metabolic state (reversing metabolic decline).

[0117] In some embodiments, brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET) used alone or in combination with other imaging methods such as magnetic resonance imaging (MRI) and CT. In some embodiments, brain imaging is, or may include, MRI-ASL or MRI-BOLD. In some embodiments of the aspects and embodiments disclosed herein, “improving cognition and / or treating neurodegenerative diseases” for a patient may include improving cognitive and executive function, improving the inflammatory state in brain or cerebrospinal fluid (CSF) samples, reducing the burden of proteinopathy (e.g., based on imaging or CSF sampling), and / or improving the patient’s local brain metabolic state (reversing metabolic decline). Similarly, in some embodiments, “identifying patients who need or expect to improve cognitive function and / or treat neurodegenerative diseases” may include identifying patients who need or expect to improve cognitive and executive function, improve the inflammatory state in brain or CSF samples, reduce the burden of proteinopathy (e.g., based on imaging or CSF sampling), and / or improve the local brain metabolic state (reversing metabolic decline). In another aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions and / or identifying whether the patient needs or desires improved cognitive function and / or treatment of neurodegenerative diseases, and administering clenbuterol or tulobuterol and naldolol to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative diseases, wherein naldolol is administered at a dose of about 15 mg or less. In a related aspect, a method is provided, wherein the method comprises performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions and / or identifying whether the patient needs or desires improved cognitive function and / or treatment of neurodegenerative diseases, and administering clenbuterol or tulobuterol and naldolol to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative diseases, wherein naldolol is administered at a subtherapeutic dose.

[0118] The method may further include subsequently performing brain imaging again on the patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions, cognitive function, and / or any improvement in the treatment of the neurodegenerative disease. In some embodiments, the brain imaging is FDG-PET used alone or in combination with other imaging methods such as MRI and CT. In some embodiments, the brain imaging is, or may include, MRI-ASL or MRI-BOLD. In another aspect, a method is provided in which the method includes performing brain imaging on a patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions, administering clenbuterol or tuloterol and naldolol to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein naldolol is administered at a dose of about 15 mg or less; and subsequently performing brain imaging again on the patient to determine local metabolic activation in the forebrain, midbrain, and brainstem regions, any improvement in cognitive function. In some embodiments, the brain imaging is FDG-PET used alone or in combination with other imaging methods such as MRI and CT. In some embodiments, the brain imaging is, or may include MRI-ASL or MRI-BOLD.

[0119] In some aspects, a method is provided comprising treating a subject identified as having cognitive decline and / or needing or expecting to improve cognitive function and / or treat neurodegenerative diseases by administering a pharmaceutical composition comprising a beta agent, a beta1-AR agonist, a beta2-AR agonist, a peripherally acting beta blocker (PABRA), or any combination thereof. In some embodiments, the method further comprises assessing the effectiveness of the treatment. In some embodiments, the treatment is assessed by testing the subject to evaluate improved cognitive function or remission of neurodegenerative diseases. In some embodiments, the method further comprises adjusting the administration of the pharmaceutical composition by adjusting the dosage of the pharmaceutical composition and / or the timing of administration of the pharmaceutical composition.

[0120] In any aspect or embodiment provided herein, the method or composition comprises a beta agent and PABRA.

[0121] As used herein, the terms “β-agonist” or “β-AR agonist” are used interchangeably to refer to an agent that acts as an agonist of the β-adrenergic receptor (β-AR). A β-agonist can be a β1-agonist, a β1-agonist, or a non-selective β-agonist. In some embodiments, a β-AR agonist is a β agent.

[0122] As used herein, the term "β1 agonist" is used to mean a β1-adrenergic receptor agonist or a β1-AR agonist. In some embodiments, the term β1 agonist is understood to comprise a compound that is primarily a β1 agonist, but it may also exhibit some peripheral agonistic activity against other adrenergic receptors such as β2-adrenergic receptors. In this application, the terms "β1-adrenergic receptor agonist," "β1-AR agonist," "β1AR agonist," and "β1 agonist" are used interchangeably. In some embodiments, the term β1-AR agonist explicitly includes both selective and partial agonists, as well as biased and unbiased agonists. Examples of β1-adrenergic agonists include, for example, xamoterol, norepinephrine, isoprenaline, dopamine, and dobutamine, and pharmaceutically acceptable salts of any of the aforementioned drugs. Some agonists and ligands of β1-AR are known. Further, the method of Kolb et al. can be used, but for β1-AR, those skilled in the art can identify novel ligands through structure-based discovery. See Proceedings of the National Academy of Sciences (Proc. Natl. Acad. Sci. USA), 2009, 106, 6843-648.

[0123] As used herein, the term "β2 agonist" is used to mean a β2-adrenergic receptor agonist or a β2-AR agonist. In some embodiments, the term β2 agonist is understood to comprise a compound that is primarily a β2 agonist, but it may also exhibit some peripheral agonistic activity against other adrenergic receptors such as β1-adrenergic receptors. In this application, the terms "β2-adrenergic receptor agonist," "β2-AR agonist," "β2AR agonist," and "β2 agonist" are used interchangeably. In some embodiments, the term β2-AR agonist explicitly includes both selective and partial agonists. β2 agonists that can be used according to various aspects and embodiments of this disclosure may be short-acting, long-acting, or ultra-long-acting. Examples of short-acting β2 agonists that can be used include salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, ritodrine, isoproterenol, salmefamol, fenoterol, terbutaline, salbutamol, and isoetharine. Examples of long-acting β2 agonists that can be used include salmeterol, bamboolol, formoterol, and clenbuterol. Examples of ultra-long-acting β2 agonists include indacaterol, vilanterol, and olodaterol. Other examples of β2 agonists include tolometrol, mabuterol, and ritodrine.

[0124] As used herein, the term "peripherally acting beta-blocker (PABRA)" means a beta-adrenergic receptor antagonist or simply a β1-, β2-, or non-selective beta-blocker. Examples of selective peripherally acting beta-blockers (PABRAs) that may be used in the methods disclosed herein in some embodiments include nadolol, atenolol, sotalol, and labetalol. In some embodiments, the beta-blockers that may be used in the methods herein are selected from one or more of the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, and nebivolol; in other embodiments, the methods do not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, or nebivolol as beta-blockers. Peripherally acting beta-blockers (PABRAs) can be used to reduce, limit, or counteract any side effects of beta agents, beta1-AR agonists, and / or beta2-AR agonists, such as performance-enhancing effects, and thus reduce any risk of abuse. For example, naldolol can be used to reduce, limit, or counteract any peripheral beta-agonist effects of beta agents.

[0125] As used herein, the term “about” means ±10% of a quantity. For example, “about 3%” would cover 2.7-3.3%, and “about 10%” would cover 9-11%. Furthermore, when “about” is used in conjunction with quantitative terms herein, it should be understood that, in addition to the stated value ±10%, the precise value of the quantitative term is considered and described. For example, the term “about 3%” explicitly considers, describes, and includes a precise 3%.

[0126] In some embodiments, a peripherally acting beta-blocker (PABRA) is administered to the patient prior to administration of a beta-AR agonist (such as a beta agent). In other embodiments, a peripherally acting beta-blocker (PABRA) is administered to the patient concurrently with administration of a beta-AR agonist (such as a beta agent). In still other embodiments, the peripherally acting beta-blocker (PABRA) is administered to the patient in the form of a single-dose formulation, a single tablet, and / or a single capsule.

[0127] In some embodiments of the compositions and methods provided herein, one or more peripherally acting beta-blockers (PABRAs) are administered before or simultaneously with a beta-AR agonist (e.g., a beta agent) to inhibit or eliminate the agonistic effect of the beta-AR agonist (e.g., a beta agent) on peripheral β1 and / or β2 adrenergic receptors. In various embodiments, it is preferred to block peripheral β1 and / or β2 adrenergic receptors according to the compositions and methods of this disclosure to eliminate or at least minimize any side effects on the treated person, such as peripheral cardiac effects.

[0128] In some embodiments, it may be desirable to administer PABRA prior to a β-AR agonist (such as a beta agent) to occupy peripheral β-ARs before the β-AR agonist approaches the receptor. Therefore, in some embodiments, PABRA and a β-AR agonist (such as a beta agent) are administered once daily (e.g., once every morning) at the doses specified herein, prior to administration of the β-AR agonist (i.e., 15 minutes to 6 hours; or 15 minutes to 3 hours; or 1 to 6 hours; or 1 to 5 hours; or 1 to 4 hours; or 1-3 hours; or 1.5 to 2.5 hours; or 2-3 hours; or 2-4 hours; or 2-5 hours; or 1.5 to 3 hours; or 1.5 to 3.5 hours; or 1.5 to 4 hours; or about 30 minutes; or about 1 hour; or about 1.5 hours; or about 2 hours; or about 2.5 hours; or about 3 hours; or about 3.5 hours; or about 4 hours; or about 5 hours; 12 hours; one day). In some embodiments, PABRA and a β-AR agonist (such as a β-dose) are administered once daily at the dose specified herein (e.g., once every morning), wherein on the first day, only PABRA (without the β-AR agonist) is administered at the dose specified herein; and for each subsequent day, both PABRA and the β-AR agonist (such as the β-dose; and at the dose specified herein) are administered concurrently (e.g., in the form of a single formulation or a combination formulation as described herein). In some embodiments, PABRA and a β-AR agonist (such as a β-dose) are administered once daily at the dose specified herein (e.g., once every morning), wherein on the first and second days, only PABRA (without the β-AR agonist) is administered at the dose specified herein; and for each subsequent day, both PABRA and the β-AR agonist (such as the β-dose; and at the dose specified herein) are administered concurrently (e.g., in the form of a single formulation or a combination formulation as described herein).

[0129] In some embodiments of the methods provided herein, the β-AR agonist (such as a β-agent) is administered orally, intravenously, intramuscularly, transdermally, by inhalation, or intranasally. In some embodiments of the methods provided herein, the β-AR agonist (such as a β-agent) is administered orally.

[0130] In some embodiments of the methods provided herein, the peripherally acting beta-blocker (PABRA) is administered orally, intravenously, intramuscularly, by inhalation, or intranasally. In some embodiments of the methods provided herein, the peripherally acting beta-blocker (PABRA) is administered orally.

[0131] In some embodiments of the methods provided herein, a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) are administered to a patient as a single formulation. In some embodiments, the single formulation is in the form of a tablet. In some embodiments, both agents (the β-AR agonist (such as a β-agent) and PABRA) are present in the tablet. In some embodiments, the tablet contains 30 to 160 μg of the β-AR agonist (such as a β-agent), and / or 0.1 mg to 10 mg of the β-AR agonist (such as a β-agent), and about 0.1 to 15 mg of the peripherally acting β-blocker (PABRA). In some embodiments, the tablet contains a subtherapeutic dose of the peripherally acting β-blocker (PABRA). In some embodiments, the tablet contains 0.01 to 15 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.2 to 0.3 mg, 0.23 to 0.27 mg; 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, about 0.01 mg, about 0.05 mg; about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of a peripherally acting beta-blocker (PABRA). In some embodiments, compared to a dose of 5 mg twice daily (or a total daily dose of 10 mg), the tablet contains 90% or less; or 85% or less; or 80% or less; or 75% or less; or 70% or less; or 65% or less; or 60% or less; or 55% or less; or 50% or less; or 45% or less; or 40% or less; or 35% or less; or 30% or less; or 25% or less; or 20% or less; or 15% or less; or 10% or less; or 5% or less; or 4% or less; or 3% or less; or 2.5% or less; or 2% or less; or 1.5% or less; or 1% or less; or 0.5% or less of the dosage. The amount of a peripherally acting beta-blocker (PABRA, such as nadolol or atenolol); or in some embodiments, the subtherapeutic dose of PABRA in the tablet may be about 90%; or about 85%; or about 80%; or about 75%; or about 70%; or about 5%; or about 60%; or about 55%; or about 50%; or about 45%; or about 40%; or about 35%; or about 30%; or about 25%; or about 20%; or about 15%; or about 10% or less; or about 5%; or about 4%; or about 3%; or about 2.5%; or about 2%; or about 1.5% or less; or about 1%; or about 0.5%.In some embodiments, tablets having the above-described dosage are administered daily. In some embodiments, tablets having the above-described dosage are administered weekly. In some embodiments, the tablet contains about 5 to 10 mg of a peripherally acting beta-blocker (PABRA). In some embodiments, a beta-AR agonist (such as a beta agent) is present in about 0.01 to 100 mg of the tablet. In some embodiments, a beta-AR agonist (such as a beta agent) is present in about 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 8 ...80 to 140 μg, 80 to 140 μg, 80 to 140 μg, 80 to 140 μg, 80 to 140 μg, 80 In tablets of 120 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg or 160 μg. In some embodiments, the β-AR agonist (such as a β-agent) is present in tablets containing 0.5-50 mg; or 1-25 mg; or 1-10 mg; or 10-20 mg; or 25-50 mg; or 2 mg; or 2-8 mg; or about 0.25 mg; or about 0.5 mg; or about 0.75 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 11 mg; or about 12 mg; or about 13 mg; or about 14 mg; or about 15 mg; or about 20 mg; or about 25 mg; or about 30 mg; or about 40 mg; or about 50 mg. In some embodiments, the above doses are total daily doses. In some embodiments, the above doses are weekly doses. In some embodiments, the dosage of the β-AR agonist (such as β-agent) and the peripherally acting β-blocker (PABRA) in the tablet is maintained for several weeks or longer.

[0132] In some embodiments of the methods provided herein, a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) are administered to the patient in a combined formulation. In some embodiments, the combined formulation comprises about 30 to 160 μg of a β-AR agonist (such as a β-agent) and 15 mg or less of a peripherally acting β-blocker (PABRA). In some embodiments, the combined formulation comprises about 0.5 to 20 mg of a β-AR agonist (such as a β-agent) and 15 mg or less of a peripherally acting β-blocker (PABRA). In some embodiments, the compound contains about 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of a peripherally acting beta-blocker (PABRA). In some embodiments, the compound contains about 5 to 10 mg of a peripherally acting beta-blocker (PABRA). In some embodiments, a β-AR agonist (such as a beta agent) is present in about 0.01 to 100 mg of the compound. In some embodiments, β-AR agonists (such as β-agents) are present in amounts of approximately 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 1 In combination formulations of 20 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg or 160 μg. In some embodiments, a β-AR agonist (such as a β-agent) is present in a compound formulation of about 0.5-50 mg; or 1-25 mg; or 1-10 mg; or 10-20 mg; or 25-50 mg; or 2 mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 0.25 mg; or about 0.5 mg; or about 0.75 mg; or about 15 mg; or about 20 mg; or about 25 mg; or about 30 mg; or about 40 mg; or about 50 mg. For some embodiments, the above doses are the total daily dose. For some embodiments, the dose of the compound formulation is administered weekly, and the dose is the total weekly dose.In some embodiments, the doses of β-AR agonists (such as β-agents) and peripherally acting β-blockers (PABRAs) are administered daily or weekly for several weeks or longer.

[0133] In some embodiments of the methods and compositions provided herein, compound 03-5, or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug, and naldolol are administered orally to a patient. In some embodiments of the methods provided herein, compound 03-5 and naldolol are administered orally to a patient, and both are present in a tablet. In some embodiments, the tablet contains about 0.01 to 100 mg of compound 03-5 and about 0.1 to 15 mg of naldolol. In some embodiments, the tablet contains about 5 to 10 mg of naldolol. In some embodiments, the tablet contains about 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of naldolol. In some embodiments, naldolol is a mixture of four diastereomers. In some embodiments, the administered naldolol is a specific enantiomer-pure isomer.

[0134] In some embodiments of the methods provided herein, compound 03-5 and naldolol are administered orally to a patient, and both agents are contained in a capsule. In some embodiments, the capsule contains about 0.01 to 100 mg of compound 03-5 and about 0.1 to 15 mg of naldolol. In some embodiments, the capsule contains about 5 to 10 mg of naldolol. In some embodiments, the capsule contains about 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of naldolol. In some embodiments, naldolol is a mixture of four diastereomers. In some embodiments, the applied naldolol is a specific enantiomer-pure isomer.

[0135] In some embodiments, compound 03-5, or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug, is present in tablets at a concentration of about 0.01 to 100 mg. In some embodiments, compound 03-5 is present in tablets at concentrations of about 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 120 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 120 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg, 80 to 120 μg, 120 to 12 ...80 to 120 μg, 80 to 120 μg, 80 to 120 μg, 80 to 120 μg In tablets of 0 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg or 160 μg. In some embodiments, compounds 03-5 are present in tablets of about 0.5-50 mg; or 1-25 mg; or 1-10 mg; or 10-20 mg; or 25-50 mg; or mg; or 2-8 mg; or about 0.25 mg; or about 0.5 mg; or about 0.75 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 0.25 mg; or about 0.5 mg; or about 0.75 mg; or about 15 mg; or about 20 mg; or about 25 mg; or about 30 mg; or about 40 mg; or about 50 mg. In some embodiments, the tablets will be the total daily dose and are expected to be administered daily for several weeks or longer. In some embodiments, the tablets will be the total weekly dose and are expected to be administered weekly for several weeks or longer.

[0136] In some embodiments, naldolol is able to reduce, limit, or counteract any side effects of compound 03-5, such as potential performance-enhancing effects, which reduces the likelihood of abuse.

[0137] Clenbuterol and certain other β-agonists have hypertrophic and lipolytic side effects, which lead to illicit abuse by athletes and individuals in the hope of gaining muscle mass, enhancing athletic performance, and / or losing weight. These side effects and abuse tendencies create obstacles to regulatory approval (such as FDA approval) and pose a degree of public health risk. However, hypertrophic and lipolytic effects are largely caused by the activation of peripheral β-receptors; therefore, the hypertrophic and lipolytic side effects, as well as the abuse tendency, can be reduced, mitigated, or eliminated by co-administering a combination of a β-AR agonist (such as a β-agent) with a PABRA as disclosed herein. Specifically, as described herein, if the β-AR agonist (such as a β-agent) and PABRA were manufactured and marketed only in a single formulation containing both agents, it would be very difficult or impossible to isolate the agents to manufacture products for illicit use for muscle gain, enhanced athletic performance, or weight loss. Therefore, in some aspects and embodiments, compositions and methods relating to a single formulation (e.g., oral tablets or capsules) having a β-AR agonist (such as a β-agent) and PABRA are provided, which are effective for improving cognition (CNS effects) but have a reduced risk of illicit use / abuse compared to formulations having only a β-AR agonist (such as a β-agent) without PABRA. In many embodiments, a subtherapeutic dose of PABRA is sufficient to counteract the side effects of the β-AR agonist (such as a β-agent); therefore, a single formulation (e.g., oral tablets) having a β-AR agonist (such as a β-agent) and PABRA as described herein may have a therapeutically active dose of the β-AR agonist (such as a β-agent) and a subtherapeutic dose of PABRA.

[0138] In some embodiments of the aspects and examples provided herein, the patient is identified as having one or more neurodegenerative diseases selected from the group consisting of: MCI (mild cognitive impairment), aMCI (amnesic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Picker's disease), HD (Huntington's disease), Ritter syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, T BI (Traumatic Brain Injury), CTE (Chronic Traumatic Encephalopathy), Stroke, WKS (Wernicke-Korsakov Syndrome; Alcoholic Dementia and Thiamine Deficiency), Normal Pressure Hydrocephalus, Hypersomnia / Symphomania, ASD (Autism Spectrum Disorder), FXS (Fragile X Syndrome), TSC (Tuberous Sclerosis Complex), Prion-related Diseases (CJD, etc.), Depression, 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 patient is identified as having one or more neurodegenerative diseases selected from the group consisting of: MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Picker's disease), HD (Huntington's disease), Ritter syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TB I (Traumatic Brain Injury), CTE (Chronic Traumatic Encephalopathy), Stroke, WKS (Wernicke-Korsakov Syndrome; Alcoholic Dementia and Thiamine Deficiency), Normal Pressure Hydrocephalus, Hypersomnia / Syllomalacia, ASD (Autism Spectrum Disorder), FXS (Fragile X Syndrome), TSC (Tuberous Sclerosis Complex), Prion-related Disorders (CJD, etc.), Depression, DLB (Lewy Body Dementia), PD (Parkinson's Disease), PDD (PD Dementia), and ADHD (Attention Deficit Hyperactivity Disorder). In some embodiments, the patient does not have Alzheimer's disease (AD). In some embodiments, the patient does not have Down syndrome. In some embodiments, the patient does not have Parkinson's disease. In some embodiments, the patient does not have Lewy body dementia.

[0139] In some embodiments, after the application, the patient undergoes a cognitive test or model. In some embodiments, after the application, the patient undergoes a cognitive test or model, wherein the cognitive test or model is a memory test; diagnostic indicators of mental state, brain function, or mental condition; situational learning test; and / or brain imaging. In some embodiments, the patient undergoes a cognitive test or model before the application. In some embodiments, before the application, the patient undergoes a cognitive test or model, such as a memory test; diagnostic indicators of mental state, brain function, or mental condition; situational learning test; and / or brain imaging, and the cognitive test or model is used to identify patients who need or wish to improve cognitive function and / or treat neurodegenerative diseases according to the methods and compositions provided herein. In some embodiments, the patient undergoes a cognitive test or model before and after the application. In some embodiments, before and after the administration, the patient undergoes a cognitive test or model, wherein the cognitive test or model is a memory test; diagnostic indicators of mental state, brain function, or mental condition; situational learning test and / or brain imaging.

[0140] In some embodiments, patients exhibit improved cognition after the administration. In some embodiments, such as as demonstrated by improvements in patient cognitive tests or models; memory tests; diagnostic indicators of mental state, brain function, or mental condition; situational learning tests; brain imaging, etc., patients exhibit improved cognition.

[0141] "Improved cognition," "cognitive improvement," or "enhanced cognition" refers to an improvement in an individual's cognitive abilities or memory, etc. In some embodiments, the methods described herein result in cognitive improvement, as demonstrated by improvements in a patient's cognitive tests, memory tests, brain imaging, and / or situated learning tests. In some embodiments, the methods described herein result in improvements in a patient's situated learning tests, wherein the situated learning test is a spatial situated learning test or the Arizona Cognitive Test Battery (ACTB).

[0142] In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a child. In some embodiments, the patient is an adult. As used herein, "child" means a person aged approximately 5 to 20 years. As used herein, "adult" means a person aged approximately 21 years and older. Attached Figure Description

[0143] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various embodiments of the invention and, together with the specification, serve to explain and illustrate the principles of this disclosure. The drawings are intended only to illustrate the main features of exemplary embodiments in a demonstrative manner.

[0144] Figure 1 Cerebral blood flow maps of patients after administration of a single dose of clenbuterol and / or naldolol are shown relative to their baseline.

[0145] Figure 2 Cerebral blood flow maps of patients relative to their baseline are shown after administration of a single dose of clenbuterol and / or nadolol.

[0146] Figure 3 Cerebral blood flow maps of patients after administration of a single dose of clenbuterol and patients after administration of a single dose of indolol are shown relative to their baseline.

[0147] Figure 4 Cerebral blood flow maps of patients after administration of single doses of clenbuterol at different amounts are shown relative to their baseline.

[0148] Figure 5 Cerebral blood flow maps relative to baseline are shown for patients after administration of a single dose of clenbuterol at different doses and for patients after administration of a single dose of clenbuterol and naldolol.

[0149] Figure 6 The diagram shows a comprehensive increase in cerebral perfusion following a single dose of 160 μg clenbuterol. The legend on the right illustrates the different regions of interest (ROIs). Data are plotted as changes in cerebral blood flow relative to baseline in different regions of the brain.

[0150] Figure 7 Perfusion MRI-ASL images of the hippocampus as the region of interest (ROI) are shown. Six healthy subjects aged 44–52 years received a single dose of 80 μg clenbuterol. Baseline versus post-dose paired t-test results: p = 0.019. Color scales are shown in the middle and indicate cerebral blood flow, with low values ​​in red and high values ​​in yellow.

[0151] Figure 8 The “estimated dose” of clenbuterol in cohort 5 of the study is shown to be the dose equivalent calculated based on PK exposure modeling at 24 hours (estimated dose 50 μg) and 48 hours (estimated dose 30 g) after administering a single dose of 80 g clenbuterol to subjects on day 1.

[0152] Figure 9 An improved adaptive tracking response to clenbuterol is shown.

[0153] Figure 10The effects of clenbuterol and β2-AR antagonists / β1-AR partial agonists on the visual-verbal learning test (VVLT) were shown.

[0154] Figure 11 The effect of compound 03-5 monotherapy (6 mg) on ​​heart rate was shown. Figure 11 A) and the effect of this compound on heart rate 2 hours after administration of naldolol (1-40 mg). Figure 11 B). Heart rate was measured using triplicate ECG recordings. Data are presented as the mean change of time-matched measurements recorded the day before the first administration of the study drug (Day -1).

[0155] Figure 12 This study demonstrates the peripheral effect of a dose-dependent increase in serum potassium levels in hypokalemia caused by low-dose nadolol inhibitory compound 03-5 in cohorts A1, A2, A3, A4, and A5 who received monotherapy with compound 03-5 (0.3 mg–6 mg), and the reduction in hypokalemia in subjects who received nadolol (1–40 mg) in cohorts D1 and D2. Data are presented as individual observations from all available subjects.

[0156] Figure 13 This is a graph illustrating the low CNS uptake of naldolol. Time-matched concentrations of compound 03-5 and naldolol in plasma and cerebrospinal fluid (CSF) from subjects in cohort D1 were determined in samples collected after administration of naldolol and compound 03-5 on day 2 (N=3–4 subjects) and day 6 (N=4 subjects). Data are presented as mean ± SEM observations from N=3–4 subjects at each dose level.

[0157] Figure 14 This study demonstrates the cognitive improvements of compound 03-5 in the presence of naldolol. CANTAB data were obtained from healthy adults aged 55–75 years (N=4) who received 3 mg naldolol and compound 03-5 (1, 3, and 10 mg) once daily on days 1, 2, and 3. All available data from two tests in the CANTAB battery assay were presented in cohort D2 (April 22, 2021, N=4). Data are presented as mean changes assessed pre-dose within the day. Detailed Implementation

[0158] In certain aspects and embodiments of this disclosure, the compositions and methods result in improved cognition, increased brain metabolic activity, and / or improved inflammation control in patients. In some embodiments, the methods described herein result in cognitive improvements, as demonstrated by improvements in patient cognitive tests or models; memory tests; diagnostic indicators of mental state, brain function, and mental condition; situated learning tests, etc. Such cognitive tests, diagnostics, and models are well known in the art. In various aspects and embodiments, any of the many accepted situated learning tests used in animals or humans can be used to assess baseline cognitive function and / or measure or quantify improved cognitive function. In some embodiments, the compositions and methods described herein can result in improvements in one or more of the following tests, diagnostics, and models. Similarly, for increased brain metabolic activity and improved inflammation control, in some embodiments, these can be imaged by FDG-PET and by sampling cerebrospinal fluid (CSF), thereby allowing the measurement of inflammatory cytokines and markers of glial cell activation. In some embodiments, magnetic resonance imaging-arterial spin labeling (MRI-ASL) can be used for neuroimaging. In some embodiments, magnetic resonance imaging-oxygen level dependent computed tomography (MRI-BOLD) can be used for neuroimaging. In various embodiments, FDG-PET can be used alone or in combination with CT and / or MRI comprising MRI-ASL and / or MRI-BOLD. For example, FDG-PET and MRI-BOLD can be used, or FDG-PET and MRI-ASL can be used. Alternatively, FDG-PET, MRI-BOLD, and MRI-ASL can be used. Alternatively, MRI comprising MRI-BOLD and MRI-ASL can be used alone or optionally in combination with CT.

[0159] β-drug

[0160] Alkyl refers to a monovalent group derived from an alkane by removing a hydrogen atom from any carbon atom, the monovalent group comprising straight and branched chains having 1 to 12 carbon atoms, and typically 1 to about 10 carbon atoms, or in some embodiments 1 to about 6 carbon atoms, or in other embodiments 1, 2, 3, or 4 carbon atoms. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl. Alkyl groups can be substituted or unsubstituted. Representative substituted alkyl groups can be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. As used herein, unless otherwise stated, the term alkyl refers to a cyclic and acyclic group.

[0161] The term "cycloalkyl" or "cycloalkyl group" refers to a monovalent group derived from a cycloalkane by removing a hydrogen atom from a ring carbon atom. A cycloalkyl group is a saturated or partially saturated non-aromatic structure having a monocyclic or polycyclic system comprising discrete, fused, bridged, and spirocyclic systems, having 3 to 14 carbon atoms, or in some embodiments, 3 to 12, 3 to 10, 3 to 8, 3, 4, 5, 6, or 7 carbon atoms. A cycloalkyl group can be substituted or unsubstituted. Representative substituted cycloalkyl groups can be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic systems include, but are not limited to, bicyclic [4.4.0]decane, bicyclic [2.2.1]heptane, spirocyclic [2.2.2]pentane, etc. (Cycloalkyl)oxy refers to -O-cycloalkyl. (Cycloalkyl)thio refers to -S-cycloalkyl. This term also covers oxidized forms of sulfur, such as -S(O)-cycloalkyl or -S(O)2-cycloalkyl.

[0162] An alkenyl group refers to a straight-chain, branched, or cycloalkyl group as defined above, having one or more double bonds between two carbon atoms. An alkenyl group can 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 can be substituted or unsubstituted. Representative substituted alkenyl groups can be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl.

[0163] An alkynyl group refers to a straight-chain, branched, or cycloalkyl group as defined above, having one or more triple bonds between two carbon atoms. An alkynyl group can 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 alkynyl group can be substituted or unsubstituted. Representative substituted alkynyl groups can be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, and -C≡C(CH3), etc.

[0164] Aryl groups are cyclic aromatic hydrocarbons comprising monocyclic and polycyclic compounds (including polycyclic compounds containing single and / or fused aryl groups). Aryl groups may contain 6 to about 18 ring carbons, or in some embodiments 6 to 14 ring carbons, or in other embodiments even 6 to 10 ring carbons. Aryl groups also include heteroaryl groups, which are aromatic cyclic compounds containing 5 or more ring members, wherein one or more ring carbon atoms are substituted with heteroatoms such as, but not limited to, N, O, and S. Aryl groups may be substituted or unsubstituted. Representative substituted aryl groups may be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Aryl groups include, but are not limited to, phenyl, biphenylene, triphenylene, naphthyl, anthracene, and pyrene. An aryloxy group refers to -O-aryl. An arylthio group refers to -S-aryl, wherein the aryl group is as defined herein. This term also covers oxidized forms of sulfur, such as -S(O)-aryl or -S(O)2-aryl. Heteroaryloxy refers to -O-heteroaryl. Heteroarylthio refers to -S-heteroaryl. This term also covers oxidized forms of sulfur, such as -S(O)-heteroaryl or -S(O)2-heteroaryl.

[0165] A suitable heterocyclic group comprises a cyclic group having atoms of at least two different elements as its ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, or S. The heterocyclic group may contain 3 to about 20 ring members, or in some embodiments 3 to 18 ring members, or about 3 to 15 ring members, 3 to 12 ring members, 3 to 10 ring members, or 3 to 6 ring members. The ring system in the heterocyclic group may be unsaturated, partially saturated, and / or saturated. The heterocyclic group may be substituted or unsubstituted. A representative substituted heterocyclic group may be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Exemplary heterocyclic groups include, but are not limited to, pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazine, azacyclic butyl, propidinyl, imidazolyl, pyrazolyl, tetrahydrothiazolyl, tetrahydrophenylthio, tetrahydrofuranyl, dioxy, furanyl, phenylthio, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, and thiocyclic butyl. Alkyl, high-piperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dioxanyl, purinyl, quinolinyl, cinnamyl, phthalazinyl, pteridinyl, and benzothiazolyl. Heterocyclic oxy groups refer to -O-heterocyclic groups. Heterocyclic thio groups refer to -S-heterocyclic groups. This term also covers oxidized forms of sulfur, such as S(O)-heterocyclic groups or -S(O)2-heterocyclic groups.

[0166] Polycyclic or polycyclic groups refer to two or more rings in which two or more carbon atoms are shared by two adjacent rings; such rings are called "fused rings." If the rings are connected by a single shared carbon atom, then it is a "spirocyclic" ring system. Rings connected by non-adjacent atoms are called "bridged" rings. Polycyclic groups can be substituted or unsubstituted. Representative polycyclic groups can be substituted once or multiple times.

[0167] Halogen groups include F, Cl, Br, and I; nitro refers to –NO2; cyano refers to –CN; isocyano refers to -N≡C; epoxy groups encompass structures in which an oxygen atom is directly attached to two adjacent or non-adjacent carbon atoms in a carbon chain or ring system, which are essentially cyclic ether structures. Epoxides are cyclic ethers with a triatomic ring.

[0168] An alkoxy group is a singular alkyl group bonded to oxygen, either substituted or unsubstituted, as defined above. Alkoxy groups can be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted once or multiple times. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0169] As used herein, the β-agent compounds of this disclosure may contain an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the specified portion are replaced by suitable substituents. Unless otherwise indicated, the "optionally substituted" group may have suitable substituents at each substituted position of the group, and at each position, the substituents may be the same or different when more than one position in any given structure can be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this disclosure are preferably combinations of substituents that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions permissible for its production, detection, and, in some embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0170] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0–4 R o ;-(CH2) 0–4 OR o ;-O(CH2) 0-4 R o -O-(CH2) 0–4 C(O)OR o ;-(CH2) 0–4 CH(OR o )2;-(CH2) 0– 4SR o ;-(CH2) 0–4 Ph, which can be derived from R o Substitution; -(CH2) 0–4 O(CH2) 0–1 Ph, which can be derived from R o Substitution; -CH=CHPh, which can be derived from R o Substitution; -(CH2) 0–4 O(CH2) 0–1 -pyridyl group, which can be derived from R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0–4 N(R o)2;-(CH2) 0–4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0–4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;-(CH2) 0–4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0–4 C(O)R o ;-C(S)R o ;-(CH2) 0–4 C(O)OR o ;-(CH2) 0–4 C(O)SR o ;-(CH2) 0–4 C(O)OSiR o 3;-(CH2) 0–4 OC(O)R o ;-OC(O)(CH2) 0–4 SR o ;SC(S)SR o ;-(CH2) 0–4 SC(O)R o ;-(CH2) 0–4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ;-(CH2) 0–4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o;-(CH2) 0–4 SSR o ;-(CH2) 0–4 S(O)2R o ;-(CH2) 0–4 S(O)2OR o ;-(CH2) 0–4 OS(O)2R o ;-S(O)2NR o 2; -S(O)(NR o )R o ; -S(O)2N=C(NR) o 2)2;-(CH2) 0–4 S(O)R o ;-N(R o )S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NH)NR o 2; -P(O)2R o ;-P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2;-SiR o 3; -(C 1–4 (linear or branched alkylene) O–N(R o )2; or -(C 1–4 (straight-chain or branched alkylene)C(O)O–N(R) o )2, where each R o It can be substituted as defined below, and is independently hydrogen, C 1–6 Aliphatic, -CH2Ph, -O(CH2) 0–1 Ph, -CH2- (5-6 membered heteroaryl ring) or a 5-6 membered saturated ring, partially unsaturated ring or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, despite the above definition, two independently occurring R o Together with its intermediate atoms, it forms a 3-12 membered saturated ring, partially unsaturated ring, or aryl monocyclic or bicyclic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0171] R o (or by using two independently occurring R) o Suitable monovalent substituents on the ring (formed together with its intermediate atoms) are independently halogens, -(CH2). 0–2 R ·;-(halogenated R) · -(CH2) 0–2 OH; -(CH2) 0–2 OR · ;-(CH2) 0–2 CH(OR · )2;-O(halogenated R · -CN; -N3; ​​-(CH2) 0–2 C(O)R · ;-(CH2) 0–2 C(O)OH;-(CH2) 0–2 C(O)OR · ;-(CH2) 0–2 SR · ;-(CH2) 0–2 SH; -(CH2) 0–2 NH2;-(CH2) 0–2 NHR · ;-(CH2) 0–2 NR · 2;-NO2;-SiR · 3; -OSiR · 3;-C(O)SR · ;-(C 1–4 (straight-chain or branched alkylene)C(O)OR · ; or -SSR · , where each R · It is either unsubstituted or, in the case of being preceded by "halogenated," substituted with only one or more halogens, and independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0–1 Ph or a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or hydroxyl groups. R o Appropriate divalent substituents on saturated carbon atoms include =O and =S.

[0172] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O; =S; =NNR * 2; =NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * ;=NR * =NOR * ;-O(C(R) * 2)) 2–3 O-; or -S(C(R) * 2)) 2–3 S-; where each independently occurring R *Selected from: hydrogen; C that can be substituted as defined below. 1-6 Aliphatic; or an unsubstituted 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the ortho-substituted carbon of the "optionally substituted" group include: -O(CR * 2) 2– 3O-, where each independently occurring R * Selected from: hydrogen; C that can be substituted as specified below. 1-6 Aliphatic; or an unsubstituted 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0173] R * Suitable substituents on aliphatic groups include halogens, -R · ;-(halogenated R) · -OH; -OR · ;-O(halogenated R) · -CN; -C(O)OH; -C(O)OR · -NH2; -NHR · ;-NR · 2; or -NO2, where each R · It is either unsubstituted or, in the case of being preceded by "halogenated," substituted by only one or more halogens, and is independently C. 1–4 Aliphatic, -CH2Ph, –O(CH2) 0–1 Ph or a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0174] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include or Each of them Independently, it is hydrogen, and can be substituted C as defined below. 1–6 Aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated rings, partially unsaturated rings, or aryl rings having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur; or, despite the above definition, two independently occurring... Together with its intermediate atoms, it forms an unsubstituted 3-12 membered saturated ring, partially unsaturated ring, or aryl monocyclic or bicyclic ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0175] Suitable substituents on aliphatic groups are: halogens, -R · ;-(halogenated R)· -OH; -OR · ;-O(halogenated R) · -CN; -C(O)OH; -C(O)OR · -NH2; -NHR · ;-NR · 2; or -NO2, where each R · It is either unsubstituted or, in the case of "halogenation" preceding it, substituted by only one or more halogens, and is independently C. 1–4 Aliphatic, -CH2Ph, -O(CH2) 0–1 Ph or a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0176] Thiols refer to -SH. Thiocarbonyl groups refer to (=S). Sulfonyl groups refer to -SO2-alkyl, -SO2-substituted alkyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic groups. Sulfonylamino groups refer to -NR. a SO2 alkyl, -NR a SO2 substituted alkyl groups, -NR a SO2 cycloalkyl, --NR a SO2 substituted cycloalkyl, -NR a SO2 aryl, -NR a SO2 substituted aryl group, --NR a SO2 heteroaryl, -NR a SO2 substituted heteroaryl, -NR a SO2 heterocyclic group, -NR a SO2 substituted heterocyclic groups, wherein each R a Independently as defined in this article.

[0177] The carboxyl group refers to -COOH or its salt. Carboxylic acid esters refer 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-heterocyclic, and -C(O)O-substituted heterocyclic. The amino group (in carboxylic acid esters) refers to -NR. a -C(O)O-alkyl, -NR a -C(O)O-substituted alkyl group, -NR a -C(O)O-aryl, -NR a-C(O)O-substituted aryl, -NR a -C(O)β-cycloalkyl, -NR a -C(O)O-substituted cycloalkyl, -NR a -C(O)O-heteroaryl, --NR a -C(O)O-substituted heteroaryl, -NR a -C(O)O- heterocyclic group and NR a -C(O)O- substituted heterocyclic group, where R a As described herein, the (carboxylic acid ester) oxy group refers to -OC(O)O-alkyl, OC(O)O-substituted alkyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)β-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic. Oxidation refers to (=O).

[0178] The terms "amine" and "amino" refer to derivatives of ammonia in which one of a plurality of hydrogen atoms has been replaced by a substituent, which includes, but is not limited to, alkyl, alkenyl, aryl, and heterocyclic groups. In some embodiments, the substituted amino group may comprise -NH-CO-R. The urethane group refers to -O(C=O)NR1R2, wherein R1 and R2 are independently hydrogen, aliphatic, aryl, or heterocyclic groups.

[0179] The amino carbonyl group refers to -C(O)N(R) b )2, where each R b Independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic. Similarly, each R b It can optionally combine with the nitrogen bound thereto to form a heterocyclic group or a substituted heterocyclic group, provided that the two Rs are... b Not all of them are hydrogen. Aminocarbonyl alkyl refers to -alkyl C(O)N(R) b )2, where each R b Independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic. Similarly, each R b It can optionally combine with the nitrogen bound thereto to form a heterocyclic group or a substituted heterocyclic group, provided that the two Rs are... b Not all of them are hydrogen. The amino group (amino carbonyl amino) refers to -NR. a C(O)N(R b )2, where R aand each R b As defined in this article, amino dicarbonylamino refers to -NR a C(O)C(O)N(R b )2, where R a and each R b As defined in this article, aminocarbonyloxy group refers to -OC(O)N(R) b )2, where each R b Independently as defined herein, the aminosulfonyl group refers to -SO2N(R b )2, where each R b Independently as defined in this article.

[0180] Imino refers to -N=R c , where R c It can be selected from hydrogen, aminocarbonylalkyloxy, substituted aminocarbonylalkyloxy, aminocarbonylalkylamino and substituted aminocarbonylalkylamino.

[0181] Alternatively, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds containing deuterium (e.g., D or H₂) 2 ) or tritium (e.g., T or H) 3 Replacement of hydrogen or by 13 C- or 14 Compounds of the present invention with C-enriched carbon-replacing carbon structures are included within and fall within the scope of the present invention. According to the present invention, such compounds can be used, for example, as analytical tools, probes in bioassays, or therapeutic agents.

[0182] Pharmaceutically acceptable salts of the compounds described herein comprise conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochlorides, hydrobromic acids, sulfates, aminosulfonates, phosphates, nitrates, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylates, sulfanilic acids, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiocarbonyl acid, etc. In other cases, the described compounds may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can also be prepared in situ during the application of the mordant or formulation, or by reacting a purified compound in its free acid form with a suitable base, such as a pharmaceutically acceptable hydroxide, carbonate, or bicarbonate of a metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine.

[0183] A “prodrug” is a derivative of an active agent that requires conversion in vivo to release the active agent. In some embodiments, the conversion is enzymatic. Prodrugs are typically (though not always necessary) pharmacologically inactive until converted to the active agent. A “promide” refers to a form of protecting group that, when used to mask functional groups within the active agent, converts the active agent into a prodrug. In some cases, the promide will be linked to the drug via a bond cleaved in vivo by enzymatic or non-enzymatic methods. For example, any convenient prodrug form of the subject compound can be prepared according to the strategies and methods described by Rautio et al., “Prodrugs: design and clinical applications,” Nature Reviews Drug Discovery, 7, 255-270 (February 2008).

[0184] This article discloses a β-drug compound according to formula (I) or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug.

[0185]

[0186] A, B, and X can each be nitrogen or carbon independently. Each R1 can be hydrogen, halogen, cyano, nitro, pentafluorosulfonyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. m can be an integer selected from 0 to 4.

[0187] R2, R3, and R4 can independently be H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. Alternatively, R2 and R3 together with carbon can form unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0188] L can be an optionally substituted C1-C5 alkyl linker, Y1, Y2, Y3 and Y4 can each be independently covalent, carbon, oxygen or nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Z can be O or S.

[0189] R5 and R6 may be hydrogen, unsubstituted or substituted alkyl, or R5 and R6 may be cyclically linked and together with Y2 to form optionally substituted cycloalkyl or heterocyclic rings. Each R7 is independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0190] n can be an integer selected from 0 to 4, R8 can be hydrogen, cyano, unsubstituted or substituted alkyl and unsubstituted or substituted aryl, and R9 is selected from the group consisting of: hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy or unsubstituted or substituted amino.

[0191] This article discloses a β-drug compound according to formula (II) or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug.

[0192]

[0193] A, B, and X can each be nitrogen or carbon independently. Each R1 can be hydrogen, halogen, cyano, nitro, pentafluorosulfonyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. m can be an integer selected from 0 to 4.

[0194] R2, R3, and R4 can independently be H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0195] Alternatively, R2 and R3 together with carbon can form unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0196] L can be an optionally substituted C1-C5 alkyl linker, Y1, Y2, Y3 and Y4 can each be independently covalent, carbon, oxygen or nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Z can be O or S.

[0197] R5 and R6 can be hydrogen, unsubstituted or substituted alkyl independently, or R5 and R6 can be cyclically linked and together with Y2 to form optionally substituted cycloalkyl or heterocyclic rings. Each R7 can be hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0198] n can be an integer selected from 0 to 4, R8 can be hydrogen, cyano, unsubstituted or substituted alkyl and unsubstituted or substituted aryl, and R9 is selected from the group consisting of: hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy or unsubstituted or substituted amino.

[0199] This article further discloses a compound according to formula (III) or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug.

[0200]

[0201] Each R1 can independently be hydrogen, halogen, cyano, nitro, pentafluorothioalkyl, unsubstituted or substituted sulfonyl, substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted -(C=O)-alkyl, unsubstituted or substituted -(C=O)-cycloalkyl, unsubstituted or substituted -(C=O)-aryl, unsubstituted or substituted -(C=O)-heteroaryl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. m can be an integer selected from 0 to 4.

[0202] R2, R3, and R4 can independently be H, halogen, hydroxyl, cyano, nitro, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0203] Alternatively, R2 and R3 together with carbon can form unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0204] L can be an optionally substituted C1-C5 alkyl linker, X1, X2, X3 and X4 can each be independently covalent, carbon, oxygen or nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, and Y can be O or S.

[0205] R5 and R6 can be hydrogen, unsubstituted or substituted alkyl, or R5 and R6 can be cyclically linked and together with Y2 to form optionally substituted cycloalkyl or heterocyclic rings. Each R7 can be hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0206] n can be an integer selected from 0 to 4, R8 can be hydrogen, cyano, unsubstituted or substituted alkyl and unsubstituted or substituted aryl, and R9 is selected from the group consisting of: hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy or unsubstituted or substituted amino.

[0207] This article further discloses a β-agent compound according to formula (I'):

[0208]

[0209] Or its pharmaceutically acceptable salt.

[0210] in:

[0211] A', B', and X' are each independently nitrogen or carbon;

[0212] Each R 1' Independently, it is halogen, -R', -CN, -NO2, -SF5, -OR x -NR x 2. -NHR x , -SO2R', -C(O)R', -C(O)NR'2;

[0213] Each R' is independently hydrogen or a optionally substituted group selected from the following: C 1-6 Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic partially unsaturated or aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 member bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0214] Each R x Independently, it is a optionally substituted group selected from the following: C 1-6Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic partially unsaturated or aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 member bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0215] m' is an integer selected from 0 to 4;

[0216] R 2' R 3' and R 4' Each of these can be independently a halogen, -R', -CN, -NO2, -OR', -NR'2,

[0217] or

[0218] R 2' and R 3' It forms, together with carbon, an optionally substituted 3-7 membered saturated carbon ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0219] L' is C that has been optionally substituted. 1-5 Alkylene;

[0220] Y 1' Y 2' Y 3' and Y 4' Each is independently a covalent bond, carbon, oxygen, or nitrogen, optionally with hydrogen, optionally with substituted C. 1-6 Alkyl groups or optionally substituted 3-7 membered saturated carbon rings;

[0221] Z' is either O or S;

[0222] R 5 'and R 6 Each is independently hydrogen or optionally substituted alkyl; or

[0223] R 5 'and R 6 ' is a ring connection, and is related to Y 2'Together they form optionally substituted 3-7 membered saturated carbon rings; optionally substituted 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycles having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0224] Each R 7 Independently, it can be -R, halogen, -CN, -NO2, -NR'2, or -OR';

[0225] n' is an integer selected from 0 to 4;

[0226] R 8 'is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring;

[0227] Each R 9 Independently, it is hydrogen, halogen, -CN, -OR x -NR'2 or optionally substituted alkyl groups; and

[0228] R 10 'and R 11' Each is independently hydrogen or optionally substituted C 1-2 Aliphatic.

[0229] This article further discloses a β-agent compound according to formula (I”):

[0230]

[0231] Or its pharmaceutically acceptable salt.

[0232] in:

[0233] A', B', and X' are each independently nitrogen or carbon;

[0234] Each R 1' Independently, it is halogen, -R', -CN, -NO2, -SF5, -OR x -NR x 2. -NHR x , -SO2R', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'CO2R' or -CO2R';

[0235] Each R' is independently hydrogen or a optionally substituted group selected from the following: C 1-6Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic partially unsaturated or aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 member bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0236] Each R x Independently, it is a optionally substituted group selected from the following: C 1-6 Aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbon rings, phenyl, 8-10 member bicyclic partially unsaturated or aromatic carbon rings, 4-8 member saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 member monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 member bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0237] m' is an integer selected from 0 to 4;

[0238] R 2' R 3' and R 4' Each of these can be independently a halogen, -R', -CN, -NO2, -OR', -NR'2,

[0239] or

[0240] R 2' and R 3' It forms, together with carbon, an optionally substituted 3-7 membered saturated carbon ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0241] L' is C that has been optionally substituted. 1-5 Alkylene;

[0242] Y 1' Y 2' Y 3' and Y 4' Each is independently a covalent bond, carbon, oxygen, or nitrogen, optionally with hydrogen, optionally with substituted C. 1-6 Alkyl groups or optionally substituted 3-7 membered saturated carbon rings;

[0243] Z' is either O or S;

[0244] R 5 'and R 6 Each is independently hydrogen or optionally substituted alkyl; or

[0245] R 5 'and R 6 ' is a ring connection, and is related to Y 2' Together they form optionally substituted 3-7 membered saturated carbon rings; optionally substituted 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycles having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0246] Each R 7 Independently, it can be -R, halogen, -CN, -NO2, -NR'2, or -OR';

[0247] n' is an integer selected from 0 to 4;

[0248] R 8 'is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring;

[0249] Each R 9 Independently, it is hydrogen, halogen, -CN, -OR x -NR'2 or optionally substituted alkyl groups; and

[0250] R 10 'and R 11' Each is independently hydrogen or optionally substituted C 1-2 Aliphatic.

[0251] As defined above and as described herein, A' is nitrogen or carbon. In some embodiments, A' is nitrogen. In some embodiments, A' is carbon.

[0252] In some embodiments, A' is selected from those depicted in Table 1 below.

[0253] As defined above and as described herein, B' is nitrogen or carbon. In some embodiments, B' is nitrogen. In some embodiments, B' is carbon.

[0254] In some embodiments, B' is selected from those depicted in Table 1 below.

[0255] As defined above and as described herein, X' is nitrogen or carbon. In some embodiments, X' is nitrogen. In some embodiments, X' is carbon.

[0256] In some embodiments, X' is selected from those depicted in Table 1 below.

[0257] As defined above, each R 1' Independently, it is halogen, -R', -CN, -NO2, -SF5, -OR x -NR x 2. -NHR x , -SO2R', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'CO2R' or -CO2R'.

[0258] In some embodiments, R 1' It is hydrogen. In some embodiments, R 1' It is a halogen. In some embodiments, R 1' It is -R'. In some embodiments, R 1' It is cyano. In some embodiments, R 1' It is -NO2. In some embodiments, R 1' Yes -SF5. In some embodiments, R 1' Yes - OR x In some embodiments, R 1' Yes – NR x 2. In some embodiments, R 1' Yes - NHR x In some embodiments, R 1' It is -SO2R'. In some embodiments, R 1' It is -C(O)R'. In some embodiments, R 1' It is -C(O)NR'2. In some embodiments, R 1' It is -NR'C(O)R'. In some embodiments, R 1' It is -NR'CO2R'. In some embodiments, R 1' It is -CO2R'.

[0259] In some embodiments, R 1' Yes -Br. In some embodiments, R 1' It is -Cl. In some embodiments, R 1' Yes, it is -F.

[0260] In some embodiments, R 1' It is -CH3. In some embodiments, R 1' It is -CH2CH3. In some embodiments, R 1' It is -CH(CH3)2.

[0261] In some embodiments, R 1'It is -CF3. In some embodiments, R 1' It is -CF2H. In some embodiments, R 1' It is -CFH2. In some embodiments, R 1' It is -CF2CH3. In some embodiments, R 1' It is -CH2CF3. In some embodiments, R 1' It is -C≡CCH. In some embodiments, R 1' It is vinyl. In some embodiments, R 1' It is -C≡CCF3. In some embodiments, R 1' It is -CO2H.

[0262] In some embodiments, R 1' Yes - CN.

[0263] In some embodiments, R 1' It is -OCH3. In some embodiments, R 1' It is -OCH2CH3. In some embodiments, R 1' It is -OCH(CH3)2. In some embodiments, R 1' Yes -OCF3. In some embodiments, R 1' It is -NHCH3. In some embodiments, R 1' It is -NHCD3. In some embodiments, R 1' It is -N(CD3)CO2tBu. In some embodiments, R 1' It is -NHCH2CH3. In some embodiments, R 1' It is -NHCH2(CH3)2. In some embodiments, R 1' It is -NHCH2CF3. In some embodiments, R 1' It is -NHPh. In some embodiments, R 1' It is -NHAc. In some embodiments, R 1' It is -N(CH3)2. In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes In some embodiments, R 1' yes

[0264] In some embodiments, R 1' Selected from those described in Table 1 below.

[0265] As defined above; each R' is independently hydrogen or a optionally substituted group selected from the following: C 1-6Aliphatic; 3-8 membered saturated or partially unsaturated monocyclic carbon rings; phenyl; 8-10 membered bicyclic partially unsaturated or aromatic carbon rings; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; 5-6 membered monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or 8-10 membered bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0266] In some embodiments, R' is hydrogen.

[0267] In some embodiments, R' is optionally substituted C 1-6 Aliphatic. For example, in some embodiments, R' is -CF3, -CF2H, or -CFH2.

[0268] In some embodiments, R' is an optionally substituted 3- to 8-membered saturated monocyclic carbon ring.

[0269] In some embodiments, R' is an optionally substituted 3-8 nucleotide partially unsaturated monocyclic carbon ring.

[0270] In some embodiments, R' is an optionally substituted phenyl group.

[0271] In some embodiments, R' is an optionally substituted 8-10 cyclic bicyclic partially unsaturated carbon ring.

[0272] In some embodiments, R' is an optionally substituted 8-10 membered bicyclic aromatic carbon ring.

[0273] In some embodiments, R' is an optionally substituted 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0274] In some embodiments, R' is an optionally substituted 4-8 member partially unsaturated monocyclic heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur.

[0275] In some embodiments, R' is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0276] In some embodiments, R' is an optionally substituted 8-10 membered bicyclic partially unsaturated ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0277] In some embodiments, R' is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0278] In some embodiments, R' is selected from those depicted in Table 1 below.

[0279] As defined above; each R x Independently, it is a optionally substituted group selected from the following: C 1-6 Aliphatic; 3-8 membered saturated or partially unsaturated monocyclic carbon rings; phenyl; 8-10 membered bicyclic partially unsaturated or aromatic carbon rings; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; 5-6 membered monocyclic heteroaromatic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or 8-10 membered bicyclic partially unsaturated or heteroaromatic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0280] In some embodiments, R x It is C that is arbitrarily substituted. 1-6 Aliphatic. For example, in some embodiments, R x It is -CF3, -CF2H, or -CFH2. In some embodiments, R x It is C 1-6 alkyl.

[0281] As defined above, m' is an integer selected from 0 to 4.

[0282] In some embodiments, m' is 0. In some embodiments, m' is 1. In some embodiments, m' is 2. In some embodiments, m' is 3. In some embodiments, m' is 4.

[0283] As defined above, R 2' R 3' and R 4' Each of these can be independently a halogen, -R', -CN, -OH, -OR', -NR'2, -NHR', -NH2,

[0284]

[0285] Or R 2' and R 3' It forms, together with carbon, an optionally substituted 3-7 membered saturated carbon ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0286] In some embodiments, R 2' It is hydrogen. In some embodiments, R 2' It is a halogen. In some embodiments, R 2'It is -R'. In some embodiments, R 2' Yes -CN. In some embodiments, R 2' It is -NO2. In some embodiments, R 2' It is -OH. In some embodiments, R 2' Yes - OR'. In some embodiments, R 2' It is -NR'2. In some embodiments, R 2' Yes -NHR'. In some embodiments, R 2' It is -NH2.

[0287] In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes In some embodiments, R 2' yes

[0288] In some embodiments, R 2' It is hydrogen. In some embodiments, R 2' It is deuterium. In some embodiments, R 2' It is -CH3. In some embodiments, R 2' It is -CD3. In some embodiments, R 2' yes

[0289] In some embodiments, R 3' It is hydrogen. In some embodiments, R 3' It is a halogen. In some embodiments, R 3' It is -R'. In some embodiments, R 3' Yes -CN. In some embodiments, R 3' It is -NO2. In some embodiments, R 3' It is -OH. In some embodiments, R 3'Yes - OR'. In some embodiments, R 3' It is -NR'2. In some embodiments, R 3' Yes -NHR'. In some embodiments, R 3' It is -NH2.

[0290] In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes In some embodiments, R 3' yes

[0291] In some embodiments, R 3' It is hydrogen. In some embodiments, R 3' It is deuterium. In some embodiments, R 3' It is -CH3. In some embodiments, R 3' It is -CD3. In some embodiments, R 3' yes

[0292] In some embodiments, R 2' and R 3' It can form a 3-7 membered saturated carbon ring with carbon, optionally substituted; a 5-6 membered monocyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; or a 3-7 membered saturated or partially unsaturated monocyclic heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0293] In some embodiments, R 2' and R 3' Together with carbon, they form optionally substituted 3-7 member saturated carbon rings.

[0294] In some embodiments, R 2' and R 3'Together with carbon, it forms a 5-6 membered monocyclic heteroaryl ring with 1-4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur, which are optionally substituted.

[0295] In some embodiments, R 2' and R 3' Together with carbon, they form optional substituted 3-7 member saturated or partially unsaturated monocyclic heterocycles with 1-2 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur.

[0296] In some embodiments, R 2' and R 3' Formed with carbon In some embodiments, R 2' and R 3' Formed with carbon In some embodiments, R 2' and R 3' Formed with carbon In some embodiments, R 2' and R 3' Formed with carbon

[0297] In some embodiments, R 4' It is hydrogen. In some embodiments, R 4' It is a halogen. In some embodiments, R 4' It is -R'. In some embodiments, R 4' Yes -CN. In some embodiments, R 4' It is -NO2. In some embodiments, R 4' It is -OH. In some embodiments, R 4' Yes - OR'. In some embodiments, R 4' It is -NR'2. In some embodiments, R 4' Yes -NHR'. In some embodiments, R 4' It is -NH2. In some embodiments, R 4' It is -CF3.

[0298] In some embodiments, R 4' yes In some embodiments, R 4' yes In some embodiments, R 4' yes In some embodiments, R 4' yes In some embodiments, R 4' yes In some embodiments, R 4' yes In some embodiments, R 4'yes In some embodiments, R 4' yes In some embodiments, R 4' yes In some embodiments, R 4' yes In some embodiments, R 4' yes

[0299] In some embodiments, R 4' It is hydrogen. In some embodiments, R 4' It is deuterium. In some embodiments, R 4' It is -CH3. In some embodiments, R 4' Yes -CD3. In some embodiments, R 4' yes

[0300] In some embodiments, R 2' R 3' and R 4' Each is selected from those described in Table 1 below.

[0301] As defined above, L' is an optionally substituted C 1-5 Alkylene.

[0302] In some embodiments, L' is -CH2-.

[0303] In some embodiments, L' is selected from those depicted in Table 1 below.

[0304] As defined above, Y 1' Y 2' Y 3' and Y 4' Each is independently a covalent bond, carbon, oxygen, or nitrogen, optionally with hydrogen, optionally with substituted C. 1-6 Alkyl groups or optionally substituted 3-7 saturated carbocyclic rings.

[0305] In some embodiments, Y 1' It is a covalent bond. In some embodiments, Y 1' It is carbon. In some embodiments, Y 1' It is oxygen. In some embodiments, Y 1' It is nitrogen, optionally replaced by hydrogen, optionally by substituted C 1-6 Alkyl groups or optionally substituted 3-7 saturated carbocyclic rings.

[0306] In some embodiments, Y 2' It is a covalent bond. In some embodiments, Y 2' It is carbon. In some embodiments, Y2' It is oxygen. In some embodiments, Y 2' It is nitrogen, optionally replaced by hydrogen, optionally by substituted C 1-6 Alkyl groups or optionally substituted 3-7 saturated carbocyclic rings.

[0307] In some embodiments, Y 3' It is a covalent bond. In some embodiments, Y 3' It is carbon. In some embodiments, Y 3' It is oxygen. In some embodiments, Y 3' It is nitrogen, optionally replaced by hydrogen, optionally by substituted C 1-6 Alkyl groups or optionally substituted 3-7 saturated carbocyclic rings.

[0308] In some embodiments, Y 3' It is a covalent bond. In some embodiments, Y 3' It's carbon.

[0309] In some embodiments, Y 4' It is a covalent bond. In some embodiments, Y 4' It is carbon. In some embodiments, Y 4' It is oxygen. In some embodiments, Y 4' It is nitrogen, optionally replaced by hydrogen, optionally by substituted C 1-6 Alkyl groups or optionally substituted 3-7 saturated carbocyclic rings.

[0310] In some embodiments, Y 4' It is a covalent bond. In some embodiments, Y 4' It's carbon.

[0311] In some embodiments, Y 1' Y 2' Y 3' and Y 4' Each is selected from those described in Table 1 below.

[0312] As defined above, Z' is O or S.

[0313] In some embodiments, Z' is O. In some embodiments, Z' is S.

[0314] In some embodiments, Z' is selected from those depicted in Table 1 below.

[0315] As defined above, R 5 'and R 6 Each is independently hydrogen or optionally substituted alkyl, or R 5 'and R 6 ' is a ring connection, and is related to Y 2'Together they form optionally substituted 3-7 membered saturated carbon rings; optionally substituted 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycles having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0316] In some embodiments, R 5 'It is hydrogen.' In some embodiments, R 5 'is optionally substituted C' 1-6 alkyl.

[0317] In some embodiments, R 6 'It is hydrogen.' In some embodiments, R 6 'is optionally substituted C' 1-6 alkyl.

[0318] In some embodiments, R 5 'and R 6 ' is a ring connection, and is related to Y 2' Together they form optionally substituted 3-7 member saturated carbon rings.

[0319] In some embodiments, R 5 'and R 6 ' is a ring connection, and is related to Y 2' Together they form a 5-6 membered monocyclic heteroaryl ring having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur, which are optionally substituted.

[0320] In some embodiments, R 5 'and R 6 ' is a ring connection, and is related to Y 2' Together they form a 3-7 member saturated or partially unsaturated monocyclic heterocycle with 1-2 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur.

[0321] In some embodiments, R 5 'and R 6 ' is a ring connection, and is related to Y 2' Together they form a 7-12 member saturated or partially unsaturated bicyclic heterocycle with 1-4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur.

[0322] In some embodiments, R 5 'and R 6 Each is selected from those described in Table 1 below.

[0323] As defined above; each R 7Independently, it can be -R, halogen, -CN, -NO2, -OH, -NR'2, -NHR', -NH2, or -OR'.

[0324] In some embodiments, R 7 'It is hydrogen.' In some embodiments, R 7 It is a halogen. In some embodiments, R 7 'is-CN.' In some embodiments, R 7 'Yes - NO2.' In some embodiments, R 7 'is -OH.' In some embodiments, R 7 'Yes-NR'2. In some embodiments, R 7 'Yes-NHR'. In some embodiments, R 7 'It is -NH2. In some embodiments, R 7 'is-OR'.

[0325] In some embodiments, each R 7 Select independently from those described in Table 1 below.

[0326] As defined above, n' is an integer selected from 0 to 4.

[0327] In some embodiments, n' is 0. In some embodiments, n' is 1. In some embodiments, n' is 2. In some embodiments, n' is 3. In some embodiments, n' is 4.

[0328] As defined above, R 8 ' is hydrogen, -CN, optionally substituted alkyl, or optionally substituted aryl ring.

[0329] In some embodiments, R 8 'It is hydrogen.' In some embodiments, R 8 'is-CN.' In some embodiments, R 8 'is optionally substituted C' 1-6 Alkyl group. In some embodiments, R 8 ' is an aryl ring that is optionally substituted.

[0330] In some embodiments, R 8 'Selected from those described in Table 1 below.'

[0331] As defined above, each R 9 Independently, it is hydrogen, halogen, -CN, -OR x -NR'2 or optionally substituted alkyl groups.

[0332] In some embodiments, R 9 'It is hydrogen.' In some embodiments, R9 It is a halogen. In some embodiments, R 9 'is-CN.' In some embodiments, R 9 'is-OR x In some embodiments, R 9 'Yes-NR'2. In some embodiments, R 9 'Yes-NHR'. In some embodiments, R 9 'It is -NH2. In some embodiments, R 9 'is optionally substituted C' 1-6 alkyl.

[0333] In some embodiments, R 9 'Selected from those described in Table 1 below.'

[0334] As defined above, R 10 'and R 11' Each is independently hydrogen or optionally substituted C 1-2 Aliphatic. In some embodiments, R 10 'and R 11' Each can be hydrogen, methyl, or ethyl.

[0335] In some embodiments, R 10 'It is hydrogen.' In some embodiments, R 10 'Is optionally substituted C1 aliphatic. In some embodiments, R 10 ' is methyl. In some embodiments, R 10 'Is optionally substituted C2 aliphatic. In some embodiments, R 10 It is an ethyl group.

[0336] In some embodiments, R 10 'Selected from those described in Table 1 below.'

[0337] In some embodiments, R 11' It is hydrogen. In some embodiments, R 11' It is optionally substituted C1 aliphatic. In some embodiments, R 11' It is methyl. In some embodiments, R 11' It is optionally a substituted C2 aliphatic. In some embodiments, R 11' It is an ethyl group.

[0338] In some embodiments, R 11' Selected from those described in Table 1 below.

[0339] This article further discloses a β-agent compound according to formula (II'):

[0340]

[0341] Or its pharmaceutically acceptable salt.

[0342] Where A', B', X', R 1' R 2' R 3' R 4' Each of m' is as defined above and is described individually and in combination as provided in the embodiments herein.

[0343] This article further discloses a β-agent compound according to formula (III'):

[0344]

[0345] Or its pharmaceutically acceptable salt.

[0346] Where R 1' R 2' R 3' R 4' Each of m' is as defined above and is described individually and in combination as provided in the embodiments herein.

[0347] This article further discloses a β-agent compound according to formula (IV'):

[0348]

[0349] Or its pharmaceutically acceptable salt.

[0350] Where R 1' R 2' R 3' and R 4' Each of these is as defined above and described individually and in combination as in the embodiments provided herein. In some such embodiments, R 1' It is -CF3. In some such embodiments, R 1' It is -CF2H. In some such embodiments, R 1' Yes -OCF3. In some such embodiments, R 1' Yes -CN. In some such embodiments, R 1' It is -C(O)NR'2. In some such embodiments, R 1' It is cyclopropyl. In some such embodiments, R 1' It is a tetrazolium. In some such embodiments, R 1' It is a phenyl group. In some such embodiments, R 1' Yes -Br. In some such embodiments, R 1' It is -CH3.

[0351] This article further discloses a β-agent compound according to formula (V'):

[0352]

[0353] Or its pharmaceutically acceptable salt.

[0354] Where R 1' Each of m' is as defined above and is described individually and in combination as provided in the embodiments herein.

[0355] This article further discloses a β-agent compound according to formula (VI'):

[0356]

[0357] Or its pharmaceutically acceptable salt.

[0358] Where R 1' As defined above and described individually and in combination as provided in the embodiments herein.

[0359] This article further discloses a β-agent compound according to formula (VII'):

[0360]

[0361] Or its pharmaceutically acceptable salt.

[0362] Where R 1' R 2' R 3' R 4' Each of m' is as defined above and is described individually and in combination as provided in the embodiments herein.

[0363] This article further discloses a β-agent compound according to formula (VIII'):

[0364]

[0365] Or its pharmaceutically acceptable salt.

[0366] Where R 1' R 2' R 3' R 4' Each of m' is as defined above and is described individually and in combination as provided in the embodiments herein.

[0367] This article further discloses a β-agent compound according to formula (IX'):

[0368]

[0369] Or its pharmaceutically acceptable salt.

[0370] Where R 1' R 2' R 3' R 4' Each of m' is as defined above and is described individually and in combination as provided in the embodiments herein.

[0371] This article further discloses a β-agent compound according to formula (X'):

[0372]

[0373] Or its pharmaceutically acceptable salt.

[0374] in

[0375] R 1' It is halogen, -R x -CN, -NO2, -SF5, -OR x , -SO2R' or -C(O)R';

[0376] R 2' R 3' and R 4' Each independently is a halogen, -R', -CN, -NO2, -OR', or -NR'2, or

[0377] R 2' and R 3' Together with carbon, it forms optionally substituted 3-7 membered cycloalkyl or heterocyclic rings; and

[0378] R' and R x As defined above and described individually and in combination as in the embodiments provided herein. In some such embodiments, R 1' It is -CF3. In some such embodiments, R 1' It is -CF2H. In some such embodiments, R 1' Yes -OCF3. In some such embodiments, R 1' Yes -CN. In some such embodiments, R 1' It is -C(O)NR'2. In some such embodiments, R 1' It is cyclopropyl. In some such embodiments, R 1' It is a tetrazolium. In some such embodiments, R 1' It is a phenyl group. In some such embodiments, R 1' Yes -Br. In some such embodiments, R 1' It is -CH3.

[0379] This article further discloses a β-agent compound according to formula (XI'):

[0380]

[0381] Or its pharmaceutically acceptable salt.

[0382] in:

[0383] R 1' It is halogen, -R', -CN, -NO2, -SF5, -OR x , -SO2R' or -C(O)R';

[0384] R 2 '、R 3' and R 4' Each independently is a halogen, -R', -CN, -NO2, -OR', or -NR'2, or

[0385] R 2 'and R 3' Together with carbon, it forms optionally substituted 3-7 membered cycloalkyl or heterocyclic rings; and

[0386] R' and R x As defined above and described individually and in combination as provided in the embodiments herein.

[0387] This article further discloses a β-agent compound according to formula (XII'):

[0388]

[0389] Or its pharmaceutically acceptable salt.

[0390] in:

[0391] R 1' It is halogen, -R', -CN, -NO2, -SF5, -OR x -SO2R' or -C(O)R'; and

[0392] R' and R x As defined above and described individually and in combination as provided in the embodiments herein.

[0393] This article further discloses a compound according to formula (XIII'):

[0394]

[0395] Or its pharmaceutically acceptable salt.

[0396] in:

[0397] R1' It is halogen, -R', -CN, -NO2, -SF5, -OR x -SO2R' or -C(O)R'; and

[0398] R' and R x As defined above and described individually and in combination as provided in the embodiments herein.

[0399] This article further discloses a β-agent compound according to formula (XIV'):

[0400]

[0401] Or its pharmaceutically acceptable salt.

[0402] in

[0403] R 1' It is a halogen, -R', -CN, or -NO2;

[0404] R 2 '、R 3' and R 4' Each independently is a halogen, -R', -CN, -NO2, -OR', or -NR'2, or

[0405] R 2 'and R 3' Together with carbon, it forms optionally substituted 3-7 membered cycloalkyl or heterocyclic rings; and

[0406] R' is as defined above and is described individually and in combination as in the embodiments provided herein.

[0407] This article further discloses a compound according to formula (XV'):

[0408]

[0409] Or its pharmaceutically acceptable salt.

[0410] in:

[0411] R 1' It is a halogen, -R', -CN, or -NO2;

[0412] R 2 '、R 3' and R 4' Each independently is a halogen, -R', -CN, -NO2, -OR', or -NR'2, or

[0413] R 2 'and R 3' Together with carbon, it forms optionally substituted 3-7 membered cycloalkyl or heterocyclic rings; and

[0414] R' is as defined above and is described individually and in combination as in the embodiments provided herein.

[0415] This article further discloses a compound according to formula (XVI'):

[0416]

[0417] Or its pharmaceutically acceptable salt.

[0418] in:

[0419] R 1' It is a halogen, -R', -CN, or -NO2; and

[0420] R' is as defined above and is described individually and in combination as in the embodiments provided herein.

[0421] This article further discloses a compound according to formula (XVII'):

[0422]

[0423] Or its pharmaceutically acceptable salt.

[0424] in

[0425] R 1' It is a halogen, -R', -CN, or -NO2;

[0426] Each R' is an optionally substituted C 1-6 aliphatic; and

[0427] R 2 '、R 3' and R 4' Each independently is a halogen, -R', -CN, -NO2, -OR', or -NR'2, or

[0428] R 2 'and R 3' Together with carbon, they can form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0429] This article further discloses a compound according to formula (XVIII'):

[0430]

[0431] Or its pharmaceutically acceptable salt.

[0432] in:

[0433] R 1' It is a halogen, -R', -CN, or -NO2;

[0434] Each R' is an optionally substituted C 1-6 aliphatic; and

[0435] R 2' R 3' and R 4' Each can be independently a halogen, -R', -CN, -NO2, -OR', or -NR'2, or R 2' and R 3' Together with carbon, they can form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0436] This article further discloses a compound according to formula (XIX'):

[0437]

[0438] Or its pharmaceutically acceptable salt.

[0439] in:

[0440] R 1' It is a halogen, -R', -CN, or -NO2; and

[0441] R' is C that has been optionally substituted. 1-6 Aliphatic.

[0442] This article further discloses a compound according to formula (XX'):

[0443]

[0444] Or its pharmaceutically acceptable salt.

[0445] in:

[0446] R 1' It is a halogen, -R', -CN, or -NO2; and

[0447] R' is C that has been optionally substituted. 1-6 Aliphatic.

[0448] This article further discloses a compound according to formula (XXI'):

[0449]

[0450] Or its pharmaceutically acceptable salt.

[0451] in

[0452] R 1' It is a halogen, -R', -CN, or -NO2;

[0453] Each R' is an optionally substituted C1-6 aliphatic; and

[0454] R 2' R 3' and R 4' Each can be independently a halogen, -R', -CN, -NO2, -OR', or -NR'2, or R 2' and R 3' Together with carbon, they can form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0455] This article further discloses a compound according to formula (XXII'):

[0456]

[0457] Or its pharmaceutically acceptable salt.

[0458] in:

[0459] R 1' It is a halogen, -R', -CN, or -NO2;

[0460] Each R' is an optionally substituted C 1-6 aliphatic; and

[0461] R 2' R 3' and R 4' Each can be independently a halogen, -R', -CN, -NO2, -OR', or -NR'2, or R 2' and R 3' Together with carbon, they can form optionally substituted 3-7 membered cycloalkyl or heterocyclic rings.

[0462] This article further discloses a compound according to formula (XXIII'):

[0463]

[0464] Or its pharmaceutically acceptable salt.

[0465] in:

[0466] R 1' It is a halogen, -R', -CN, or -NO2; and

[0467] R' is C that has been optionally substituted. 1-6 Aliphatic.

[0468] This article further discloses a compound according to formula (XXIV'):

[0469]

[0470] Or its pharmaceutically acceptable salt.

[0471] in:

[0472] R 1' It is a halogen, -R', -CN, or -NO2; and

[0473] R' is C that has been optionally substituted. 1-6 Aliphatic.

[0474] This article further discloses a compound according to formula (XXV'):

[0475]

[0476] Or its pharmaceutically acceptable salt.

[0477] Where A', B', X', R 1' R 2' R 3' R 4' Each of m' is as defined above and is described individually and in combination as provided in the embodiments herein.

[0478] Table 1 below shows exemplary β-agent compounds of this disclosure.

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526] In some embodiments, the β agent is an optically pure stereoisomer of the compounds in Table 1, a pharmaceutically acceptable salt, a solvate, or a prodrug.

[0527] Human Model / Test

[0528] Numerous contextual learning tests recognized and / or accepted in the art are used, and in various embodiments, these tests can be used in conjunction with the compositions and methods disclosed herein to assess baseline cognitive function and / or measure or quantify improved cognitive function in human subjects. For example, the contextual learning tests used may be based on single-task learning, multi-task learning, or spatial contextual memory. Contextual learning tests based on spatial contextual memory may be advantageous in assessing, for example, how well an individual can navigate a shopping mall, a neighborhood, or an urban public transportation or subway system, and in assessing any improvement in the ability to perform these tasks resulting from the processing methods described herein.

[0529] A simple example of a spatial contextual learning test is contextual cues, where humans learn to use repetitive spatial configurations to facilitate target search. A higher-order spatial contextual learning test is serial learning, where humans learn to use subtle sequential rules to respond to a series of events more quickly and accurately. See, for example, J.H. Howard Jr. et al., *Neuropsychology*, Vol. 18(1), January 2004, pp. 124-134.

[0530] In some embodiments, the Mini-Mental State Examination (MMSE) and / or the Montreal Cognitive Assessment (MOCA) may be used to assess cognition.

[0531] The Arizona Cognitive Suite (ACTB). The testing protocol that can be used in various embodiments is the Arizona Cognitive Suite (ACTB). See Edgin, J. et al., *Journal of Neurodevelopmental Disorders* (2010) 2:149-164. The ACTB was specifically developed to assess cognitive phenotypes in DS and includes a variety of tests related to various task requirements and brain function. More specifically, the tests include: 1) benchmarks such as the KBIT II verbal subscale and KBIT II nonverbal subscale IQ tests; 2) hippocampal function; 3) prefrontal cortex function; 4) cerebellar function; 5) finger sequencing task; 6) NEPSY visual-motor precision; and 7) simple reaction time.

[0532] In some embodiments, cognition can be assessed using the Cambridge Neuropsychological Tests Automated Suite (CANTAB) (see, for example, Sahakian et al., (1988). Brain. 111(3):695–718). Cognitive domains such as attention, visuospatial working memory, episodic memory, process speed, and executive function can be assessed using the CANTAB suite, which includes the following:

[0533] • Reaction Time (RTI)

[0534] Paired Learning (PAL)

[0535] Verbal recognition memory (VRM) enables instant free recall.

[0536] • Rapid Visual Information Processing (RVP)

[0537] Spatial working memory (SWM),

[0538] Adaptive tracking, and

[0539] • VRM delayed free recall and forced selection recognition.

[0540] The following provides the relevance of the domains / tests, test descriptions, and certain key capabilities as assessed by ACTB:

[0541]

[0542] In some embodiments, the aforementioned suite of tests can be performed to assess all major cognitive processes balanced by the practical needs of testing within a time constraint. In some embodiments, the cognitive tests described herein can be used on patients receiving treatment herein to monitor their cognitive status and progress.

[0543] In some embodiments, test kits can be performed on individuals in the test group and control group to demonstrate the effectiveness of various aspects and embodiments of the compositions and methods described herein. The test group can be treated with any of the treatment regimens described herein, and the control group is treated with a placebo, such as by intranasal administration of a 5% glucose saline solution.

[0544] Improvement in cognitive function is defined herein as an improvement in at least one, and preferably at least 10%, and more preferably at least 20%, of a score on at least two or more tests listed in the ATCB. Any of the areas / tests listed in the ATCB above may be included in the assessment of whether improvement has occurred. Testing may be performed after or during treatment to determine if a change in dosage or frequency of treatment is necessary.

[0545] Brain imaging. Typically, any non-invasive procedure can be used to establish a baseline of brain pathology (presence or absence) and to develop a treatment plan based on that baseline. However, in some embodiments, magnetic resonance imaging (MRI) may be preferred for neuroimaging examinations because it allows for precise measurement of the 3D volume of brain structures, particularly the hippocampus and related regions. Such techniques are well known, as described in U.S. Patent No. 6,490,472, which is incorporated herein by reference in its entirety.

[0546] Furthermore, non-invasive optical imaging systems can also be used to monitor neuropathological events. See, for example, U.S. Patent Publication 2011 / 0286932, which is incorporated herein by reference in its entirety. The technique described therein requires administering a fluorescent marker to a person to stain the Aβ peptide, imaging the retina of the person with DS using an optical imaging system, and examining the image of the stained Aβ peptide to determine whether a brain lesion (such as AD encephalopathy) has occurred.

[0547] In some embodiments, fluorodeoxyglucose positron emission tomography (FDG-PET) can be used for neuroimaging to determine cognitive function and / or identify neurodegenerative diseases, according to the compositions and methods described herein. The use of FDG-PET for monitoring cognitive function and / or diagnosing cognitive impairment or neurodegenerative diseases, and / or identifying patients who require or expect treatment to improve cognitive function, is described, for example, in Brown et al., *Radio Graphics*, (2014) 34:684-701, and Shivamurthy et al., *AJR*, (2015) 204:W76-W85; both of which are incorporated herein by reference in their entirety. In various embodiments, FDG-PET can be used alone or in combination with CT and / or MRI comprising MRI-ASL and / or MRI-BOLD. For example, FDG-PET and MRI-BOLD can be used, or FDG-PET and MRI-ASL can be used. Alternatively, FDG-PET, MRI-BOLD, and MRI-ASL can be used. Alternatively, MRI including MRI-BOLD and MRI-ASL can be used alone or optionally in combination with CT.

[0548] Alzheimer's disease

[0549] Alzheimer's disease neuropathology refers to the accumulation of highly resistant amyloid fibers that cause lesions in adjacent areas of the brain. These amyloid fibers accumulate to neurotoxic levels, leading to the destruction of nerve fibers, which in turn results in the observed behaviors associated with Alzheimer's disease. The observed behavioral symptoms become increasingly severe as the disease progresses and typically include vocabulary loss, incorrect word substitution (malphobia), loss of literacy skills, increased risk of falls, distractibility, speech loss, emotional apathy, and even muscle wasting.

[0550] Down syndrome

[0551] The establishment of several trisomy mouse models has greatly facilitated the understanding of the neurobiological basis of cognitive dysfunction in DS. Among the mouse models, the Ts65Dn mouse is the best characterized. It has approximately 140 extra copies of mouse genes on chromosome 16, which are orthologous to genes on human chromosome 21 (HSA21). Almost all HSA21 genes that have potential roles in neurological abnormalities are also found in Ts65Dn mice. Similar to DS, structural and functional changes in the hippocampus and failure to induce long-term potentiation (LTP) have been widely reported in Ts65Dn mice. The Ts65Dn mouse is the most widely used mouse for DS research and is considered the accepted model for studying human DS. Olson, LE et al., Developmental Dynamics, July 2004; 230(3):581-9.

[0552] DS is characterized by degeneration and dysfunction of multiple neuronal populations in the central nervous system (CNS). Among these, the hippocampus, the primary site for processing episodic learning, exhibits significant abnormalities in DS. Consequently, failure of episodic learning is common in individuals with DS. To elucidate the neurobiological basis of failed episodic learning in DS, the integrity of subcortical regions that project extensively into the hippocampus has been examined. These subcortical regions exert a strong regulatory influence on hippocampal neurons through extensive innervation. Among these subcortical regions, the LC is particularly important. LC neurons in the brainstem are the sole suppliers of the numerous norepinephrine (NE)-producing terminals of the hippocampus and play a significant role in arousal, attention, and navigational memory. Significant age-related degeneration of NE-producing neurons in the LC was found in Ts65Dn mice. Interestingly, the loss of LC terminals in Ts65Dn mice led to further deterioration of cognitive dysfunction in these mice. Similarly, in DS, LC neurons undergo extensive age-dependent degeneration. In Ts65Dn mice, the crucial role of norepinephrine (NE) system dysfunction in cognitive impairment was supported by the fact that increasing brain NE levels with L-threo-3,4-dihydroxyphenylserine (L-DOPS), a NE prodrug, restored contextual learning. Although L-DOPS is currently in a Phase III clinical trial for the treatment of primary autonomic failure associated with Parkinson's disease, it has not yet received FDA approval, and its long-term effects, particularly in children, remain to be explored.

[0553] Regarding the pharmaceutical agents described herein, the terms “modulator” and “regulatory” refer to the upregulation (i.e., activation or stimulation) or downregulation (i.e., inhibition or suppression) of a response. A “modulatory agent” is a regulating pharmaceutical agent, compound, or molecule and can be, for example, an agonist, antagonist, activator, inhibitor, inhibitor, or suppressor. As used herein, the terms “inhibition,” “reduction,” and “elimination” refer to any inhibition, reduction, decrease, suppression, downregulation, or prevention of expression, activity, or symptoms, and include partial or complete inhibition of activity or symptoms. Partial inhibition may imply a level of expression, activity, or symptoms of, for example, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%. The terms “elimination” or “eradication” indicate a complete reduction of activity or symptoms.

[0554] As used herein, the terms “symptom” or “disease” refer to any disorder or abnormality of function; a pathological physical or mental state. See Dorland's Illustrated Medical Dictionary (WBSaunders Co., 27th edition, 1988).

[0555] As used herein, in one embodiment, the term "treating / treatment" for any disease or condition means alleviating said disease or condition (i.e., slowing or stopping or reducing the development of at least one symptom of the disease or its clinical symptoms). In another embodiment, "treating / treatment" means alleviating or improving at least one physical parameter, including physical parameters that the patient may not be able to discern. In yet another embodiment, "treating / treatment" means modulating a disease or condition physically (e.g., stabilizing identifiable symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treating / treatment" means preventing or delaying the onset, development, or progression of a disease or condition.

[0556] In some embodiments, optically pure (S)-β agonists are used to achieve a degree to which the β2 agonist has a stereocenter substantially free of (R)-β agonists. In some embodiments, optically pure (R)-β agonists substantially free of (S)-β agonists are used. As used herein, the term "pure" means a substance isolated from at least some or most of its components that are associated with it in nature or at the time of its initial formation or prior to purification. Generally, such purification involves the action of the human hand. Pure agents can be partially purified, substantially purified, or pure. Such agents can be, for example, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or greater than 99% pure. In some embodiments, nucleic acids, peptides, or small molecules are purified such that they constitute at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more of the total nucleic acid, peptide, or small molecule material present in the formulation. In some embodiments, organic substances, such as nucleic acids, peptides, or small molecules, are purified such that they constitute at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more of the total organic material present in the formulation. Purity can be based on, for example, dry weight, peak size on chromatographic tracking (GC, HPLC, etc.), molecular abundance, electrophoresis methods, band intensity on gels, spectral data (e.g., NMR), elemental analysis, high-throughput sequencing, mass spectrometry, or any quantitative method acceptable in the art. In some embodiments, water, buffer substances, ions, and / or small molecules (e.g., synthetic precursors such as nucleotides or amino acids) may optionally be present in the purified formulation. Purified agents can be prepared by separating them from other substances (e.g., other cellular substances) or by producing them in a manner that achieves the desired purity.

[0557] In some embodiments, the contemplated method may comprise, for example, administration of a prodrug of the compound described herein or a pharmaceutical composition thereof. The term “prodrug” refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Conversion can occur at various sites, such as in the intestinal lumen or during transport in the intestine, blood, or liver, via various mechanisms, such as esterases, amidases, phosphatases, oxidative and / or reductive metabolism. Prodrugs are well known in the art (e.g., see Rautio, Kumpulainen et al., *Nature Reviews Drug Discovery*, 2008, 7, 255). In some embodiments, the prodrug structure is constructed according to the disclosure in U.S. Patent No. 9,849,134, which is incorporated herein by reference in its entirety.

[0558] For example, if the compound of this disclosure or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as: (C 1-8 )alkyl, (C 2-12 alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthaloyl, 4-crotonic acid lactone, γ-butyrolactone-4-yl, di-N,N-(C 1-2 )alkylamino-(C 2-3 )alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1-2 )alkyl, N,N-di(C 1-2 )alkylcarbamoyl-(C 1-2 )alkyl and piperidin-, pyrrolidine-, or morpholino (C 2-3 )alkyl.

[0559] Similarly, if the compounds of this disclosure contain an alcohol functional group, the prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group as follows: (C 1-6 )alkylcarbonyloxymethyl, 1-((C 1-6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C 1-6 )alkylcarbonyloxy)ethyl(C 1-6 )alkoxycarbonyloxy)methyl, N--(C 1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkyl carbonyl, α-amino (C 1-4 )alkyl carbonyl, aryl alkyl carbonyl and α-aminoalkyl carbonyl, or α-aminoalkyl carbonyl-α-aminoalkyl carbonyl, wherein each α-aminoalkyl carbonyl is independently selected from naturally occurring L-amino acids, P(O)(OH)2, --P(O)(O(C 1-6 Alkyl groups or glycosyl groups (free radicals generated by removing the hydroxyl groups of hemiacetal carbohydrates).

[0560] If the compounds of this disclosure incorporate an amine functional group, the prodrug can be formed, for example, by creating an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, a (oxodioxolane)methyl derivative, an N-Mannich base, an imine, or an enamine. Additionally, secondary amines can be metabolically cleaved to generate a biologically active primary amine, or tertiary amines can be metabolically cleaved to generate a biologically active primary or secondary amine. See, for example, Simplicio et al., *Molecules*, 2008, 13, 519, and its references.

[0561] As used herein, “therapeuticly effective amount” means the amount of a compound or composition (as described herein) that causes at least one desired change in cells, cell populations, tissues, individuals, patients, etc. In some embodiments, as used herein, a therapeutically effective amount means the amount of a compound or composition (as described herein) that prevents or provides a clinically significant change in a disease or condition (e.g., a reduction of at least about 30%, at least about 50%, or at least about 90%) or one or more features of the disease or condition described herein. In some embodiments, the term “therapeuticly effective amount” means the amount of a compound or composition as described herein that is effective or sufficient to improve a patient’s cognition and / or treat a patient’s neurodegenerative disease. The related term “frequency” means the number of times treatment is administered to a patient to achieve improved cognition and / or treatment of a patient’s neurodegenerative disease.

[0562] Diagnosis and assessment of treatment

[0563] In various aspects, the methods of this disclosure include diagnosing or otherwise identifying whether a patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases. This can be performed in a variety of ways as discussed herein and known in the art. For example, a diagnosis can be made by brain imaging. In various embodiments, FDG-PET can be used alone or in combination with CT and / or MRI comprising MRI-ASL and / or MRI-BOLD. For example, FDG-PET and MRI-BOLD can be used, or FDG-PET and MRI-ASL can be used. Alternatively, FDG-PET, MRI-BOLD, and MRI-ASL can be used. Alternatively, MRI comprising MRI-BOLD and MRI-ASL can be used alone or optionally in combination with CT.

[0564] In addition to identifying suitable patients for treatment, diagnosis allows for further determination of various aspects of the type and mode of treatment to be administered. For example, based on the diagnosis, the active pharmaceutical ingredient to be administered, the dosage of such active ingredient, and the schedule for administration can be determined.

[0565] Diagnostic methods used in conjunction with the methods of this disclosure can utilize detectable markers to diagnose or otherwise identify patients who need or wish to improve cognitive function and / or treat neurodegenerative diseases. The term "marker" (also referred to as "detectable marker") means any part of an entity that facilitates the detection and optionally quantification of itself or an entity to which it is attached. Markers can be associated with or otherwise linked to a variety of biological or other entities. Generally, markers can be detected by, for example, spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, chemical, or other methods. In some embodiments, a detectable marker produces, for example, an optically detectable signal (e.g., light emission and / or absorption) that can be detected visually or using suitable instruments such as an optical microscope, spectrophotometer, fluorescence microscope, fluorescence sample reader, fluorescence-activated cell sorter, camera, or any device containing a photodetector. Labels that can be used in various embodiments include, for example, organic materials (including organic small molecule fluorophores (sometimes called "dyes"), quenchers (e.g., dark quenchers), polymers, fluorescent proteins); enzymes; inorganic materials such as metal chelates, metal particles, colloidal metals, metal and semiconductor nanocrystals (e.g., quantum dots); compounds that exhibit luminescence upon enzyme-catalyzed oxidation, such as naturally occurring or synthetic luciferins (e.g., firefly luciferin or coelenterate and structure-related compounds); haptens (e.g., biotin, dinitrophenyl, digoxigenin); and radioactive atoms (e.g., radioactive isotopes, such as...). 3 H, 14 C 32 P, 33 P, 35 S, 125 I) Stable isotopes (e.g., 13 C 2 H); magnetic or paramagnetic molecules or particles, etc. Fluorescent dyes include, for example, acridine dyes; BODIPY, coumarin, anthocyanin dyes, naphthalene (e.g., dansyl chloride, dansylamide), xanthan dyes (e.g., fluorescein, rhodamine), and any derivatives of the foregoing. Examples of fluorescent dyes include Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Fluor dyes Fluorescent dyes include FITC, TAMRA, Oregon Green, and Texas Red. Fluorescent proteins include green fluorescent protein (GFP), blue, sapphire, yellow, red, orange, and cyan fluorescent proteins and fluorescent variants such as enhanced GFP (eGFP), mFruit (e.g., mCherry, mTomato, mStrawberry), and R-phycoerythrin. Enzymes used as labels include, for example, enzymes that act on substrates to produce colored, fluorescent, or luminescent substances. Examples include luciferase, β-galactosidase, horseradish peroxidase, and alkaline phosphatase. Luciferases include luciferases derived from various insects (e.g., fireflies, beetles) and marine organisms (e.g., cnidarians such as *Renilla* (e.g., *Renilla reniformis*); copepods such as *Gaussia* (e.g., *Gaussia princeps*) or *Metridia* (e.g., *Metridia longa*, *Metridia pacifica*)), as well as modified versions of naturally occurring proteins. Various systems for labeling and / or detecting labeled or tagged entities are known in the art. (In Iain Johnson, I. and Spence, MTZ (eds.), *Molecular*) The Molecular Manual The *Handbook*, a guide to fluorescent probes and labeling technologies, describes a wide range of detectable labels and methods for their use, detection, modification, and / or incorporation or conjugation (e.g., covalent or non-covalent linkage) into biomolecules such as nucleic acids or proteins. The 11th edition (LifeTechnologies / Invitrogen Corp.) is available at invitrogen.com / site / us / en / home / References / Molecular-Probes-The-Handbook.html and Hermanson, G.T., *Bioconjugate Techniques*, 2nd edition, Academic Press (2008). Many labels can be obtained as derivatives, which are linked to or incorporated with reactive functional groups, allowing the labels to be readily conjugated to biomolecules or to other entities of interest, including suitable second functional groups (which may be naturally present in the biomolecule or introduced during or after synthesis). For example, reactive esters (e.g., succinimide esters), carboxylic acid esters, isothiocyanates, or hydrazide groups can react with amino groups; carbodiimides can react with carboxyl groups; maleimides, iodoacetamides, or alkyl bromides (e.g., methyl bromides) can react with thiols (mercaptoyl groups); and alkynes can react with azides (via click chemistry reactions, such as copper-catalyzed or copper-free azide-alkyne cycloaddition). Thus, for example, N-hydroxysuccinimide (NHS) functionalized derivatives of fluorophores or haptens (e.g., biotin) can react with primary amines, such as lysine side chains present in proteins or primary amines incorporated into nucleic acids during synthesis in aminoally modified nucleotides. In various embodiments, the label can be directly linked to the entity, or it can be linked to the entity via spacers or linkers, such as alkyl, alkylene, aminoallyl, aminoalkynyl, or oligoethylene spacers or linkers, which can have a length of, for example, 1 to 4, 4-8, 8-12, 12-20 atoms, or more. In various embodiments, the labeled or labeled entity can be directly detectable or indirectly detectable. The label or labeled portion can be directly detectable (i.e., it can be detected without any additional reaction or reagent, e.g., a fluorophore is directly detectable) or it can be indirectly detectable (e.g., it becomes detectable by reacting with or binding to another detectable entity, e.g., a hapten can be detected by immunostaining after reacting with an appropriate antibody including a reporter gene such as a fluorophore or an enzyme; an enzyme acts on a substrate to produce a directly detectable signal).In addition to detecting the marker or the marked entity, or in place of detecting the marker or the marked entity, the marker can be used for a variety of purposes. For example, the marker can be used to separate or purify substances that include the marker or are attached to the marker.

[0566] The term "labeled" is used herein to indicate that an entity (e.g., a molecule, such as a biomolecule or small molecule, an organic compound, a probe, a cell, tissue, etc.) includes or is physically associated with a label (e.g., via covalent or non-covalent association) such that the entity can be detected. In some embodiments, a detectable label is selected such that it produces a measurable signal, and the intensity of the signal is related to (e.g., proportionally) the amount of label. In some embodiments, two or more different labels or labeled entities are used in or present in the composition. In some embodiments, labels can be selected to distinguish each other. For example, they can absorb or emit light of different wavelengths. In some embodiments, labels can be selected to interact with each other. For example, the first label can be a donor molecule that transfers energy to a second label, which acts as an acceptor molecule via nonradiative dipole coupling, such as resonance energy transfer (RET), for example, Foster resonance energy transfer (FRET, often also referred to as fluorescence resonance energy transfer).

[0567] Nuclear imaging is one of the most important tools in diagnostic medicine, with approximately 12 to 14 million nuclear medicine procedures performed annually in the United States alone. Therefore, diagnostic nuclear imaging is crucial for studies that determine the causes of medical problems based on organ function, in contrast to radiographic studies that determine the presence of disease based on static structural appearance.

[0568] Diagnostic radiopharmaceuticals and radiotracers are typically designed or selected to selectively bind to specific receptors via binding motifs, such as antibodies, specific inhibitors, or other target-specific ligands. Therefore, these targeting markers can be more rapidly concentrated in areas of interest, such as inflamed tissues, tumors, dysfunctional organs, or organs undergoing enhanced expression of certain proteins. Consequently, the degree to which circulating radiopharmaceuticals are absorbed by specific organs or pathological tissues differs from their absorption by other or non-pathological tissues. For example, highly vascularized tissues (e.g., tissues with growing tumors) can concentrate more radiopharmaceuticals than surrounding tissues, while ischemic tissues can concentrate less. Nuclear imaging relies on these general phenomena of varying radiopharmaceutical distributions based on different tissues and pathologies. Therefore, in radionuclide imaging, specific tissue types (e.g., tumor tissues) can be distinguished from other tissues.

[0569] Radiopharmaceuticals used in differential diagnostic procedures in pathology can be conjugated to a targeting (recognition-binding) moiety and contain various radioisotopes as described below. Therefore, such radiopharmaceuticals contain a recognition moiety, such as a monoclonal antibody (which binds to a highly specific predetermined target), fibrinogen (which is converted into fibrin during blood clotting), glucose, and other chemical moiety and agents. Commonly used diagnostically conjugated radiopharmaceuticals contain, for example, 2-[ 18 F]Fluoro-2-deoxy-D-glucose ( 18 FDG) 111 In-spray peptide ([ 111 In-DTPA-D-Phe 1 ]-Octreotide), L-3-[ 123 I]-Iodo-α-methyl-tyrosine (IMT), O-(2-[ 18 F]Fluoroethyl)-L-tyrosine (L-[ 18 F]FET), 111 In-carosumab pendetide (CYT-356, Prostascint) and 111 In-Satumomab Pendetide (Oncoscint).

[0570] Two fundamental techniques are widely used in nuclear imaging: positron emission tomography (PET) and single-photon emission computed tomography (SPECT). PET detects photons generated by the positron-electron annihilation of positrons from an object placed in the object being imaged, such as a diagnostic radiopharmaceutical tracer in a patient, and analyzes the photon energy and trajectory to generate a tomographic image of the patient. SPECT generates images through computer analysis of photon emission events from a diagnostic radiopharmaceutical tracer with gamma emission isotopes. Both PET and SPECT require the detection and analysis of single-photon events, characterized by low signal-to-noise ratios and scarcity relative to background radiation. Other limitations on the image quality of PET and SPECT include sensitivity, temporal and spatial resolution, dynamic range, response time, and the count rate characteristics of the data acquisition probe device, such as a photomultiplier.

[0571] Radioisotopes that emit both high-energy gamma and / or low-energy gamma, beta and / or positron radiation and can be used, or are part of a compound, as radiopharmaceuticals include, but are not limited to, technetium-99m. 99m Tc), Gallium-67 ( 67 Ga), thallium-201( 201 Tl), 111 Indium-( 111 In), Iodine-123 (123 I), iodine-125( 125 I), iodine-131( 131 I), Xenon-133 ( 133 Xe) and fluorine-18 ( 18 F). In addition to 99m Tc, 131 I and 133 Xe, all of these isotopes are produced in a particle accelerator.

[0572] Non-limiting examples of commonly used radioactive tracers include monoclonal antibodies for imaging colorectal tissue with colorectal cancer. 99m Tc-asimozide ( 99m Tc-Arcitumomab)(CEA-ScanTM), 99m Tc-sta-technetium ( 99m Tc-sestamibi (Cardiolite™) and imaging of myocardial perfusion in the subjects' hearts. 99m Tc-tetrophos ( 99m Tc-tetrofosmin (Myoview™) is a monoclonal antibody used for imaging prostate tissue in patients with prostate cancer. 111 In-carosumab prostaScint™ is a monoclonal antibody used for imaging inflamed and infected tissues. 99m Tc-fasciozoltamide (Technetium) 99m Tc-Fanolesomab (NeutroSpec™), and monoclonal antibodies against the CD20 antigen. 90 Y / 111In-Zewaling ( 90 Y / 111In-Zevalin (Ibritumomab Tiuxetan) is an antigen found on the surface of both normal and malignant B lymphocytes.

[0573] Any diagnostic radiopharmaceutical can be used in the kit of this embodiment. Exemplary radiopharmaceuticals that can be used in this context of the invention include, but are not limited to, those mentioned above. 3 H-water, 3 H-inulin, 11 C-carbon monoxide, 13 N-ammonia, 14 C-inulin, 15 O--H2O、 15 O--O2、 18 F-fluorodeoxyglucose, 18 F-sodium fluoride, 51 Cr-red blood cells (RBCs)57 Co-Vitamin B12 (Cyanocobalamin), 58 Co-Vitamin B12 (Cyanocobalamin), 59 Fe-Citrate, 60 Co-Vitamin B12 (Cyanocobalamin), 67 Ga-Citrate, 68 Ga-Citrate, 75 Se-Selenomethionine, for inhalation, oral administration or injection 81m Kr-Krypton, 82 Rb, 85 Sr-Nitrate, 90 Y / 111 In-Ibritumomab tiuxetan ( 90 Y / 111 In-Zevalin), 99m Tc-Albumin microspheres, 99m Tc-Disofenin ( 99m Tc-disofenin), Lidofenin and Mebrofenin, 99 mTc-DMSA, 99m Tc-DTPA (injection), 99m Tc-DTPA (aerosol), 99m Tc-ECD (Ethylene cysteine dimer), 99m Tc-Exametazime ( 99m Tc-exametazime) (HMPAO), 99m Tc-Gluceptate, 99m Tc-HEDP, 99m Tc-HMDP, 99m Tc-HSA, 99m Tc-MAA, 99m Tc-MAG.sub.3, 99m Tc-MDP, 99m Tc-Tiludronate (Myoview), 99m Tc-Sestamibi (Cardiolite), 99m Tc-Oral administration, 99m Tc-Pertechnetate, 99m Tc-Pyrophosphate, 99m Tc-RBC in vitro and in vivo labeling, 99m Tc-Sulfur colloid, 99m Tc-Teboroxime ( 99m Tc-teboroxime), 99m Tc-White blood cells, 111 In-Ibritumomab tiuxetan ( 111In-Zewaling), 111 In-DTPA, 111 In-platelets, 111 In-RBC, 111 In-leukocytes, 123 Sodium iodohippurate, 123 I-IMP, 123 I-mIBG, 123 Sodium iodide, 124 Sodium iodide, 125 I-fibrinogen, 125 I-IMP, 125 I-mIBG, 125 Sodium iodide, 126 Sodium iodide, 130 Sodium iodide, 131 Sodium iodohippurate, 131 I-HSA, 131 I-MAA, 131 I-mIBG, 131 I-Rose Red 131 Sodium iodide, 127 Xe - Inhalation and Injection, 133 Xe-inhalation and injection, 197 Hg-Chlor-mercury 198 Au-colloids and 201 Tl-chloride.

[0574] The diagnostic methods described herein can also be used to evaluate the effectiveness of specific treatment regimens. For example, a diagnosis or other evaluation can be performed on patients who have been identified as needing or expecting improvement in cognitive function and / or treatment for neurodegenerative diseases and are currently receiving treatment to determine the effectiveness of a treatment regimen. While diagnosis or evaluation can be performed by any method known in the art, cognitive tests or brain imaging can be used to determine improvements in cognitive function or disease. In embodiments, cognitive tests or brain imaging can be used alone or in combination. In embodiments utilizing brain imaging, FDG-PET can be used alone or in combination with CT and / or MRI including MRI-ASL and / or MRI-BOLD. For example, FDG-PET and MRI-BOLD can be used, or FDG-PET and MRI-ASL can be used. Alternatively, FDG-PET, MRI-BOLD, and MRI-ASL can be used. Alternatively, MRI including MRI-BOLD and MRI-ASL can be used alone or optionally in combination with CT.

[0575] The evaluation of therapeutic efficacy can be used to modify a patient's treatment regimen. For example, the evaluation can be used to change the dosage, timing of administration, and / or activity of a pharmaceutical composition. In one example, by administering it in combination with different agents, the dosage of a specific agent administered to the patient can be reduced. In this way, treatment can be optimized by modifying the pharmaceutical composition to include different combinations of beta agents, beta1-AR agonists, beta2-AR agonists, and peripherally acting beta blockers (PABRAs). The dosage can also be varied depending on the timing of administration. For example, a shorter duration between administrations of the pharmaceutical composition may require a lower dose of the active agent, while a longer duration between administrations may require a higher dose of the active agent; both of these situations can improve the treatment regimen determined by the patient's diagnosis or evaluation.

[0576] In one embodiment, the patient may be assessed once during the treatment process to optimize the treatment plan. Alternatively, the patient may be assessed multiple times during the treatment process to continuously optimize the treatment plan under the guidance of medical professionals.

[0577] Dosage, administration and drug formulation

[0578] The term "pharmaceutically acceptable salt" means an acid addition salt that is commonly used in human or veterinary medicine and is considered safe for use. Examples of this disclosure include, but are not limited to, salts obtained from acids such as acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, ethanedisulfonic acid, fumaric acid, gentian acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydroxyethanesulfonic acid, lactic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, and tartaric acid. Any hydrated form of such salts is also included in this definition. Thus, for example, both fumarates and hemifumarates, as well as any of their hydrates, are specifically considered. For example, fumaric acid dihydrate may be specifically mentioned.

[0579] In some embodiments, the pharmaceutical formulation may be in unit dosage form. In such forms, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged formulation containing discrete amounts of the formulation, such as tablets, capsules, and powders packaged in vials or ampoules. Similarly, the unit dosage form may be capsules, tablets, sachets, or lozenges themselves, or may be any appropriate number of these packaging forms. Preferably, the unit dosage form is a tablet. If desired, the composition may also contain other compatible therapeutic agents. Preferred pharmaceutical formulations may deliver the compounds of this disclosure in the form of a sustained-release formulation.

[0580] For the binders, compositions, or compounds according to this disclosure, the dosage form may optionally be a liquid dosage form. Solutions may be prepared in water with a suitable mixture of surfactants, such as hydroxypropyl cellulose, or emulsifiers such as polysorbate. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as in oils. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003–20th edition) and The United States Pharmacopeia: The National Formulary (USP 24NF19) (published in 1999). Formulations optionally contain excipients, including, but not limited to, buffers, antioxidants, stabilizers, carriers, diluents, and pH adjusters. Suitable drug forms for injectable applications include sterile aqueous solutions or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the doses and concentrations used and contain buffers such as phosphoric acid, citric acid, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl ammonium chloride; benzyl methoxyamine chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methyl or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) peptides; proteins, such as serum albumin. White, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants such as Tween, Pluronics or polyethylene glycol (PEG).

[0581] In various embodiments, the dosage of the drug can be determined by the weight of the human patient. For example, for a pediatric human patient weighing about 0 to about 5 kg (e.g., about 0, or about 1, or about 2, or about 3, or about 4, or about 5 kg), the absolute dose of the drug is about 30 to 160 μg; or for a pediatric human patient weighing about 6 to about 8 kg (e.g., about 6, or about 7, or about 8 kg), the absolute dose of the drug is about 30 to 160 μg; or for a pediatric human patient weighing about 9 to about 13 kg (e.g., 9, or about 10, or about 11, or about 12... For pediatric human patients weighing approximately 13 kg, the absolute dose of the drug is approximately 30 to 160 μg; or for pediatric human patients weighing approximately 14 to approximately 20 kg (e.g., approximately 14, or approximately 16, or approximately 18, or approximately 20 kg), the absolute dose of the drug is approximately 30 to 160 μg; or for pediatric human patients weighing approximately 21 to approximately 30 kg (e.g., approximately 21, or approximately 23, or approximately 25, or approximately 27, or approximately 30 kg), the absolute dose of the drug is approximately 30 to 160 μg. The dosage is about 30 to 160 μg; or for pediatric human patients weighing about 31 to about 33 kg (e.g., about 31 kg, or about 32 kg, or about 33 kg), the absolute dose of the drug is about 30 to 160 μg; or for adult human patients weighing about 34 to about 50 kg (e.g., about 34, or about 36, or about 38, or about 40, or about 42, or about 44, or about 46, or about 48, or about 50 kg), the absolute dose of the drug is... The absolute dose of the drug is about 30 to 160 μg; or for adult patients weighing about 51 to about 75 kg (e.g., about 51, or about 55, or about 60, or about 65, or about 70, or about 75 kg); or for adult patients weighing more than about 114 kg (e.g., about 114, or about 120, or about 130, or about 140, or about 150 kg).

[0582] In some embodiments, the agent according to the methods provided herein is administered orally, subcutaneously (sc), intravenously (iv), intramuscularly (im), intranasally, or topically. The agent described herein can be administered independently as one to four times daily; or one to two times weekly; or one to four times monthly; or one to six times annually; or once every two, three, four, or five years. The duration of administration can be one day or one month, two months, three months, six months, one year, two years, three years, and even a lifetime for a human patient. Dosage can be administered as a single dose or divided into multiple doses. In some embodiments, the agent is administered about once to about three times (e.g., once, twice, or three times).

[0583] The compounds disclosed herein can generally be prepared or isolated using synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as methods described in detail in the examples herein. In one embodiment, compounds selected from those shown in Table 1 are prepared using the methods illustrated in Scheme A.

[0584] Option A.

[0585]

[0586] In one embodiment, compounds selected from those shown in Table 1 are prepared by the method shown in Scheme B.

[0587] Option B.

[0588]

[0589] In one embodiment, compounds selected from those shown in Table 1 are prepared by the method shown in Scheme C.

[0590] Option C.

[0591]

[0592] In one embodiment, compounds selected from those shown in Table 1 are prepared by the method shown in Scheme D.

[0593] Option D.

[0594]

[0595] In one embodiment, compounds selected from those shown in Table 1 are prepared by the method shown in Scheme E.

[0596] Option E.

[0597]

[0598] In one embodiment, compounds selected from those shown in Table 1 are prepared by the method shown in Scheme F.

[0599] Option F.

[0600]

[0601] In one embodiment, compounds selected from those shown in Table 1 are prepared by the method shown in Scheme G.

[0602] Option G.

[0603]

[0604] Example

[0605] This disclosure will be further described in the following examples, which do not limit the scope of this disclosure.

[0606] Example 1: Treatment of human patients with clenbuterol.

[0607] Patients were screened using FDG-PET brain imaging. Those diagnosed with one or more of the following conditions were identified: MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Picker's disease), HD (Huntington's disease), Ritter 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), and CT scans. E (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakov 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 (CJD, etc.), depression, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), or ADHD (attention deficit hyperactivity disorder).

[0608] Patients were given a single dose of clenbuterol ranging from 30 to 160 μg. Some patients also received a single dose of 5 mg naldolol to counteract any side effects of clenbuterol. Patients were followed up for 3 days after each single dose of clenbuterol and / or naldolol. Following treatment with clenbuterol and / or naldolol, patients demonstrated a robust and comprehensive increase in cerebral blood flow from baseline.

[0609] As in Figure 1 As shown, the first group of patients received a single dose of clenbuterol at a dose of 160 μg, and the second group of patients received a single dose of clenbuterol at a dose of 160 μg and 5 mg of naldolol. Clenbuterol resulted in a robust overall increase in cerebral blood flow (CBF) relative to baseline in these patients compared to their baseline levels before the single-dose treatment. The second group of patients also exhibited a robust overall increase in cerebral blood flow (CBF) relative to baseline, in which naldolol was administered together with clenbuterol to counteract any side effects of clenbuterol.

[0610] As in Figure 3As shown, the first group of patients received a single dose of clenbuterol (160 μg), and the second group of patients received a single dose of indrol (60 mg). Treatment with clenbuterol showed a positive increase in cerebral blood flow relative to baseline. Treatment with indrol showed a decrease in cerebral blood flow relative to baseline.

[0611] As in Figure 4 and 5 As shown, one group of patients was given a single dose of clenbuterol at varying amounts, ranging from 30 to 160 μg, while another group was given a single dose of clenbuterol at 160 μg and 5 mg of naldolol to counteract any side effects of clenbuterol. Patients were followed up for 3 days. Clenbuterol at doses ranging from 30 to 160 μg resulted in a robust overall increase in cerebral blood flow (CBF) relative to baseline in these patients, compared to their baseline before single-dose treatment. Patients given a single dose of clenbuterol at 160 μg and 5 mg of naldolol also showed a robust overall increase in cerebral blood flow (CBF) relative to baseline.

[0612] In some embodiments, cognitive tests and / or FDG-PET imaging may be used. In some embodiments, magnetic resonance imaging-arterial spin labeling (MRI-ASL) may be used for neuroimaging. In some embodiments, magnetic resonance imaging-oxygen level-dependent computed tomography (MRI-BOLD) may be used for neuroimaging.

[0613] Example 2: Synthesis of compounds 03-5 and 03-48.

[0614] The following schemes demonstrate the synthesis of compounds 03-5 and 03-48.

[0615]

[0616] Step 1: Synthesis of 2-cyano-6-vinylpyridine

[0617] A stirred mixture of 2-chloro-6-cyanopyridine (8.0 g, 69.3 mmol), 1-vinyltri-n-butyltin (21.97 g, 69.29 mmol, 20.34 mL), and Pd(PPh3)4 (3.34 g, 3.61 mmol) in anhydrous toluene (150 mL) was bubbled with N2 for 5 minutes, then heated to 80 °C overnight. After cooling, the reaction mixture was poured into an aqueous solution of KF (40 g, 200 mL) and stirred for 30 minutes. The mixture was then filtered through diatomaceous earth and the solids were washed with EtOAc (2 x 50 mL). The aqueous phase of the filtrate was separated and extracted with EtOAc (2 x 250 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography with elution in hexane / EtOAc (silica, 95 / 5 to 90 / 10) to provide 2-cyano-6-vinylpyridine (6.5 g, 86%) as a pale yellow liquid. MS (m / z): 131.1 (M+H) + .

[0618] Step 2: Synthesis of 6-(ethylene oxide-2-yl)picolinonitrile

[0619] mCPBA (61.56 g, 249.72 mmol) was slowly added in portions over a 30-minute period to a stirred solution of 2-cyano-6-vinylpyridine (6.5 g, 49.94 mmol) in DCM (300 mL) at 0 °C, and the mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was cooled to 5 °C, and a saturated aqueous solution of NaHCO3 was added and extracted with DCM (200 mL × 2). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography with hexane / EtOAc (silica, 90 / 10 to 80 / 20) elution to provide 6-(ethylene oxide-2-yl)picolinonitrile (3.85 g, 52%) as a colorless liquid. MS (m / z): 147.1 (M+H) + .

[0620] Step 3: (S)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile and (R)-6-(2-(tert-butylamino)- Synthesis of 1-hydroxyethyl)picolinonitrile

[0621] tert-butylamine (6.66 g, 91.0 mmol) was added to a stirred solution of 6-(ethylene oxide-2-yl)picolinonitrile (3.5 g, 18.2 mmol) in ethanol (25 mL). The reaction mixture was stirred in a sealed tube at approximately 80 °C for 3 hours, with the reaction monitored by TLC and LCMS. After the reaction was complete, the solvent was evaporated to obtain a residue, which was purified by reversed-phase chromatography to provide the desired product as a racemic mixture. Racemic mixtures were separated by SFC (Chiralpak AS-H (30*250) mm, 5 μm column) using CO2:80% cosolvent:20% (0.2% isopropylamine in IPA as eluent) to provide compound 03-5(S)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile (1.05 g, 26.3%) and compound 03-48(R)-6-(2-(tert-butylamino)-1-hydroxyethyl)picolinonitrile (0.98 g, 24.5%) as white solids. Compound 03-5: 1 ¹H NMR 400MHz, DMSO-d⁶: δ 8.03 (t, J = 8.00 Hz, 1H), 7.90 (dd, J = 0.80 Hz, 7.60 Hz, 1H), 7.82 (d, J = 8.00 Hz, 1H), 5.63 (s, 1H), 4.60 (q, J = 4.40 Hz, 1H), 2.86–2.80 (m, 1H), 2.67–2.49 (m, 1H), 1.44–1.40 (m, 1H), 0.98 (s, 9H). Compound 03-48: 1 HNMR400MHz, DMSO-d6: δ8.03(t,J=7.60Hz,1H),7.90(d,J=6.80Hz,1H),7.82(d,J=8.00Hz,1H ),5.62(s,1H),4.60(s,1H),2.81-2.82(m,1H),2.62-2.64(m,1H),1.44(s,1H),0.98(s,9H).

[0622] Example 3: Cerebral perfusion.

[0623] Several recent studies have demonstrated the clinical relevance of cerebral perfusion (De Vis 2018, Staffaroni 2019). These studies have shown that cerebral perfusion declines with age, is associated with the progression of Alzheimer's disease (AD), and is strongly correlated with cognitive performance, resulting in subjects with higher cerebral perfusion tending to perform better on cognitive tests. Furthermore, studies in AD patients have shown that the clinical effect of donepezil can be predicted by the increase in perfusion observed after a single dose of the drug, resulting in subjects with increased perfusion after acute administration being similar to those with cognitive improvement after 6 months of treatment with the drug (Tepmongkol 2019). In clinical studies, healthy subjects were administered clenbuterol at doses ranging from 20 to 160 μg, and ASL MRI was performed before and after administration to determine whether this neuroimaging method could detect clinically relevant CNS signals. Neuroimaging data from studies using ASL MRI demonstrated a clinically relevant signal: an increase in cerebral perfusion after a single dose of clenbuterol. Specifically, 160 μg of clenbuterol resulted in a robust and comprehensive increase in cerebral perfusion, particularly in areas such as the hippocampus, thalamus, and cortex, all of which are closely associated with the pathogenesis of neurodegenerative diseases (see [link to relevant documentation]). Figure 6 ).

[0624] In region-of-interest (ROI) analyses with a focus on the hippocampus, it is well known that the hippocampus is affected by neurodegenerative diseases, and a single dose of 80 μg of clenbuterol resulted in a robust increase in perfusion (see [link to analysis]). Figure 7 In a cohort of six healthy subjects treated with a single dose of 80 μg clenbuterol, hippocampal perfusion increased in every subject, with an average increase of 25%. Neuroimaging data from studies using ASL MRI showed that 80 and 160 μg doses of clenbuterol stimulated a robust, comprehensive increase in perfusion. Specifically, brain regions considered to be associated with neuropathology of neurodegenerative diseases showed significant improvements in perfusion within the range of 25%. Figure 6 and 7 ROI analysis of the hippocampus in six healthy subjects aged 44 to 52 years showed a strong increase in this brain region in each subject. Figure 7 Along with other cohorts undergoing ASL MRI, a clear dose-response relationship was observed between clenbuterol dose and cerebral perfusion. Figure 8 As measured by CBF, doses below 30 μg did not produce a significant increase in cerebral perfusion, and a dose of 40 μg produced the smallest increase, while doses of 80 and 160 μg produced a comprehensive increase in cerebral perfusion, particularly in brain regions associated with neurodegenerative diseases, such as the hippocampus and thalamus, with a robust increase of 20% to 25%. Figure 8(Bartsch 2015, Leh 2016). It was hypothesized that administration of β-AR agonists (such as beta-agonists) would have a positive effect on clinically relevant symptoms such as memory and cognition by improving brain perfusion, particularly in brain regions associated with common symptoms in neurodegenerative diseases such as PD and AD. Specifically regarding cognition, preliminary data from the study indicated that a single dose of 160 μg clenbuterol improved cognition in healthy subjects, as measured by adaptive tracking and word recall.

[0625] Example 4: Treatment of human patients with beta-agonists and PABRA

[0626] Repeat the procedures described in Examples 1 and 3, replacing clenbuterol or other β2-AR agonists with a β-drug (e.g., compound 03-5). The starting dose of the β-drug was determined by preclinical studies and optimized for clinical use.

[0627] Example 5: Clinical Efficacy

[0628] Adaptive tracking measures visual-motor coordination and alertness. In this test, subjects use a joystick to move a small dot so that the dot remains within a continuously moving circle on a computer screen (Boland 1984). During the test, the speed of the circle is adjusted in response to the subject's ability to keep the dot within the circle, thus ensuring the test is suitable for individual subjects. Results showed that adaptive tracking performance improved after a single dose of 160 μg clenbuterol, as measured by the percentage of time the subject was able to keep the dot within the moving circle (see [link to study]). Figure 9 The improvements observed in the subjects were similar to those observed in subjects treated with the acetylcholinesterase inhibitor donepezil, which is clinically used to treat mild to moderate AD (Groeneveld 2016).

[0629] The Visual Verbal Learning Test (VVLT) is a learning and memory test (de Haas 2009). Subjects are presented with 30 words on a screen, one at a time, for one second each time, with a one-second interval between words, for a total of one minute. This is repeated in three trials. After each trial, subjects are asked to recall as many words as possible. After the third trial, there is a 2.5-hour delay, and then subjects are given a delayed recall test. Clenbuterol improves VVLT performance in immediate recall (trial 1, not shown) and delayed recall (see [link to test]). Figure 10The effect of clenbuterol was an improvement of approximately 1.5 to 2 correctly recalled words, which is clinically significant. Because this was a crossover study, everyone who completed Part A was given three agents plus a placebo. The β2-AR agonists tested in this study, namely clenbuterol and salbutamol, had a positive effect on VVLT. Conversely, the β2-AR antagonist / β1-AR partial agonist indolol had an adverse effect on this learning and memory test.

[0630] Example 4: Treatment of human patients with compound 03-5 and naldolol

[0631] In the study, healthy volunteers were enrolled in two cohorts for subject-specific dose titration of compound 03-5 and / or naldolol to explore mitigating the peripheral effects of compound 03-5, such as dose / dose combinations on heart rate, while preserving the possible central effects of compound 03-5 on cerebral perfusion and pupillary light reflex.

[0632] A. Queue D1.

[0633] Cohort D1 included 8 healthy subjects, and the effect of treatment with repeated administration of compound 03-5 on ECG was evaluated in the presence of progressively increasing doses of naldolol, as illustrated in the diagram below.

[0634]

[0635] On the dosing days of compound 03-5, a single dose of naldolol (up to 40 mg) will be administered pre- or co-administered with compound 03-5 on one or more dosing days. The doses of compound 03-5 and / or naldolol may vary over 7 dosing days. For example, the dose of compound 03-5 may be 3 mg from day 1 to day 6, increasing to 6 mg on day 7 under the guidance of DLRM, while the dose of naldolol may be increased from 1 mg on day 2 to 5 mg on both days 6 and 7.

[0636] Part D will begin after the DLRM reviews the security and PK (if any) data of the first queue in Part B for at least day 4. Inclusion in Part D will begin after the DLRM review.

[0637] One CSF sample will be collected from each subject in this cohort to determine the concentrations of compound 03-5 and naldolol (if relevant): approximately 2 hours after administration on day 2 from 4 subjects and approximately 2 hours after administration on day 6 from the remaining 4 subjects.

[0638] Eight healthy subjects aged 18–50 years were enrolled in cohort D1 and received escalating doses of compound 03-5 (3–12 mg) once daily, administered within 2 hours prior to naldolol (1–40 mg). On all dosing days, the study drug was administered orally after an overnight fast of at least 8 hours.

[0639] Routine measurements of ECG, vital signs, safety laboratory procedures, health checks, and plasma sample collection were performed according to the event timeline (Table 1) for pharmacokinetic (PK) analysis. Single cerebrospinal fluid (CSF) samples were collected from 7 of the 8 subjects included in cohort D1 on day 2 (N=3) or day 6 (N=4) to determine the concentrations of compounds O3-5 and naldolol.

[0640] Table 2. Event Timeline of Queue D1

[0641]

[0642]

[0643] AE = Adverse Event; ECG = Electrocardiogram; HIV = Human Immunodeficiency Virus; PK = Pharmacokinetics; EOS = End of Study

[0644] 1 The subjects were admitted to the hospital on day -1.

[0645] 2 The subject was discharged on the afternoon of the 9th day.

[0646] 3 Informed consent was obtained before any research-related procedures were performed.

[0647] 4 SARS-CoV-2 assessment includes detecting current infection from throat or nasal swabs during screening, and / or assessing possible persistent infection based on body temperature (>37.3°C), blood oxygen (<90%), and the investigator’s judgment at the start of isolation.

[0648] 5 For women of childbearing age, a serum β-hCG pregnancy test is performed at screening, followed by a urine test strip on day -1 and at EOS. For postmenopausal women, an FSH test is performed at screening.

[0649] 6 After resting in a supine position for at least 5 minutes on day -1, vital signs were assessed at the following times: body temperature, respiration, three blood pressure measurements, and three heart rate measurements (performed three times at approximately 1-minute intervals while in a supine position).

[0650] • Screening time and on day -1

[0651] • On days 1 through 7: administer twice an hour before administering naldolol, twice an hour before administering daily compound 03-5, and 0.25±0.1, 0.5±0.25, 1±0.25, 2±0.25, 4±0.5, 8±1, and 12±1 hours after the first daily compound 03-5.

[0652] • On day 8, administer compound 03-5 24±1 hours after the last administration.

[0653] • On day 9, administer compound 03-5 48±2 hours after the last administration.

[0654] • Day 15 (EOS), administer medication at any time during the site visit.

[0655] 7 For safety laboratories including hematology, clinical chemistry, urinalysis, and cardiac troponin, assessments should be performed 2–6 hours after administration of compound 03-5 on days 1, 2, 4, and 7, and at any other time on all other scheduled assessment days.

[0656] 8 Three ECGs should be obtained at the following times. Unless otherwise specified, subjects will need to rest in a supine position for at least 5 minutes before recording ECGs.

[0657] • During screening;

[0658] • On day -1, the schedule is the same as that of day 1 (±0.5 hours);

[0659] • On days 1 to 7: administer naldolol twice within 1 hour before administration, administer compound 03-5 twice within 1 hour before daily administration, and administer compound 03-5 0.25±0.1, 0.5±0.25, 1±0.25, 2±0.25, 3±0.5, 4±0.5, 6±0.5, 8±1, 10±1, 12±1, and 14±1 hours after daily administration;

[0660] • On day 8: Administer compound 03-5 24±1 and 36±1 hours after the last dose on day 7;

[0661] • On day 9: Administer 48 ± 2 hours after the last dose of compound 03-5;

[0662] • Day 15 (EOS), administer the medication at any time during the site visit.

[0663] 9Plasma PK samples were collected at the following times for analysis of the concentrations of compounds O3-5 and naldolol:

[0664] • On days 1 through 7, administer 1 hour before the first dose of naldolol (if administered), 0.5 hours before the first dose of compound 03-5, and 0.25±0.1, 0.5±0.1, 1±0.25, 2±0.5 (collected within 30 minutes of CSF sample collection), 4±0.5, 6±1, and 12±1 hours after the first dose of compound 03-5.

[0665] • On day 8: Administer compound 03-5 24 (±1) and 36 (±1) hours after the last administration;

[0666] • And on day 9, 48 (±2) hours after the last administration of compound 03-5.

[0667] 10 Single CSF samples were collected from each subject included in this cohort to determine the concentrations of compounds O3-5 and naldolol.

[0668] • An attempt was made with 4 subjects, but successful collection was achieved in only 3 subjects 2 ± 0.5 hours after administration on day 2.

[0669] • Approximately 2 ± 0.5 were collected from the remaining 4 subjects after administration on day 6.

[0670] Time-matched plasma PK samples were collected within 0.5 hours of CSF collection.

[0671] 11 The predicted C20 ... max At that time, a brief health check was performed.

[0672] 12 The study ended on day 15 ± 3.

[0673] 13 According to the dose escalation plan provided in the study diagram, on each of the 7 dosing days, 2 hours before administering compound 03-5 (3-12 mg).

[0674] Pre-administer naldolol (1-40 mg).

[0675] A. Queue D2.

[0676] In cohort D2, eight healthy volunteers aged 55–75 years were admitted on day -1 and isolated at the research facility for five days. During this isolation period, subjects received an escalating dose of the open-label compound 03-5 (1–10 mg) once daily from day 1 to day 3, administered 2 hours after pre-administration of open-label naldolol (3 mg), according to the diagram below, for three dosing days. Subjects remained hospitalized for observation until all study procedures were completed on day 4.

[0677]

[0678] Compound 03-5 was administered in escalating doses on Day 1 (1 mg), Day 2 (3 mg), and Day 3 (10 mg). All subjects underwent two CANTAB administrations the day before administration (Day 1) to familiarize them with the platform, and again approximately 3 hours before administration on Days 1, 2, and 3, and approximately 3 hours after administration of Compound 03-5.

[0679] Table 3. Event Timeline of Queue D2

[0680]

[0681] AE = Adverse Event; ECG = Electrocardiogram; HIV = Human Immunodeficiency Virus; PK = Pharmacokinetics; EOS = End of Study

[0682] 1 The subjects were admitted to the hospital on day -1.

[0683] 2 The subject was discharged on the afternoon of the 4th day.

[0684] 3 Informed consent was obtained before any research-related procedures were performed.

[0685] 4 SARS-CoV-2 assessment includes detecting current infection from throat or nasal swabs during screening, and / or assessing possible persistent infection based on body temperature (>37.3°C), blood oxygen (<90%), and the investigator’s judgment at the start of isolation.

[0686] 5 For women of childbearing age, a serum β-hCG pregnancy test is performed at screening, followed by a urine test strip on day -1 and at EOS. For postmenopausal women, an FSH test is performed at screening.

[0687] 6Two hours prior to administration of compound 03-5, pre-administer naldolol (3 mg). Compound 03-5 was administered once daily in increments of 1, 3, and 10 mg on days 1, 2, and 3.

[0688] 7 CANTAB was administered twice on day -1, once to familiarize the subject with the test and equipment, and a second time at least 3 hours later (as a pre-dose measure). On days 1, 2, and 3, CANTAB was administered 2 hours before naldolol administration and repeated starting 3 ± 1 hours after compound 03-5 administration.

[0689] 9 At the operable sites, the pupillary light reflex of each eye was measured twice at the following times:

[0690] • On Day 1: After the last administration of compound 03-5 on Day 1, at 2±0.5, 4±2, and 6±1 hours before administration.

[0691] • On day 2: 2 ± 0.5, 4 ± 2, and 6 ± 1 hours after the last administration of compound 03-5 on day 2.

[0692] • On day 3: 2 ± 0.5, 4 ± 2, and 6 ± 1 hours after the last administration of compound 03-5 on day 3.

[0693] 10 After resting in a supine position for at least 5 minutes on day -1, vital signs were assessed at the following times: body temperature, respiration, three blood pressure measurements, and three heart rate measurements (performed three times at approximately 1-minute intervals while in a supine position).

[0694] • Screening time and on day -1

[0695] • On days 1, 2, and 3: administer nadolol once within 2 hours before administration, administer compound 03-5 once within 1 hour before administration, and administer compound 03-5 once within 1±0.25, 2±0.25, 3±0.5, 4±0.5, 5±1, 6±1, 7±1, 8±1, 9±1, and 10±1 hours after administration.

[0696] • On day 4: Administer 24 ± 1 hour after the last administration of compound 03-5 on day 3.

[0697] • Day 15 (EOS), administer medication at any time during the site visit.

[0698] 11 A brief health check was performed 2 hours after the first administration of compound 03-5 or within a 4-hour window on day 1, day 2 and day 3 thereafter.

[0699] 12 Safety laboratories with a standard panel including hematology, clinical chemistry, urinalysis, and cardiac troponin were evaluated between 2 and 6 hours after administration of compound 03-5 at any time on days 1, 2, and 3, and on day 15 (EOS).

[0700] 13 Three ECGs were obtained at the following times. Subjects rested in a supine position for at least 5 minutes before ECG recording.

[0701] • During screening;

[0702] • On day -1, the schedule is the same as that of day 1 (±0.5 hours).

[0703] • On days 1, 2, and 3: administer nadolol once within 2 hours before administration, administer compound 03-5 once within 2 hours before daily administration, and administer compound 03-5 0.25±0.2, 0.5±0.25, 1±0.25, 2±0.25, 3±0.5, 4±0.5, 5±1, 6±1, 7±1, 8±1, 9±1, and 10±1 hours after daily administration;

[0704] • On day 4: 24±1 hours and 30±1 hours after the last administration of compound 03-5 on day 3;

[0705] • Day 15 (EOS), administer the medication at any time during the site visit.

[0706] 14 Plasma PK samples were collected at the following times for analysis of compounds O3-5 and naldolol:

[0707] • On days 1, 2, and 3, within 1 hour before administration of naldolol, within 0.5 hours before administration of compound 03-5, and at the following times after the first daily administration of compound 03-5: 1 ± 0.25, 2 ± 0.25, 4 ± 0.5, and 6 ± 1.

[0708] • On day 4: 24±1 and 30±1 hours after the last administration of compound 03-5 on day 3.

[0709] 15 The study ended (EOS) on day 15 ± 5.

[0710] result.

[0711] In the early cohort, a maximum mean increase in heart rate of up to approximately 30 beats per minute was observed after monotherapy with 6 mg of compound 03-5. Figure 11This effect was significantly reduced by pre-administration of 1 mg naldolol, with a mean maximum increase of 7 beats per minute. It was also noted that the effects of compound 03-5 on blood glucose and potassium, tachycardia, tremor, and palpitations were consequently reduced. These effects of compound 03-5 are similar to those of widely reported β2-AR agonists on the market, such as salbutamol.

[0712] In cohort D1, as in other cohorts, pre-administration of 1 mg of naldolol significantly attenuated the effects of oral administration of compound 03-5 at doses of up to 6 mg, thereby increasing heart rate and other peripheral effects of compound 03-5, including hyperglycemia and hypokalemia. Figure 11 and Figure 12 .

[0713] Following administration of compound 03-5 (3 mg [N=3] or 12 mg [N=4]) and naldolol (2 mg [N=3] or 20 mg [N=4]), drug concentrations in the cerebrospinal fluid (CSF) of subjects included in cohort D1 were measured. Estimated CSF concentrations of naldolol indicated that the concentrations were largely peripherally limited, with time-matched plasma concentrations detected at approximately 2–3%. In contrast, the CSF concentration of compound 03-5 was approximately 50% of the time-matched plasma concentration. Figure 13 .

[0714] in conclusion.

[0715] Nardolol is approved for the treatment of xx in humans at doses ranging from 40 mg to 320 mg / day.

[0716] In the early cohort, a maximum mean increase in heart rate of up to approximately 20 beats per minute was observed after monotherapy with 6 mg of compound 03-5. This effect was significantly reduced to a mean maximum increase of 7 beats per minute by pre-administration of 1 mg naldolol.

[0717] In cohort D1, pre-administration of naldolol (1 mg to 40 mg) blocked the peripheral effects of compound O3-5 (3–12 mg) on ​​heart rate, glucose, potassium, and other clinically observed effects associated with β2-AR agonists, such as tachycardia, tremor, and palpitations. The latest preliminary data on CSF concentrations of naldolol in cohort D1 of this study suggest that naldolol is a β-AR antagonist with very low CNS penetration.

[0718] In cohort D2, pre-administration of naldolol (3 mg) also blocked the peripheral effects of compound O3-5 (1-10 mg) on ​​heart rate, etc. However, improvements in cognitive performance were observed with CANTAB, which is presumably mediated by the selective stimulation of β2-AR in the brain by compound O3-5.

[0719] The effect of low-dose nadolol (3 mg) in controlling the adverse peripheral effects of selective β2-AR agonists without inhibiting pro-cognitive central effects, coupled with evidence of low CNS penetration of nadolol observed in cohort D1, supports the use of low-dose nadolol to specifically and selectively control the peripheral effects of β2-AR agonists used to treat CNS diseases.

[0720] Aspects and embodiments of this disclosure

[0721] In one aspect, this disclosure provides a method comprising: administering a beta agent and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and / or identifying specific types of neurodegenerative diseases based on spatial patterns derived from the brain imaging results.

[0722] In another aspect, this disclosure provides a method comprising: administering a beta agent and a peripherally acting beta-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise performing brain imaging on the patient to determine cognitive function to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying a specific type of neurodegenerative disease based on spatial patterns of the brain imaging results, and / or subsequently performing brain imaging on the patient again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0723] In another aspect, this disclosure provides a method comprising: performing brain imaging on a patient to determine the patient's cognitive function; identifying a specific type of neurodegenerative disease based on spatial patterns from the brain imaging results; administering a beta agent and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less; and subsequently performing brain imaging on the patient again to determine any improvement in cognitive function.

[0724] In another aspect, this disclosure provides a method comprising: administering a beta agent and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and / or to identify specific types of neurodegenerative diseases based on spatial patterns derived from the brain imaging results.

[0725] In another aspect, this disclosure provides a method comprising: administering a beta agent and a peripherally acting beta-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying a specific type of neurodegenerative disease based on spatial patterns of the brain imaging results; and / or subsequently performing brain imaging on the patient again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0726] In another aspect, this disclosure provides a method comprising: performing brain imaging on a patient to determine the patient's cognitive function; identifying a specific type of neurodegenerative disease based on spatial patterns from the brain imaging results; administering a beta agent and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less; and subsequently performing brain imaging on the patient again to determine any improvement in cognitive function.

[0727] In another aspect, this disclosure provides a method comprising: administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and / or identifying specific types of neurodegenerative diseases based on spatial patterns derived from the brain imaging results.

[0728] In another aspect, this disclosure provides a method comprising: administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying a specific type of neurodegenerative disease based on spatial patterns of the brain imaging results, and subsequently performing brain imaging again on the patient to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0729] In another aspect, this disclosure provides a method comprising: performing brain imaging on a patient to determine the patient's cognitive function; identifying a specific type of neurodegenerative disease based on spatial patterns from the brain imaging results; administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less; and subsequently performing brain imaging on the patient again to determine any improvement in cognitive function.

[0730] In another aspect, this disclosure provides a method comprising: administering tuloterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and / or identifying specific types of neurodegenerative diseases based on spatial patterns of the brain imaging results; and subsequently administering tuloterol and the peripherally acting beta-blocker (PABRA) to the patient.

[0731] In another aspect, this disclosure provides a method comprising: administering tuloterol and a peripherally acting beta-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying a specific type of neurodegenerative disease based on spatial patterns of the brain imaging results, and / or subsequently performing brain imaging on the patient again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0732] In another aspect, this disclosure provides a method comprising: performing brain imaging on a patient to determine the patient's cognitive function; identifying a specific type of neurodegenerative disease based on spatial patterns from the brain imaging results; administering tuloterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a dose of about 15 mg or less; and subsequently performing brain imaging on the patient again to determine any improvement in cognitive function.

[0733] In another aspect, this disclosure provides a method comprising: treating a subject identified as having cognitive decline and / or needing or expecting to improve cognitive function and / or treat neurodegenerative diseases by administering a pharmaceutical composition comprising a β-AR agonist (such as a beta-agonist), a β1-AR agonist, a β2-AR agonist, a peripherally acting beta blocker (PABRA), or any combination thereof, wherein the peripherally acting beta blocker (PABRA) is administered at a dose of about 15 mg or less. In some embodiments, the method further comprises assessing the effectiveness of the treatment by testing the subject to evaluate improved cognitive function or remission of neurodegenerative disease. In some embodiments, the method further comprises adjusting the administration of the pharmaceutical composition by adjusting the dose of the pharmaceutical composition and / or the timing of administration of the pharmaceutical composition.

[0734] In one aspect, this disclosure provides a method comprising: administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and / or identifying specific types of neurodegenerative diseases based on spatial patterns derived from the brain imaging results.

[0735] In another aspect, this disclosure provides a method comprising: administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to a patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise performing brain imaging on the patient to determine cognitive function to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying a specific type of neurodegenerative disease based on spatial patterns of the brain imaging results, and / or subsequently performing brain imaging on the patient again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0736] In another aspect, this disclosure provides a method comprising: performing brain imaging on a patient to determine the patient's cognitive function; identifying a specific type of neurodegenerative disease based on spatial patterns from the brain imaging results; administering a β-AR agonist (such as a β agent) and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose; and subsequently performing brain imaging on the patient again to determine any improvement in cognitive function.

[0737] In another aspect, this disclosure provides a method comprising: administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and / or to identify specific types of neurodegenerative diseases based on spatial patterns derived from the brain imaging results.

[0738] In another aspect, this disclosure provides a method comprising: administering a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to the patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying a specific type of neurodegenerative disease based on spatial patterns of the brain imaging results; and / or subsequently performing brain imaging on the patient again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0739] In another aspect, this disclosure provides a method comprising: performing brain imaging on a patient to determine the patient's cognitive function; identifying a specific type of neurodegenerative disease based on spatial patterns from the brain imaging results; administering a β-AR agonist (such as a β agent) and a peripherally acting β-blocker (PABRA) to the patient, wherein the peripherally acting β-blocker (PABRA) is administered at a subtherapeutic dose; and subsequently performing brain imaging on the patient again to determine any improvement in cognitive function.

[0740] In another aspect, this disclosure provides a method comprising: administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and / or identifying specific types of neurodegenerative diseases based on spatial patterns derived from the brain imaging results.

[0741] In another aspect, this disclosure provides a method comprising: administering clenbuterol and a peripherally acting beta-blocker (PABRA) to a patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying a specific type of neurodegenerative disease based on spatial patterns of the brain imaging results, and subsequently performing brain imaging again on the patient to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0742] In another aspect, this disclosure provides a method comprising: performing brain imaging on a patient to determine the patient's cognitive function; identifying a specific type of neurodegenerative disease based on spatial patterns from the brain imaging results; administering clenbuterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose; and subsequently performing brain imaging on the patient again to determine any improvement in cognitive function.

[0743] In another aspect, this disclosure provides a method comprising: administering tuloterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for neurodegenerative diseases, and / or identifying specific types of neurodegenerative diseases based on spatial patterns of the brain imaging results; and subsequently administering tuloterol and the peripherally acting beta-blocker (PABRA) to the patient.

[0744] In another aspect, this disclosure provides a method comprising: administering tuloterol and a peripherally acting beta-blocker (PABRA) to a patient to improve the patient's cognition and / or treat the patient's neurodegenerative disease, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose. The method may further comprise performing brain imaging on the patient to determine cognitive function and / or to identify whether the patient needs or desires improved cognitive function and / or treatment for the neurodegenerative disease, identifying a specific type of neurodegenerative disease based on spatial patterns of the brain imaging results, and / or subsequently performing brain imaging on the patient again to determine any improvement in cognitive function and / or treatment of the neurodegenerative disease.

[0745] In another aspect, this disclosure provides a method comprising: performing brain imaging on a patient to determine the patient's cognitive function; identifying a specific type of neurodegenerative disease based on spatial patterns from the brain imaging results; administering tuloterol and a peripherally acting beta-blocker (PABRA) to the patient, wherein the peripherally acting beta-blocker (PABRA) is administered at a subtherapeutic dose; and subsequently performing brain imaging on the patient again to determine any improvement in cognitive function.

[0746] In another aspect, this disclosure provides a method comprising: treating a subject identified as having cognitive decline and / or needing or expecting to improve cognitive function and / or treat neurodegenerative diseases by administering a pharmaceutical composition comprising a beta agent, a beta1-AR agonist, a beta2-AR agonist, a peripherally acting beta blocker (PABRA), or any combination thereof, wherein the peripherally acting beta blocker (PABRA) is administered at a subtherapeutic dose. In some embodiments, the method further comprises assessing the effectiveness of the treatment by testing the subject to evaluate improved cognitive function or remission of neurodegenerative diseases. In some embodiments, the method further comprises adjusting the administration of the pharmaceutical composition by adjusting the dose of the pharmaceutical composition and / or the timing of administration of the pharmaceutical composition.

[0747] In any aspect or embodiment of the present disclosure described herein, the brain imaging is fluorodeoxyglucose positron emission tomography (FDG-PET), magnetic resonance imaging-arterial spin labeling (MRI-ASL), or magnetic resonance imaging-oxygen level dependent computed tomography (MRI-BOLD).

[0748] In any aspect or embodiment of the present disclosure described herein, the β agent is administered at a dose of about 0.01 to 100 mg.

[0749] In any aspect or embodiment of the present disclosure described herein, the β agent is administered at a dose of about 30 to 160 μg.

[0750] In any aspect or embodiment of the present disclosure described herein, the β agent is administered at doses of approximately 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg. Doses of 80 to 120 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, or 160 μg may be administered.

[0751] In any aspect or embodiment of the present disclosure described herein, the β agent is administered at a dose of about 0.5-20 mg; or 1-10 mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg.

[0752] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose is the total daily dose of a beta-agonist, administered daily for several weeks or longer.

[0753] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose is the total weekly dose of the β agent, and is administered weekly for several weeks or longer.

[0754] In any aspect or embodiment of the present disclosure described herein, the β agent is compound 03-5, or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug.

[0755] In any aspect or embodiment of the present disclosure described herein, the peripherally acting beta-blocker (PABRA) is naldolol.

[0756] In any aspect or embodiment of the present disclosure described herein, naldorol is a mixture of four diastereomers.

[0757] In any aspect or embodiment of the present disclosure described herein, the applied naldorol is a particular enantiomer.

[0758] In any aspect or embodiment of the present disclosure described herein, the peripheral beta-blocker (PABRA) is administered at a dose of about 0.1 mg to 15 mg.

[0759] In any aspect or embodiment of the present disclosure described herein, the peripherally acting beta-blocker (PABRA) is administered in doses of about 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0760] In any aspect or embodiment of the present disclosure described herein, the above dose is the total daily dose of the peripherally acting beta-blocker (PABRA) and is administered daily for several weeks or longer.

[0761] In any aspect or embodiment of the present disclosure described herein, the β agent, β1-AR agonist, β2-AR agonist and / or peripherally acting β blocker (PABRA) are each administered orally.

[0762] In any aspect or embodiment of the present disclosure described herein, the β-drug and peripherally acting β-blocker (PABRA) are each administered orally, and both drugs are present in a tablet.

[0763] In any aspect or embodiment of the present disclosure described herein, naldolol is provided in amounts of about 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0764] In any aspect or embodiment of the present disclosure described herein, the neurodegenerative disease is selected from one or more of the following: MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Picker's disease), HD (Huntington's disease), Ritter syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TB I (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakov 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 (CJD, etc.), depression, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), and Down syndrome.

[0765] In any aspect or embodiment of the present disclosure described herein, the neurodegenerative disease is selected from one or more of the following: MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Picker's disease), HD (Huntington's disease), Ritter 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-Korsakov Syndrome; Alcoholic Dementia and Thiamine Deficiency), Normal Pressure Hydrocephalus, Hypersomnia / Symphomania, ASD (Autism Spectrum Disorder), FXS (Fragile X Syndrome), TSC (Tuberous Sclerosis Complex), Prion-related Diseases (CJD, etc.), Depression, DLB (Lewy Body Dementia), PD (Parkinson's Disease), PDD (PD Dementia), and ADHD (Attention Deficit Hyperactivity Disorder).

[0766] In any aspect or embodiment of the present disclosure described herein, the patient does not have Alzheimer's disease.

[0767] In any aspect or embodiment of the present disclosure described herein, the patient does not have Down syndrome.

[0768] In any aspect or embodiment of the present disclosure described herein, the patient does not have Parkinson's disease.

[0769] In any aspect or embodiment of the present disclosure described herein, the patient does not have Lewy body dementia.

[0770] In any aspect or embodiment of the present disclosure described herein, a pharmaceutical tablet is provided comprising: a beta agent in an amount of about 30 to 160 μg and a peripherally acting beta blocker (PABRA) in an amount of about 15 mg or less.

[0771] In any aspect or embodiment of the present disclosure described herein, the amount of the β agent is from about 0.01 to 100 mg.

[0772] In any aspect or embodiment of the present disclosure described herein, the amount of the β agent is about 0.5-50 mg; or 1-25 mg; or 1-10 mg; or 10-20 mg; or 25-50 mg; or mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 15 mg; or about 20 mg; or about 25 mg; or about 30 mg; or about 40 mg; or about 50 mg.

[0773] In any aspect or embodiment of the present disclosure described herein, the β agent is administered at doses of approximately 30 to 160 μg, 50 to 160 μg, 80 to 160 μg, 100 to 160 μg, 120 to 160 μg, 140 to 160 μg, 30 to 140 μg, 50 to 140 μg, 80 to 140 μg, 100 to 140 μg, 120 to 140 μg, 30 to 120 μg, 50 to 120 μg. Doses of 80 to 120 μg, 100 to 120 μg, 30 to 100 μg, 50 to 100 μg, 80 to 100 μg, 30 to 80 μg, 50 to 80 μg, 30 to 50 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, or 160 μg may be administered.

[0774] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose of the β agent is a total daily dose, and is administered daily for several weeks or longer.

[0775] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose of the β agent is a weekly dose, and is administered weekly for several weeks or longer.

[0776] In any aspect or embodiment of the present disclosure described herein, the peripheral beta-blocker (PABRA) is provided in amounts of about 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.1 to 5 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 10 mg, 10 mg or less, 7 mg or less, 5 mg or less, 1 mg or less, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0777] In any aspect or embodiment of the present disclosure described herein, the peripheral beta-blocker (PABRA) is provided in an amount of about 0.1 to 15 mg.

[0778] In any aspect or embodiment of the present disclosure described herein, the peripheral beta-blocker (PABRA) is provided in an amount of about 5 to 10 mg.

[0779] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose of the peripherally acting beta-blocker (PABRA) is a total daily dose, and is administered daily for several weeks or longer.

[0780] In any aspect or embodiment of the present disclosure described herein, the aforementioned dose of the peripherally acting beta-blocker (PABRA) is a weekly dose, and is administered weekly for several weeks or longer.

[0781] In any aspect or embodiment of the present disclosure described herein, the peripherally acting beta-blocker (PABRA) is naldolol.

[0782] In any aspect or embodiment of the present disclosure described herein, naldorol is a mixture of four diastereomers.

[0783] In any aspect or embodiment of the present disclosure described herein, the applied naldorol is a particular enantiomer.

[0784] In any aspect or embodiment of the present disclosure described herein, a combination formulation is provided comprising: a beta agent in an amount of about 30 to 160 μg and a peripherally acting beta blocker (PABRA) in an amount of 15 mg or less.

[0785] In any aspect or embodiment of the present disclosure described herein, the amount of the β agent is about 50 to 160 μg.

[0786] In any aspect or embodiment of the present disclosure described herein, the amount of the β agent is about 80 to 160 μg.

[0787] In any aspect or embodiment of the present disclosure described herein, the amount of the β agent is about 0.5 to 20 mg.

[0788] In any aspect or embodiment of the present disclosure described herein, the amount of the β agent is about 2 to 8 mg.

[0789] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose of the β agent is a total daily dose, and is administered daily for several weeks or longer.

[0790] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose of the β agent is a weekly dose, and is administered weekly for several weeks or longer.

[0791] In any aspect or embodiment of the present disclosure described herein, the amount of the peripheral beta-blocker (PABRA) is about 0.1 to 15 mg.

[0792] In any aspect or embodiment of the present disclosure described herein, the amount of the peripheral beta-blocker (PABRA) is about 5 to 10 mg.

[0793] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose of the peripherally acting beta-blocker (PABRA) is a total daily dose, and is administered daily for several weeks or longer.

[0794] In any aspect or embodiment of the present disclosure described herein, the peripherally acting beta-blocker (PABRA) is naldolol.

[0795] In any aspect or embodiment of the present disclosure described herein, naldorol is a mixture of four diastereomers.

[0796] In any aspect or embodiment of the present disclosure described herein, the applied naldorol is a particular enantiomer.

[0797] In any aspect or embodiment of the present disclosure described herein, a single formulation is provided comprising: a beta agent in an amount of about 30 to 160 μg and a peripherally acting beta blocker (PABRA) in an amount of 15 mg or less.

[0798] In any aspect or embodiment of the present disclosure described herein, the amount of the β agent is from about 0.01 to 100 mg.

[0799] In any aspect or embodiment of the present disclosure described herein, the amount of the β agent is about 0.5-50 mg; or 1-25 mg; or 1-10 mg; or 10-20 mg; or 25-50 mg; or mg; or 2-8 mg; or about 1 mg; or about 2 mg; or about 3 mg; or about 4 mg; or about 5 mg; or about 6 mg; or about 7 mg; or about 8 mg; or about 10 mg; or about 15 mg; or about 20 mg; or about 25 mg; or about 30 mg; or about 40 mg; or about 50 mg.

[0800] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose of the β agent is a total daily dose, and is administered daily for several weeks or longer.

[0801] In any aspect or embodiment of the present disclosure described herein, the amount of the peripheral beta-blocker (PABRA) is about 0.1 to 15 mg.

[0802] In any aspect or embodiment of the present disclosure described herein, the amount of the peripheral beta-blocker (PABRA) is about 5 to 10 mg.

[0803] In any aspect or embodiment of the present disclosure described herein, the above-mentioned dose of the peripherally acting beta-blocker (PABRA) is a total daily dose, and is administered daily for several weeks or longer.

[0804] In any aspect or embodiment of the present disclosure described herein, the peripherally acting beta-blocker (PABRA) is naldolol.

[0805] In any aspect or embodiment of the present disclosure described herein, naldorol is a mixture of four diastereomers.

[0806] In any aspect or embodiment of the present disclosure described herein, the applied naldorol is a particular enantiomer.

[0807] While this disclosure has been specifically shown and described with reference to specific embodiments, some of which are preferred embodiments, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the spirit and scope of this disclosure as disclosed herein.

[0808] All references cited in this disclosure are incorporated herein by reference in their entirety. Various embodiments of this disclosure may be characterized by the potential claims listed in paragraphs following this paragraph (and before the actual claims provided at the end of this application). These potential claims form part of the written description of this application. Therefore, the subject matter of the following potential claims may be presented as actual claims in subsequent proceedings relating to or based on this application and claiming priority. The inclusion of such potential claims should not be construed as meaning that the actual claims do not cover the subject matter of the potential claims. Therefore, the decision not to present these potential claims in subsequent proceedings should not be construed as a donation of subject matter to the public.

[0809] The embodiments described above are intended to be exemplary only; many variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of this disclosure, as defined in any of the appended claims.

Claims

1. Use of β-drugs and peripherally acting β-blockers in the preparation of a daily medicament for improving cognition and / or treating neurodegenerative diseases in a subject, wherein the β-drug is compound 03-5 present in an amount of 3 or 6 mg, and the structural formula of compound 03-5 is as follows: ,and The peripherally acting β-blocker is naldolol in a dose of 3 mg.

2. The use according to claim 1, wherein compound 03-5 is present in an amount of 3 mg, and naldolol is present in an amount of 3 mg.

3. The use according to any one of the preceding claims, wherein the neurodegenerative disease is mild cognitive impairment.

4. The use according to any one of claims 1-2, wherein the neurodegenerative disease is Parkinson's disease or dementia.

5. The use according to any one of the preceding claims, wherein the β agent is compound 03-5 present in an amount of 6 mg, and the peripheral β-blocker is naldolol present in an amount of 3 mg.

6. Use of β-drugs and peripherally acting β-blockers in the preparation of daily medicines for improving cognitive function in subjects, wherein i) The β-agent is compound 03-5 present in an amount of 0.3, 1, 3 or 6 mg, and the peripherally acting β-blocker is naldolol present in an amount of 1 or 2 mg, or ii) The β agent is compound 03-5 present in an amount of 0.3 or 1 mg, and the peripheral β blocker is naldolol present in an amount of 3 mg.

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