CN114340740A

CN114340740A - Beta adrenergic agonists and methods of use thereof

Info

Publication number: CN114340740A
Application number: CN202080054317.7A
Authority: CN
Inventors: A·P·福特; 余家新; D·S·卡特; 陈伟
Original assignee: Kulassen Therapy
Current assignee: Kulassen Therapy
Priority date: 2019-07-01
Filing date: 2020-06-30
Publication date: 2022-04-12
Also published as: WO2021003161A1; CA3144093A1; MX2021015850A; TW202116767A; IL289350A; JP2022538907A; AU2020300999A1; EP3993878A1; EP3993878A4

Abstract

The present disclosure relates to compounds and the use of such compounds in the treatment of diseases associated with adrenergic receptors.

Description

Beta adrenergic agonists and methods of use thereof

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional patent application No. 62/869,448 filed on day 7/1 in 2019, U.S. provisional patent application No. 62/934,482 filed on day 12/11/2019, U.S. provisional patent application No. 63/018,431 filed on day 30/4/2020, U.S. provisional patent application No. 16/831,285 filed on day 26/3/2020, and U.S. provisional patent application No. 16/831,370 filed on day 26/3/2020, the contents of each of which are incorporated herein by reference in their entirety.

Technical Field

The present disclosure relates generally to compounds, and in some embodiments, to beta adrenergic agonists and uses in the treatment of diseases associated with adrenergic receptors.

Background

PCT application publication No. WO2017197324 discloses "[ a ] adrenergic receptor modulating compounds and methods of treating a disease or disorder associated with an adrenergic receptor in a subject comprising administering a therapeutically effective amount of the subject compounds".

U.S. patent application publication No. 20130096126 discloses "a method for enhancing learning or memory in a mammal having impaired learning or memory or both, said mammal having a neurodegenerative disorder, said method requiring the step of administering an amount of at least one compound or salt thereof which is a β 1-adrenergic receptor agonist, partial agonist or receptor ligand effective to improve learning or memory or both in said mammal".

U.S. patent application publication No. 20140235726 discloses a "method of improving cognition in a patient with down's syndrome, the method requiring administration of one or more β 2 adrenergic receptor agonists to the patient in an amount and with a frequency effective to improve the patient's cognition as measured by a situational learning test".

U.S. patent application publication No. 20160184241 discloses a "method of improving cognition in a patient with down's syndrome, the method requiring intranasal administration of one or more β 2-ADR agonists or a pharmaceutically acceptable salt of both to the patient in an amount and frequency effective to improve cognition in the patient, such as a measured situational learning test".

Disclosure of Invention

The present disclosure is based, at least in part, on the identification of compounds that modulate adrenergic receptors and methods of using the same to treat diseases associated with adrenergic receptors. Disclosed herein are compounds according to formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof.

In some embodiments of formula (I), each R₁Independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amino, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, 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 of formula (I), m is an integer selected from 0 to 3.

In some embodiments of formula (I), a, B, and X are each independently nitrogen or carbon.

In some embodiments of formula (I), P is N, O, or CR₂(ii) a Q is N, O or CR₂(ii) a G is NR₅Or O; and/or Z is NR₅O, S or CR₃R₄. In some embodiments, R₂Selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy. In certain embodiments, each R₃And R₄Selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

In some embodiments of formula (I), R₅Is selected from one or more of the group consisting of: h is 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.

L is optionally substituted C₁-C₅An alkyl linker; each X₁、X₂、X₃And X₄Independently is a covalent bond, carbon, oxygen, or nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; y is O or S; r₆And R₇Independently selected from hydrogen, unsubstituted or substituted alkyl, or R₆And R₇And X₂The rings are linked and taken together to form an optionally substituted cycloalkyl or heterocycle; each R₈Independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; r₉Selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and R is₁₀Selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl and unsubstituted or substitutedA substituted alkoxy group.

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

In some embodiments of formula (II), each R₁Independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amino, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, 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 of formula (II), m is an integer selected from 0 to 3.

In some embodiments of formula (II), a, B, and X are each independently nitrogen or carbon.

In some embodiments of formula (II), P is N, O or CR₂(ii) a Q is N, O or CR₂(ii) a G is NR₅Or O; and/or Z is NR₅O, S or CR₃R₄。

In some embodiments of formula (II), R₂Selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

In some embodiments of formula (II), each R₃And R₄Selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

In some embodiments of formula (II),R₅、R₆and R₇Independently selected from the group consisting of: h, 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,

or R₅And R₆Together with carbon to form an unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic ring; l is optionally substituted C₁-C₅An alkyl linker; each X₁、X₂、X₃And X₄Independently is a covalent bond, carbon, oxygen, or nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; y is O or S; r₈And R₉Independently selected from hydrogen, unsubstituted or substituted alkyl, or R₈And R₉And X₂The rings are linked and taken together to form an optionally substituted cycloalkyl or heterocycle; each R₁₀Independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; r₁₁Selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and R is₁₂Selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

Also disclosed herein are compounds according to formula (I'):

or a pharmaceutically acceptable salt, wherein:

a ', B', W 'and X' are each independently a nitrogen atom or a carbon atom;

ring D' is a fused ring selected from a benzo 5-9 membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R1' is independently hydrogen, halogen, R^A、-CN、-NO₂、-SF₅、-O^-、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR’C(O)R’、-NR’CO₂R' or-CO₂R’；

Each R^AIndependently is an optionally substituted group selected from: c_1-6Aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

two R^AThe radicals forming, on the same carbon or optionally together with their intervening atoms, an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, except for the linkage of two R^AThe group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur other than carbon;

each R' is independently hydrogen or an optionally substituted group selected from: c_1-6An aliphatic group, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

two R 'groups on the same carbon or nitrogen optionally together with their intervening atoms form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen connecting the two R' groups;

m' is an integer selected from 0 to 3;

R²' is selected from hydrogen, R^A、-OR’、

L' is optionally substituted C_1-5An alkylene group;

X¹’，X³' and X⁴'each independently is selected from a covalent bond, -CR'₂A divalent group of-O-and-NR;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹' and R¹⁰' are each independently hydrogen or optionally substituted alkyl, or:

R⁹' and R¹⁰' is cyclic and is linked to X²Together form an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

each R¹³' independently is hydrogen, halogen, R^A-CN, -OR 'OR-NR'₂(ii) a And R is⁷' and R⁸' each independently is hydrogen or optionally substituted C_1-2Aliphatic radical。

As described herein, structures are depicted as

Including, for example, structure

Also disclosed herein are compounds according to formula (II'):

or a pharmaceutically acceptable salt, wherein:

a ', B', W 'and X' are each independently a nitrogen atom or a carbon atom;

each R^1’Independently hydrogen, halogen, R^A、-CN、-NO₂、-SF₅、-O^-、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR’C(O)R’、-NR’CO₂R', or-CO₂R’；

Each R^AIndependently is an optionally substituted group selected from: c_1-6An aliphatic group, a phenyl group, a 4-to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

m' is an integer selected from 0 to 3;

R⁴’，R⁵' and R⁶' is independently selected from hydrogen, halogen, R^A、-CN、-NO₂、-OR’、-NR’₂、

Or:

R⁴' and R⁵' optionally together with the carbon to which they are attached form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic 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;

l' is optionally substituted C_1-5An alkylene group;

X¹’，X³' and X⁴'each independently is selected from a covalent bond, -CR'₂-、-O-，and-NR' -;

X²' is a carbon atom or a nitrogen atom;

y' is O or S; r⁹' and R¹⁰' are each independently hydrogen or optionally substituted alkyl, or:

R⁹' and R¹⁰' is cyclic and is linked to X₂Together form an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

each R¹³' independently is hydrogen, halogen, R^A-CN, -OR 'OR-NR'₂(ii) a And

R⁷' and R⁸' each independently is hydrogen or optionally substituted C_1-2An aliphatic group.

Also disclosed herein are compounds according to formula (III'):

formula (III') or a pharmaceutically acceptable salt thereof, wherein:

a ', B ' and X ' are each independently a nitrogen atom or a carbon atom;

p ' and Q ' are each independently-N, -NR ' -, -CR ' -, or-CR '₂-；

G 'is-NR' -or-O-;

z ' is NR ', -O, - (S) or ═ CR '₂；

i is a single or double bond;

each R¹' independently is hydrogen, halogen, R^A、-CN、-NO₂、-SF₅、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR’C(O)R’、-NR’CO₂R' or-CO₂R’；

Each R^AIndependently is an optionally substituted group selected from: c_1-6An aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

two R' groups on the same carbon or nitrogen optionally together with their intervening atoms form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen connecting the two R groups;

m is an integer selected from 0 to 3;

R⁴’、R⁵' and R⁶' each is independently selected from hydrogen, halogen, R^A、-CN、-NO₂、-OR’、-NR’₂、

Or:

R⁴' and R⁵' optionally together with the carbon to which they are attached form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

l' is optionally substituted C_1-5An alkylene group;

X¹’，X³' and X⁴'each independently is selected from a covalent bond, -CR'₂A divalent group of-O-and-NR' -;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹' and R¹⁰'is cyclic and together with X2' forms an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN; and

each R¹³' independently is hydrogen, halogen, R^A-CN, -OR 'OR-NR'₂。

Also disclosed herein are compounds having the structure:

or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof.

Also disclosed herein are compounds having the structure:

Also disclosed herein are compounds having the following structures.

Also disclosed herein are compounds having the structure:

Also disclosed herein are compounds having the structure:

Also disclosed herein are compounds according to formula (IV'):

or a pharmaceutically acceptable salt thereof, wherein:

a ', B ' and X ' are each independently a nitrogen atom or a carbon atom;

each R¹' independently is hydrogen, halogen, R^A、-CN、-NO₂、-SF₅、-O^-、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR’C(O)R’、-NR’CO₂R' or-CO₂R’；

Each R^AIndependently is an optionally substituted group selected from: c_1-6An aliphatic group, phenyl, a 4-to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

m' is an integer selected from 0 to 3;

R^3a' and R^3b' independently is hydrogen, R^A、-OR’、-C(O)R’、-C(O)NR’₂or-CO₂R', or:

R^3a' and R^3b' optionally together with their intervening atoms form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring other than R^3a' and R^3b' the attached nitrogen has 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Or:

l' is optionally substituted C_1-5An alkylene group;

X¹’、X³' and X⁴'each independently is selected from a covalent bond, -CR'₂A divalent group of-O-and-NR' -;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹' and R¹⁰' is cyclic and is linked to X²' together form an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

Also disclosed herein are compounds according to formula (V'):

or a pharmaceutically acceptable salt thereof, wherein:

Each R^AIndependently is an optionally substituted group selected from: c_1-6Aliphatic radical, phenyl, 4-to 7-membered saturated or partially unsaturated hetero atom having 1 to 2 hetero atoms independently selected from nitrogen, oxygen and sulfurA ring and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

m' is an integer selected from 0 to 3;

Or:

l is optionally substituted C_1-5An alkylene group;

X²' is a carbon atom or a nitrogen atom;

Y¹' is O or S;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²is hydrogen, R^Aor-CN; and

each R¹³' independently is hydrogen, halogen R^A-CN, -OR 'OR-NR'₂。

Also disclosed herein are compounds having the structure:

or a pharmaceutically acceptable salt thereof.

Also disclosed herein are compounds having the structure:

or a pharmaceutically acceptable salt thereof.

Also disclosed herein are compounds according to formula (VI'):

or a pharmaceutically acceptable salt thereof,

wherein A ', B ', X ', R^1′、R^3a′、R^3b′、R^4′、R^5′、R⁶And m' are as defined above and described individually and in combination in the examples provided herein.

Also disclosed herein are compounds according to formula (VII'):

or a pharmaceutically acceptable salt thereof,

wherein A ', B ', X ', R^1′、R^4′、R^5′、R⁶And m' are as defined above and described individually and in combinations in the examples provided herein.

Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, i.e., a compound having the structure of formula (I), formula (I '), formula (II '), formula (III '), formula (IV '), formula (V '), formula (VI '), formula (VII '), or a pharmaceutically acceptable excipient.

In certain embodiments, the compounds disclosed herein are agonists, partial agonists or antagonists of adrenergic receptors; in some embodiments, the compound is a β 1-adrenergic receptor agonist, a β 2-adrenergic receptor agonist, or a non-selective β 1/β 2-adrenergic receptor agonist; in some embodiments, the compound is a β 1-adrenergic receptor agonist; in some embodiments, the compound is a β 2-adrenergic receptor agonist; in some embodiments, the compound is a non-selective beta 1/beta 2-adrenergic agonist.

Also disclosed are methods of treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, i.e., a compound having the structure of formula (I), formula (I '), formula (II '), formula (III '), formula (IV '), formula (V '), formula (VI '), or formula (VII '). In some embodiments, the disease is an adrenergic or receptor-related disease. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the subject is a human.

In some embodiments, the disease is selected from the group consisting of myocardial infarction, stroke, ischemia, alzheimer's disease, parkinson's disease, giardiasis (amyotrophic lateral sclerosis), huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebrovascular inflammation, epilepsy, tourette's syndrome, wilson's disease, pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, friedrich's ataxia, ataxia telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject by oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular injection, epidermal, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernous, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route.

In some embodiments, the disease is one or more neurodegenerative diseases selected from the group consisting of: MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, dementia of mixed type, FTD (frontotemporal dementia; pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Charcot-Deg's syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernike-Korsakoff's syndrome; alcoholic dementia and thiamine deficiency), normothermic hydrocephalus, hypersomnia/narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis syndrome), 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's Syndrome (DS). In some embodiments, the disease is a neurodegenerative disease, which is one or more diseases selected from the group consisting of: MCI, alpha MCI, vascular dementia, dementia of mixed type, FTD (frontotemporal dementia; pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Charcot's syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (Chronic traumatic encephalopathy), stroke, WKS (Wernike-Korsakoff's syndrome; Alcoholic dementia and Thiamine deficiency), normothermic hydrocephalus, hypersomnia/narcolepsy, ASD (autism spectrum disorder), FXS (Fragile X syndrome), TSC (tuberous sclerosis syndrome), prion-related diseases (CJD, etc.), depression, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia) and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not have Alzheimer's Disease (AD). In some embodiments, the subject does not have down syndrome.

In certain embodiments of the methods disclosed herein, the methods comprise administering to the subject a compound as disclosed herein and a peripherally acting beta-blocker (PABRA).

As used herein, the term "peripherally acting beta-blocker (PABRA)" means a beta adrenergic receptor antagonist or simply a beta 1-, beta 2-or non-selective beta-blocker. Examples of selective peripherally acting beta-blockers (PABRA) that may be used in the methods disclosed herein in certain embodiments include nadolol, atenolol, sotalol, and labetalol. In certain embodiments, the beta-blocker useful in the methods herein is one or more selected from the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, and nevigolol; in other embodiments, the method does not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, or nevadolol as a beta-blocker.

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

In certain embodiments of the compositions and methods provided herein, one or more peripheral acting beta-blockers (PABRAs) are administered prior to or concurrently with the compounds of the present disclosure to inhibit or preclude agonism of the peripheral beta 1 and/or beta 2 adrenergic receptors by the compounds of the present disclosure. In various embodiments, it is preferred that compositions and methods according to the present disclosure block peripheral β 1 and/or β 2 adrenergic receptors to exclude or at least minimize any adverse peripheral cardiac, metabolic, or muscular effects on the treated human.

In some embodiments of the methods provided herein, a β 1 agonist, a β 2 agonist, or a non-selective β 1/β 2 agonist is administered to the patient in addition to the compounds disclosed herein.

As used herein, the term "β 1 agonist" is used to mean a β 1-adrenergic receptor agonist or a β 1-ADR agonist. In certain embodiments, the term β 1 agonist is understood to include compounds that are primarily β 1 agonists, but may also exhibit some peripheral agonism at other adrenergic receptors (e.g., β 2-adrenergic receptors). In the present application, the terms "β 1-adrenergic receptor agonist", "β 1-ADR agonist", "β 1AR agonist" and "β 1 agonist" are used interchangeably. In certain embodiments, the term β 1-ADR agonist specifically includes selective and partial agonists, as well as biased and unbiased agonists. Examples of β 1 adrenergic agonists include, for example, zamotterol, norepinephrine, isoproterenol, dopamine, pindolol, and dobutamine, and pharmaceutically acceptable salts of any of the foregoing. Partial agonists and ligands for β 1-ADR are known. In addition, the method of Kolb et al is used, but for β 1-ADR, one skilled in the art can determine new ligands by structure-based discovery. See proceedings of the national academy of sciences of the United states of America 2009,106, 6843-.

As used herein, the term β 2 agonist is used to mean a β 2-adrenergic receptor agonist or a β 2-ADR agonist. In certain embodiments, the term β 2 agonist is understood to include compounds that are primarily β 2 agonists, but whose other adrenergic receptors (e.g., β 1-adrenergic receptors) exhibit some peripheral agonism. In the present application, the terms "β 2-adrenergic receptor agonist", "β 2-ADR agonist", "β 2AR agonist" and "β 2 agonist" are used interchangeably. In some embodiments, the term β 2-ADR agonist specifically includes selective agonists and partial agonists. The β 2 agonists that may be used according to various aspects and embodiments of the present disclosure may be short-acting, long-acting, or super-long-acting. Examples of short-acting beta 2 agonists that may be used are salbutamol, levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, oteracil, isoproterenol, salmeterol, fenoterol, terbutaline, salbutamol and isotalrine. Examples of long-acting β 2 agonists that may be used are salmeterol, bambuterol, formoterol and clenbuterol. Examples of ultralong-acting β 2 agonists include indacaterol, vilanterol, and olodaterol.

It has been surprisingly found that the compounds of the present disclosure exhibit unexpectedly beneficial properties, as demonstrated in the examples section herein. For example, it has been unexpectedly found that the compounds of the present disclosure act as low nM (<10nM) partial agonists of the β 2 adrenergic receptor.

Drawings

Detailed Description

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

The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular terms "a", "an" and "the" include reference unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The term "comprising" means "including". Thus, "comprising a or B" means "including a, B or a and B" without excluding further elements. The term "about" will be understood by one of ordinary skill in the art. Each amount given herein refers to the actual value given, whether or not the term "about" is used explicitly, and it also means an approximation of such given value that would reasonably be inferred based on the ordinary skill in the art.

It is also understood that all base sizes or amino acid sizes, and all molecular weights or molecular weight values given for a nucleic acid or polypeptide are approximate and provided for description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Definitions of terms commonly used in molecular biology are described in Benjimine, column, Gene V, Oxford university Press, 1994(ISBN 0-19-854287-9); kendrew et al (eds.), "encyclopedia of molecular biology," published by Heiwell science, Inc., 1994(ISBN 0-632-02182-9); and Robert a. meyers (editors), "molecular biology and biotechnology: integrated desk reference, VCHPublishers, 1995(ISBN 1-56081-.

Unless otherwise indicated, the nomenclature of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group, followed by naming the adjacent functional group toward the point of attachment. One of ordinary skill in the art will recognize that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 different groups, pentavalent carbon, etc.). Such impermissible substitution patterns are readily recognized by those of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. All sequences provided in the published gene bank accession number obtained on day 11 of 8/2011 are incorporated herein by reference. In the event of a conflict, the present specification, including multiple terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Alkyl refers to a monovalent group derived from an alkane by removing a hydrogen atom from any carbon atom, including straight and branched chains having from 1 to 12 carbon atoms, and typically from 1 to about 10 carbons, or in some embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 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. The alkyl group may be substituted or unsubstituted. Representative substituted alkyl groups may be mono-substituted or substituted more than once, such as but not limited to mono-, di-or tri-substituted. The term alkyl, as used herein, unless otherwise indicated, refers to both cyclic and acyclic groups.

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

Alkenyl refers to straight and branched chain and cycloalkyl groups as defined above having one or more double bonds between two carbon atoms. Alkenyl groups may have 2 to about 12 carbon atoms, or in some embodiments 1 to about 10 carbons, or in other embodiments 1 to about 6 carbon atoms, or in other embodiments 1,2, 3, or 4 carbon atoms. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as but not limited to mono-, di-or tri-substituted. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH ═ CH (CH)₃)、-CH＝C(CH₃)₂、-C(CH₃)＝CH₂Cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, and the like.

Alkynyl refers to straight and branched chain as well as cycloalkyl groups as defined above having one or more triple bonds between two carbon atoms. Alkynyl groups may have 2 to about 12 carbon atoms, or in some embodiments 1 to about 10 carbons, or in other embodiments 1 to about 6 carbon atoms, or in other embodiments 1,2, 3, or 4 carbon atoms. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as but not limited to mono-, di-or tri-substituted. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and-C ≡ C (CH)₃) And the like.

Aryl is a cyclic aromatic hydrocarbon, which includes monocyclic and polycyclic compounds, including polycyclic compounds containing individual and/or fused aryl groups. The aryl group can contain from 6 to about 18 ring carbons, or in some embodiments, from 6 to 14A plurality of ring carbons, or even 6 to 10 ring carbons in other embodiments. Aryl also includes heteroaryl, which is an aromatic ring compound containing 5 or more ring members in which one or more ring carbon atoms are replaced with a heteroatom such as, but not limited to N, O and S. The aryl group may be substituted or unsubstituted. Representative substituted aryl groups may be mono-substituted or substituted more than once, such as but not limited to mono-, di-or tri-substituted. Aryl groups include, but are not limited to, phenyl, biphenylene, triphenylene, naphthyl, anthracenyl, and pyrenyl. Aryloxy means-O-aryl. Arylthio means-S-aryl, wherein aryl is as defined herein. The term also includes oxidized forms of sulfur, such as-S (O) -aryl or-S (O)₂-an aryl group. Heteroaryloxy means-O-heteroaryl. Heteroarylthio means-S-heteroaryl. The term also includes oxidized forms of sulfur, such as-S (O) -heteroaryl or-S (O)₂-a heteroaryl group. N-oxides are also contemplated. In some embodiments, the compounds of the present disclosure are in the form of N-oxides.

Suitable heterocyclic groups include cyclic groups having as ring members at least two atoms of different elements, one or more of which is a heteroatom, such as, but not limited to N, O or S. A heterocyclyl group may include 3 to about 20 ring members, or in some embodiments 3 to 18, or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring system in a heterocyclyl group may be unsaturated, partially saturated and/or saturated. Heterocyclic groups may be substituted or unsubstituted. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as but not limited to mono-, di-or tri-substituted. Exemplary heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, hydroxytetrahydro, piperidinyl, morpholinyl, thiomorpholinyl, thioxanthyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, hydroxytetrahydro, tetrahydrofuryl, dioxolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanylThiobutyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, diazepinyl, thiazepinyl, 1,2, 3, 6-tetrahydropyridinyl, dihydrohydroxytetrahydrido, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolizinyl, heterocyclyloxy means an-O-heterocyclyl group. Heterocyclylthio means-S-heterocyclyl. The term also includes oxidized forms of sulfur, such as-S (O) -heterocyclyl or-S (O)₂-a heterocyclic group.

A polycyclic or polycyclic group refers to two or more rings in which two or more carbons are common to two adjacent rings, wherein the rings are "fused rings"; if the rings are joined by a common carbon atom, these are "spiro" ring systems. Rings that are linked together by non-adjacent atoms are referred to as "bridged" rings. Polycyclic groups may be substituted or unsubstituted. Representative polycyclic groups may be substituted one or more times.

Halogen groups include F, Cl, Br and I; nitro means-NO₂(ii) a Cyano means-CN; isocyano means-N ≡ C; epoxy groups encompass structures in which an oxygen atom is directly attached to two adjacent or non-adjacent carbon atoms of a carbon chain or ring system that is essentially a cyclic ether structure. Epoxides are cyclic ethers having a triatomic ring.

An alkoxy group is a single substituted or unsubstituted alkyl group as defined above bonded to an oxygen. The cycloalkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.

Thiol means-SH. Thiocarbonyl means (═ S). Sulfonyl means-SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-cycloalkyl, -SO₂-substituted cycloalkyl, -SO₂-aryl, -SO₂-substituted aryl, -SO₂-heteroaryl, -SO₂-substituted heteroaryl, -SO₂-heterocyclyl and-SO₂-substitutedA heterocyclic group. Sulfonylamino is-NRaSO₂Alkyl, -NRaSO₂-substituted alkyl, -NRaSO₂Cycloalkyl, -NRaSO₂Substituted cycloalkyl, -NRaSO₂Aryl, -NRaSO₂Substituted aryl, -NRaSO₂Heteroaryl, -NRaSO₂Substituted heteroaryl, -NRaSO₂Heterocyclyl, -NRaSO₂Substituted heterocyclic radical, in which each R^aIndependently as defined herein.

Carboxyl means-COOH or a salt thereof. Carboxy esters are meant to be-C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl, -C (O) O-substituted aryl, -C (O) β -cycloalkyl, -C (O) O-substituted cycloalkyl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl, -C (O) O-heterocyclyl, and-C (O) O-substituted heterocyclyl. (carboxy ester) amino means- -NRa-C (O) O-alkyl, - -NRa-C (O) O-substituted alkyl, - -NRa-C (O) O-aryl, - -NRa-C (O) O-substituted aryl, - -NRa- -C (O) β -cycloalkyl, - -NRa-C (O) O-substituted cycloalkyl, - -NRa-C (O) O-heteroaryl, - -NRa-C (O) O-substituted heteroaryl, - -NRa-C (O) O-heterocyclyl and- -NRa-C (O) O-substituted heterocyclyl, where Ra is as described herein. (carboxy ester) oxy means-O-C (O) O-alkyl, -O-C (O) O-substituted alkyl, -O-C (O) O-aryl, -O-C (O) O-substituted aryl, -O-C (O) β -cycloalkyl, -O-C (O) O-substituted cycloalkyl, -O-C (O) O-heteroaryl, -O-C (O) O-substituted heteroaryl, -O-C (O) O-heterocyclyl and-O-C (O) O-substituted heterocyclyl. Oxo means (═ O).

The terms "amine" and "amino" refer to derivatives of ammonia in which one or more hydrogen atoms have been replaced with substituents including, but not limited to, alkyl, alkenyl, aryl, and heterocyclyl. In some embodiments, the substituted amino group can include-NH-CO-R. Carbamate means-O (C ═ O) NR₁R₂Wherein R is₁And R₂Independently hydrogen, an aliphatic group, an aryl group or a heterocyclic group.

Aminocarbonyl means-C (O) N (R)^b)₂Wherein each R is^bIndependently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl. This is achieved byEach R is^bMay optionally be joined together with the nitrogen bound thereto to form a heterocyclic group or a substituted heterocyclic group, provided that two R are^bNot all are hydrogen. Aminocarbonylalkyl refers to-alkyl C (O) N (R)^b)₂Wherein each R is^bIndependently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl. Furthermore, each R^bMay optionally be joined together with the nitrogen bound thereto to form a heterocyclic group or a substituted heterocyclic group, provided that two R are^bNot all are hydrogen. Aminocarbonylamino represents-NRaC (O) N (R)^b)₂Wherein R is^aAnd each R^bAs defined herein. Aminodicarbonylamino refers to-NRaC (O) C (O) N (R)^b)₂Wherein R is^aAnd each R^bAs defined herein. Aminocarbonyloxy means-O-C (O) N (R)^b)₂Wherein each R is^bIndependently as defined herein. Aminosulfonyl means-SO₂N(R^b)₂Wherein each R is^bIndependently as defined herein.

Imino means-N ═ R^cWherein R is^cMay be selected from the group consisting of hydrogen, aminocarbonylalkoxy, substituted aminocarbonylalkoxy, aminocarbonylalkylamino and substituted aminocarbonylalkylamino

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

Suitable monovalent substituents on the substitutable carbon atom of the optionally substituted group are independently halogen; - (CH)₂)_0–4R^o；-(CH₂)_0-4OR^o；-O(CH₂)_0-4R^o，-O-(CH₂)_0-4C(O)OR^o；-(CH₂)_0-4CH(OR^o)₂；-(CH₂)_0- ₄SR^o；-(CH₂)_0-4Ph, which may be represented by R^oSubstitution; - (CH)₂)_0-4O(CH₂)_0-1Ph, which may be represented by R^oSubstitution; -CH ═ CHPh, which may be substituted for R^o；-(CH₂)_0–4O(CH₂)_0-1-a pyridyl group, which may be substituted by R^oSubstitution; -NO₂；-CN；-N₃；-(CH₂)_0-4N(R^o)₂；-(CH₂)_0-4N(R^o)C(O)R^o；-N(R^o)C(S)R^o；-(CH₂)_0-4N(R^o)C(O)NR^o ₂；-N(R^o)C(S)NR^o ₂；-(CH₂)_0-4N(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)_0-4C(O)R^o；-C(S)R^o；-(CH₂)_0-4C(O)OR^o；-(CH₂)_0-4C(O)SR^o；-(CH₂)_0-4C(O)OSiR^o ₃；-(CH₂)_0-4OC(O)R^o；-OC(O)(CH₂)_0-4SR^o；SC(S)SR^o；-(CH₂)_0-4SC(O)R^o；-(CH₂)_0-4C(O)NR^o ₂；-C(S)NR^o ₂；-C(S)SR^o；-SC(S)SR^o；-(CH₂)_0-4OC(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)_0-4SSR^o；-(CH₂)_0-4S(O)₂R^o；-(CH₂)_0-4S(O)₂OR^o；-(CH₂)_0-4OS(O)₂R^o；-S(O)₂NR^o ₂；-S(O)(NR^o)R^o；-S(O)₂N＝C(NR^o ₂)₂；-(CH₂)_0-4S(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_1–4Straight or branched alkylene) O-N (R)^o)₂；or-(C_1–4Straight or branched alkylene) C (O) O-N (R)^o)₂Wherein each R is^oMay be substituted as defined below and independently is hydrogen. C_1–6Aliphatic radical, -CH₂Ph、-O(CH₂)_0–1Ph, -CH2- (5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independently occurring R's, although defined above^oTogether with their intervening atoms, form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

R1^oA suitable monovalent substituent of (or via R1)^oRings formed by two independent occurrences together with their intervening atoms) are independently halogen; - (CH)₂)_0–2R^·；-(haloR^·)；-(CH₂)_0–2OH；-(CH₂)_0–2OR^·；-(CH₂)_0-2CH(OR·)₂；-O(haloR^·)；-CN；-N₃；-(CH₂)_0-2C(O)R^·；-(CH₂)_0-2C(O)OH；-(CH₂)_0-2C(O)OR^·；-(CH₂)_0-2SR^·；-(CH₂)_0-2SH；-(CH₂)_0-2NH₂；-(CH₂)_0-2NHR^·；-(CH₂)_0-2NR^· ₂；-NO₂,-SiR^· ₃；-OSiR^· ₃；-C(O)SR^·；-(C_1–4Linear OR branched alkylene) C (O) OR^·(ii) a or-SSR^·Wherein each R^·Unsubstituted or wherein the preceding "halogen" is substituted only by one or more halogens and is independently selected from the group consisting of C1-4 aliphatic, -CH2Ph, -O (CH)₂)_0-1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom of R include ═ O and ═ S.

Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: o; (ii) S; NNR ═ NNR^* ₂；＝NNHC(O)R^*；＝NNHC(O)OR^*；＝NNHS(O)₂R^*；＝NR^*；＝NOR^*；-O(C(R^* ₂))_2–3O-; or-S (C (R)^* ₂))_2-3S-; wherein each independently occurs R^*Selected from hydrogen, C which may be substituted as defined below_1-6An aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to the substitutable carbon in the ortho position of the "optionally substituted" group include: -O (CR)^*2)_2-3O-, in which each occurrence of R is independent^*Selected from hydrogen, C which may be substituted as defined below_1-6Aliphatic radical, or unsubstituted 5-to 6-membered having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfurA saturated, partially unsaturated or aryl ring.

R^*Suitable substituents on the aliphatic radical of (A) include halogen, -R^·；-(haloR^·) (ii) a -OH, -or R^·(ii) a -O (halo R)^·)；-CN；-C(O)OH；-C(O)OR^·；-NH₂；-NHR^·；-NR^· ₂(ii) a or-NO₂(ii) a Wherein each R^·Unsubstituted or wherein the former halogen is substituted only by one or more halogens, and independently is a C1-4 aliphatic radical, -CH₂Ph；-O(CH₂)_0-1Ph; or 5-6 membered saturated; partially unsaturated; or an aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the substitutable nitrogen of the "optionally substituted" group include

Or

Each of which

Independently hydrogen, C which may be substituted as defined below_1-6An aliphatic radical, unsubstituted-OPh or an unsubstituted 5-to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring, although having the above definition

Together with their intervening atoms, form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic radical of (A) are independently halogen, -R^·(ii) a - (halogenated R)^·) (ii) a -a hydroxyl group; -OR^·(ii) a -O (halo R)^·)；-CN；-C(O)OH；-C(O)OR^·；-NH₂；-NHHR^·；-NR^· ₂(ii) a or-NO₂(ii) a Wherein each R^·Unsubstituted or wherein the preceding "halogen" is substituted only by one or more halogens, and is independently a C1-4 aliphatic radical, -CH₂Ph；-O(CH₂)_0- ₁Ph; or 5-6 membered saturated; partially unsaturated; or an aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Furthermore, unless otherwise indicated, structures described herein are also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, including hydrogen deuterium (e.g., D or H)²) Or tritium (e.g., T or H)³) Substituted or carbon quilt¹³C-or¹⁴C-enriched carbon substituted compounds having the structure of the present invention and are within the scope of the present disclosure. These compounds are useful, for example, as analytical tools, probes in bioassays, or as therapeutics according to the present disclosure.

Pharmaceutically acceptable salts of the compounds described herein include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochlorides, hydrobromides, sulfates, sulfamates, phosphates, nitrates, and the like; salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isothiocyanates and the like. In other embodiments, the compounds of the invention 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 manufacture of the administration vehicle or dosage form, or by separately reacting the purified compound in its free acid form with a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation), ammonia, or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethyleneimine, ethanolamine, diethanolamine, piperazine and the like.

As used herein, "prodrug" refers to an activated derivative that requires conversion in vivo to release an active agent. In certain embodiments, the conversion is an enzymatic conversion. Prodrugs are generally, although not necessarily, pharmacologically inactive until converted to an active agent. As used herein, "prodrug moiety" refers to a form of protecting group that, when used to mask a functional group in a drug molecule, converts an active agent into a prodrug. In some cases, the precursor moiety will be attached to the drug via a bond that is cleaved in vivo by enzymatic or non-enzymatic means. Any convenient prodrug form of the subject compounds may be prepared, for example, according to the strategies and methods described by Rautio et al. Prodrug: design and clinical application, nature reviews drug discovery 7,255-.

Disclosed herein are compounds according to formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof.

Formula (I) in some embodiments of formula (I), each R¹Independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amino, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynylSubstituted 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 of formula (I), m is an integer selected from 0 to 3.

In some embodiments of formula (I), A, B and X are each independently nitrogen or carbon.

In some embodiments of formula (I), P is N, O or CR₂(ii) a Q is N, O or CR₂(ii) a G is NR₅Or O; and/or NR₅O, S, or CR₃R₄. In some embodiments, R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy. In certain embodiments, each R₃And R₄Selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

In some embodiments of formula (I), R₅Is selected from one or more of the group consisting of: H. 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,

l is an optionally substituted C1-C5 alkyl linker; each X₁、X₂、X₃And X₄Independently is a covalent bond, carbon, oxygen, or nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; y is O or S; r₆And R₇Independently selected from hydrogen, unsubstituted or substituted alkanesOr R is₆And R₇And X₂The rings are linked and taken together to form an optionally substituted cycloalkyl or heterocycle; each R₈Independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; r₉Selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and R is₁₀Selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

Also disclosed herein are compounds according to formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof

In some embodiments of formula (II), each R1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amino, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, 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, substituted or substituted- (C ═ O) -heteroaryl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

In some embodiments of formula (II), m is an integer selected from 0 to 3.

In some embodiments of formula (II), A, B and X are each independently nitrogen or carbon.

In some embodiments of formula (II), R₅、R₆And R₇Independently selected from the group consisting of: H. 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,

or R5 and R6 together with carbon form an unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic ring; l is an optionally substituted C1-C5 alkyl linker; each X1, X2, X3, and X4 is independently a covalent bond, carbon, oxygen, or nitrogen optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; y is O or S; r8 and R9 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R8 and R9 are linked to the X2 ring and together form an optionally substituted cycloalkyl or heterocyclic ring; each R10 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; r11 is selected from hydrogen, halogen, cyano unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and R12 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

Also disclosed herein are compounds according to formula (I'):

a formula (I') or a pharmaceutically acceptable salt, wherein:

a ', B', W 'and X' are each independently a nitrogen atom or a carbon atom;

each R^1’Independently hydrogen, halogen, R^A、-CN、-NO₂、-SF₅、-O-、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR’C(O)R’、-NR’CO₂R' or-CO₂R’；

each R' is independently hydrogen or an optionally substituted group selected from: c_1-6Aliphatic radical, phenyl radical, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, 8-10 membered bicyclic partially unsaturated or aromatic radicalA carbocyclic ring of groups, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic moiety unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

m' is an integer selected from 0 to 3;

R²' selected from hydrogen and C_1-4Alkyl radical, R^A、-OR’

L' is optionally substituted C_1-5An alkylene group;

X¹’、X³' and X⁴'each independently is a divalent group selected from a covalent bond, -CR'₂-, -O-and-NR' -;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹' and R¹⁰' together with X2 form an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

each R¹³' independently is hydrogen, halogen, R^A-CN, -OR 'OR-NR'₂(ii) a And R⁷' and R⁸' each independently is hydrogen or optionally substituted C_1-2An aliphatic group.

Also disclosed herein are compounds according to formula (II'):

a formula (II') or a pharmaceutically acceptable salt, wherein:

a ', B', W 'and X' are each independently a nitrogen atom or a carbon atom;

ring D' is a fused ring selected from benzo, 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R^1’Independently hydrogen, halogen, R^A、-CN、-NO₂、-SF₅、-O^-、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR’C(O)R’、-NR’CO₂R' or-CO₂R’；

Each R^AIndependently is an optionally substituted group selected from: c_1-6An aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

two R^AThe radicals forming, on the same carbon or optionally together with their intervening atoms, an optionally substituted 3-6 membered saturated or partially unsaturated carbonRings or heterocycles other than two R^AThe group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur other than carbon;

m' is an integer selected from 0 to 3;

R⁴’、R⁵' and R⁶' each is independently selected from hydrogen, halogen, R^A、-CN、-NO₂、-OR’、-NR’₂

Or:

R⁴' and R⁵' optionally together with the carbon to which they are attached form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfurAn optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle;

l' is optionally substituted C_1-5An alkylene group;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

Also disclosed herein are compounds according to formula (III'):

formula (III') or a pharmaceutically acceptable salt thereof, wherein:

a ', B ' and X ' are each independently a nitrogen atom or a carbon atom;

p ' and Q ' are each independently-N, -NR ' -, -CR ' -, or-CR '₂-；

G 'is-NR' -or-O-;

z ' is NR ', -O, - (S) or ═ CR '₂；

Is a single or double bond;

m' is an integer selected from 0 to 3;

R⁴’、R⁵' and R⁶' each is independently selected from hydrogen, halogen, R^A、-CN、-NO₂、-OR’、-NR’₂，

Or:

l' is optionally substituted C_1-5An alkylene group;

X²' is a carbon atom or a nitrogen atom;

y' is O or S; (ii) a

R⁹' and R¹⁰'is cyclic and together with X2' forms an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfurA heterocycle;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN; and

each R¹³' independently is hydrogen, halogen, R^A-CN, -OR 'OR-NR'₂。

Also disclosed herein are compounds according to formula (IV'):

formula (IV') or a pharmaceutically acceptable salt thereof, wherein:

a ', B ' and X ' are each independently a nitrogen atom or a carbon atom;

each R' is independently hydrogen or an optionally substituted group selected from: c_1-6An aliphatic group, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfurAn aromatic ring, or:

m' is an integer selected from 0 to 3;

R^3a' and R^3b' an optionally substituted 4-to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, optionally having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, except for the nitrogen attached;

Or:

l' is optionally substituted C_1-5An alkylene group;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹and R¹⁰' are each independently hydrogen or optionally substituted alkyl, or:

R⁹' and R¹⁰'together with X2' form an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

each R¹³' independently is R^AHalogen, R^A-CN, -OR 'OR-NR'₂(ii) a And

Each independently hydrogen or optionally substituted C_1-2An aliphatic group.

Also disclosed herein are compounds according to formula (V'):

formula (V') or a pharmaceutically acceptable salt thereof, wherein:

m' is an integer selected from 0 to 3;

Or:

R⁴' and R⁵' optionally together with the carbon to which they are attached form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur3-7 membered saturated or partially unsaturated monocyclic heterocycle of a heteroatom of (a);

l' is optionally substituted C_1-5An alkylene group;

X²' is a carbon atom or a nitrogen atom;

Y¹' is O or S;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²is hydrogen, R^Aor-CN; and

each R¹³' independently is R^AHalogen, R^A-CN, -OR 'OR-NR'₂。

As defined above and described herein, a' is a nitrogen atom or a carbon atom.

In some embodiments, a' is a nitrogen atom. In some embodiments, a' is a carbon atom.

In some embodiments a' is selected from those described in table 1 below.

As defined above and described herein, B' is a nitrogen atom or a carbon atom.

In some embodiments, B' is a nitrogen atom. In some embodiments, B' is a carbon atom.

In some embodiments B' is selected from those described in table 1 below.

As defined above and described herein, X' is a nitrogen atom or a carbon atom.

In some embodiments, X' is a nitrogen atom. In some embodiments, X' is a carbon atom.

In some embodiments X' is selected from those described in table 1 below.

W' is a nitrogen atom or a carbon atom, as defined above and described herein.

In some embodiments, W is a nitrogen atom. In some embodiments, W is a carbon atom.

In some embodiments W' is selected from those described in table 1 below.

In some embodiments, any of the nitrogen atoms described above is optionally in the form of an N-oxide.

As defined above and described herein, P ' and Q ' are each independently-N ═ NR ' -, -CR ' ═ or-CR '₂-。

In some embodiments, P' is-N ═ N. In some embodiments, P 'is-NR'. In some embodiments, P 'is-CR'. In some embodiments, P 'is-CR'₂-. In some embodiments, P' is-CH ═ CH. In some embodiments, Q' is-N ═ N. In some embodiments, Q 'is-NR'. In some embodiments, Q 'is-CR'. In some embodiments, Q is-CR'₂-. In some embodiments, Q' is-CH ═ CH.

In some embodiments, P 'and Q' are selected from those described in table 1 below.

As defined above and described herein, G 'is-NR' -or-O-.

In some embodiments, G 'is-NR' -. In some embodiments, G '-NR' -. In some embodiments, G' is-O-. In some embodiments, G' is-NH-. In some embodiments, G' is-NMe-.

In some embodiments G' is selected from those described in table 1 below.

As defined aboveAnd as used herein, Z ' is ═ NR ', ═ O, ═ S, or ═ CR '₂。

In some embodiments, Z is ═ NR'. In some embodiments, Z' is ═ O. In some embodiments, Z' is ═ S. In some embodiments, Z 'is ═ CR'₂。

In some embodiments Z' is selected from those described in table 1 below.

As defined above and described herein is a single or double bond.

In some embodiments of the present invention, the,

is a single bond. In some embodiments of the present invention, the,

is a double bond.

In some embodiments selected from those described in table 1 below.

Ring D' is a fused ring selected from benzo, a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, as defined above and described herein.

In some embodiments, ring D' is benzo. In some embodiments, ring D' phenyl. In some embodiments, ring D' is a 5-9 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring D' is a 5-to 7-membered saturated or partially unsaturated cyclic or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments, ring D' is

In some embodiments ring D' is selected from those described in table 1 below.

As defined above and described herein, each R^1'Independently of one another is halogen, R^A、-CN、-NO₂、-SF₅、-O^-、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR′C(O)R’、-NR’CO₂R', or CO₂R’。

In some embodiments, R^1'Is hydrogen. In some embodiments, R^1'Is a halogen. In some embodiments, R^1'Is R^A. In some embodiments, R^1′is-CN. In some embodiments, R^1'is-NO₂. In some embodiments, R^1'is-SF₅. In some embodiments, R^1'is-O^-. In some embodiments, R^1'is-OR'. In some embodiments, R^1''is-NR'₂. In some embodiments, R^1'is-SO₂R' is provided. In some embodiments, R^1'is-C (O) R'. In some embodiments, R^1′Is C (O) NR'₂. In some embodiments, R^1'Is NR 'C (O) R'. In some embodiments, R^1'Is R' CO₂R' is provided. In some embodiments, R^1'Is' CO₂R' is provided. In some embodiments, R^1'Is Br. In some embodiments, R^1'Is Cl. In some embodiments, R¹' is F. In some embodiments, R¹' is CH₃. In some embodiments, R^1'Is CH₂CH₃. In some embodiments, R^1'Is CH (CH)₃)₂. In some embodiments, R^1'Is CF₃. In some embodiments, R^1'Is CF₂H. In some embodiments, R^1'Is CFH₂. In some embodiments, R^1'Is CF₂CH₃. In some embodiments, R^1'Is CH₂CF₃. In some embodiments, R^1'is-C ≡ CCH. In some embodiments, R¹' is vinyl. In some embodiments, R^1'therefore-C.ident.CCF₃. In some embodiments, R^1'Is CO₂H. In some embodiments, R¹' is OH. In some embodiments, R¹' is OCH₃. In some embodiments, R¹' is OCH₂CH₃. In some embodiments, R¹' is-OCH (CH)₃)₂. In some embodiments, R^1′is-OCF₃. In some embodiments, R^1′is-NHCH₃. In some embodiments, R^1'is-NHCD₃. In some embodiments, R^1'is-N (CD)₃)CO₂tBu. In some embodiments, R^1'is-NHCH₂CH₃. In some embodiments, R^1'is-NHCH₂(CH₃)₂. In some embodiments, R^1'is-NHCH₂CF₃. In some embodiments, R^1'is-NHPh. In some embodiments, R^1'is-NHAc. In some embodiments, R^1'is-N (CH)₃)₂. In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments，R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, R^1'Is that

In some embodiments, L1 is selected from those described in table 1 below.

As defined above and described herein, each R' is independently hydrogen or an optionally substituted group selected from: c_1-6An aliphatic group, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic moiety unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic moiety unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two R 'groups on the same carbon or nitrogen optionally together with their intervening atoms form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to the carbon or nitrogen connecting the two R' groups, Heteroatoms of oxygen and sulfur.

In some embodiments, R' is hydrogen. In some embodiments, R' -S (O) R. In some embodiments, R' is optionally substituted C_1-6An aliphatic group. For example, in some embodiments, R' is-CF₃，-CF₂H or-CFH₂. In some embodiments, R' is an optionally substituted 3-8 membered saturated monocyclic ring. In some embodiments, R' is an optionally substituted 3-8 membered partially unsaturated monocyclic ring. In some embodiments, R' is optionally substituted phenyl. In some embodiments, R' is an optionally substituted 8-10 membered bicyclic moiety unsaturated middle ring. In some embodiments, R' is an optionally substituted 8-10 membered bicyclic aromatic ring. 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. In some embodiments, R' is an optionally substituted 4-8 membered partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some implementationsIn an example, R' is an optionally substituted 8-10 membered bicyclic moiety unsaturated ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R' is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R 'groups on the same middle or nitrogen optionally together with their intervening atoms form an optionally substituted 4-10 membered saturated or partially unsaturated cyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the middle or nitrogen linking the two R' groups.

In some embodiments, R' is selected from those described in table 1 below.

As defined above and described herein, m' is an integer selected from 0 to 4.

In some embodiments, m' is 0. In the examples, m' is 1. In some embodiments, m' is 2. In some embodiments, m' is 3. In some embodiments, m' is 4.

In some embodiments, m is selected from those described in table 1 below.

As defined above and described herein, each R^AIndependently is an optionally substituted group selected from: c_1-6Aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R on the same carbon^AThe groups or optionally together with their intervening atoms form an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring of heteroatoms selected from nitrogen, oxygen and sulfur.

In some embodiments, is optionally substituted phenyl. In some embodiments, R^AIs optionally substituted C_1-6An aliphatic group. In some embodiments, R^AIs an optionally substituted 3-7 membered saturated monocyclic ring. In some embodiments, R^AIs an optionally substituted 3-7 membered partially unsaturated monocyclic ring. In some embodiments, R^AIs optionally substituted benzeneAnd (4) a base. In some embodiments, ring B is a 5-6 membered R having 1-4 heteroatoms independently selected from nitrogen, oxygen RA sulfur^AAn aromatic ring. In some embodiments, two R^AThe radicals forming, on the same carbon or optionally together with their intervening atoms, an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, except for the linkage of two R^AThe group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur other than carbon.

As defined above, R^2’Is hydrogen, R^A、-OR’、

In some embodiments, R^2’Is hydrogen. In some embodiments, R^2’Is R^A. In some embodiments, R^2’is-OR'. In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some implementationsIn the examples, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is CH₃. In some embodiments, R^2’Is a CD₃. In some embodiments, R^2’Is C (CH)₃)₃. In some embodiments, R^2’Is C (CD)₃)₃. In some embodiments, R^2’Is C (CH)₃)₂CH₂OR'. In some embodiments, R^2’Is C (CH)₃)₂CH₂And (5) OH. In some embodiments, R^2’Is iPr. In some embodiments, R^2’Is CH₂And (4) iPr. In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments R^2’Selected from those described in table 1 below.

As defined above and as described herein, R^3a'And R^3b'Independently of each other is hydrogen, R^A、-OR'、-C(O)R'、-C(O)NR'₂or-CO 2R', or R^3a'And R^3b'Optionally together with the intervening atoms to form R^3a'And R^3b'The nitrogen attached is independently selected from the group consisting of nitrogen, oxygen and sulfur and an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms.

In some embodiments, R^3a'Is hydrogen. In some embodiments, R^3a'Is R^A. In some embodiments, R^3a'is-OR'. In some embodiments, R^3a'Is C (O) R'. In some embodiments, R^3a'is-C (O) NR'₂. In some embodiments, R^3a'is-CO₂R' is provided. In some embodiments, R^3b'Is hydrogen. In the examples, R^3b'Is R^A. In some embodiments, R^3b'is-OR'. In some embodiments, R^3b'is-C (O) R'. In some embodiments, R^3b'is-C (O) NR'₂. In some embodiments, R^3b'is-CO₂R' is provided. In some embodiments, R^3a'And R^3b'Optionally together with their intervening atoms form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring other than R^3a'And R^3b'The attached nitrogen has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^3a'And R^3b'Selected from those described in table 1 below.

As defined above, R^4'、R^5'And R^6'Each independently of the others is hydrogen, halogen, C_1-6Alkyl or C_1-6Alkoxy radical, R^A、-CN、-NO₂、-OR’、-NR’₂,、

Or R^4'And R^5'Optionally together with the carbon to which they are attached form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, R^2’Is hydrogen. In some embodiments, R^2’Is R^A. In some embodiments, R^2’is-OR'. In some embodiments, R^2’is-NR'₂. In some embodiments, R^2’Is that

In some embodiments, R^2’' is

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’Is that

In some embodiments, R^2’is-CH₃. In some embodiments, R^2’is-CD₃. In some embodiments, R^2’is-C (CH)₃)₃. In some embodiments, R^2’is-C (CD)₃)₃. In some embodiments, R^2’Is that

In some casesIn the examples, R^4’Is hydrogen. In some embodiments, R^4’Is a halogen. In some embodiments, R^4’Is R^A. In some embodiments, R^4’is-CN. In some embodiments, R^4’is-NO₂. In some embodiments, R^4’is-OR'. In some embodiments, R^4’is-CH₂OR'. In some embodiments, R^4’is-CH₂And (4) iPr. In some embodiments, R^4’is-NR'₂. In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’Is that

In some embodiments, R^4’And R^5’Optionally together with the carbon to which they are attached form an optionally substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R^4’And R^5’Optionally together with the carbon to which they are attached form an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^4’And R^5’Optionally together with the carbon to which they are attached form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^4’is-CH₃. In some embodiments, R^4’is-CD₃. In some embodiments, R⁴' is

In some embodiments, R^5’Is hydrogen. In some embodiments, R^5’Is a halogen. In some embodiments, R^5’Is R^A. In some embodiments, R^5’is-CN. In some embodiments, R^5’is-NO₂. In some embodiments, R^5’is-OR'. In some embodiments, R^5’is-NR'₂. In some embodiments, R^5’Is that

In some embodimentsIn, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’Is that

In some embodiments, R^5’is-CH₃. In some embodiments, R^5’is-CD₃. At one endIn some embodiments, R^5’Is that

In some embodiments, R^4’And R^5’Is that

In some embodiments, R^4’And R^5’Is that

In some embodiments, R^4’And R^5’Is that

In some embodiments, R^4’And R^5’Is that

In some embodiments, R^4’And R^5’Is that

In some embodiments, R^4’And R^5’Is that

In some embodiments, R^6’Is hydrogen. In some embodiments, R^6’Is a halogen. In some embodiments, R^6’Is R^A. In some embodiments, R^6’is-CN. In some embodiments, R^6’is-NO₂. In some embodiments, R^6’is-OR'. In some embodiments, R^6’is-NR'₂. In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^{6' is}

In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^6’Is that

In some embodiments, R^6’is-CH₃. In some embodiments, R^6’is-CD₃。

In some embodimentsIn, R^6’Is that

In some embodiments, R^2’、R^4’、R^5’And R^6’Each selected from those depicted in table 1 below.

L' is optionally substituted C, as defined above and described herein_1-5An alkylene group.

In some embodiments, L' is optionally substituted C_1-5An alkylene group. In some embodiments, L' is-CH₂-。

In some embodiments, L' is selected from those described in table 1 below.

As defined above and described herein, X^1'、X^3'And X^4'Each independently selected from covalent bonds, -CR'₂A divalent group of-O-and-NR' -.

In some embodiments, X^1’Is a covalent bond. In some embodiments, X¹'is-CR'₂-. In some embodiments, X^1’is-O-. In some embodiments, X^1’is-NR' -. In some embodiments, X^3’Is a covalent bond. In some embodiments, X^3’is-CR'₂-. In some embodiments, X^3’is-O-. In some embodiments, X³is-NR' -. In some embodiments, X^4’Is a covalent bond. In some embodiments, X^4’is-CR'₂-. In some embodiments, X^4’is-O-. In some embodiments, X^4’is-NR' -.

In some embodiments, X^1’、X^3’And X^4’Selected from those described in table 1 below.

As defined above and described herein, X^2’Is a carbon atom or a nitrogen atom.

In some embodiments, X^2’Is a carbon atom. In some embodiments, X^2’Is a nitrogen atom.

In some embodiments, X^2’Selected from those described in table 1 below.

As defined above and described herein, Y' is ═ O or ═ S.

In some embodiments, Y' is ═ O. In some embodiments, Y' is ═ S.

In some embodiments, Y' is selected from those described in table 1 below.

As defined above and as described herein, R^9'And R^10'Each independently hydrogen or optionally substituted alkyl, or R^9'And R^10'And X^2'Are linked and linked together to form an optionally substituted ring selected from: a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^9'Is hydrogen. In some embodiments, R^9'Is optionally substituted C_1-6An alkyl group. In some embodiments, R^10'Is hydrogen. In some embodiments, R^10'Is optionally substituted C_1-6An alkyl group. In some embodiments, R^9'And R^10'Is cyclic-linked and is linked to X^2'Together form an optionally substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R^9'And R^10'Is cyclic-linked and is linked to X^2'Together form an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^9'And R^10'Is cyclic-linked and is linked to X^2'Together form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^9'And R^10'Is cyclic-linked together with X2' to form an optionally substituted 7-12 membered saturated or partially unsaturated bis having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfurAnd (3) a cyclic heterocyclic ring.

In some embodiments, R^9’And R^10’Each selected from those depicted in table 1 below.

As defined above and described herein, each R^11’Independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR'.

In some embodiments, R^11’Is hydrogen. In some embodiments, R^11’Is a halogen. In some embodiments, R^11’is-CN. In some embodiments, R^11’is-NO₂. In some embodiments, R^11’is-NR'₂. In some embodiments, R^11’is-OR.

In some embodiments, each R is^11’Independently selected from those depicted in table 1 below.

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

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.

As defined above and described herein, R^12’Is hydrogen, R^Aor-CN.

In some embodiments, R^12’Is hydrogen. In some embodiments, R^12’Is R^A. In some embodiments, R^12’is-CN.

In some embodiments, R^13’Selected from those described in table 1 below.

As defined above and described herein, each R^13’Independently hydrogen, halogen, R^A、-CN、-OR’、-NR’₂。

In some embodiments, R^13’Is hydrogen. In some embodiments, R^13’Is halogen. In some embodiments, R^13’is-CN. In some embodiments, R^13’is-OR'. In some embodiments, R^13’is-NR'₂。

In some embodiments, R^13’Selected from those described in table 1 below.

As defined above and described herein, R^7’And R^8’Each independently hydrogen or optionally substituted C_1-2An aliphatic group.

In some embodiments, R^7’Is hydrogen. In some embodiments, R^8’Is optionally substituted C₁An aliphatic group. In some embodiments, R^7’Is methyl. In some embodiments, R^7’Is optionally substituted C₂An aliphatic group. In some embodiments, R^7’Is ethyl. In some embodiments, R^8’Is hydrogen. In some embodiments, R^8’Is optionally substituted C₁An aliphatic group. In some embodiments, R^8’Is methyl. In some embodiments, R^8’Is optionally substituted C₂An aliphatic group. In some embodiments, R^8’Is ethyl.

In some embodiments, R^7’And R^8’Selected from those depicted in table 1 below.

In some embodiments, the present disclosure provides compounds of formula (I ') wherein ring D ' is benzo, a ' is a carbon atom, and R is^10’And R^11’Hydrogen as shown to provide a compound of formula (I' -a):

or a pharmaceutically acceptable salt thereof, wherein B ', W ', X ', R^1'，R^2'And m' are as defined above and described in the examples herein, individually and in combination.

In some embodiments, the present disclosure provides compounds of formula (I ') wherein ring D' is

A' is a carbon atom, and R¹⁰' and R¹¹' isHydrogen as shown to provide a compound of formula (I' -b):

A'

Is a carbon atom, and R^10’And R^11’Is hydrogen as shown to provide a compound of formula (I' -c):

or a pharmaceutically acceptable salt thereof, wherein B ', W ', X ', R¹’，R²Each of 'and m' is as defined above and described in the examples herein, individually and in combination.

As shown, A' is a carbon atom, and R^10'And R^11'Is hydrogen to provide a compound of formula (I' -d):

or it may be pharmaceuticallyAn acceptable salt, wherein B ', W ', X ', R^1'，R^2'And m' are as defined above and described in the examples herein, individually and in combination.

A ', B', W ', and X' is a carbon atom, and R¹⁰' and R¹¹'is hydrogen as shown to provide a compound of formula (I' -e):

or a pharmaceutically acceptable salt thereof, wherein R^1’、R^2’And m' are as defined above and described in the examples herein, individually and in combination.

The term "treatment" is used interchangeably herein with the term "method of treatment" and refers to both 1) a therapeutic treatment or measure that cures, slows, alleviates, and/or halts the progression of a diagnosed pathological condition or disorder and 2) a prophylactic/preventative measure. An individual in need of treatment may include an individual who already has a particular medical disease or disorder as well as an individual who may ultimately obtain the disorder (i.e., an individual at risk or in need of prophylactic measures).

The term "subject" as used herein refers to any individual or patient undergoing the methods of the invention. Typically, the subject is a human, although as understood by those skilled in the art, the subject may be an animal.

The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like, refer to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Typically, the response is an improvement in the patient's symptoms or a desired biological outcome. In some embodiments, the amount should be sufficient to modulate an adrenergic receptor.

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

In some embodiments, an effective amount of an adrenergic receptor-modulating compound is an amount in the range of about 10pg to 100mg, such as about 10pg to 50pg, about 50pg to 150pg, about 150pg to 250pg, about 250pg to 500pg, about 500pg to 750pg, about 750pg to 1ng, about 1ng to 10ng, about 10ng to 50ng, about 50ng to 150ng, about 150ng to 250ng, about 250ng to 500ng, about 500ng to 750ng, about 750ng to 1mg, about 1pg to 10pg, from about 10pg to 50pg, from about 50pg to 150pg, from about 150pg to 250pg, from about 250pg to 500pg, from about 500 to 750, from about 750 to 1mg, from about 1mg to 50mg, from about 1mg to 100mg, or from about 50mg to 100 mg. The amount may be a single dose or may be a total daily dose. The total daily dose may be from about 10pg to 100mg, or may be from about 100mg to 500mg, or may be from about 500mg to 1000 mg.

Also disclosed herein are pharmaceutical compositions of compounds thereof, e.g., having the structure of formula (I), formula (I '), formula (II'), formula (III), formula (IV), formula (VI '), and formula (VII'). The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be administered to a patient with a compound of the present disclosure without destroying its pharmacological activity. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

In pharmaceutical compositions comprising only the compounds described herein as active ingredients, the methods of administering these compositions may additionally comprise the step of administering to the subject an additional agent or therapy. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological agents, agents that modulate cardiovascular function, agents that modulate inflammation, immune function, blood cell production; hormones and antagonists, drugs affecting gastrointestinal function, chemotherapeutic agents for microbial diseases and/or chemotherapeutic agents for neoplastic diseases. Other pharmacological therapies may include any other drugs or biological agents found in any drug class. For example, other drug classes may include allergy/cold/ENT therapy, analgesics, anesthetics, anti-inflammatory agents, antimicrobials, antivirals, asthma/pulmonary therapy, cardiovascular therapy, dermatological therapy, endocrine/metabolic therapy, gastrointestinal therapy, cancer therapy, immunological therapy, neurological therapy, ophthalmic therapy, psychiatric therapy, or rheumatological therapy. Other examples of agents or therapies that can be administered with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressive agents, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

The term "therapeutically effective amount" as used herein, means an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, subject, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes one or more of the following: (1) preventing diseases; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder (i.e., arresting further development of pathology and/or symptomatology) in an individual who is experiencing or exhibiting pathology or symptomatology of the disease, condition or disorder, and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, condition or disorder.

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

Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the body and play an important role in regulating a variety of physiological processes, including cognition, stress-related behavior, inflammation and smooth muscle contraction/expansion, cardiac muscle contraction, airway responsiveness and cognition. Adrenergic receptors mediate central and peripheral actions of Norepinephrine (NA) and epinephrine. There are a variety of ADR subtypes, including alpha-adrenergic receptors and beta-adrenergic receptors. Each subtype is expressed in a different pattern and is involved in different physiological processes. Thus, ligands that selectively target one subtype are valuable as research tools to identify the role of different ADR subtypes and as therapeutics for a variety of diseases associated with dysfunction of the NA and adrenergic systems

The beta-adrenergic receptors also include three subtypes: beta 1-adrenergic receptors (. beta.1-ADR),. beta.2-adrenergic receptors (. beta.2-ADR) and. beta.3-adrenergic receptors (. beta.3-ADR). Because these subtypes are expressed in different patterns and are involved in different physiological processes, ligands that can selectively target one subtype have therapeutic potential for a variety of diseases. However, since these subtypes share a high level of sequence homology, discovery of subtype-selective ligands is challenging. Many existing beta-adrenergic receptor agonists also exhibit poor Blood Brain Barrier (BBB) penetration, which is necessary in efforts for drug discovery for Central Nervous System (CNS) indications.

As a class of G protein-coupled receptors, adrenergic receptors signal via G protein-dependent pathways and β -arrestin-dependent pathways. G-protein or β -arrestin signaling can mediate different physiological responses. Recently, it has become clear that agonists can show preferential activation of signaling pathways. The ability of a ligand to activate a receptor and respond in a pathway-dependent manner is referred to as "signal bias" or "functional selectivity". Since G-proteins and β -arrestins mediate different physiological processes, biased agonists may provide improved therapeutic selectivity and reduced side effects. Accordingly, the present disclosure relates to beta-adrenergic receptor subtype selective agonists with improved Blood Brain Barrier (BBB) penetration.

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

The adrenergic receptor modulating compound can be a partial agonist of the targeted adrenergic receptor. In some cases, an effective amount of an adrenergic receptor-modulating compound is an amount sufficient to achieve partial agonism of an adrenergic receptor in a cell, e.g., where the subject compound achieves 10% or more of receptor activation, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, relative to a control, e.g., a fully activated receptor. Partial agonism may be assessed using any convenient method, such as a cell-based assay using a known full agonist as a 100% activation control, where the relative maximal activation of the receptor may be measured relative to the full agonist.

The adrenergic receptor modulating compound can be an antagonist of a target adrenergic receptor. In some cases, an effective amount of an adrenergic receptor modulating compound is an amount sufficient to inhibit or reduce the activity of a targeted adrenergic receptor in a sample by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or even more, relative to a control (e.g., a sample not contacted with the targeted compound).

In some embodiments of the method, the target adrenergic receptor is a β 1-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β 2-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β 3-adrenergic receptor. In some embodiments, the compound is an agonist of both the β 1-adrenergic receptor and the β 2-adrenergic receptor. In certain instances, the compounds are more selective for the beta 2-adrenergic receptor than for the beta 1-adrenergic receptor.

The target adrenergic receptor can be a receptor responsible for mediating an intracellular signal or pathway in a cell. In some embodiments, the sample comprises cells and the modulation of an adrenergic receptor modulates a physiological process in the cells. Any convenient physiological process can be used to target modulation in a cell using the methods of the invention. In some embodiments, the physiological process involves cardiac function, and in some cases, the physiological process involves cognitive function. In certain instances, the physiological process involves an inflammatory pathway or disorder. The methods of the invention can modulate the intracellular concentration of a signaling molecule, such as cAMP, in a cell. The subject methods can provide for partial or complete blockade of target adrenergic receptors to result in modulation (e.g., activation) of cAMP in a sample. In some embodiments, the method does not modulate the beta-arrestin pathway of the cell. In some cases, the cell is an inflammatory cell and the function of the cell is modulated. The methods of the invention can provide for inhibition of inflammatory pathways in cells. In some cases, TNF- α is inhibited in a cell, e.g., by reducing the concentration or production of TNF- α, by practicing the subject methods. In certain embodiments of the method, the cell is a neuron. In some embodiments, modulating adrenergic receptors enhances neurogenesis.

The compounds of the present disclosure may be used in conventional ways to control, prevent, treat, or treat diseases described herein, including, but not limited to, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gilles disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebrovascular disease, epilepsy, Tourette's syndrome, Wilson's disease, pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatoniosis, mitochondrial encephalomyopathy, Neuronal ceroid lipofuscinosis, brain autosomal dominant such treatment methods, the level and requirements of which can be selected by one of ordinary skill in the art from available methods and techniques.

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

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

In some embodiments, the subject methods comprise administering a therapeutically effective amount of one or more additional active agents. Combination therapy refers to the use of an adrenergic receptor-modulating compound in combination with another therapeutic agent for the treatment of a single disease or condition. In particular embodiments, a compound of the disclosure is administered concurrently with the administration of another therapeutic agent, which may be administered as a component of a composition comprising a compound of the disclosure or as a component of a different composition.

The subject compounds can be administered in combination with other therapeutic agents in a variety of therapeutic applications. Therapeutic applications of interest for combination therapy include those in which the activity of the target adrenergic receptor is a cause or compound factor of disease progression. Thus, the compounds of the present invention are useful in combination therapies requiring inhibition of a target adrenergic receptor in a patient. Examples of disease conditions that can be treated by combination therapies comprising the subject compounds include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental diseases, respiratory conditions, asthma, memory impairment, depression, inflammatory diseases, stroke, ischemic brain or tissue injury, and cancer. The agents of interest that may be used in combination with the adrenergic receptor modulating compounds of the present invention include, but are not limited to, antidepressants, antipsychotics, beta-blockers, vasoconstrictors, anti-hypotensives, decongestants, chemotherapeutic agents, agents for Alzheimer's disease, and anti-inflammatory agents.

The adrenergic receptor modulating compounds of the present invention can be used in combination with any agent useful in the treatment of cardiac disorders such as cardiogenic shock, hypertension, congestive heart failure, coronary heart disease, arrhythmia, myocardial infarction, or ischemic heart disease. Targeted agents that may be used in combination with the adrenergic receptor modulating compounds of the present invention include, but are not limited to, dinopamide, dobutamine, zamoterol, acebutolol, atenolol, betaxolol, bisoprolol, pindolol, esmolol, metoprolol, nebivolol, vortioxetine, carvedilol, labetalol, phentolamine, prazosin, cilazoline, methoxylamine, synephrine, etiforin, metoprolol, midodrine, and coumarin.

The adrenergic receptor modulating compounds of the present invention can be used in combination with any agent useful in the treatment of neurodegenerative or neurodevelopmental diseases, such as alzheimer's disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue injury, down's syndrome or autism. Agents of interest that may be used in combination with the adrenergic receptor modulating compounds of the present invention include, but are not limited to, acepromazine. In some embodiments, the adrenergic receptor-modulating compounds of the present invention can be used in combination with a cholinesterase inhibitor or an NMDA receptor modulator for the treatment of a disease, such as a neurodegenerative or neurodevelopmental disease. Agents of interest include, but are not limited to, donepezil, aricept, galantamine, Razadyne, memantine, Namenda, rivastigmine, Exelon, tacrine, and Cognex. Other agents of interest that may be used in combination with the present adrenergic receptor-modulating compounds include, but are not limited to, 4-NEMD, 7-Me-macenidine, Agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, guanabenz, guanfacine, maderadine, medetomidine, methamphetamine, mivafloxacin, rimernidine, romidepidine, tolonidine, xylazine, aripiprazole, asenapine, atidine, cilazoline, clozapine, efazepam, idazoxan, lurasidone, meparone, mianserin, mirtazapine, natane, olanzapine, paliperidone, rotigotine, quetiapine, noquetiapine, sertindole, and other agents of interest that may be used in combination with the present adrenergic receptor-modulating compounds include, but are not limited to, bitolterol, fenoterol, doxepinasterol, and other agents of interest that may be used in combination with the present adrenergic receptor-modulating compounds, Isoproterenol or isoproterenol, levalbuterol or levalbuterol, metaproterenol or metaproterenol, pirbuterol, procaterol, salbutamol or salbutamol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, mevalonol, odaterol, vilanterol, fenoterol, hexoprenaline, isosultrine, ritodrine, salbutamol or salbutamol, terbutaline, zilpaterol, ICI-118,551, and butoxamine.

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

According to a preferred embodiment, the composition of the present disclosure is formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human. Such pharmaceutical compositions are useful for ameliorating, treating or preventing any of the diseases described herein in a subject.

The agents of the present disclosure are typically administered as pharmaceutical compositions comprising the active therapeutic agent, i.e., a variety of other pharmaceutically acceptable components. See generally Remington's Pharmaceutical Sciences, 15 th edition, Mike Publishing company, Iston, Pa. (Mack Publishing, Easton Pa.) (1980). The preferred form depends on the intended mode of administration and therapeutic application. Depending on the desired formulation, the composition may also include a pharmaceutically acceptable non-toxic carrier or diluent, which is defined as a vehicle commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate buffered saline, ringer's solution, dextrose solution and hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants or nontoxic, non-therapeutic, non-immunogenic stabilizers and the like.

In some embodiments, the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds formulated with one or more pharmaceutically acceptable carriers (additives) and/or diluents for treating diseases described herein, including, but not limited to, stroke, ischemia, alzheimer's disease, ankylosing spondylitis, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, atherosclerosis, crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, systemic lupus erythematosus, nephritis, ulcerative colitis, and parkinson's disease. Although the compounds may be administered alone, it is preferred that the compounds be administered as pharmaceutical formulations (compositions) as described herein. The compounds may be formulated for administration in any convenient manner for use in human or veterinary medicine, similar to other drugs.

As described in detail below, the pharmaceutical compositions of the present invention may be specifically formulated for administration in solid or liquid form, including those suitable for use in: oral administration, e.g., infusions (aqueous or non-aqueous solutions or suspensions) applied to the tongue, tablets (e.g., tablets targeted for buccal, sublingual and systemic absorption), pills, powders, granules, pastes; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous or epidural injection, e.g., as a sterile solution or suspension or sustained release formulation; topical application, e.g., as a cream, ointment, or controlled release patch or spray, to the skin, lung, or oral cavity; intravaginal or intrarectal, e.g., vaginal rings, creams or foams; under the tongue; an eye portion; transdermal; or nasal, pulmonary or other mucosal surfaces.

Wetting agents, emulsifiers and lubricants, for example, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, mold release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogensulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, metal chelating agents such as ascorbyl palmitate, Butylhydroxyanisole (BHA), Butylhydroxytoluene (BHT), lecithin, propyl gallate, and α -tocopherol, and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

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

In certain embodiments, the formulations of the present invention comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle-forming agents (e.g., bile acids), and polymeric carriers (e.g., polyesters and polyanhydrides); and oligomers of the compounds disclosed herein. In certain embodiments, the foregoing formulations render oligomers of the compounds described in this disclosure orally bioavailable.

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

The pharmaceutical compositions may be in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids (e.g., oleic acid and its glyceride derivatives) are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils (e.g., olive oil or castor oil, especially in their polyoxyethylated versions). These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as those described in the swiss pharmacopoeia, or similar alcohols. Other commonly used surfactants (e.g., tweens, spans, and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

In some cases, it is desirable to slow the absorption of the drug by subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the drug then depends on its rate of dissolution, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered pharmaceutical form is achieved by dissolving or suspending the drug in an oily vehicle.

Injectable depot forms are made by forming a microcapsule matrix of the described compounds in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug oligomer to polymer, and the nature of the particular polymer used, the release rate of the drug oligomer can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Long-acting injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The compositions of the pharmaceutically acceptable medicaments of the present disclosure may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used comprise lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Useful diluents for oral administration in capsule form include lactose and dried corn starch. When aqueous suspensions and solutions are administered orally in combination with propylene glycol, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or as mouth rinses and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the invention may also be administered in the form of pills, lozenges or pastes.

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

Tablets may be prepared by compression or moulding, optionally containing one or more accessory ingredients. Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agents. Molded tablets may be prepared in a suitable machine wherein a mixture of the powdered compound is moistened with an inert liquid diluent. If a solid carrier is used, the formulation may be in the form of a tablet, in powder or pellet form in a hard gelatin capsule, or in the form of a lozenge or troche. The amount of solid carrier may vary, for example from about 25 to 800mg, preferably from about 25 to 400 mg. When a liquid carrier is used, the preparation may be in the form of, for example, a syrup, an emulsion, a soft gelatin capsule, a sterile injectable liquid such as an ampoule or a non-aqueous liquid suspension. When the composition is in the form of a capsule, any conventional encapsulation is suitable, for example, the use of the above-described carriers in a hard gelatin capsule shell.

Tablets and other solid dosage forms of the pharmaceutical and nutraceutical compositions of the invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may alternatively or additionally be formulated so as to provide slow or controlled release of the active ingredient therein, for example, using hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, for example by freeze drying. They may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may preferably be of a composition that it releases the active ingredient only in a certain part of the gastrointestinal tract, or optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in the form of microcapsules of one or more of the above-mentioned excipients, if appropriate.

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

In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

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

The pharmaceutical compositions described in the present disclosure may be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the compounds of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient. These materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of the pharmaceutical compositions of the present disclosure is particularly useful when the desired treatment involves an area or organ that is readily accessible by topical administration. For topical application to the skin, the pharmaceutical compositions should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical application of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated as suitable lotions or creams containing the active group b. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present disclosure may also be administered topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Transdermal patches for topical administration are also included in the present disclosure.

The pharmaceutically acceptable compositions of the present disclosure are administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared in the form of aqueous saline solutions using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other solubilizing or dispersing agents.

For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably as solutions in isotonic, pH adjusted sterile saline, with or without a preservative (e.g., benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated as ointments, such as petrolatum.

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

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

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. In certain embodiments, it may be desirable to include one or more antibacterial and/or antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, and the like. Alternatively or additionally, it may be desirable to include isotonic agents, for example, sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

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

When the compounds of the present invention are administered to humans and animals as pharmaceutical, nutraceutical agents, they may be administered as such or as compositions containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

The formulations of the invention may be administered orally, parenterally, topically or rectally. They must be given in a form suitable for the relevant administration route. For example, they are administered in the form of tablets or capsules by injection, inhalation, ophthalmic lotion, ointment, suppository, etc., by injection, infusion or inhalation; topical application via lotion or ointment; and rectal administration by suppository. Oral administration is preferred.

The compounds may be treated with humans and other animals by any suitable route of administration, including oral, nasal (e.g., by spray), rectal, intravaginal, parenteral, intracisternal, and topical, e.g., by powders, ointments or drops, including buccal and sublingual.

Regardless of the route of administration chosen, the compounds of the invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the invention may be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, and which is non-toxic to the patient.

Kits comprising the disclosed adrenergic receptor modulating compounds are also provided. The system of the present disclosure includes a collection of active agents brought together, for example by a healthcare practitioner, for administration to a subject, such as a patient. Such systems may include an adrenergic receptor-modulating compound and one or more additional active agents disclosed herein. The present invention provides kits comprising an adrenergic receptor-modulating compound, which kits can comprise one or more doses of the adrenergic receptor-modulating compound and optionally one or more doses of one or more other active agents. Conveniently, the formulations may be presented in unit dosage form. In such kits, in addition to a container containing a formulation (e.g., a unit dose), there is an informative package insert describing the use of the formulation of the invention in the methods disclosed herein, e.g., instructions for using the unit dose of the invention for treating a cell proliferative disorder. These instructions can be present in the subject systems and kits in a variety of forms, one or more of which can be present in the kit. One form in which such instructions may be present is information printed on a suitable medium or substrate, such as one or more sheets of paper on which the information is printed, in the packaging of the kit, in package instructions, and the like. Another way is a computer readable medium, such as a diskette, CD, etc., on which information is recorded. Another way that may exist is a website address, which may be used via the internet to access information at the removed site. Any convenient means may be present in the kit.

Table 1 shows exemplary compounds of the present invention.

Table 1. compounds of the present disclosure.

Also disclosed herein are pharmaceutical compositions comprising a compound having the structure of formula (I), formula (I '), formula (II '), formula (III '), formula (IV '), formula (V '), formula (VI '), formula (VII '), and a pharmaceutically acceptable excipient. Also disclosed are methods of treating a subject having a disease associated with an adrenergic receptor, the method comprising administering to the subject a therapeutically effective amount of a compound having the structure of formula (I), formula (I '), formula (II '), formula (III '), formula (IV '), formula (V '), formula (VI '), or formula (VII '), thereby treating the subject. In some embodiments, the disease is a neurodegenerative disease and the subject is a human.

In some embodiments, the disease is selected from the group consisting of myocardial infarction, stroke, ischemia, alzheimer's disease, parkinson's disease, giardiasis (amyotrophic lateral sclerosis), huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebrovascular inflammation, epilepsy, tourette's syndrome, wilson's disease, pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, friedrich's ataxia, ataxia telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject by oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, epidermal, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernous, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route. In one embodiment, the compound is selected from those listed in table 1.

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

Examples of the invention

Example I

Synthesis of compounds

Scheme 1 Synthesis of Compound 02-1

Scheme 1 shows the synthesis of compound 02-1.¹H NMR(400MHz,DMSO-d₆)δ7.86(d,J＝1.6Hz,1H),7.52(d,J＝1.6Hz,1H),6.12(s,2H),5.16(bs,1H),4.40(m,1H),2.62(m,2H),1.29(bs,1H),1.00(s,9H)；LC-MS:m/z 244.2(M+1)⁺.

Scheme 2 Synthesis of Compound 02-2

Scheme 2 shows the synthesis of compound 02-2.¹H NMR(400MHz,DMSO-d₆)δ8.37(d,J＝2.3Hz,1H),8.08(d,J＝2.2Hz,1H),6.77(s,2H),4.48(d,J＝4.9Hz,1H),3.86–3.79(m,1H),3.69(dd,J＝11.5,5.1Hz,1H),1.25(s,9H)；LC-MS:m/z 278.2(M+1)⁺.

Scheme 3 Synthesis of Compound 02-3

Scheme 3 shows the synthesis of compound 02-3.

Step 1: synthesis of 4-methyl-6-vinylpyridazin-3-amine. To 6-chloro-4-methylpyridazin-3-amine (0.72g, 5.01mmol), potassium vinyltrifluoroborate (0.87g, 6.51mmol) and K₂CO₃(2.07g, 15.03mmol) in dioxane/H₂Pd (dppf)2Cl was added to the stirred solution in O (16mL/4mL)₂(0.367g, 0.501 mmol). The mixture obtained is treated with N₂Purged and then heated to 85 ℃ for 12 hours. After cooling, the reaction mixture was diluted with EtOAc. The organic layer was separated and washed with brine (30 mL). The aqueous layer was extracted with EtOAc (30 mL. times.3), the combined organic layers were washed with brine (30 mL. times.3). The aqueous layer was extracted with EtOAc (30 mL. times.3). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using DCM/CH₃OH (30/1 to 10/1) gave 4-methyl-6-vinylpyridazin-3-amine as a yellow solid (0.55g, 82%). LC-MS M/z 136.1(M +1)⁺。

Step 2: synthesis of 4-methyl-6-vinylpyridazine-3-N (Boc) 2. To a stirred solution of 4-methyl-6-vinylpyridazin-3-amine (0.55g, 4.1mmoL), di-tert-butyl dicarbonate (1.8g, 8.2mmoL) and triethylamine (1.8mL, 12.3mmoL) in dichloromethane (16mL) was added DMAP (0.025g, 0.21 mmoL). The resulting mixture was stirred at room temperature for 4 hours. Will be reversedThe mixture was concentrated under reduced pressure. The residue was purified by flash chromatography using DCM/CH₃OH (40/1-15/1) to give 4-methyl-6-vinylpyridazine-3-N (Boc)₂As a white solid (1g, 73%). LC-MS M/z 336.1(M +1)⁺。

And step 3: 6-N (Boc)₂Synthesis of-5-methylpyridazine-3-carbaldehyde. To 4-methyl-6-vinylpyridazine-3-N (Boc)₂(0.5g, 1.49mmol) in acetone/H₂NaIO was added to a stirred solution in O (16mL/4mL)₄(0.96g, 4.47mmol) and K₂O_sO₄.H₂O (0.03g,0.075 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between EtOAc (30mL) and brine (30 mL). Na for organic layer₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with PE/EtOAc (30/1-2/1) to afford 6-N (Boc)₂-5-methylpyridazine-3-carbaldehyde (0.3g, 59.7%). LC-MS M/z 337.2(M +1)⁺.

And 4, step 4: 1- (6-N (Boc)₂-5-methylpyridazin-3-yl]Synthesis of (E) -2- (tert-butylamino) ethan-1-ol. Tert-butylisocyanide (0.06g, 0.70mmol) was added to 6-N (Boc) at-20 deg.C₂-5-methylpyridazine-3-carbaldehyde (0.2g, 0.58mmol), hexamethylphosphoramide (0.012g, 0.058mmol) and SiCl₄(0.125g, 0.66mmol) in dichloromethane (4 mL). After stirring for 4 hours at-20 ℃ BH was added₃NH₃(0.026g, 0.88 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with dichloromethane (10 mL). Adding the organic solution to Na₂CO₃In aqueous solution (10 wt.%, 20 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with DCM (10 mL). The aqueous layer was separated and extracted with DCM (10 mL. times.2). The combined organic layers were passed over Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using DCM/CH₃OH (30/1-10/1) to give 1- (6-N (Boc)₂-5-Methylpyridazin-3-yl) -2- (tert-butylamino) ethan-1-ol (0.025g, 10%). LC-MS M/z 425.3(M +1)⁺。

And 5: 1Synthesis of- (6-amino-5-methylpyridazin-3-yl) -2- (tert-butylamino) ethan-1-ol. To a stirred solution of 1- (6-N (Boc) 2-5-methylpyridazin-3-yl) -2- (tert-butylamino) ethan-1-ol (0.025g, 0.058mmol) in dichloromethane (3mL) was added 4NHCl (3mL, 12mmol) in dioxane. The reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure to give 1- (6-amino-5-methylpyridazin-3-yl) -2- (tert-butylamino) ethan-1-ol (0.012g, 59.7%).¹HNMR(400MHz,DMSO-d₆)δ9.29(s,1H),8.65(s,1H),8.47(s,2H),7.90(d,J＝1.3Hz,1H),6.74(s,1H),5.06–4.96(m,1H),3.21–3.13(m,2H),2.31(d,J＝1.2Hz,3H),1.32(s,9H).LC-MS:m/z225.23(M+1)⁺.

Scheme 4 Synthesis of Compound 02-4

Scheme 4 shows the synthesis of compound 02-4.¹H NMR (400MHz, chloroform-d) δ 7.83(s,1H),4.45(s,2H),3.88(dd, J ═ 9.0,4.9Hz,1H),3.55(dd, J ═ 10.4,4.9Hz,1H),3.32(t, J ═ 9.7Hz,1H),2.39(d, J ═ 0.7Hz,3H),1.06(s, 9H); LC-MS M/z 225.2(M +1)⁺.

Scheme 5 Synthesis of Compound 04-1

Scheme 5 shows the synthesis of compound 04-1.

Step 1: synthesis of 5-bromoquinolin-2 (1H) -one. (a) To a solution of 5-bromoquinoline (7.6g, 36.5mmol) in DCM (100mL) was added m-CPBA (8.1g, 47mmol) in three portions at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. Thereafter, an aqueous 1N NaOH solution (120mL) was added to the reaction, and the resulting mixture was extracted with DCM (100 mL. times.3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give 5-bromoquinoline 1-oxide (5.1g, 63%) as a pale yellow solid. LC-MS M/z223.9(M +1)⁺. (b) To 5-bromoquinoline 1-oxide (5.1) at 0 deg.Cg, 23mmol) in DMF (50mL) was added trifluoroacetic anhydride (24g, 115mmol) in three portions. Compound (32) (500mg, 1.63mmol, 1.05 equiv.) is added followed by DIEA (418. mu.L, 1.5 equiv.) at ice bath temperature. The reaction product was stirred at room temperature overnight. The reaction mixture was washed with saturated NaHCO₃And (4) quenching the aqueous solution. Adding NaHCO₃The solution (300mL) was extracted with DCM (100 mL. times.3). The combined organic layers were washed with brine, over anhydrous MgSO₄Drying, filtration and concentration gave 5-bromoquinolin-2 (1H) -one (4g, 78%) as a yellow solid. LC-MS M/z223.9(M +1)⁺。

Step 2: synthesis of 5-acetylquinolin-2 (1H) -one. To a stirred solution of 5-bromoquinolin-2 (1H) -one and 1-ethoxyvinyltri-n-butyltin (1.1eq.) in dioxane was added Pd (PPh)₃)₄(0.05 eq.). The mixture obtained is treated with N₂Purge (3 fold) and then heat to 120 ℃ for 6 hours. After cooling, 1.5n hcl (2eq.) was introduced into the flask and stirring was continued at room temperature overnight. The reaction solution was then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. The crude product was purified by flash chromatography to give 5-acetylquinolin-2 (1H) -one. LC-MS M/z 188.1(M +1)⁺。

And step 3: synthesis of 5- (2-bromoacetyl) quinolin-2 (1H) -one. To a stirred solution of 5-acetylquinolin-2 (1H) -one and HBr (40%) in NaOH was added pyridine tribromide (1.2 eq.). The resulting mixture was stirred at 40 ℃ overnight. After cooling to room temperature, the mixture was taken up with saturated NaHCO₃And (4) quenching the aqueous solution. The reaction mixture was then extracted with EtOAc. The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. The crude product was purified by flash chromatography to give 5- (2-bromoacetyl) quinolin-2 (1H) -one. LC-MS M/z 267.1(M +1)⁺。

And 4, step 4: -5- (2-bromo-1-hydroxyethyl) quinolin-2 (1H) -one. To a stirred solution of 5- (2-bromoacetyl) quinolin-2 (1H) -one in toluene was added (R) -2-methyl-CBS-oxazaborolidine (0.2eq.) at-35 ℃. The resulting mixture was stirred at-35 ℃ for 30 h.

BH was then added dropwise via syringe₃THF (1N solution in THF, 1 eq.). After addition, the reaction was warmed to-15 ℃. After 2 hours, the reaction mixture was taken up with saturated NaHCO₃Aqueous solution (10mL) was quenched and extracted with EtOAc. The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated. The crude product was purified by flash chromatography to give (R) -5- (2-bromo-1-hydroxyethyl) quinolin-2 (1H) -one. LC-MS M/z 269.1(M +1)⁺。

And 5: synthesis of (R) -5- (2- (tert-butylamino) -1-hydroxyethyl) quinolin-2 (1H) -one (Compound 04-1). To a stirred solution of (R) -5- (2-bromo-1-hydroxyethyl) quinolin-2 (1H) -one in dichloromethane was added tert-butylamine (60 eq.). The resulting mixture was stirred at 40 ℃ for 48 hours. The reaction was concentrated and the residue was redissolved with EtOAc. The organic layer was washed with saturated NaHCO₃Washed with aqueous solution and brine, over Na₂SO₄Dried and concentrated. The crude product was purified by HPLC (C18, MeCN/H)₂O (0.1% formic acid), (1% to 100%)) to give (R) -5- (2- (tert-butylamino) -1-hydroxyethyl) quinolin-2 (1H) -one (04-1) as a white solid (5-step yield: 12%).¹H NMR(400MHz,DMSO-d₆)δ11.82(br,1H),8.21(d,J＝9.9Hz,1H),7.52(t,J＝7.9Hz,1H),7.36(dd,J＝7.6,1.1Hz,1H),7.28(d,J＝8.5Hz,1H),6.57(d,J＝9.9Hz,1H),5.38(dd,J＝9.6,2.8Hz,1H),3.00–2.85(m,2H),1.24(s,9H).LC-MS:m/z 261.2(M+1)⁺.

Scheme 6 Synthesis of Compounds 04-5

Scheme 6 shows the synthesis of compound 04-5.

Step 1: 3-bromo-2-chloropyridine-4-amine. To a stirred solution of 2-chloropyridin-4-amine (10g, 77.78mmoL) in dichloromethane (250mL) was added N-bromosuccinimide (13.8g, 77.78 mmoL). The resulting mixture was stirred at room temperature for 12 hours. The reaction was concentrated. The crude product is purified by flash chromatography (silica, petroleum ether/ethyl acetate: 20/1 to 3/1),3-bromo-2-chloropyridin-4-amine was obtained as a yellow solid (7.1g, 43.9%). LC-MS: M/z 206.94,208.97(M +1, M +2)⁺。

Step 2: (E) synthesis of ethyl (E) -3- (4-amino-2-chloropyridin-3-yl) acrylate. To a stirred solution of 3-bromo-2-chloropyridin-4-amine (2g, 9.6mmoL), ethyl acrylate (1.9g, 19.3mmoL), Et3N (2.91g, 28.8mmoL) and tricyclohexylphosphine (1.3g, 4.8mmoL) in DMF (100mL) was added Pd (OAc2) (431mg, 1.9mmoL, 0.2 eq). The mixture obtained is treated with N₂Purge (3 fold) and then heat to 100 ℃ for 24 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL). The organic layer was washed with brine (30mL × 3) and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, petroleum ether/ethyl acetate: 30/1 to 1/1) to give ethyl (E) -3- (4-amino-2-chloropyridin-3-yl) acrylate as a yellow solid (1.2g, 55.3%). LC-MS: M/z 227.1,229.1(M +1, M +2)⁺。

And step 3: synthesis of 5-chloro-1, 6-naphthyridin-2 (1H) -one to a stirred solution of ethyl (E) -3- (4-amino-2-chloropyridin-3-yl) acrylate (2.5g, 11.01mmoL) in DIPEA (20mL) was added DBU (3.3g, 22.02 mmoL). The resulting mixture was stirred at 120 ℃ for 8 hours. The reaction mixture was concentrated. The residue was purified by flash chromatography (silica, DCM/CH)₃OH: 40/1 to 15/1) to give 5-chloro-1, 6-naphthyridin-2 (1H) -one (1g, 50.2%). LC-MS: M/z 181.0,183.0(M +1, M +2)⁺。

And 4-7: synthesis of (S) -5- (2- (tert-butylamino) -1-hydroxyethyl) -1, 6-naphthyridin-2 (1H) -one (Compound 04-5). Using 5-chloro-1, 6-naphthyridin-2 (1H) -one instead of 5-bromoquinolin-2 (1H) -one as starting material, using a procedure analogous to the synthesis of compound 04-1, (S) -5- (2- (tert-butylamino) -1-hydroxyethyl) -1, 6-naphthyridin-2 (1H) -one (04-5) was obtained as a white solid, 12mg, 4-step yield: 9.2%).¹H NMR(400MHz,DMSO-d₆)δ12.03(br,1H),8.42(d,J＝5.7Hz,1H),8.34(d,J＝9.9Hz,1H),7.21(d,J＝5.7Hz,1H),6.63(d,J＝9.9Hz,1H),5.25(t,J＝6.3Hz,1H),3.16(d,J＝6.7Hz,2H),1.22(d,J＝12.6Hz,9H).LC-MS:m/z 262.2.(M+1)⁺.

Scheme 7 Synthesis of Compounds 04-23

Scheme 7 shows the synthesis of compounds 04-23.

Step 1: synthesis of 4-bromo-7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole. To a stirred solution of 4-bromo-7-fluoro-1H-indazole 1(2.5g, 11.62mmol) in DMF (20mL) was added NaH (60%, 0.79g, 19.75mmol) portionwise at 0 ℃. The resulting mixture was stirred for 1 hour, then 2- (trimethylsilyl) ethoxymethyl chloride (3.1mL, 2.92g, 17.44mmol) was added. The mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (50 mL. times.3). The combined organic layers were washed with H₂O (100mL × 3), washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 20% EtOAc in petroleum ether to give 4-bromo-7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole as a yellow oil (1.9g, 48%). LC-MS M/z 346.3M +1)⁺。

Step 2 Synthesis of 7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -4-vinyl-1H-indazole. To a stirred solution of 4-bromo-7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole (1.9g, 5.51mmol) in dioxane/H2O (20mL/2mL) was added potassium vinyltrifluoroborate (1.47g, 11.01mmol), Pd (dppf) Cl under N2₂Ethane potassium trifluoroborate CH₂Cl₂(0.45g，0.55mmol)，Cs₂CO₃(5.38g, 16.5 mmol). The mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was filtered through a pad of celite and washed with EtOAc (100 mL). H for filtrate₂O, brine washing, Na₂SO₄Drying, filtering, and concentrating under reduced pressure. The residue was purified by column chromatography, eluting with 10% EtOAc/petroleum ether, to give 7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -4-vinyl-1H-indazole as an oil (1.6g, 99%). LCMS M/z 293.3(M +1)⁺。

And step 3: synthesis of (E) -1- (7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) ethane-1, 2-diol. To a solution of 7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -4-vinyl-1H-indazole (1.6g, 5.47mmol) at t-BuOH/H at 0 deg.C₂To a stirred solution in O (20mL/20mL) was added AD-mix-. beta.8.25 g, followed by stirring at room temperature for 16 hours. After completion of the reaction, the mixture was saturated with Na₂SO₃The solution (20mL) was quenched and extracted with EtOAc (100 mL). The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with 50% EtOAc/petroleum ether, to give (R) -1- (7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) ethane-1, 2-diol as a yellow oil (2.1g, 99%). LCMS M/z 327.3(M +1)⁺。

And 4, step 4: synthesis of (E) -7-fluoro-4- (oxiran-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole. (i) To a solution of (R) -1- (7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) ethane-1, 2-diol (2.1g, 6.4mmol) in CH₂Cl₂To a stirred solution (20mL) were added n-Bu2SnO (0.16g, 0.64mmol), p-TsCl (1.4g, 7.1mmol) and Et3N (776mg, 7.6 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction was quenched with water and the mixture was extracted with DCM22(50mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30% EtOAc/petroleum ether to give methyl (R) -2- (7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) -2-hydroxyethyl 4-benzenesulfonate (2.76g, 90%) as a yellow oil. LCMS M/z 481.3(M +1)⁺. (ii) To a stirred solution of methyl (R) -2- (7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) -2-hydroxyethyl 4-benzenesulfonate (2.76g, 5.76mmol) in methanol (10mL) was added K₂CO₃(3.97g, 28.8 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give a residue, which was redissolved in CH₂Cl₂. Then the organic layer is treated with H₂O washing with Na₂SO₄Drying, filtering and vacuum concentrating to obtain (R) -7-fluoro-4- (epoxy)Ethan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole as an oil (2.1g) which was used in the next step without further purification.

And 5: synthesis of (E) -2- (tert-butylamino) -1- (7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) ethan-1-ol. To a solution of (R) -7-fluoro-4- (oxiran-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole (2.1g, 6.48mmol) in ethanol/H₂To a stirred solution in O (4mL/8mL) was added tert-BuNH₂(2.37g, 32.42 mmol). The reaction mixture was stirred at 60 ℃ for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography, eluting with 5% methanol in dichloromethane, to give (R) -2- (tert-butylamino) -1- (7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) ethan-1-ol as a yellow oil (2g, 81%). LCMS M/z 382.3(M +1)⁺。

Step 6: synthesis of (E) -2- (tert-butylamino) -1- (7-fluoro-1H-indazol-4-yl) ethan-1-ol. To (R) -2- (tert-butylamino) -1- (7-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl) ethan-1-ol (2g, 5.24mmol) in CH at 0 deg.C₂Cl₂(8mL) to the stirred solution was added CF₃COOH (10 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified by column chromatography with 10% MeOH in CH₂Cl₂Solution (containing 1% NH)₄OH) to give (R) -2- (tert-butylamino) -1- (7-fluoro-1H-indazol-4-yl) ethan-1-ol (0.7g, 90% purity, HPLC). By reverse phase HPLC (CH of 0.1% TFA)₃CN/H₂O solution) and lyophilized with 1n HCl aqueous solution (1mL) to give (R) -2- (tert-butylamino) -1- (7-fluoro-1H-indazol-4-yl) ethan-1-ol HCl salt as a white solid (0.37g, 25%).¹H NMR(400MHz,CD₃OD)δ8.39–9.33(m,1H),7.22–7.17(m,1H),7.12(dd,J＝10.3,8.0Hz,1H),5.31–5.25(m,1H),3.22(d,J＝9.1Hz,2H),1.39(s,9H)；HPLC:99.2％@254nM；LCMS:m/z 252.3(M+1)⁺；SFC:99％ee[AD-H column,mobile phase:HEP:IPA(0.1％DEA)＝95:5].

Scheme 8 Synthesis of Compounds 04-144 and Compounds 04-145

Scheme 8 illustrates the synthesis of compounds 04-144 and compounds 04-145.

Step 1: 4-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-c]And (3) synthesizing pyridine. To 4-chloro-1H-pyrazolo [4,3-c ] at 0 DEG C]To a stirred solution of pyridine (4g, 27.35mmol) in DMF (25mL) was added NaH (60%, 1.64g, 41 mmol). The resulting mixture was stirred for 0.5h, then SEMCl (5.93g, 35.55mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL. times.3). The combined organic layers were washed with H₂O (100mL × 3), washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with 30% EtOAc in petroleum ether to give 4-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4, 3-c)]Pyridine as a yellow oil (3g, 39%). LC-MS M/z 284.2M +1)⁺。

Step 2-1- ((2- (trimethylsilyl) ethoxy) methyl) -4-vinyl-1H-pyrazolo [4,3-c]And (3) synthesizing pyridine. In N₂4-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-c]Pyridine (3g, 10.57mmol) in dioxane/H₂To a stirred solution of O (20mL/2mL) were added potassium vinyltrifluoroborate (2.83g, 21.14mmol), Pd (dppf) Cl₂Ethane potassium trifluoroborate CH₂Cl₂(856mg, 1.05mmol) and Cs2CO₃(10.33g, 31.71 mmol). The mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was filtered through a pad of celite and washed with EtOAc (100 mL). H for filtrate₂O (20 mL. times.2), brine (30mL), Na₂SO₄Drying, filtering, and concentrating under reduced pressure. The residue was purified by column chromatography, eluting with 10% EtOAc/petroleum ether, to give 1- ((2- (trimethylsilyl) ethoxy) methyl) -4-vinyl-1H-pyrazolo [4, 3-c)]Pyridine as an oil (2.5g, 81%). LC-MS M/z 293.3M +1)⁺。

And step 3: 4- (2- (tert-butylamino) -1-hydroxyethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-c]Synthesis of pyridine 5-oxide. To 1- ((2- (trimethylsilyl) ethoxy) methyl) -4-vinyl-1H-pyrazolo [4, 3-c) at room temperature]Pyridine (2.0g, 7.26mmol) in CH₂Cl₂(10mL) in a stirred solution saturated NaHCO was added portionwise₃Solution (10mL) and mCPBA (3.76g, 21.78 mmol). The resulting mixture was stirred for 10 minutes, then t-BuNH was added₂(2.5g, 34.31mmol) and ethanol (5 mL). The resulting mixture was stirred at 60 ℃ for 16 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography using 10% CH₃CH of OH₂Cl₂Eluting the solution to obtain 4- (2- (tert-butylamino) -1-hydroxyethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4, 3-c)]Pyridine 5-oxide (1.2g, 76% HPLC purity), which was used in the next step without further purification. LC-MS M/z 381.2M +1)⁺。

And 4, step 4: 2- (tert-butylamino) -1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-c]Pyridine-4-yl) ethan-1-ol synthesis. Reacting 4- (2- (tert-butylamino) -1-hydroxyethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-c]A mixture of pyridine 5-oxide (0.6g, 1.58mmol) and Pd/C (10% on carbon, 0.06g) in ethanol (6mL) under a balloon of hydrogen was stirred at room temperature for 24 hours, then at 60 ℃ for 48 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give 2- (tert-butylamino) -1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4,3-c]Pyridin-4-yl) ethan-1-ol (0.3g) which was used in the next step without further purification. LC-MS m/z365.2M +1)⁺。

And 5: -2- (tert-butylamino) -1- (1H-pyrazolo [4, 3-c)]Pyridin-4-yl) ethan-1-ol and (R) -2- (tert-butylamino) -1- (1H-pyrazolo [4, 3-c)]Pyridine-4-yl) ethan-1-ol synthesis. TBAF (1M in THF, 4ml, 4mmol) was added to 2- (tert-butylamino) -1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [4, 3-c)]Pyridin-4-yl) ethan-1-ol (0.3g, 0.82mmol), andthe mixture was stirred at 50 ℃ for 48 hours. The mixture was passed through preparative TLC (10% CH)₃CH of OH₂Cl₂Solution) and further purified by reverse phase chromatography to give 2- (tert-butylamino) -1- (1H-pyrazolo [4, 3-c)]Pyridin-4-yl) ethan-1-ol as a colorless oil (0.11g, 57%). LC-MS M/z 235.2M +1)⁺. Racemic 2- (tert-butylamino) -1- (1H-pyrazolo [4, 3-c)]Pyridin-4-yl) ethan-1-ol (0.11g, 0.47mmol) was purified by SFC (column: ig-h; mobile phase: HEP/ethanol (0.1% DEA) ═ 70/30) to give (R) -2- (tert-butylamino) -1- (1H-pyrazolo [4, 3-c)]Pyridin-4-yl) ethan-1-ol (0.02g, 36%) and (S) -2- (tert-butylamino) -1- (1H-pyrazolo [4, 3-c)]Pyridin-4-yl) ethan-1-ol (0.02g, 36%) as a white solid. (R) -2- (tert-butylamino) -1- (1H-pyrazolo [4, 3-c)]Pyridin-4-yl) ethan-1-ol: 1H NMR (400MHz, CD)₃OD) δ 9.03(s, 1H), 8.45(d, J ═ 6.9Hz, 1H), 8.08(d, J ═ 6.4Hz, 1H), 5.95(d, J ═ 9.4Hz, 1H), 3.58(d, J ═ 12.9Hz, 1H), 3.39(t, J ═ 11.5Hz, 1H), 1.43(s, 9H); LC-MS: m/z235.3(M +1) +; SFC: 98.7% ee. (S) -2- (tert-butylamino) -1- (1H-pyrazolo [4, 3-c)]Pyridin-4-yl) ethan-1-ol:¹H NMR(400MHz,CD₃OD)δ9.03(s,1H),8.45(d,J＝6.9Hz,1H),8.08(d,J＝6.4Hz,1H),5.95(d,J＝9.4Hz,1H),3.58(d,J＝12.9Hz,1H),3.39(t,J＝11.5Hz,1H),1.43(s,9H)；LC-MS:m/z 235.3(M+1)⁺；SFC:98.3％ee.

example 2

Evaluation of synthetic adrenergic receptor agonists

cAMP Homogeneous Time Resolved Fluorescence (HTRF): experimental methods. Compound efficacy was determined using the cAMPGs dynamic HTRF assay (Cisbio, catalog No. 62AM4PEC) essentially according to the manufacturer's instructions (also detailed below).

Preparation of compounds: candidate β -adrenergic compounds dissolved in DMSO to 10mM were diluted in a solution containing 1mM 3-isobutyl-1-methylxanthene (IBMX; Cayman chemical Co., Cat. No. 13347). Serial dilutions were made in 96-well V-bottom polypropylene compound microplates (Corning, cat # 3363) in stimulation buffer containing 1mM IBMX to 2X the final desired concentration. The standard series dilution curve is10 points, 5-fold dilution, starting from the highest concentration of 10. mu.M. Controls present on each assay plate were 0.1% DMSO (vehicle control), 1 μ M isoproterenol (full β -adrenergic agonist control) and 15 μ M zamoterol (partial β -adrenergic agonist control). 5 stamping 50 μ L from 2X compound plates onto white 384 well small volume hibase assay plates (Greiner bio-one; catalog No. 784075) provided 4 technical replicates of each compound at each concentration. The assay plate was centrifuged at 500Xg for 10 seconds. Compound and IBMX were prepared at 2X final dose to compensate for cell addition.

Cell preparation: 1X stimulation buffer, wash PBS (dulbecco phosphate buffered saline, -Mg-Ca; caisson laboratory, cat # PBL01), analyze PBS (Dulbecco's phosphate buffered saline, + Mg, + Ca; caissonlabs, cat # PBL02) and Versene (0.02% EDTA disodium salt in PBS, without calcium or magnesium; the caisson's laboratory (cat # EDL01) was preheated to 37 ℃. cells expressing β -adrenergic receptors were washed in washing PBS to remove growth medium, then released from the surface by incubation with Versene at 37 ℃ for 5-10 minutes, cells were harvested using assay PBS, counting by hemocytometer or by hand by automatic cell counter, pellet by centrifugation (200 × g, 5 min) and resuspend in 1 × stimulation buffer at 37 ℃ to a final density of 1.5 × 106 cells/ml.5 add 50 μ Ι _ of suspension to all wells of 384-well assay plate.

(7500 pieces in total

) From Axygen

Plate seals (Corning PCR-SP) cover assay plates and incubate for 30 min in a humidified 37 ℃ environment supplemented with 5% CO 2.

HTRF reagent addition, reading and data analysis: after stimulating the cells with the test compound for 30 minutes, the assay plates were centrifuged at 500Xg for 10 seconds and subjected to the addition of 5 μ LCAMP-D2The incubation was stopped and the assay was run at 1: 21, and lysis buffer 2(Cisbio62 CL)₂FDF) was added to all cells. Subsequently, 1: mu.L of anti-camp-eu donor diluted 21 was added to the cells. The plate was sealed and the reaction was gently "vortexed" at 900rpm for at least 30 minutes at room temperature on a heidolphtramax 1000. The plate was centrifuged again at 500Xg for 10 seconds and HTRF was measured at 50 flashes per well using a tecan spark plate reader. The HTRF ratio (665nm/620nm × 10, 000) was determined and plotted in graphpadPrism to generate a concentration-effect curve. Estimates of potency (EC50 and pEC50) were derived from four-parameter nonlinear regression of the concentration-effect curves, and estimates of relative efficacy were determined by comparing the magnitude of the HTRF signal window (min-max dose) of the test compound to the signal window of the full agonist control isoproterenol. The efficacy data are shown in tables 2 and 3 below.

Table 2. pharmacological data for the compounds disclosed herein.

EC₅₀(nM):A<10nM；B＝10-100nM；C＝100nM-1μM；D>1μM

Table 3. pharmacological data for the compounds disclosed herein.

pEC₅₀:A>8；B＝8-7；C＝<7-6；D<6

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are considered to be within the scope of the invention and are covered by the claims.

In addition to the various embodiments described in the foregoing specification, the following additional embodiments are also contemplated herein.

An embodiment 1. a compound according to formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

each R1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amino, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, 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 3,

each A, B and X is independently nitrogen or carbon,

p is N, O or CR₂Q is N, O or CR₂G is NR₅Or O, and/or Z is NR₅O, S or CR₃R₄、

R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy,

Each of R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy,

R5 is one or more selected from the group consisting of H, 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, and substituted heteroaryl,

L is an optionally substituted C1-C5 alkyl linker,

X₁、X₂、X₃and X₄Each independently being a covalent bond, carbon, oxygen or nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl,

y is O or S, and Y is O or S,

R₆and R₇Independently selected from hydrogen, unsubstituted or substituted alkyl, or R₆And R₇And X₂The rings are linked and taken together to form an optionally substituted cycloalkyl or heterocycle,

each R₈Independently selected from hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstitutedOr substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl,

n is an integer of 0 to 4; and

R₉selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and R is₁₀Selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

An embodiment 2. a compound according to formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

formula (II) each R1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amino, pentafluorosulfanyl, unsubstituted or substituted sulfonyl, 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 3,

each A, B and X is independently nitrogen or carbon,

p is N, O or CR₂Q is N, O or CR₂G is NR₅Or O, and/or Z is NR₅O, S or CR₃R₄，

R₂Selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy,

each R₃And R₄Selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy,

r5, R6, and R7 are independently selected from H, 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,

or R⁵And R⁶Together with carbon, form an unsubstituted or substituted 3-7 membered cycloalkyl or heterocycle; l is an optionally substituted C1-C5 alkyl linker,

X¹、X²、X³and X⁴Each independently being a covalent bond, carbon, oxygen or nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl,

y is O or S, and Y is O or S,

R₈and R₉Independently selected from hydrogen, unsubstituted or substituted alkyl, or R8 and R9 with X²The rings are linked and taken together to form an optionally substituted cycloalkyl or heterocycle,

each R₁₀Independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,

n is an integer selected from 0 to 4,

R₁₁selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy and unsubstituted or substituted amino,

R₁₂selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

Example 3. a compound having the structure:

Example 4. a compound having the structure:

Example 5. a compound having the structure:

Example 6. a compound having the structure:

Example 7. a compound having the structure:

Embodiment 8. a pharmaceutical composition comprising a compound as described in any one of embodiments 1-2 and a pharmaceutically acceptable excipient.

The compound of any one of embodiments 1-7, wherein the compound is an agonist, partial agonist or antagonist of an adrenergic receptor;

embodiment 10. the compound of any of embodiments 1-7, wherein the compound is a β 1-adrenergic receptor agonist, a β 2-adrenergic receptor agonist, or a non-selective β 1/β 2-adrenergic receptor agonist.

The compound of any one of embodiments 1-7, wherein the compound is a β 1-adrenergic receptor agonist.

The compound of any of embodiments 1-7, wherein the compound is a β 2-adrenergic receptor agonist.

The compound of any one of embodiments 1-7, wherein the compound is a non-selective β 1/β 2-adrenergic agonist.

Example 14. a method of treating a subject having a disease, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-2.

Embodiment 15. the method of embodiment 14, wherein the disease is an adrenergic receptor-associated disease.

Embodiment 16. the method of embodiment 14, wherein the disease is a neurodegenerative disease.

The method of claim 14, wherein the subject is a human.

Example 18. the method according to example 14, wherein the disease is selected from the group consisting of myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gilles disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebrovascular inflammation, epilepsy, Tourette's syndrome, Wilson's disease, pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, friedrich's ataxia, ataxia telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis.

Example 19. the method of example 14, wherein the compound is administered to the subject by oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, epidermal, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route.

Example 20. the method according to example 14, wherein the disease is a neurodegenerative disease, which neurodegenerative disease is one or more selected from the group consisting of: MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, dementia of mixed type, FTD (frontotemporal dementia; pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Charcot-Deg's syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernike-Korsakoff's syndrome; alcoholic dementia and thiamine deficiency), normotensive hydrocephalus, hypersomnia/narcolepsy, ASD (autism spectrum disorder), FXS (Fragile X syndrome), TSC (tuberous sclerosis syndrome), 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's Syndrome (DS).

Embodiment 21. the method according to embodiment 14, wherein the disease is a neurodegenerative disease, which neurodegenerative disease is one or more selected from the group consisting of: MCI, alpha MCI, vascular dementia, dementia of mixed type, FTD (frontotemporal dementia; pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Charcot's syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (Chronic traumatic encephalopathy), stroke, WKS (Wernike-Korsakoff's syndrome; Alcoholic dementia and Thiamine deficiency), normothermic hydrocephalus, hypersomnia/narcolepsy, ASD (autism spectrum disorder), FXS (Fragile X syndrome), TSC (tuberous sclerosis syndrome), prion-related diseases (CJD, etc.), depression, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia) and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not have Alzheimer's Disease (AD).

Embodiment 22. the method of any one of embodiments 14-21, wherein the subject does not have down syndrome.

The method of any one of embodiments 14-22, wherein administering to the subject further comprises a peripherally acting beta-blocker (PABRA) together with the compound.

Embodiment 24. the method of embodiment 23, wherein the subject is administered a peripherally acting beta blocker (PABRA) prior to administration of the compound.

Embodiment 25. the method of embodiment 23, wherein the subject is administered a peripherally acting beta blocker (PABRA) at the same time as the compound.

Embodiment 26 the method of any one of embodiments 14-22, wherein a β 1 agonist, a β 2 agonist, or a non-selective β 1/β 2 agonist is administered to the patient in addition to the compound.

Claims

1. A compound according to formula (I'):

or a pharmaceutically acceptable salt thereof, wherein

A ', B', W 'and X' are each independently a nitrogen atom or a carbon atom;

two R^AThe groups form an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, other than the carbon linking the two RA groups, on the same carbon or optionally together with their intervening atoms;

m' is an integer selected from 0 to 3;

R^2’selected from hydrogen, R^A、-OR’、

L' is optionally substituted C_1-5An alkylene group;

X^1’、X^3’and X^4’Each independently a divalent group-CR 'selected from covalent bonds'₂-, -O-and-NR' -;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹' and R¹⁰' and X²Together form an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

R⁷' and R⁸' independently of one another areHydrogen or optionally substituted C_1-2An aliphatic group.

2. A compound according to formula (II'):

or a pharmaceutically acceptable salt, wherein:

a ', B', W 'and X' are each independently a nitrogen atom or a carbon atom;

each R¹' independently is hydrogen, halogen, R^A、-CN、-NO₂、-SF₅、-O-、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR’C(O)R’、-NR’CO₂R' or-CO₂R’；

each R' is independently hydrogen or an optionally substituted group selected from: c_1-6An aliphatic radical, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heteroring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfurA ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and an 8-10 membered bicyclic moiety unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

m' is an integer selected from 0 to 3;

Or:

l' is optionally substituted C_1-5An alkylene group;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹' and R¹⁰' and X²Together form an optionally substituted 3-7 membered saturated carbocyclic ring(ii) a 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

3. A compound according to formula (III'):

or a pharmaceutically acceptable salt thereof, wherein:

a ', B ' and X ' are each independently a nitrogen atom or a carbon atom;

p ' and Q ' are each independently-N, -NR ' -, -CR ' -, or-CR '₂-；

G 'is-NR' -or-O-;

z ' is NR ', -O, - (S) or ═ CR '₂；

Is a single or double bond;

Each R^AIndependently is an optionally substituted group selected from: c_1-6An aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

m' is an integer selected from 0 to 3;

Or:

R⁴' and R⁵' optionally together with the carbon to which they are attached form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfurA ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

l' is optionally substituted C_1-5An alkylene group;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹' and R¹⁰' and X²' together form an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN; and

each R¹³' independently is hydrogen, halogen, R^A-CN, -OR 'OR-NR'₂。

4. A compound according to formula (IV'):

or a pharmaceutically acceptable salt thereof, wherein:

a ', B ' and X ' are each independently a nitrogen atom or a carbon atom;

each R¹' independently of one another are hydrogen, halogen, R^A、-CN、-NO₂、-SF₅、-O^-、-OR’、-NR’₂、-SO₂R’、-C(O)R’、-C(O)NR’₂、-NR’C(O)R’、-NR’CO₂R' or-CO₂R’；

Each R^AIndependently is an optionally substituted group selected from: c_1-6An aliphatic group, a phenyl group, a 4-to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

m' is an integer selected from 0 to 3;

R^3a' and R^3b' independently is hydrogen, R^A、-OR’、-C(O)R’、-C(O)NR’₂or-CO₂R' or:

R^3a' and R^3b' optionally together with their intervening atoms form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, except R^3a' and R^3b' attached nitrogen has 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Or:

l' is optionally substituted C_1-5An alkylene group;

X¹’、X³' and X⁴'each independently is a divalent group selected from a covalent bond, -CR'₂-, -O-, and-NR' -;

X²' is a carbon atom or a nitrogen atom;

y' is O or S;

R⁹' and R¹⁰' and X²' are linked together in a ring to form an optionally substituted 3-7 membered saturated carbocyclic 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; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R^11’Independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²' is hydrogen, R^Aor-CN;

each R¹³' independently is hydrogen, halogen, R^A-CN, -OR ', OR-NR'₂(ii) a And

5. A compound according to formula (V'):

or a pharmaceutically acceptable salt thereof, wherein:

m' is an integer selected from 0 to 3;

Or:

l' is optionally substituted C_1-5An alkylene group;

X¹’、X³', and X⁴'each independently is a divalent group selected from a covalent bond, -CR'₂-, -O-, and-NR' -;

X²' is a carbon atom or a nitrogen atom;

Y¹' is O or S;

R⁹' and R¹⁰' and X²' together form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; has 1-2An optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle of heteroatoms independently selected from nitrogen, oxygen and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R¹¹' independently is R^AHalogen, -CN, -NO₂、-NR’₂OR-OR';

n' is an integer selected from 0 to 4;

R¹²is hydrogen, R^Aor-CN; and

each R¹³' independently is hydrogen, halogen, R^A-CN, -OR 'OR-NR'₂。

6. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

7. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

8. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

9. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

10. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1 to 5, wherein the compound is selected from any one of the compounds depicted in Table 1.

12. A pharmaceutical composition comprising a compound of any one of claims 1-11 and a pharmaceutically acceptable excipient.

13. The compound of any one of claims 1-11, wherein the compound is an agonist, partial agonist, or antagonist of an adrenergic receptor;

14. the compound of any one of claims 1-11, wherein the compound is a β 1-adrenergic receptor agonist, a β 2-adrenergic receptor agonist, or a non-selective β 1/β 2-adrenergic receptor agonist.

15. The compound of any one of claims 1-11, wherein the compound is a β 1-adrenergic receptor agonist.

16. The compound of any one of claims 1-11, wherein the compound is a β 2-adrenergic receptor agonist.

17. The compound of any one of claims 1-11, wherein the compound is a non-selective β 1/β 2-adrenergic agonist.

18. A method of treating a subject having a disease, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-11.

19. The method of claim 18, wherein the disorder is an adrenergic receptor-related disorder.

20. The method according to claim 18, wherein the disease is a neurodegenerative disease.

21. The method according to claim 18, wherein the subject is a human.

22. The method according to claim 18, wherein the disease is selected from the group consisting of myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gilles disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebrovascular inflammation, epilepsy, Tourette's syndrome, Wilson's disease, pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, friedrich's ataxia, ataxia telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis.

23. The method of claim 18, wherein the compound is administered to the subject by an oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, epidermal, extraamniotic, intraarterial, intraarticular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route.

24. The method of claim 18, wherein the disease is a neurodegenerative disease selected from the group consisting of MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, dementia of mixed type, FTD (frontotemporal dementia; pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Charcot-Der's syndrome), olive pontine cerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernike-Korsakoff's syndrome; alcohol dementia and thiamine deficiency), normothermic hydrocephalus, hypersomnia/narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), and Skoff's syndrome, TSC (tuberous sclerosis syndrome), 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).

25. The method according to claim 18, wherein the disease is a neurodegenerative disease selected from one or more of the group consisting of MCI, acmi, vascular dementia, dementia of mixed type, FTD (frontotemporal dementia); pick's disease, HD (huntington's disease), rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (chard's syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (west-korsakoff's syndrome; alcoholic dementia and thiamine deficiency), normopropionic hydrocephalus, hypersomnia/narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis syndrome), prion-related diseases (CJD, etc.), depression, DLB (lewy body dementia), PD (parkinson's disease), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder). In some embodiments, the subject does not have Alzheimer's Disease (AD)

26. The method of any one of claims 18-25, wherein the subject does not have down syndrome.

27. The method of any one of claims 18-26, wherein administering to the subject further comprises administering a peripherally acting beta-blocker (PABRA) with the compound.

28. The method of claim 27, wherein a peripheral acting beta blocker (PABRA) is administered to the subject prior to administration of the compound.

29. The method of claim 27, wherein a peripheral acting beta blocker (PABRA) is administered to the subject concurrently with administration of the compound.

30. The method of any one of claims 18-26, wherein a β 1 agonist, a β 2 agonist, or a non-selective β 1/β 2 agonist is administered to the patient in addition to the compound.