Beta-adrenergic agonists and methods of use thereof

Abstract

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

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 869,448, filed July 1, 2019, U.S. Provisional Application No. 62 / 934,482, filed November 12, 2019, U.S. Provisional Application No. 63 / 018,431, filed April 30, 2020, U.S. Application No. 16 / 831,285, filed March 26, 2020, and U.S. Application No. 16 / 831,370, filed March 26, 2020, the contents of each of which are incorporated by reference in their entirety herein.

[0002] Field The present disclosure relates generally to chemical compounds, in some embodiments, that are beta-adrenergic agonists, and their use in treating diseases associated with adrenergic receptors. [Background technology]

[0003] background PCT Publication No. WO2017 / 197324 (Patent Document 1) discloses "adrenergic receptor modulating compounds and methods for treating a subject for a disease or condition associated with an adrenergic receptor, comprising administering a therapeutically effective amount of a subject compound."

[0004] U.S. Patent Application Publication No. 2013 / 0096126 (Patent Document 2) discloses "a method for enhancing learning or memory, or both, in a mammal having a learning, memory, or both impairment due to a neurodegenerative disorder, the method comprising the step of administering at least one compound that is a β1 adrenergic receptor agonist, partial agonist, or receptor ligand, or a salt thereof, in an amount effective to improve learning, memory, or both, in the mammal."

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

[0006] US Patent Application Publication No. 2016 / 0184241 (Patent Document 4) discloses "a method for improving cognition in a patient with Down's syndrome, the method comprising intranasally administering to the patient one or more β2-ADR agonists or pharmacologically acceptable salts, or both, in an amount and frequency effective to improve the patient's cognition as measured in a contextual learning test." [Prior art documents] [Patent documents]

[0007] [Patent Document 1] PCT Publication No. WO2017 / 197324 [Patent Document 2] US Patent Application Publication No. 2013 / 0096126 [Patent Document 3] US Patent Application Publication No. 2014 / 0235726 [Patent Document 4] US Patent Application Publication No. 2016 / 0184241 Summary of the Invention

[0008] overview The present disclosure is based at least in part on the identification of compounds that modulate adrenergic receptors and methods of using them to treat diseases associated with adrenergic receptors. Disclosed herein are compounds according to formula (I), or optically pure stereoisomers, pharma- ceutically acceptable salts, solvates, or prodrugs thereof. TIFF0007676355000001.tif69128

[0009] In some embodiments of Formula (I), each R 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.

[0010] In some embodiments of Formula (I), m is an integer selected from 0-3.

[0011] In some embodiments of Formula (I), each A, B, and X is independently nitrogen or carbon.

[0012] In some embodiments of formula (I), P is N, O, or CR2, Q is N, O, or CR2, G is NR5 or O, and / or Z is NR5, O, S, or CR3R4. In some embodiments, R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy. In certain embodiments, each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0013] In some embodiments of formula (I), R5 is 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, TIFF0007676355000002.tif59145, L is an optionally substituted C1-C5 alkyl linker; each of X1, X2, X3, and X4 is independently a covalent bond, hydrogen, unsubstituted or substituted alkyl, or carbon, oxygen, or nitrogen, which may be substituted with an unsubstituted or substituted cycloalkyl; Y is O or S; R6 and R7 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R6 and R7 are cyclically linked and together with X2 form an optionally substituted cycloalkyl or heterocycle; each R8 is independently hydrogen, halogen, or aryl; n is an integer selected from 0 to 4; R is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; R 10 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0014] Also disclosed herein are compounds according to formula (II), or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF0007676355000003.tif60128

[0015] In some embodiments of formula (II), each R 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.

[0016] In some embodiments of Formula (II), m is an integer selected from 0-3.

[0017] In some embodiments of Formula (II), each A, B, and X is independently nitrogen or carbon.

[0018] In some embodiments of formula (II), P is N, O, or CR2, Q is N, O, or CR2, G is NR5 or O, and / or Z is NR5, O, S, or CR3R4.

[0019] In some embodiments of Formula (II), R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0020] In some embodiments of Formula (II), each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0021] In some embodiments of formula (II), 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, TIFF0007676355000004.tif61150; or or R5 and R6 together with the carbon form a 3-7 membered cycloalkyl or heterocycle; L is an optionally substituted C1-C5 alkyl linker; each X1, X2, X3, and X4 is independently a carbon, oxygen, or nitrogen which may be substituted with a covalent bond, 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 cyclically linked and together with X2 form an optionally substituted cycloalkyl or heterocycle; 10 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R 11 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; R 12 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0022] Also referred to herein is a compound of formula (I'): Disclosed is a compound according to TIFF0007676355000005.tif34128, or a pharma- ceutically acceptable salt thereof, 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, a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1’ are independently hydrogen, halogen, R A , -CN, -NO2, -SF5, -O - , -OR', -NR'2, -SOR', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'COR', or -COR'; Each R A is independently 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle 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 Two R on the same carbon or A The groups, optionally together with their intervening atoms, may be two R A forming an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon to which the group is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently hydrogen or C 1~6an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 2 ' is hydrogen, R A , -OR', Selected from TIFF0007676355000006.tif98150, L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2together with Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2; R 7 ' and R 8 Each ' is independently hydrogen or an optionally substituted C 1~2 It is aliphatic.

[0023] As described herein, The structure depicted as TIFF0007676355000007.tif15128 is, for example, the structure Contains TIFF0007676355000008.tif17128.

[0024] Also referred to herein is the compound of formula (II'): Disclosed is a compound according to TIFF0007676355000009.tif34128, or a pharma- ceutically acceptable salt thereof, 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, a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1’ are independently hydrogen, halogen, R A , -CN, -NO2, -SF5, -O - , -OR', -NR'2, -SOR', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'COR', or -COR'; Each R A is independently 1~6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocycle 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 Two R on the same carbon or A The groups, optionally together with their intervening atoms, may be two R A forming an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon to which the group is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 4 ', R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000010.tif100155 or R 4 ' and R 5 ' optionally form, together with the carbon to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2together with Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2; R 7 ' and R 8 Each ' is independently hydrogen or an optionally substituted C 1~2 It is aliphatic.

[0025] Also referred to herein is the compound of formula (III'): The present invention discloses a compound according to TIFF0007676355000011.tif46128, or a pharma- ceutically acceptable salt thereof, comprising: 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; TIFF0007676355000012.tif2128 is a single or double bond, Each R 1’ are independently 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 A is independently 1~6 an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is an integer selected from 0 to 3; R 4 ', R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000013.tif101150 or R 4 ' and R 5' optionally form, together with the carbons to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2 ' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 ' is hydrogen, R A or -CN, Each R 13' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2.

[0026] Further provided herein are compounds having the structure: Disclosed is a compound having the formula: TIFF0007676355000014.tif42128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0027] Further provided herein are compounds having the structure: Disclosed is a compound having the formula: TIFF0007676355000015.tif51128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0028] Further provided herein are compounds having the structure: Disclosed is a compound having the formula: TIFF0007676355000016.tif51128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0029] Further provided herein are compounds having the structure: Disclosed is a compound having the formula: TIFF0007676355000017.tif47128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0030] Further provided herein are compounds having the structure: Disclosed is a compound having the formula: TIFF0007676355000018.tif39128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0031] Also referred to herein is a compound of formula (IV'): The present invention discloses a compound according to TIFF0007676355000019.tif38128, or a pharma- ceutically acceptable salt thereof, comprising: A', B', and X' are each independently a nitrogen atom or a carbon atom; Each R 1’ are independently hydrogen, halogen, R A , -CN, -NO2, -SF5, -O - , -OR', -NR'2, -SOR', -C(O)R', -C(O)NR'2-NR'C(O)R', -NR'COR', or -COR'; Each R A is independently 1~6 an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 3a ' and R 3b ' are independently hydrogen, R A , -OR', -C(O)R', -C(O)NR'2, or -CO2R', or R3a ' and R 3b ' optionally together with their intervening atoms, R 3a ' and R 3b ' forms an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the nitrogen to which it is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 ', R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000020.tif102149 or R 4 ' and R 5 ' optionally form, together with the carbons to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2; R 7 ' and R 8 Each ' is independently hydrogen or an optionally substituted C 1~2 It is aliphatic.

[0032] Also referred to herein is a compound of formula (V'): The present invention discloses a compound according to TIFF0007676355000021.tif37128, or a pharma- ceutically acceptable salt thereof, comprising: Each R 1’ are independently 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 A is independently 1~6an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 4 ', R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000022.tif96149 or R 4 ' and R 5' optionally form, together with the carbons to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y 1 ' is O or S, R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2 ' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 is hydrogen, R A or -CN, Each R 13' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2.

[0033] Further provided herein are compounds having the structure: Disclosed is a compound having the formula: TIFF0007676355000023.tif23128, or a pharma- ceutically acceptable salt thereof.

[0034] Further provided herein are compounds having the structure: Disclosed is a compound having the formula: TIFF0007676355000024.tif23128, or a pharma- ceutically acceptable salt thereof.

[0035] Further provided herein is a compound of formula (VI'): A compound according to TIFF0007676355000025.tif33128, or a pharma- ceutically acceptable salt thereof, is disclosed; In the formula, A', B', X', R 1’ , R 3a’ , R 3b’ , R 4’ , R 5’ , and R 6’ Each of m', m', and m', both alone and in combination, is as defined above and as described in the embodiments provided herein.

[0036] The present specification further provides a compound of formula (VII'): A compound according to TIFF0007676355000026.tif33128, or a pharma- ceutically acceptable salt thereof, is disclosed; In the formula, A', B', X', R 1’ , R 4’ , R 5’ , R 6’ and m', both alone and in combination, are as defined above and as described in the embodiments provided herein.

[0037] 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 (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), Formula (VII'), or a pharma- ceutically acceptable excipient.

[0038] In certain embodiments, the compounds disclosed herein are agonists, partial agonists or antagonists of adrenergic receptors, in some embodiments, the compounds are β1-adrenergic receptor agonists, β2-adrenergic receptor agonists or non-selective β1 / β2-adrenergic receptor agonists, in some embodiments, the compounds are β1-adrenergic receptor agonists, and in some embodiments, the compounds are non-selective β1 / β2-adrenergic receptor agonists.

[0039] Further disclosed are methods of treating a subject having a disease, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, i.e., a compound having the structure of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), or Formula (VII'). In some embodiments, the disease is an adrenergic receptor-associated disease. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the subject is a human.

[0040] In some embodiments, the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia-telangiectasia, spinal dysmyopathy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, intravaginal, sublingual, or rectal routes.

[0041] In some embodiments, the disease is MCI (mild cognitive impairment), aMCI (amnestic mild cognitive impairment), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff's syndrome). symptoms; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (CJD, etc.), depressive disorder, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (Parkinson's disease dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early Alzheimer's disease, and Down's syndrome (DS). In some embodiments, the disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke's syndrome), or other conditions. The neurodegenerative disease is one or more selected from the group consisting of Korsakoff's syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related disease (such as CJD), depressive disorder, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (Parkinson's disease 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's syndrome.

[0042] In certain embodiments of the methods disclosed herein, the methods include administering to a subject a compound disclosed herein and a peripherally acting beta blocker (PABRA).

[0043] As used herein, the term "peripherally acting beta blocker (PABRA)" refers to 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 can be used in certain embodiments of the methods disclosed herein include nadolol, atenolol, sotalol, and labetalol. In certain embodiments, the beta blocker that can be used in the methods herein is one or more selected from the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, and nebivolol, and in other embodiments, the method does not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, or nebivolol as a beta blocker.

[0044] In certain embodiments, a peripherally acting beta blocker (PABRA) is administered to the subject prior to administration of a compound of the present disclosure, while in other embodiments, a peripherally acting beta blocker (PABRA) is administered to the subject simultaneously with administration of a compound of the present disclosure.

[0045] In certain embodiments of the compositions and methods provided herein, one or more peripherally acting beta blockers (PABRA) are administered prior to or simultaneously with the compounds of the present disclosure to inhibit or eliminate the activation effect of peripheral beta 1 and / or beta 2 adrenergic receptors by the compounds of the present disclosure. In various embodiments, it is preferred to block peripheral beta 1 and / or beta 2 adrenergic receptors according to the aforementioned compositions and methods of the present disclosure in order to eliminate or at least minimize any adverse peripheral cardiac, metabolic or muscular effects on the treated human.

[0046] In some embodiments of the methods provided herein, a β1 antagonist and / or a β2 agonist, or a non-selective β1 / β2 agonist, is further administered to the patient.

[0047] As used herein, the term "β1 agonist" is used to mean a β1 adrenergic receptor agonist or a β1-ADR agonist. In certain embodiments, the term β1 agonist includes compounds that are, of course, primarily β1 agonists, but may also exhibit some peripheral activation effects on other adrenergic receptors, such as the β2 adrenergic receptor. In this application, the terms "β1 adrenergic receptor agonist", "β1-ADR agonist", "β1AR agonist" and "β1 agonist" may be used interchangeably. In certain embodiments, the term β1-ADR agonist explicitly includes both selective and partial agonists, and biased and unbiased agonists. Examples of β1 adrenergic agonists include, for example, xamoterol, noradrenaline, isoprenaline, dopamine, pindolol and dobutamine, as well as pharmacologically acceptable salts of any of the above. Partial agonists and ligands of β1-ADR are known.In addition, using the methodology of Kolb et al., but instead for β1-ADR, those skilled in the art can determine new ligands by structure-based discovery.See Proc.Natl.Acad.Sci.USA 2009,106,6843-648.

[0048] As used herein, the term β2 agonist is used to mean β2 adrenergic receptor agonist or β2-ADR agonist. In certain embodiments, the term β2 agonist includes compounds that are, of course, primarily β2 agonists, but may also exhibit some peripheral activation effects on other adrenergic receptors, such as β1 adrenergic receptors. In this application, the terms "β2 adrenergic receptor agonist", "β2-ADR agonist", "β2AR agonist" and "β2 agonist" may be used interchangeably. In some embodiments, the term β2-ADR agonist explicitly includes both selective agonists and partial agonists. β2 agonists that may be used according to various aspects and embodiments of the present disclosure may be short-acting, long-acting or ultra-long-acting. Examples of short-acting β2 agonists that can be used are salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, oritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and isoetharine.Examples of long-acting β2 agonists that can be used are salmeterol, bambuterol, formoterol, and clenbuterol.Examples of ultra-long-acting β2 agonists include indacaterol, vilanterol, and olodaterol.

[0049] Surprisingly, the compounds of the present disclosure have been found to exhibit unexpectedly beneficial properties, as demonstrated in the Examples section herein.For example, surprisingly, the compounds of the present disclosure have been found to act as low nM (<10 nM) partial agonists of β2 adrenergic receptors. [The present invention 1001] Formula (I'): TIFF0007676355000027.tif34128 or a pharma- ceutically acceptable salt thereof, 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, a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R1’ are independently hydrogen, halogen, R A , -CN, -NO 2 ,-SCIENCE FICTION 5 、-O - , -OR', -NR' 2 , -SO 2 R', -C(O)R', -C(O)NR' 2 , -NR'C(O)R', -NR'CO 2 R', or -CO 2 R', Each R A But independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle 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 Two R on the same carbon or A groups, optionally together with their intervening atoms, form the two R A forming an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon to which the group is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which said two R' groups are attached, one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 2 ' is hydrogen, R A , -OR', TIFF0007676355000028.tif98150 is selected from L' is an optionally substituted C 1~5 is alkylene, X 1 ’、X 3 ', and X 4 ', each independently, a covalent bond, -CR' 2 is a divalent group selected from -, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; or R 9 ' and R 10 ' is circularly connected, and X 2 together with Each R 11 ' but independently, R A , halogen, -CN, -NO 2 , -NR' 2 , or -OR', n' is an integer selected from 0 to 4; R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR' 2 and R 7 ' and R 8 ' are each independently hydrogen or an optionally substituted C 1~2 Is aliphatic, The compound or a pharma- ceutically acceptable salt thereof. [The present invention 1002] Formula (II'): TIFF0007676355000029.tif34128 or a pharma- ceutically acceptable salt thereof, 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, a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1’ are independently hydrogen, halogen, R A , -CN, -NO 2 ,-SCIENCE FICTION 5 、-O - , -OR', -NR' 2 , -SO 2 R', -C(O)R', -C(O)NR' 2 , -NR'C(O)R', -NR'CO 2 R', or -CO 2 R', Each R A But independently, C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocycle 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 Two R on the same carbon or A groups, optionally together with their intervening atoms, form the two R A forming an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon to which the group is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which said two R' groups are attached, one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 4 ’、R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO 2 , -OR', -NR' 2 、 TIFF0007676355000030.tif97149 or R 4 ' and R 5 ' optionally form, together with the carbon to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ’、X 3 ', and X 4 ', each independently, a covalent bond, -CR' 2 is a divalent group selected from -, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; or R 9 ' and R 10 ' is circularly connected, and X 2 together with Each R 11 ' but independently, R A , halogen, -CN, -NO 2 , -NR' 2 , or -OR', n' is an integer selected from 0 to 4; R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR' 2 and R 7 ' and R 8 ' are each independently hydrogen or an optionally substituted C 1~2 Is aliphatic, The compound or a pharma- ceutically acceptable salt thereof. [The present invention 1003] Formula (III'): TIFF0007676355000031.tif46128 or a pharma- ceutically 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 - and G' is -NR'- or -O-; Z' is =NR', =O, =S, or =CR' 2 and TIFF0007676355000032.tif2128 is a single bond or a double bond, Each R 1’ are independently hydrogen, halogen, R A , -CN, -NO 2 ,-SCIENCE FICTION 5 , -OR', -NR' 2 , -SO 2 R', -C(O)R', -C(O)NR' 2 , -NR'C(O)R', -NR'CO 2 R', or -CO 2 R', Each R A But independently, C 1~6 an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which said two R' groups are attached, one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 4 ’、R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO 2 , -OR', -NR'2 、 TIFF0007676355000033.tif97149 or R 4 ' and R 5 ' optionally form, together with the carbon to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ’、X 3 ', and X 4 ', each independently, a covalent bond, -CR' 2 is a divalent group selected from -, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; or R 9 ' and R 10 ' is circularly connected, and X 2 ' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 11 ' but independently, R A , halogen, -CN, -NO 2 , -NR' 2 , or -OR', n' is an integer selected from 0 to 4; R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR' 2 That is, The compound or a pharma- ceutically acceptable salt thereof. [The present invention 1004] Formula (IV'): TIFF0007676355000034.tif38128 or a pharma- ceutically acceptable salt thereof, wherein A', B', and X' are each independently a nitrogen atom or a carbon atom; Each R 1 ' are independently hydrogen, halogen, R A , -CN, -NO 2 ,-SCIENCE FICTION 5 、-O - , -OR', -NR' 2 , -SO 2 R', -C(O)R', -C(O)NR' 2 , -NR'C(O)R', -NR'CO 2 R', or -CO 2 R', Each R A But independently, C 1~6 an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which said two R' groups are attached, one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 3a ' and R 3b ' are independently hydrogen, R A , -OR', -C(O)R', -C(O)NR' 2 , or -CO 2 R', or R 3a ' and R 3b ' optionally together with their intervening atoms, R 3a ' and R 3b ' forms an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the nitrogen to which it is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 ’、R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO 2 , -OR', -NR' 2 、 TIFF0007676355000035.tif96149 or R 4 ' and R 5 ' optionally form, together with the carbon to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C<h2 style=";text-align:left;direction:ltr"> 1~5 <h2 style=";text-align:left;direction:ltr"> is alkylene, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> X <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> ’、X <h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> ', and X <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> ', each independently, a covalent bond, -CR' <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> is a divalent group selected from -, -O-, and -NR'-; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> X <h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> ' is a carbon atom or a nitrogen atom, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Y' is O or S; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 9 <h2 style=";text-align:left;direction:ltr"> ' and R <h2 style=";text-align:left;direction:ltr"> 10 <h2 style=";text-align:left;direction:ltr"> ' are each independently hydrogen or optionally substituted alkyl; or <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 9 <h2 style=";text-align:left;direction:ltr"> ' and R <h2 style=";text-align:left;direction:ltr"> 10 <h2 style=";text-align:left;direction:ltr"> ' is circularly connected, and X <h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> ' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Each R <h2 style=";text-align:left;direction:ltr"> 11 <h2 style=";text-align:left;direction:ltr"> ' but independently, R <h2 style=";text-align:left;direction:ltr"> A <h2 style=";text-align:left;direction:ltr"> , halogen, -CN, -NO <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> , -NR' <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> , or -OR', <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> n' is an integer selected from 0 to 4; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> ' is hydrogen, R <h2 style=";text-align:left;direction:ltr"> A <h2 style=";text-align:left;direction:ltr"> or -CN, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Each R <h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> ' are independently hydrogen, halogen, R <h2 style=";text-align:left;direction:ltr"> A <h2 style=";text-align:left;direction:ltr"> , -CN, -OR', or -NR' <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> and <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 7 <h2 style=";text-align:left;direction:ltr"> ' and R <h2 style=";text-align:left;direction:ltr"> 8 <h2 style=";text-align:left;direction:ltr"> ' are each independently hydrogen or an optionally substituted C <h2 style=";text-align:left;direction:ltr"> 1~2 <h2 style=";text-align:left;direction:ltr"> Is aliphatic, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The compound or a pharma- ceutically acceptable salt thereof. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1005] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Formula (V'): <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007676355000036.tif37128<h2 style=";text-align:left;direction:ltr"> or a pharma- ceutically acceptable salt thereof, wherein <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Each R <h2 style=";text-align:left;direction:ltr"> 1’ <h2 style=";text-align:left;direction:ltr"> are independently hydrogen, halogen, R<h2 style=";text-align:left;direction:ltr"> A <h2 style=";text-align:left;direction:ltr"> , -CN, -NO <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> ,-SCIENCE FICTION <h2 style=";text-align:left;direction:ltr"> 5<h2 style=";text-align:left;direction:ltr"> , -OR', -NR' <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> , -SO <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> R', -C(O)R', -C(O)NR' <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> , -NR'C(O)R', -NR'CO <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> R', or -CO <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> R', <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Each R <h2 style=";text-align:left;direction:ltr"> A <h2 style=";text-align:left;direction:ltr"> But independently, C <h2 style=";text-align:left;direction:ltr"> 1~6 <h2 style=";text-align:left;direction:ltr"> an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Each R' is independently hydrogen or C <h2 style=";text-align:left;direction:ltr"> 1~6 <h2 style=";text-align:left;direction:ltr"> an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which said two R' groups are attached, one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> m' is an integer selected from 0 to 3; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> ’、R <h2 style=";text-align:left;direction:ltr"> 5 <h2 style=";text-align:left;direction:ltr"> ', and R <h2 style=";text-align:left;direction:ltr"> 6 <h2 style=";text-align:left;direction:ltr"> ' are each independently hydrogen, halogen, R <h2 style=";text-align:left;direction:ltr"> A <h2 style=";text-align:left;direction:ltr"> , -CN, -NO <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> , -OR', -NR' <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> 、 <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007676355000037.tif97149<h2 style=";text-align:left;direction:ltr"> or <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> ' and R <h2 style=";text-align:left;direction:ltr"> 5 <h2 style=";text-align:left;direction:ltr"> ' optionally form, together with the carbon to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> L' is an optionally substituted C <h2 style=";text-align:left;direction:ltr"> 1~5 <h2 style=";text-align:left;direction:ltr"> is alkylene, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> X <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> ’、X <h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> ', and X <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> ', each independently, a covalent bond, -CR' <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> is a divalent group selected from -, -O-, and -NR'-; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> X <h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> ' is a carbon atom or a nitrogen atom, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Y <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> ' is O or S, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 9 <h2 style=";text-align:left;direction:ltr"> ' and R <h2 style=";text-align:left;direction:ltr"> 10 <h2 style=";text-align:left;direction:ltr"> ' are each independently hydrogen or optionally substituted alkyl; or <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 9 <h2 style=";text-align:left;direction:ltr"> ' and R10 ' is circularly connected, and X 2 ' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 11 ' but independently, R A , halogen, -CN, -NO 2 , -NR' 2 , or -OR', n' is an integer selected from 0 to 4; R 12 is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR' 2 That is, The compound or a pharma- ceutically acceptable salt thereof. [The present invention 1006] The following structure: TIFF0007676355000038.tif46128 or a pharma- ceutically acceptable salt thereof. [The present invention 1007] The following structure: TIFF0007676355000039.tif53128 or a pharma- ceutically acceptable salt thereof. [The present invention 1008] The following structure: TIFF0007676355000040.tif53128 or a pharma- ceutically acceptable salt thereof. [The present invention 1009] The following structure: TIFF0007676355000041.tif53128 or a pharma- ceutically acceptable salt thereof. [The present invention 1010] The following structure: TIFF0007676355000042.tif46128 or a pharma- ceutically acceptable salt thereof. [The present invention 1011] Any one of the compounds of 1001 to 1005 of the present invention selected from any one of the compounds shown in Table 1. [The present invention 1012] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1011 and a pharma- ceutically acceptable excipient. [The present invention 1013] The compound of any one of claims 1001 to 1011, which is an agonist, partial agonist, or antagonist of an adrenergic receptor. [The present invention 1014] Any of the compounds of the present invention 1001 to 1011, which are β1-adrenergic receptor agonists, β2-adrenergic receptor agonists, or non-selective β1 / β2-adrenergic receptor agonists. [The present invention 1015] Any of the compounds of the present invention 1001 to 1011, which are β1-adrenergic receptor agonists. [The present invention 1016] Any of the compounds of the present invention 1001 to 1011, which are β2-adrenergic receptor agonists. [The present invention 1017] Any of the compounds of the present invention 1001 to 1011, which are non-selective β1 / β2-adrenergic agonists. [The present invention 1018] A method for treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1011. [The present invention 1019] The method of the present invention, wherein the disease is an adrenergic receptor-associated disease. [The present invention 1020] The method of claim 1018, wherein the disease is a neurodegenerative disease. [The present invention 1021] The method of claim 1018, wherein the subject is a human. [The present invention 1022] The method of the present invention, wherein the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia-telangiectasia, spinal dysmyopathy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. [The present invention 1023] The method of the present invention 1018, wherein the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intraarachnoid, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, intravaginal, sublingual, or rectal routes. [The present invention 1024] The diseases include MCI (mild cognitive impairment), aMCI (amnestic mild cognitive impairment), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; alcohol-related dementia), and The method of the present invention 1018, wherein the neurodegenerative disease is one or more selected from the group consisting of dementia and thiamine deficiency, normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (Parkinson's disease dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early Alzheimer's disease, and Down's syndrome (DS). [The present invention 1025] The diseases include MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; A) In some embodiments, the subject is one or more neurodegenerative diseases selected from the group consisting of Alzheimer's disease (AD), ... [The present invention 1026] Any of the methods of claims 1018 to 1025, wherein the subject does not have Down's syndrome. [The present invention 1027] The method of any one of claims 1018 to 1026, wherein administering to said subject further comprises a peripherally acting beta blocker (PABRA) together with said compound. [The present invention 1028] The method of claim 1027, wherein a peripherally acting beta blocker (PABRA) is administered to said subject prior to administration of said compound. [The present invention 1029] The method of claim 1027, wherein a peripherally acting beta blocker (PABRA) is administered to said subject simultaneously with said administration of said compound. [The present invention 1030] The method of any of claims 1018 to 1026, wherein a β1 agonist, a β2 agonist, or a non-selective β1 / β2 agonist is administered to said patient in addition to said compound. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] Detailed Description In the following detailed description of the embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of the disclosed embodiments. However, it will be apparent to those skilled in the art that the embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0051] The following explanations of terms and methods are provided to better explain the present disclosure and guide those skilled in the art in practicing the present disclosure. The singular terms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. The term "comprises" means "includes". Thus, "comprising A or B" means "including A, B, or A and B" without excluding additional elements. The term "about" will be understood by those skilled in the art. Regardless of whether the term "about" is explicitly used, all quantities given herein refer to the actual given value, and it is also meant to refer to an approximation to such a given value that would be reasonably estimated based on the skilled artisan.

[0052] It should be further understood that all base or amino acid sizes and all molecular weight or molecular mass values ​​given for nucleic acids or polypeptides are approximate and are provided for illustration purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.

[0053] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.The definition of general terms in molecular biology can be found in Benjamin Lewin, Genes V, published by Oxford University Press, 1994 (ISBN 0-19-854287-9), Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9), and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).

[0054] Unless otherwise stated, the nomenclature of substituents not expressly defined herein is arrived at by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. Those skilled in the art will recognize that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with five different groups, pentavalent carbon, etc.). Such impermissible substitution patterns are easily recognized by those skilled 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 disclosed Genbank accession numbers are incorporated by reference herein as available on August 11, 2011. In case of conflict, the present specification, including explanations of terms, will take precedence. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0055] Alkyl groups refer to monovalent groups derived from an alkane by removing a hydrogen atom from any carbon atom, including straight and branched chains of 1 to 12 carbon atoms, and typically having 1 to about 10 carbons, or in some embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl groups. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be singly or more than twice substituted, such as, but not limited to, mono-, di-, or tri-substituted. As used herein, unless otherwise indicated, the term alkyl refers to both cyclic and non-cyclic groups.

[0056] The term "cyclic alkyl" or "cycloalkyl" refers to a monovalent group derived from a cycloalkane by removing a hydrogen atom from a ring carbon atom. Cycloalkyl groups are saturated or partially saturated non-aromatic structures having single or multiple rings, including isolated, fused, bridged, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments, 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted. Representative substituted cycloalkyl groups may be mono-substituted or substituted two or more times, such as, but not limited to, mono-substituted, di-substituted, or tri-substituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of polycyclic ring systems include, but are not limited to, bicyclic [4.4.0] decane, bicyclic [2.2.1] heptane, spiro [2.2] pentane, and the like. (Cycloalkyl)oxy refers to -O-cycloalkyl. (Cycloalkyl)thio refers to -S-cycloalkyl. The term also encompasses oxidized forms of sulfur, such as -S(O)-cycloalkyl, or -S(O)2-cycloalkyl.

[0057] Alkenyl groups refer to straight chain and branched chain and cycloalkyl groups as defined above having one or more double bonds between two carbon atoms. Alkenyl groups can have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbons, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 1, 2, 3, or 4 carbon atoms. Alkenyl groups can be substituted or unsubstituted. Representative substituted alkenyl groups can be mono-substituted or substituted two or more times, such as, but not limited to, mono-substituted, di-substituted, or tri-substituted. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0058] Alkynyl groups refer to straight chain and branched chain and cycloalkyl groups as defined above having one or more double bonds between two carbon atoms. Alkynyl groups can have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbons, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 1, 2, 3, or 4 carbon atoms. Alkynyl groups can be substituted or unsubstituted. Representative substituted alkynyl groups can be singly substituted or substituted two or more times, such as, but not limited to, mono-substituted, di-substituted, or tri-substituted. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and -C≡C(CH3), among others.

[0059] Aryl groups are cyclic aromatic hydrocarbons, including single and multiple ring compounds, including multiple ring compounds containing separate and / or fused aryl groups. Aryl groups may contain 6 to about 18 ring carbons, or in some embodiments, 6 to 14 ring carbons, or even 6 to 10 ring carbons in other embodiments. Aryl groups also include heteroaryl groups, which are aromatic ring compounds containing 5 or more ring members, in which one or more ring carbon atoms are replaced with heteroatoms, such as, but not limited to, N, O, and S. Aryl groups 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-substituted, di-substituted, or tri-substituted. Aryl groups include, but are not limited to, phenyl, biphenyl, triphenyl, naphthyl, anthryl, and pyrenyl groups. Aryloxy refers to -O-aryl. Arylthio refers to -S-aryl, where aryl is as defined herein. The term also encompasses oxidized forms of sulfur, such as -S(O)-aryl, or -S(O)2-aryl. Heteroaryloxy refers to -O-heteroaryl. Heteroarylthio refers to -S-heteroaryl. The term also encompasses oxidized forms of sulfur, such as -S(O)-heteroaryl, or -S(O)2-heteroaryl. N-oxides are also contemplated. In some embodiments, the compounds of the present disclosure are in the form of N-oxides.

[0060] Suitable heterocyclyl groups include cyclic groups having atoms of at least two different elements as their ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, or S. Heterocyclyl groups can contain from 3 to about 20 ring members, or in some embodiments, from 3 to 18 ring members, or from about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring system in a heterocyclyl group can be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups can be substituted or unsubstituted. Representative substituted heterocyclyl groups can be mono- or multiply substituted, such as, but not limited to, mono-, di-, or tri-substituted. Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, and triazolyl. Heterocyclyloxy refers to -O-heterocyclyl. Heterocyclylthio refers to -S-heterocyclyl. The term also encompasses oxidized forms of sulfur, such as -S(O)-heterocyclyl, or -S(O)2-heterocyclyl.

[0061] Polycyclic or polycyclic groups refer to two or more rings in which two or more carbons are common to two adjacent rings, and the rings are "fused rings," and when the rings are linked by one common carbon atom, they are "spiro" ring systems. Rings that are linked through non-adjacent atoms are "bridged" rings. Polycyclic groups may be substituted or unsubstituted. Representative polycyclic groups may be substituted one or more times.

[0062] Halogen groups include F, Cl, Br, and I, nitro groups refer to -NO2, cyano groups refer to -CN, isocyano groups refer to -N≡C, and epoxy groups encompass structures in which an oxygen atom is directly bonded 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 with a three atom ring.

[0063] An alkoxy group is a substituted or unsubstituted alkyl group as defined above, which is single-bonded to oxygen. An alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups.

[0064] Thiol refers to -SH. Thiocarbonyl refers to (=S). Sulfonyl refers to -SO2-alkyl, -SO2-substituted alkyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclyl, and -SO2-substituted heterocyclyl. Sulfonylamino refers to -NR a SO2 alkyl, -NR a SO2-substituted alkyl, -NR a SO2 cycloalkyl, --NR a SO2-substituted cycloalkyl, -NR aSO2 aryl, -NR a SO2-substituted aryl, -NR a SO2 Heteroaryl, -NR a SO2-substituted heteroaryl, -NR a SO2Heterocyclyl, -NR a SO2-substituted heterocyclyl, each R a are independently as defined herein.

[0065] Carboxyl refers to -COOH or a salt thereof. Carboxy ester refers to -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)β-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclyl, and -C(O)O-substituted heterocyclyl. (Carboxy ester)amino refers to -NR a -C(O)O-alkyl, -NR a -C(O)O-substituted alkyl, -NR a -C(O)O-aryl, -NR a -C(O)O-substitution, -NR a -C(O)Oβ-cycloalkyl, -NR a -C(O)O-substituted cycloalkyl, -NR a -C(O)O-heteroaryl, -NR a -C(O)O-substituted heteroaryl, -NR a -C(O)O-heterocyclyl, and -NR a -C(O)O-substituted heterocyclyl, and each R a are independently as described herein. (Carboxy ester)oxy refers to -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)β-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclyl, and -OC(O)O-substituted heterocyclyl. Oxo refers to (=O).

[0066] The terms "amine" and "amino" refer to derivatives of ammonia in which one or more hydrogen atoms are replaced with substituents including, but not limited to, alkyl, alkenyl, aryl, and heterocyclyl groups. In some embodiments, a substituted amino can include -NH-CO-R. A carbamate group refers to ^O(C=O)NR1R2, where R1 and R2 are independently hydrogen, an aliphatic group, an aryl group, or a heterocyclyl group.

[0067] Aminocarbonyl is -C(O)N(R b )2, each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. b may optionally be combined with the nitrogen to which it is attached to form a heterocyclyl or substituted heterocyclyl group, provided that both R b and -C(O)N(R b )2, each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. b may optionally be combined with the nitrogen to which it is attached to form a heterocyclyl or substituted heterocyclyl group, provided that both R b and -NR a C(O)N(R b ) 2, wherein R a and each R b is as defined herein. Aminodicarbonylamino is -NR a C(O)C(O)N(R b ) 2, wherein R a and each Rb is as defined herein. Aminocarbonyloxy is -OC(O)N(R b )2, each R b are independently as defined herein. Aminosulfonyl is -SON(R b )2, each R b are independently as defined herein.

[0068] Imino is -N=R c In the formula, R c may be selected from hydrogen, aminocarbonylalkyloxy, substituted aminocarbonylalkyloxy, aminocarbonylalkylamino, and substituted aminocarbonylalkylamino.

[0069] As described herein, the compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, 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 either the same or different at all positions. The combinations of substituents envisioned by the present disclosure are preferably combinations that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more purposes disclosed herein.

[0070] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH) 0~4 R°, -(CH2) 0~4 OR°, -O(CH2) 0~4R°, -O-(CH2) 0~4 C(O)OR°, -(CH2) 0~4 CH(OR°)2, -(CH2) 0~4 SR°, -(CH2) 0~4 Ph, which may be substituted with R°, may be substituted with R° -(CH2) 0~4 O(CH2) 0-1 Ph, -CH=CHPh, which may be substituted with R°, -(CH2) which may be substituted with R° 0~4 O(CH2) 0~1 -Pyridyl, -NO2, -CN, -N3, -(CH2) 0~4 N(R°)2, -(CH2) 0~4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0~4 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0~4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0~4 C(O)R°, -C(S)R°, -(CH2) 0~4 C(O)OR°, -(CH2) 0~4 C(O)SR°, -(CH2) 0~4 C(O)OSiR°3, -(CH2) 0~4 OC(O)R°, -OC(O)(CH2) 0~4 SR°, SC(S)SR°, -(CH2) 0~4 SC(O)R°, -(CH2) 0~4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0~4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0~4 SSR°, -(CH2) 0~4 S(O)2R°, -(CH2) 0~4 S(O)2OR°, -(CH2) 0~4 OS(O)2R°, -S(O)2NR°2, -S(O)(NR°)R°, -S(O)2N=C(NR°2)2, -(CH2) 0~4S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, -SiR°3, -(C 1~4 Linear or branched alkylene)ON(R°)2, or -(C 1~4 linear or branched alkylene)C(O)ON(R°), where each R° may be substituted as defined below and is independently hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 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, notwithstanding the above definitions, two independent occurrences of R° together 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.

[0071] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° taken together with their intervening atoms) are independently halogen, -(CH2), 0~2 R ● , -(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 S.R. ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0-2NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only by one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 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 a saturated carbon atom of R° include =O and =S.

[0072] Preferred divalent substituents on a saturated carbon atom of an "optionally substituted" group are ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where R * Each independent occurrence of 1~6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbons of the "optionally substituted" group include -O(CR * 2) 2~3 O-, wherein R * Each independent occurrence of1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0073] R * Suitable substituents on the aliphatic group include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0074] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † In the formula, each R † are independently hydrogen, optionally substituted as defined below, 1~6an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of 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.

[0075] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0076] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, deuterium (e.g., D or H 2 ) or tritium (e.g., T or H 3 ) for hydrogen, or 13 C or 14 Compounds having the structures of the present invention that include the replacement of carbon with C-rich carbon are included and are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present disclosure.

[0077] The pharma- ceutically acceptable salts of the compounds described herein include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds from non-toxic organic or inorganic acids.For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like.In other cases, the compounds described may contain one or more acidic functional groups, and thus can form pharma- ceutically acceptable salts with pharma- ceutically acceptable bases. These salts can also be prepared in situ during the administration vehicle or dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharma-ceutically acceptable metal cation, ammonia, or a pharma-ceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0078] "Prodrug" refers to a derivative of an active drug that requires conversion in the body to release the active drug. In certain embodiments, the conversion reaction is an enzymatic conversion reaction. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to an active drug. "Promoiety" refers to a form of protecting group that, when used to mask a functional group in an active drug, converts the active drug into a prodrug. In some cases, the promoiety is attached to the drug via a bond that is cleaved by enzymatic or non-enzymatic means in vivo. Any convenient prodrug form of the compound of the present invention can be prepared according to the strategies and methods described, for example, by Rautio et al. ("Prodrugs: design and clinical applications", Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0079] Disclosed herein are compounds according to Formula (I), or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF0007676355000043.tif69128

[0080] In some embodiments of Formula (I), each R 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.

[0081] In some embodiments of Formula (I), m is an integer selected from 0-3.

[0082] In some embodiments of Formula (I), each A, B, and X is independently nitrogen or carbon.

[0083] In some embodiments of formula (I), P is N, O, or CR2, Q is N, O, or CR2, G is NR5 or O, and / or Z is NR5, O, S, or CR3R4. In some embodiments, R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy. In certain embodiments, each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0084] In some embodiments of formula (I), R5 is 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, TIFF0007676355000044.tif59145, L is an optionally substituted C1-C5 alkyl linker; each of X1, X2, X3, and X4 is independently a covalent bond, hydrogen, unsubstituted or substituted alkyl, or carbon, oxygen, or nitrogen, which may be substituted with an unsubstituted or substituted cycloalkyl; Y is O or S; R6 and R7 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R6 and R7 are cyclically linked and together with X2 form an optionally substituted cycloalkyl or heterocycle; each R8 is independently hydrogen, halogen, or aryl; n is an integer selected from 0 to 4; R is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; R 10 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0085] Also disclosed herein are compounds according to formula (II), or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. TIFF0007676355000045.tif60128

[0086] In some embodiments of formula (II), each R 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.

[0087] In some embodiments of Formula (II), m is an integer selected from 0-3.

[0088] In some embodiments of Formula (II), each A, B, and X is independently nitrogen or carbon.

[0089] In some embodiments of formula (II), P is N, O, or CR2, Q is N, O, or CR2, G is NR5 or O, and / or Z is NR5, O, S, or CR3R4.

[0090] In some embodiments of Formula (II), R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0091] In some embodiments of Formula (II), each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0092] In some embodiments of formula (II), 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, TIFF0007676355000046.tif61150, or R5 and R6 together with the carbon form a 3-7 membered cycloalkyl or heterocycle; L is an optionally substituted C1-C5 alkyl linker; each X1, X2, X3, and X4 is independently a carbon, oxygen, or nitrogen which may be substituted with a covalent bond, 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 cyclically linked and together with X2 form an optionally substituted cycloalkyl or heterocycle; 10 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R 11 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; R 12 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0093] Also referred to herein is the compound of formula (I'): Disclosed is a compound according to TIFF0007676355000047.tif34128, or a pharma- ceutically acceptable salt thereof, 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, a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1’ are independently hydrogen, halogen, R A , -CN, -NO2, -SF5, -O - , -OR', -NR'2, -SOR', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'COR', or -COR'; Each R A is independently 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle 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 Two R on the same carbon or A The groups, optionally together with their intervening atoms, may be two R A forming an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon to which the group is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently hydrogen or C 1~6an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 2 ' is hydrogen, R A , -OR', Selected from TIFF0007676355000048.tif98149, L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2together with Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2; R 7 ' and R 8 Each ' is independently hydrogen or an optionally substituted C 1~2 It is aliphatic.

[0094] Also referred to herein is the compound of formula (II'): Disclosed is a compound according to TIFF0007676355000049.tif34128, or a pharma- ceutically acceptable salt thereof, 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, a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1’ are independently hydrogen, halogen, R A , -CN, -NO2, -SF5, -O- , -OR', -NR'2, -SOR', -C(O)R', -C(O)NR'2, -NR'C(O)R', -NR'COR', or -COR'; Each R A is independently 1~6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocycle 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 Two R on the same carbon or A The groups, optionally together with their intervening atoms, may be two R A forming an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon to which the group is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 4 ', R 5 ', and R 6' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000050.tif97149 or R 4 ' and R 5 ' optionally form, together with the carbon to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2 together with Each R 11 ' is independentlyA , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2; R 7 ' and R 8 Each ' is independently hydrogen or an optionally substituted C 1~2 It is aliphatic.

[0095] Also referred to herein is the compound of formula (III'): Disclosed is a compound according to TIFF0007676355000051.tif46128, or a pharma- ceutically 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; TIFF0007676355000052.tif2128 is a single or double bond, Each R 1’ are independently 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 A is independently 1~6 an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 4 ', R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000053.tif97149 or R 4 ' and R 5 ' optionally form, together with the carbons to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2 ' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2.

[0096] Also referred to herein is a compound of formula (IV'): The present invention discloses a compound according to TIFF0007676355000054.tif38128, or a pharma- ceutically acceptable salt thereof, comprising: A', B', and X' are each independently a nitrogen atom or a carbon atom; Each R 1’ are independently hydrogen, halogen, R A, -CN, -NO2, -SF5, -O - , -OR', -NR'2, -SOR', -C(O)R', -C(O)NR'2-NR'C(O)R', -NR'COR', or -COR'; Each R A is independently 1~6 an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 3a ' and R 3b ' are independently hydrogen, R A , -OR', -C(O)R', -C(O)NR'2, or -CO2R', or R 3a ' and R 3b ' optionally together with their intervening atoms, R 3a ' and R 3b' forms an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the nitrogen to which it is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 ', R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000055.tif99149 or R 4 ' and R 5 ' optionally form, together with the carbons to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y' is O or S; R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 ' is hydrogen, R A or -CN, Each R 13 ' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2; R 7 ' and R 8 Each ' is independently hydrogen or an optionally substituted C 1~2 It is aliphatic.

[0097] Also referred to herein is a compound of formula (V'): The present invention discloses a compound according to TIFF0007676355000056.tif37128, or a pharma- ceutically acceptable salt thereof, wherein Each R 1’ are independently 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 A is independently 1~6an optionally substituted group selected from an aliphatic group, a phenyl group, a 4- to 7-membered saturated or partially unsaturated heterocycle 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; Each R' is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, an 8- to 10-membered bicyclic partially unsaturated or aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered bicyclic partially unsaturated or aromatic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; two R' groups on the same carbon or nitrogen, optionally taken together with their intervening atoms, form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R' groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m' is an integer selected from 0 to 3; R 4 ', R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000057.tif96149 or R 4 ' and R 5' optionally form, together with the carbons to which they are attached, an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L' is an optionally substituted C 1~5 is alkylene, X 1 ', X 3 ', and X 4 each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-; X 2 ' is a carbon atom or a nitrogen atom, Y 1 ' is O or S, R 9 ' and R 10 ' are each independently hydrogen or optionally substituted alkyl; R 9 ' and R 10 ' is a cyclic linkage, X 2 ' together with an optionally substituted 3- to 7-membered saturated carbocycle, an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'; n' is an integer selected from 0 to 4, R 12 is hydrogen, R A or -CN, Each R 13' are independently hydrogen, halogen, R A , -CN, -OR', or -NR'2.

[0098] As defined above and described herein, A' is a nitrogen atom or a carbon atom.

[0099] In some embodiments, A' is a nitrogen atom.In some embodiments, A' is a carbon atom.

[0100] In some embodiments, A' is selected from those shown in Table 1 below.

[0101] As defined above and described herein, B' is a nitrogen or carbon atom.

[0102] In some embodiments, B' is a nitrogen atom. In some embodiments, B' is a carbon atom.

[0103] In some embodiments, B' is selected from those shown in Table 1 below.

[0104] As defined above and described herein, X' is a nitrogen atom or a carbon atom.

[0105] In some embodiments, X' is a nitrogen atom. In some embodiments, X' is a carbon atom.

[0106] In some embodiments, X' is selected from those shown in Table 1 below.

[0107] As defined above and described herein, W' is a nitrogen atom or a carbon atom.

[0108] In some embodiments, W' is a nitrogen atom.In some embodiments, W' is a carbon atom.

[0109] In some embodiments, W' is selected from those shown in Table 1 below.

[0110] In some embodiments, any of the above mentioned nitrogen atoms are optionally in the form of an N-oxide.

[0111] As defined above and described herein, P' and Q' are each independently -N=, -NR'-, -CR'=, or -CR'2-.

[0112] In some embodiments, P' is -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=. In some embodiments, Q' is -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=.

[0113] In some embodiments, P' and Q' are selected from those shown in Table 1 below.

[0114] As defined above and described herein, G' is -NR'- or -O-.

[0115] In some embodiments, G' is -NR'-. In some embodiments, G' is -O-. In some embodiments, G' is -NH-. In some embodiments, G' is -NMe-.

[0116] In some embodiments, G' is selected from those shown in Table 1 below.

[0117] As defined above and described herein, Z' is =NR', =O, =S, or =CR'2.

[0118] 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.

[0119] In some embodiments, Z' is selected from those shown in Table 1 below.

[0120] As defined above and described herein, TIFF0007676355000058.tif2128 is a single or double bond.

[0121] In some embodiments, TIFF0007676355000059.tif1128 is a single bond. TIFF0007676355000060.tif1128 is a double bond.

[0122] In some embodiments, TIFF0007676355000061.tif1128 is selected from those shown in Table 1 below.

[0123] As defined above and described herein, 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 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0124] In some embodiments, Ring D' is benzo. In some embodiments, Ring D' is a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D' is a 5-7 membered saturated or partially saturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D' is TIFF0007676355000062.tif15128. In some embodiments, ring D' is TIFF0007676355000063.tif15128. In some embodiments, ring D' is TIFF0007676355000064.tif19128. In some embodiments, ring D' is TIFF0007676355000065.tif19128. In some embodiments, ring D' is TIFF0007676355000066.tif15128. In some embodiments, ring D' is TIFF0007676355000067.tif15128. In some embodiments, ring D' is TIFF0007676355000068.tif21128. In some embodiments, ring D' is TIFF0007676355000069.tif16128. In some embodiments, ring D' is TIFF0007676355000070.tif21128. In some embodiments, ring D' is TIFF0007676355000071.tif15128. In some embodiments, ring D' is TIFF0007676355000072.tif15128. In some embodiments, ring D' is TIFF0007676355000073.tif16128. In some embodiments, ring D' is TIFF0007676355000074.tif16128. In some embodiments, ring D' is TIFF0007676355000075.tif15128. In some embodiments, ring D' is TIFF0007676355000076.tif14128. In some embodiments, ring D' is TIFF0007676355000077.tif15128. In some embodiments, ring D' is TIFF0007676355000078.tif22128. In some embodiments, ring D' is TIFF0007676355000079.tif15128. In some embodiments, ring D' is TIFF0007676355000080.tif20128. In some embodiments, ring D' is TIFF0007676355000081.tif20128. In some embodiments, ring D' is TIFF0007676355000082.tif17128. In some embodiments, ring D' is TIFF0007676355000083.tif17128. In some embodiments, ring D' is TIFF0007676355000084.tif21128. In some embodiments, ring D' is TIFF0007676355000085.tif18128. In some embodiments, ring D' is TIFF0007676355000086.tif17128. In some embodiments, ring D' is TIFF0007676355000087.tif17128. In some embodiments, ring D' is TIFF0007676355000088.tif17128. In some embodiments, ring D' is The file is TIFF0007676355000089.tif22128.

[0125] In some embodiments, Ring D' is selected from those shown in Table 1 below.

[0126] Each R is as defined above and described herein. 1’ are independently 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'.

[0127] In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 ' is R A In some embodiments, R 1’ is -CN. In some embodiments, R 1 In some embodiments, R 1’ is -SF5. In some embodiments, R 1 ' is -O - In some embodiments, R 1 In some embodiments, R' is -OR'. 1 In some embodiments, R′ is NR′. 1 In some embodiments, R 1 In some embodiments, R 1’ is -C(O)R'. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R′ is —Br. 1 In some embodiments, R 1 In some embodiments, R 1In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R′ is vinyl. 1 In some embodiments, R′ is —C≡CCF3. 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1’ -OCF 3 In some embodiments, R 1’ -NHCH 3 In some embodiments, R 1 '-NHCD 3 In some embodiments, R 1 In some embodiments, R′ is —N(CD3)CO2tBu. 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1In some embodiments, R 1 In some embodiments, R 1 'teeth, TIFF0007676355000090.tif11128. In some embodiments, R 1 'teeth, TIFF0007676355000091.tif14128. In some embodiments, R 1 'teeth, TIFF0007676355000092.tif6128. In some embodiments, R 1 'teeth, TIFF0007676355000093.tif8128. In some embodiments, R 1 'teeth, TIFF0007676355000094.tif9128. In some embodiments, R 1 'teeth, TIFF0007676355000095.tif9128. In some embodiments, R 1 'teeth, TIFF0007676355000096.tif12128. In some embodiments, R 1 'teeth, TIFF0007676355000097.tif13128. In some embodiments, R 1 'teeth, TIFF0007676355000098.tif9128. In some embodiments, R 1 'teeth, TIFF0007676355000099.tif11128. In some embodiments, R 1 'teeth, TIFF0007676355000100.tif9128. In some embodiments, R 1 'teeth, TIFF0007676355000101.tif11128. In some embodiments, R 1 'teeth, TIFF0007676355000102.tif9128. In some embodiments, R 1 'teeth, TIFF0007676355000103.tif14128. In some embodiments, R 1 'teeth, TIFF0007676355000104.tif9128. In some embodiments, R 1 'teeth, TIFF0007676355000105.tif10128. In some embodiments, R 1 'teeth, TIFF0007676355000106.tif9128. In some embodiments, R 1 'teeth, TIFF0007676355000107.tif10128. In some embodiments, R 1 'teeth, TIFF0007676355000108.tif9128. In some embodiments, R 1 'teeth, TIFF0007676355000109.tif11128. In some embodiments, R 1 'teeth, TIFF0007676355000110.tif10128. In some embodiments, R 1 'teeth, TIFF0007676355000111.tif13128. In some embodiments, R 1 'teeth, TIFF0007676355000112.tif17128. In some embodiments, R 1 'teeth, TIFF0007676355000113.tif12128. In some embodiments, R 1 'teeth, TIFF0007676355000114.tif7128. In some embodiments, R 1 'teeth, TIFF0007676355000115.tif11128. In some embodiments, R 1 'teeth, TIFF0007676355000116.tif11128. In some embodiments, R 1 'teeth, The file is TIFF0007676355000117.tif9128.

[0128] In some embodiments, R 1 ' is selected from those shown in Table 1 below.

[0129] As defined above and described herein, each R' is independently hydrogen, or C 1~6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic aromatic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or aromatic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two R' groups on the same carbon or nitrogen optionally taken together with their intervening atoms form an optionally substituted 4-10 membered saturated or partially unsaturated monocyclic heterocycle having, in addition to the carbon or nitrogen to which the two R' groups are attached, 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0130] In some embodiments, R' is hydrogen. In some embodiments, R' is an optionally substituted C 1~6It is aliphatic. For example, in some embodiments, R' is -CF3, -CF2H, or -CFH2. In some embodiments, R' is an optionally substituted 3-8 membered saturated monocyclic carbocycle. In some embodiments, R' is an optionally substituted 3-8 membered partially unsaturated monocyclic carbocycle. In some embodiments, R' is an optionally substituted phenyl. In some embodiments, R' is an optionally substituted 8-10 membered bicyclic partially unsaturated carbocycle. In some embodiments, R' is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. 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, R' is an optionally substituted 5-6 membered monocyclic aromatic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R' is an optionally substituted 8-10 membered bicyclic partially unsaturated ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R' is an optionally substituted 8-10 membered bicyclic aromatic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, 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, in addition to the carbon or nitrogen to which the two R groups are attached, 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0131] In some embodiments, R' is selected from those shown in Table 1 below.

[0132] As defined above and described herein, m' is an integer selected from 0 to 4.

[0133] In some embodiments, m' is 0. In some embodiments, m' is 1. In some embodiments, m' is 2. In some embodiments, m' is 3. In some embodiments, m' is 4.

[0134] In some embodiments, m is selected from those shown in Table 1 below.

[0135] Each R is as defined above and described herein. A is independently 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle 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 a group selected from the same carbon or two R A The group is composed of two R A The group forms an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon to which it is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0136] In some embodiments, R A is optionally substituted C 1~6 In some embodiments, R A is an optionally substituted 3- to 7-membered saturated monocyclic carbocyclic ring. In some embodiments, R A is an optionally substituted 3- to 7-membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R A is optionally substituted phenyl. In some embodiments, R A is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the same carbon or two R A The groups, optionally together with their intervening atoms, may be two R AThe group forms an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the carbon to which it is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0137] As defined above, R 2 ' is hydrogen, R A , -OR', The file is TIFF0007676355000118.tif103150.

[0138] In some embodiments, R 2 In some embodiments, R 2 ' is R A In some embodiments, R 2 In some embodiments, R' is -OR'. 2 'teeth, TIFF0007676355000119.tif19128. In some embodiments, R 2 'teeth, TIFF0007676355000120.tif17128. In some embodiments, R 2 'teeth, TIFF0007676355000121.tif23128. In some embodiments, R 2 'teeth, TIFF0007676355000122.tif16128. In some embodiments, R 2 'teeth, TIFF0007676355000123.tif24128. In some embodiments, R 2 'teeth, TIFF0007676355000124.tif19128. In some embodiments, R 2 'teeth, TIFF0007676355000125.tif16128. In some embodiments, R 2 'teeth, TIFF0007676355000126.tif14128. In some embodiments, R2 'teeth, TIFF0007676355000127.tif21128. In some embodiments, R 2 'teeth, TIFF0007676355000128.tif19128. In some embodiments, R 2 'teeth, TIFF0007676355000129.tif17128. In some embodiments, R 2 'teeth, TIFF0007676355000130.tif19128. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R′ is -CD3. 2 In some embodiments, R′ is —C(CH). 2 In some embodiments, R′ is —C(CD3)3. 2 In some embodiments, R' is -C(CH3)2CH2OR'. 2 In some embodiments, R′ is —C(CH)CHOH. 2 In some embodiments, R′ is -iPr. 2 In some embodiments, R 2 'teeth, TIFF0007676355000131.tif14128. In some embodiments, R 2 'teeth, TIFF0007676355000132.tif10128. In some embodiments, R 2 'teeth, TIFF0007676355000133.tif10128. In some embodiments, R 2 'teeth, TIFF0007676355000134.tif10128. In some embodiments, R 2 'teeth, TIFF0007676355000135.tif10128. In some embodiments, R2 'teeth, TIFF0007676355000136.tif14128. In some embodiments, R 2 'teeth, The file is TIFF0007676355000137.tif13128.

[0139] In some embodiments, R 2 ' is selected from those shown in Table 1 below.

[0140] R, as defined above and described herein, 3a ' and R 3b ' are independently hydrogen, R A , -OR', -C(O)R', -C(O)NR'2, or -CO2R', or R 3a ' and R 3b ' optionally together with their intervening atoms, R 3a ' and R 3b ' forms an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the nitrogen to which it is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0141] In some embodiments, R 3a In some embodiments, R 3a ' is R A In some embodiments, R 3a In some embodiments, R' is -OR'. 3a In some embodiments, R 3a In some embodiments, R 3a In some embodiments, R 3b In some embodiments, R 3b ' is R A In some embodiments, R 3b In some embodiments, R' is -OR'. 3bIn some embodiments, R 3b In some embodiments, R 3b In some embodiments, R 3a ' and R 3b ' optionally together with their intervening atoms, R 3a ' and R 3b ' forms an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the nitrogen to which it is attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0142] In some embodiments, R 3a ' and R 3b ' is selected from those shown in Table 1 below.

[0143] As defined above, R 4 ', R 5 ', and R 6 ' are each independently hydrogen, halogen, R A , -CN, -NO2, -OR', -NR'2, TIFF0007676355000138.tif97149 or R 4 ' and R 5 ' are optionally joined together with the carbon to which they are attached to form an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] In some embodiments, R 2 In some embodiments, R 2 ' is R A In some embodiments, R 2 In some embodiments, R' is -OR'. 2In some embodiments, R′ is NR′. 2 'teeth, TIFF0007676355000139.tif19128. In some embodiments, R 2 'teeth, TIFF0007676355000140.tif17128. In some embodiments, R 2 'teeth, TIFF0007676355000141.tif23128. In some embodiments, R 2 'teeth, TIFF0007676355000142.tif16128. In some embodiments, R 2 'teeth, TIFF0007676355000143.tif24128. In some embodiments, R 2 'teeth, TIFF0007676355000144.tif19128. In some embodiments, R 2 'teeth, TIFF0007676355000145.tif16128. In some embodiments, R 2 'teeth, TIFF0007676355000146.tif15128. In some embodiments, R 2 'teeth, TIFF0007676355000147.tif21128. In some embodiments, R 2 'teeth, TIFF0007676355000148.tif19128. In some embodiments, R 2 'teeth, TIFF0007676355000149.tif17128. In some embodiments, R 2 'teeth, TIFF0007676355000150.tif19128. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R′ is -CD3.2 In some embodiments, R′ is —C(CH). 2 In some embodiments, R′ is —C(CD3)3. 2 'teeth, The file is TIFF0007676355000151.tif14128.

[0145] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 ' is R A In some embodiments, R 4 In some embodiments, R′ is —CN. 4 In some embodiments, R 4 In some embodiments, R' is -OR'. 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R′ is NR′. 4 'teeth, TIFF0007676355000152.tif19128. In some embodiments, R 4 'teeth, TIFF0007676355000153.tif17128. In some embodiments, R 4 'teeth, TIFF0007676355000154.tif23128. In some embodiments, R 4 'teeth, TIFF0007676355000155.tif16128. In some embodiments, R 4 'teeth, TIFF0007676355000156.tif24128. In some embodiments, R 4 'teeth, TIFF0007676355000157.tif19128. In some embodiments, R 4'teeth, TIFF0007676355000158.tif16128. In some embodiments, R 4 'teeth, TIFF0007676355000159.tif15128. In some embodiments, R 4 'teeth, TIFF0007676355000160.tif21128. In some embodiments, R 4 'teeth, TIFF0007676355000161.tif19128. In some embodiments, R 4 'teeth, TIFF0007676355000162.tif17128. In some embodiments, R 4 'teeth, TIFF0007676355000163.tif19128. In some embodiments, R 4 ' and R 5 ' optionally together with the carbon to which they are attached form an optionally substituted 3- to 7-membered saturated carbocyclic ring. 4 ' and R 5 ' optionally form, together with the carbon to which they are attached, an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 ' and R 5 ' optionally form, together with the carbon to which they are attached, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R′ is -CD3. 4 'teeth, The file is TIFF0007676355000164.tif12128.

[0146] In some embodiments, R5 In some embodiments, R 5 In some embodiments, R 5 ' is R A In some embodiments, R 5 In some embodiments, R′ is —CN. 5 In some embodiments, R 5 In some embodiments, R' is -OR'. 5 In some embodiments, R 5 'teeth, TIFF0007676355000165.tif19128. In some embodiments, R 5 'teeth, TIFF0007676355000166.tif17128. In some embodiments, R 5 'teeth, TIFF0007676355000167.tif23128. In some embodiments, R 5 'teeth, TIFF0007676355000168.tif16128. In some embodiments, R 5 'teeth, TIFF0007676355000169.tif24128. In some embodiments, R 5 'teeth, TIFF0007676355000170.tif19128. In some embodiments, R 5 'teeth, TIFF0007676355000171.tif16128. In some embodiments, R 5 'teeth, TIFF0007676355000172.tif15128. In some embodiments, R 5 'teeth, TIFF0007676355000173.tif21128. In some embodiments, R 5 'teeth, TIFF0007676355000174.tif19128. In some embodiments, R 5 'teeth, TIFF0007676355000175.tif17128. In some embodiments, R 5 'teeth, TIFF0007676355000176.tif19128. In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R′ is -CD3. 5 'teeth, The file is TIFF0007676355000177.tif12128.

[0147] In some embodiments, R 4 ' and R 5 'teeth, TIFF0007676355000178.tif10128. In some embodiments, R 4 ' and R 5 'teeth, TIFF0007676355000179.tif10128. In some embodiments, R 4 ' and R 5 'teeth, TIFF0007676355000180.tif10128. In some embodiments, R 4 ' and R 5 'teeth, TIFF0007676355000181.tif10128. In some embodiments, R 4 ' and R 5 'teeth, TIFF0007676355000182.tif14128. In some embodiments, R 4 ' and R 5 'teeth, The file is TIFF0007676355000183.tif13128.

[0148] In some embodiments, R 6In some embodiments, R 6 In some embodiments, R 6 ' is R A In some embodiments, R 6 In some embodiments, R′ is —CN. 6 In some embodiments, R 6 In some embodiments, R' is -OR'. 6 In some embodiments, R 6 'teeth, TIFF0007676355000184.tif19128. In some embodiments, R 6 'teeth, TIFF0007676355000185.tif17128. In some embodiments, R 6 'teeth, TIFF0007676355000186.tif23128. In some embodiments, R 6 'teeth, TIFF0007676355000187.tif16128. In some embodiments, R 6 'teeth, TIFF0007676355000188.tif24128. In some embodiments, R 6 'teeth, TIFF0007676355000189.tif19128. In some embodiments, R 6 'teeth, TIFF0007676355000190.tif16128. In some embodiments, R 6 'teeth, TIFF0007676355000191.tif15128. In some embodiments, R 6 'teeth, TIFF0007676355000192.tif21128. In some embodiments, R 6 'teeth, TIFF0007676355000193.tif19128. In some embodiments, R 6 'teeth, TIFF0007676355000194.tif17128. In some embodiments, R 6 'teeth, TIFF0007676355000195.tif18128. In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R′ is -CD3. 6 'teeth, The file is TIFF0007676355000196.tif12128.

[0149] In some embodiments, R 2 ', R 4 ', R 5 ', and R 6 Each ' is selected from those shown in Table 1 below.

[0150] L′ is an optionally substituted C 1~5 It is alkylene.

[0151] In some embodiments, L' is an optionally substituted C 1~5 In some embodiments, L' is -CH2-.

[0152] In some embodiments, L' is selected from those shown in Table 1 below.

[0153] As defined above and described herein, X 1 ', X 3 ', and X 4 Each ' is independently a divalent group selected from a covalent bond, -CR'2-, -O-, and -NR'-.

[0154] In some embodiments, X 1In some embodiments, X′ is a covalent bond. 1 In some embodiments, X′ is —CR′—. 1 In some embodiments, X′ is —O—. 1 In some embodiments, X′ is —NR′—. 3 In some embodiments, X′ is a covalent bond. 3 In some embodiments, X′ is —CR′—. 3 In some embodiments, X′ is —O—. 3 In some embodiments, X is -NR'-. 4 In some embodiments, X′ is a covalent bond. 4 In some embodiments, X′ is —CR′—. 4 In some embodiments, X′ is —O—. 4 ' is -NR'-.

[0155] In some embodiments, X 1 ', X 3 ', and X 4 ' is selected from those shown in Table 1 below.

[0156] As defined above and described herein, X 2 ' is a carbon atom or a nitrogen atom.

[0157] In some embodiments, X 2 In some embodiments, X′ is a carbon atom. 2 ' is a nitrogen atom.

[0158] In some embodiments, X 2 ' is selected from those shown in Table 1 below.

[0159] As defined above and described herein, Y' is ═O or ═S.

[0160] In some embodiments, Y' is ═O. In some embodiments, Y' is ═S.

[0161] In some embodiments, Y' is selected from those shown in Table 1 below.

[0162] R, as defined above and described herein, 9 ' and R 10 Each ' is independently hydrogen or an optionally substituted alkyl, or R 9 ' and R 10 ' is a cyclic linkage, X 2 ' together with each other form an optionally substituted ring selected from a 3- to 7-membered saturated carbocycle, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0163] In some embodiments, R 9 In some embodiments, R 9 ' may be substituted C 1~6 In some embodiments, R 10 In some embodiments, R 10 ' may be substituted C 1~6 In some embodiments, R 9 ' and R 10 ' is a cyclic linkage, X 2 Together with R′, form an optionally substituted 3- to 7-membered saturated carbocyclic ring. 9 ' and R 10 ' is a cyclic linkage, X 2 Together with R′, form an optionally substituted 5-8 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9 ' and R 10' is a cyclic linkage, X 2 Together with R′, form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 9 ' and R 10 ' is a cyclic linkage, X 2 ' together with , form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0164] In some embodiments, R 9 ' and R 10 are each selected from those shown in Table 1 below.

[0165] Each R is as defined above and described herein. 11 ' is independently A , halogen, -CN, -NO2, -NR'2, or -OR'.

[0166] In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R′ is —CN. 11 In some embodiments, R 11 In some embodiments, R 11 ' is -OR'.

[0167] In some embodiments, each R 11 are independently selected from those shown in Table 1 below.

[0168] As defined above, n' is an integer selected from 0 to 4.

[0169] 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.

[0170] R, as defined above and described herein, 12 ' is hydrogen, R A , or -CN.

[0171] In some embodiments, R 12 In some embodiments, R 12 ' is R A In some embodiments, R 12 ' is -CN.

[0172] In some embodiments, R 12 ' is selected from those shown in Table 1 below.

[0173] Each R is as defined above and described herein. 13 ' are independently hydrogen, halogen, R A , -CN, -OR', -NR'2.

[0174] In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R′ is —CN. 13 In some embodiments, R' is -OR'. 13 ' is -NR'2.

[0175] In some embodiments, R 13 ' is selected from those shown in Table 1 below.

[0176] As defined above and described herein, R 7 ' and R 8Each ' is independently hydrogen or an optionally substituted C 1~2 It is aliphatic.

[0177] In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R′ is an optionally substituted C1 aliphatic. 7 In some embodiments, R 7’ is an optionally substituted C2 aliphatic. In some embodiments, R 7 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R′ is an optionally substituted C1 aliphatic. 8 In some embodiments, R 8 In some embodiments, R′ is an optionally substituted C2 aliphatic. 8 ' is ethyl.

[0178] In some embodiments, R 7 ' and R 8 ' is selected from those shown in Table 1 below.

[0179] In some embodiments, the present disclosure provides compounds of formula (I'), where ring D' is benzo, A' is a carbon atom as shown, and R 10 ' and R 11 When ' is hydrogen, the compound of formula (I'-a) or a pharma- ceutically acceptable salt thereof, wherein B', W', X', R 1 ', R 2 Each of ', ', and m', both alone and in combination, is as defined above and described in the embodiments herein.

[0180] In some embodiments, the disclosure provides compounds of formula (I'), wherein ring D' is TIFF0007676355000198.tif15128, A' is a carbon atom, and R 10 ' and R 11 When ' is hydrogen, the compound of formula (I'-b) or a pharma- ceutically acceptable salt thereof, wherein B', W', X', R 1 ', R 2 Each of ', ', and m', both alone and in combination, is as defined above and described in the embodiments herein.

[0181] In some embodiments, the disclosure provides compounds of formula (I'), wherein ring D' is TIFF0007676355000200.tif15128, A' is a carbon atom, and R 10 ' and R 11 When ' is hydrogen, the compound of formula (I'-c) or a pharma- ceutically acceptable salt thereof, wherein B', W', X', R 1 ', R 2 Each of ', ', and m', both alone and in combination, is as defined above and described in the embodiments herein.

[0182] In some embodiments, the disclosure provides compounds of formula (I'), wherein ring D' is TIFF0007676355000202.tif16128, A' is a carbon atom, and R 10 ' and R 11 When ' is hydrogen, the compound of formula (I'-d) or a pharma- ceutically acceptable salt thereof, wherein B', W', X', R 1 ', R 2 Each of ', ', and m', both alone and in combination, is as defined above and described in the embodiments herein.

[0183] In some embodiments, the disclosure provides compounds of formula (I'), wherein ring D' is TIFF0007676355000204.tif15128, A', B', W', and X' are carbon atoms, and R 10 ' and R 11 When ' is hydrogen, the compound of formula (I'-e) or a pharma- ceutically acceptable salt thereof, wherein R 1 ', R 2 Each of ', ', and m', both alone and in combination, is as defined above and described in the embodiments herein.

[0184] The term "treatment" is used interchangeably herein with the term "method of treatment" and refers to both 1) curing, slowing, alleviating symptoms, and / or halting the progression of a diagnosed pathological condition, disease or disorder, and 2) as well as preventative / prophylactic measures. Those in need of treatment can include individuals who already have a particular medical disease or disorder, as well as those who may ultimately acquire the disorder (i.e., those at risk or in need of preventative measures).

[0185] The term "subject" as used herein refers to any individual or patient on whom the subject method is performed. Generally, the subject is a human, although as will be understood by those skilled in the art, the subject may also be an animal.

[0186] The terms "therapeutically effective amount", "effective dose", "therapeutically effective dose", "effective amount" and the like refer to an amount of the compound of interest that induces a biological or medical response in a tissue, system, animal, or human that is desired by administering the compound. Generally, the response is either an improvement in the patient's symptoms or a desired biological outcome. In some embodiments, such an amount should be sufficient to modulate adrenergic receptors.

[0187] In some embodiments, an effective amount of an adrenergic receptor modulating compound is from about 50 ng / ml to 50 pg / ml (e.g., from about 50 ng / ml to 40 pg / ml, from about 30 ng / ml to 20 pg / ml, from about 50 ng / ml to 10 μg / ml, from about 50 ng / ml to 1 μg / ml, from about 50 ng / ml to 800 ng / ml, from about 50 ng / ml to 700 ng / ml, from about 50 ng / ml to 600 ng / ml, from about 50 ng / ml to 500 ng / ml, from about 50 ng / ml to 400 ng / ml, from about 60 ng / ml to 4 In one embodiment, the amount is in the range of about 00ng / ml, about 70ng / ml to 300ng / ml, about 60ng / ml to 100ng / ml, about 65ng / ml to 85ng / ml, about 70ng / ml to 90ng / ml, about 200ng / ml to 900ng / ml, about 200ng / ml to 800ng / ml, about 200ng / ml to 700ng / ml, about 200ng / ml to 600ng / ml, about 200ng / ml to 500ng / ml, about 200ng / ml to 400ng / ml, or about 200ng / ml to about 50ng / ml).

[0188] In some embodiments, an effective amount of an adrenergic receptor modulating compound is from about 10 pg to 100 mg, e.g., from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1 ng, from about 1 ng to 10 ng, from about 10 ng to 50 ng, from about 50 ng to 150 ng, from about 150 ng to 250 ng. g, about 250ng to 500ng, about 500ng to 750ng, about 750ng to 1mg, about 1pg to 10pg, about 10pg to 50pg, about 50pg to 150pg, about 150pg to 250pg, about 250pg to 500pg, about 500pg to 750pg, about 750pg to 1mg, about 1mg to 50mg, about 1mg to 100mg, or about 50mg to 100mg. This amount can be a single dose or a total daily amount. The total daily amount can be in the range of about 10pg to 100mg, or in the range of about 100mg to 500mg, or in the range of about 500mg to 1000mg.

[0189] Also disclosed herein are pharmaceutical compositions comprising the compounds disclosed herein, e.g., compounds having the structure of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III'), Formula (IV), Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Formula (IV), Formula (VI'), and Formula (VII'). The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be administered to a patient, together with a compound of the present disclosure, and which does not destroy the pharmacological activity thereof. Pharmaceutically acceptable carriers which may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, protamine sulfate, partial glyceride mixtures of water, salts or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0190] In pharmaceutical compositions containing only the compounds described herein as active ingredients, the method of administering these compositions may further include administering additional drugs or therapeutic agents to the subject. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production, hormones and antagonists, drugs that affect gastrointestinal function, chemotherapy for microbial diseases, and / or chemotherapy for neoplastic diseases. Other pharmacological therapies include any other drug or biologic found in any drug class. For example, other drug classes can include allergy / cold / ENT therapy, painkillers, anesthetics, anti-inflammatory agents, antibacterial agents, antiviral agents, asthma / pulmonary therapy, cardiovascular therapy, dermatology therapy, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunotherapy, neurotherapy, ophthalmology therapy, psychiatric therapy, or rheumatology therapy. Other examples of drugs or therapies that may be administered with the compounds described herein include matrix metalloprotease inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

[0191] The term "therapeutically effective amount" as used herein refers to an amount of an active compound or pharmaceutical agent that elicits the biological or pharmacological response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, including one or more of the following: (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who is susceptible to the disease, condition, or disorder but has not yet experienced or displayed the pathology or symptomology of the disease; (2) inhibiting the disease, e.g., inhibiting the disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomology); and (3) ameliorating the disease, e.g., ameliorating the disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology).

[0192] In some embodiments, the compounds disclosed herein may be adrenergic receptor modulating compounds (e.g., adrenergic receptor agonists, partial agonists, or antagonists). The adrenergic receptor modulating compounds of the present disclosure may, in some embodiments, be useful for modulating the activity of a target adrenergic receptor in vitro or in vivo. Aspects of the subject methods include contacting a sample with an effective amount of an adrenergic receptor modulating compound (e.g., as described herein) to determine whether a desired activity is present.

[0193] Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the body and play important roles in the control of multiple physiological processes, including cognition, stress-related behavior, inflammation, and smooth muscle contraction / dilation, myocardial contraction, airway reactivity, and cognition. Adrenergic receptors mediate the central and peripheral actions of noradrenaline (NA) and adrenaline. There are multiple subtypes of ADRs, including α-adrenergic receptors and β-adrenergic receptors. Each subtype is expressed in a different pattern and is involved in different physiological processes. Thus, ligands that selectively target one subtype are of great utility both as research tools to identify the role of different ADR subtypes and as therapeutic agents for multiple diseases associated with dysfunction of NA and the adrenergic system.

[0194] β-adrenergic receptors further comprise three subtypes: β1-adrenergic receptors (β1-ADR), β2-adrenergic receptors (β2-ADR), and β3-adrenergic receptors (β3-ADR). These subtypes are expressed in different patterns and involved in different physiological processes, so ligands that can selectively target one subtype have therapeutic potential for multiple diseases. However, the discovery of subtype-selective ligands is challenging due to the high level of sequence homology shared by these subtypes. Many of the existing agonists for β-adrenergic receptors also exhibit poor blood-brain barrier (BBB) ​​penetration, which is necessary for drug discovery efforts for central nervous system (CNS) indications.

[0195] As a class of G protein-coupled receptors, adrenergic receptors transmit signals through G protein and β-arrestin-dependent pathways. G protein or β-arrestin signaling can mediate different physiological responses. Recently, it has been revealed that agonists can exhibit biased activation of signaling pathways. The ability of a ligand to activate a receptor and generate a response in a pathway-dependent manner has been called "signaling bias" or "functional selectivity." Because G proteins and β-arrestins mediate different physiological processes, biased agonists can provide improved therapeutic selectivity with reduced side effects. Thus, the present disclosure is directed to β-adrenergic receptor subtype-selective agonists with improved blood-brain barrier (BBB) ​​penetration.

[0196] Adrenergic receptor modulating compound can be an agonist of target adrenergic receptor.In some cases, the effective amount of adrenergic receptor modulating compound is sufficient to activate the activity related to adrenergic receptor in cell by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or more, or even more, compared to a control, for example, a control cell that shows a known receptor activity level.

[0197] Adrenergic receptor modulating compound can be a partial agonist of target adrenergic receptor.In some cases, the effective amount of adrenergic receptor modulating compound is, for example, an amount sufficient to achieve partial agonism of the adrenergic receptor in cells, where the subject compound achieves 10% or more activation of the receptor, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more activation of the receptor, relative to a control, for example, a fully activated receptor.Partial agonism can be evaluated using any convenient method, such as a cell-based assay using a known full agonist as a 100% activation control, and the relative maximum activation of the receptor can be measured relative to the full agonist.

[0198] The adrenergic receptor modulating compound can be an antagonist of the target adrenergic receptor.In some cases, the effective amount of the adrenergic receptor modulating compound is sufficient to inhibit or reduce the activity of the target adrenergic receptor in the sample by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or even more, relative to a control, for example, a sample that is not contacted with the target compound.

[0199] In some embodiments of the method, the target adrenergic receptor is a β1-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β2-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β3-adrenergic receptor. In some embodiments, the compound is an agonist of both the β1-adrenergic receptor and the β2-adrenergic receptor. In certain cases, the compound is selective for the β2-adrenergic receptor over the β1-adrenergic receptor.

[0200] The target adrenergic receptor may be one responsible for mediating an intracellular signal or pathway in the cell. In some embodiments, the sample includes a cell, and modulating the adrenergic receptor modulates a physiological process of the cell. Any convenient physiological process may be targeted for modulation in the cell using the subject methods. In some embodiments, the physiological process is a process involved in cardiac function, and in certain instances, the physiological process is a process involved in cognitive function. In certain cases, the physiological process is one involved in an inflammatory pathway or pathology. The subject methods can provide for mediation of intracellular concentrations of signaling molecules, such as cAMP, in the cell. The subject methods can provide partial or complete blocking of the target adrenergic receptor, resulting in modulation (e.g., activation) of cAMP in the sample. In some embodiments, the method does not modulate the β-arrestin pathway of the cell. In some cases, the cell is an inflammatory cell, and the function of the cell is modulated. The subject methods can provide for inhibition of an inflammatory pathway in the cell. In some cases, TNF-α is inhibited in the cell, e.g., the concentration or production of TNF-α is reduced by performing the subject methods. In certain embodiments of the method, the cell is a neuron. In some embodiments, modulation of adrenergic receptors enhances neurogenesis.

[0201] The compounds of the present disclosure may be used in conventional methods to control, prevent, or treat the diseases described herein, including, but not limited to, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia-telangiectasia, spinal dysmyopathy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis, cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), and diabetic retinopathy. Such treatment methods, their dosage levels, and requirements can be selected by those skilled in the art from available methods and techniques.

[0202] As used herein, "co-administration," "co-administered," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the described compounds may be administered simultaneously with another therapeutic agent, or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form that includes the described compounds, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "co-administered" when a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "co-administered" when a patient or individual simultaneously exhibits therapeutically appropriate levels of the agents in a particular target tissue or sample (e.g., in the brain, in serum, etc.).

[0203] When the compounds of the present disclosure are administered in combination therapy with other agents, they may be administered sequentially or simultaneously to the patient. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure includes a combination of ivermectin, or any other compound described herein, and another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0204] In some embodiments, the method of the present invention comprises administering a therapeutically effective amount of one or more additional active agents.Combination therapy means that the adrenergic receptor modulating compound can be used in combination with another therapeutic agent to treat a single disease or condition.In certain embodiments, the compound of the present disclosure is administered simultaneously with the administration of another therapeutic agent, and the other therapeutic agent can be administered as a component of a composition that includes the compound of the present disclosure or as a component of a different composition.

[0205] The compounds of the present invention can be administered in combination with other therapeutic agents in various therapeutic applications.Target therapeutic applications for combination therapy include those in which the activity of the target adrenergic receptor is a causative or compounding factor in disease progression.Thus, the subject compounds find use in combination therapy where inhibition of the target adrenergic receptor in a subject is desired.Examples of disease conditions that can be treated by combination therapy with the subject compounds include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental diseases, respiratory disorders, asthma, memory disorders, depression, inflammatory diseases, stroke, ischemic brain or tissue damage, and cancer.Target drugs that can be used in conjunction with the subject adrenergic receptor modulating compounds include, but are not limited to, antidepressants, antipsychotics, beta-blockers, vasoconstrictors, hypotensives, palliatives, chemotherapeutic agents, drugs used in Alzheimer's disease, and anti-inflammatory agents.

[0206] The adrenergic receptor modulating compounds of the present invention can be used with any drug useful for treating cardiac conditions such as cardiogenic shock, hypertension, congestive heart failure, coronary heart disease, arrhythmia, myocardial infarction, or ischemic heart disease. Drugs of interest that can be used in conjunction with the subject adrenergic receptor modulating compounds include, but are not limited to, denopamine, dobutamine, xamoterol, acebutolol, atenolol, betaxolol, bisoprolol, pindolol, esmolol, metoprolol, nebivolol, vortioxetine, carvedilol, labetalol, phentolamine, prazosin, cirazoline, methoxamine, synephrine, etilefrine, metaraminol, midrine, and coumarin.

[0207] The adrenergic receptor modulating compound of the present invention can be used with any drug useful for treating neurodegenerative or neurodevelopmental diseases, such as Alzheimer's disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue damage, Down's syndrome or autism. Drugs of interest that can be used in conjunction with the subject adrenergic receptor modulating compound include, but are not limited to, acepromazine. In some embodiments, the adrenergic receptor modulating compound of the present invention can be used in combination with a cholinesterase inhibitor or an NMDA receptor modulating agent to treat diseases, such as neurodegenerative or neurodevelopmental diseases. Drugs of interest include, but are not limited to, donepezil, aricept, galantamine, razadyne, memantine, namenda, rivastigmine, exelon, tacrine, and cognex. Other drugs of interest that may be used in conjunction with the subject adrenergic receptor modulating compounds include 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tiamenidine, tizanidine, tolonidine, ximen ... These include, but are not limited to, aztreonine, xylometazoline, aripiprazole, asenapine, atipamezole, cirazoline, clozapine, efaroxan, idazoxan, lurasidone, melperone, mianlin, mirtazapine, napitan, olanzapine, paliperidone, phenoxybenzamine, phentolamine, piribedil, rauwolscine, risperidone, rotigonin, quetiapine, norquetiapine, setiptiline, tolazoline, yohimbine, ziprasidone, and zotepine.Other drugs of interest that may be used in conjunction with the subject adrenergic receptor modulating compounds include, but are not limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levosalbutamol or levalbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol, salbutamol or albuterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, mirveterol, olodaterol, vilanterol, fenoterol, hexoprenaline, isoxsuprelin, ritodrine, salbutamol or albuterol, terbutaline, zilpeterol, ICI-118,551, and butoxamine.

[0208] The compounds utilized in the compositions and methods of the present disclosure may also be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include those that enhance biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), enhance oral availability, enhance solubility to allow administration by injection, alter metabolism, and / or alter excretion rate.

[0209] According to a preferred embodiment, the compositions of the present disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human. Such pharmaceutical compositions are used to ameliorate, treat or prevent any of the diseases described herein in the subject.

[0210] The agents of the present disclosure are often administered as pharmaceutical compositions containing active therapeutic agents, i.e., various other pharma- ceutical acceptable components. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended method of administration and therapeutic use. Depending on the desired formulation, the composition may also contain pharma- ceutical acceptable non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0211] In some embodiments, the present disclosure provides pharma- ceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described, formulated with one or more pharma- ceutically acceptable carriers (additives) and / or diluents, for use in treating diseases described herein, including, but not limited to, stroke, ischemia, Alzheimer's disease, ankylosing spondylitis, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, systemic lupus erythematosus, nephritis, ulcerative colitis, and Parkinson's disease.While it is possible to administer the compounds described alone, it is preferred to administer the compounds described herein as pharmaceutical formulations (compositions) described herein.The compounds described may be formulated for administration in any convenient manner for use in human or veterinary medicine, by analogy with other pharmaceuticals.

[0212] As described in detail, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including, for example, oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection as a sterile solution or suspension, or sustained release formulation; topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin, lungs, or buccal cavity; vaginal or rectal, e.g., as a pessary, cream, or foam; sublingually; intraocularly; transdermally, or adapted for administration to the nasal, pulmonary, and other mucosal surfaces.

[0213] Wetting agents, emulsifying agents, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0214] Examples of pharma- ceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0215] Formulations for use according to the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient. In some embodiments, this amount will range from about 5% to about 70%, about 10% to about 50%, or about 20% to about 40%.

[0216] In certain embodiments, the formulations described herein comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides, and a compound of the present disclosure. In certain embodiments, the formulations described herein render the compounds of the present disclosure orally bioavailable.

[0217] The method of preparing the formulation or composition containing the described compound comprises the step of bringing the disclosed compound into association with carrier and optionally one or more accessory ingredients.Generally, the formulation can be prepared by bringing the disclosed compound into association uniformly and intimately with liquid carrier, or finely divided solid carrier, or both, and then shaping the product as necessary.

[0218] The pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as 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, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma-ceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as those described in the Swiss Pharmacopeia (Pharmacopeia Helvetica), or similar alcohols. For formulation purposes, other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharma- ceutically acceptable solid, liquid, or other dosage forms, may also be used.

[0219] In some cases, it may be desirable to delay the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous substances that are poorly water-soluble.The absorption rate of drugs then depends on their dissolution rate, which in turn can depend on the size and crystalline form of the crystals.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drugs in oil vehicles.

[0220] Injectable depot forms are prepared by forming microencapsule matrices of the described compounds in biodegradable polymers such as polylactide-polyglycolide.The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used.Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0221] The pharmaceutical composition of the present disclosure can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.For oral administration of aqueous suspensions and solutions and propylene glycol, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners and / or flavors and / or colorants can be added.

[0222] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each containing a predetermined amount of the disclosed compound as an active ingredient. The compounds described herein may also be administered as a bolus, electuary, or paste.

[0223] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be combined with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; wetting agents, e.g., humectants, e.g., glycerol; Agents; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and solution retarders such as sodium carbonate; absorption promoters, such as absorbents such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, pharmaceutical compositions may also contain buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard shell gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0224] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets can be made in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid diluent. When a solid carrier is used, the preparation can be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary, for example, from about 25 to 800 mg, preferably from about 25 mg to 400 mg. When a liquid carrier is used, the preparation can be in the form of a sterile injectable liquid, such as, for example, a syrup, emulsion, soft gelatin capsule, ampoule or non-aqueous liquid suspension. When the composition is in the form of a capsule, any of the usual encapsulations are suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.

[0225] Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. They can alternatively or additionally be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres to provide the desired release profile. They can be formulated for rapid release, for example, lyophilization. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be compositions that release the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0226] The liquid dosage form for oral administration of the compound of the present disclosure includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can contain inert diluent commonly used in the art, such as water or other solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0227] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0228] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0229] The pharmaceutical composition of the present disclosure may also be administered in the form of suppository for rectal administration.These compositions can be prepared by mixing the compound of the present disclosure with suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature, and therefore melts in rectum to release active ingredient.Such materials include but are not limited to cocoa butter, beeswax and polyethylene glycol.

[0230] Topical administration of the pharmaceutical composition of the present disclosure is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active component suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present disclosure may also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present disclosure.

[0231] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulations, and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0232] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0233] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present disclosure to the body.The compound can be dissolved or dispersed in a suitable medium to produce such an administration form.The absorption enhancer can also be used to increase the flux of the compound through the skin.Either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel can control the rate of such flux.

[0234] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, etc. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0235] Such compositions may contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersing agents. In certain embodiments, it may be desirable to include one or more antibacterial and / or antifungal agents, such as paraben, chlorobutanol, phenol sorbic acid, etc. Alternatively or additionally, it may be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the composition. In addition, prolonged absorption of injectable pharmaceutical forms may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0236] In certain embodiments, the compounds or pharmaceutical preparations described are administered orally. In other embodiments, the compounds or pharmaceutical preparations described are administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0237] When the compounds described herein are administered to humans and animals as pharmaceuticals, they may be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0238] The preparations described herein can be given orally, parenterally, topically, or rectally. They are, of course, given in a form suitable for the relevant administration route. For example, they are given in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc. (administration by injection, infusion or inhalation, topical administration by lotion or ointment, and rectal administration by suppositories). Oral administration is preferred.

[0239] Such compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, by spray, rectally, intravaginally, parenterally, intracisternally, and topically (powders, ointments, or drops, including buccal and sublingual).

[0240] Regardless of the route of administration selected, the compounds described herein, which may be used in a suitable hydrated form, and / or pharmaceutical compositions of the disclosure, are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0241] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0242] Kits are also provided that include the disclosed adrenergic receptor modulating compounds. The disclosed system includes a collection of active agents, for example, by a medical practitioner, for administration to a subject, such as a patient. Such systems may include the adrenergic receptor modulating compounds disclosed herein and one or more additional active agents. Kits are provided that include the adrenergic receptor modulating compounds, which may include one or more doses of the adrenergic receptor modulating compounds, and optionally one or more doses of additional active agents. Conveniently, the formulations may be provided in unit dosage form. In such kits, in addition to the container containing the formulation, e.g., the unit dose, there is an information package insert that describes the use of the subject formulations in the methods as disclosed herein, e.g., instructions for using the subject unit dose to treat cell proliferative disease conditions. These instructions may be present in the systems and kits of the present invention in various forms, one or more of which may be present in the kit. One form in which these instructions may be present may be as information printed on a suitable medium or substrate, e.g., one or more pieces of paper on which the information is printed, the kit packaging, the package insert, and the like. Another means is a computer readable medium on which the information is recorded, such as a diskette, CD, etc. Yet another means that may be present is a website address that may be used via the internet to access the information at the transported site. Any convenient means may be present in the kit.

[0243] Table 1 below shows exemplary compounds of the present disclosure.

[0244] Table 1: Compounds of the present disclosure TIFF0007676355000206.tif207122TIFF0007676355000207.tif230122TIFF0007676355000208.tif208122TIFF0007676355000209.tif227122TIFF0007676355000210.tif200122TIFF0007676355000211.tif212122TIFF0007676355000212.tif207122TIFF0007676355000213.tif220122TIFF0007676355000214.tif234122TIFF0007676355000215.tif235122TIFF0007676355000216.tif221122TIFF0007676355000217.tif230122TIFF0007676355000218.tif194122TIFF0007676355000219.tif224122TIFF0007676355000220.tif206122TIFF0007676355000221.tif212122TIFF0007676355000222.tif217122TIFF0007676355000223.tif213122TIFF0007676355000224.tif195122TIFF0007676355000225.tif233122TIFF0007676355000226.tif208122TIFF0007676355000227.tif219122TIFF0007676355000228.tif227122TIFF0007676355000229.tif232122TIFF0007676355000230.tif220122TIFF0007676355000231.tif223122TIFF0007676355000232.tif221122TIFF0007676355000233.tif225122TIFF0007676355000234.tif220122TIFF0007676355000235.tif207122TIFF0007676355000236.tif221122TIFF0007676355000237.tif214122TIFF0007676355000238.tif213122TIFF0007676355000239.tif218122TIFF0007676355000240.tif188128TIFF0007676355000241.tif222122TIFF0007 676355000242.tif215122TIFF0007676355000243.tif211122TIFF0007676355000244.tif189128TIFF0007676355000245.tif2 07122TIFF0007676355000246.tif226122TIFF0007676355000247.tif218122TIFF0007676355000248.tif232122TIFF00076763 55000249.tif207122TIFF0007676355000250.tif230122TIFF0007676355000251.tif217122TIFF0007676355000252.tif37128.

[0245] Also disclosed herein is a pharmaceutical composition comprising a compound having the structure of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), Formula (VII') and a pharma- ceutically acceptable excipient. Further disclosed is a method of treating a subject having a disease associated with an adrenergic receptor, the method comprising administering to the subject a therapeutically effective amount of a compound having the structure of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), or Formula (VII'). In some embodiments, the disease is a neurodegenerative disease and the subject is a human.

[0246] In some embodiments, the disease is selected from the group consisting of myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia-telangiectasia, spinal dysmyopathy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. In some embodiments, the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, intravaginal, sublingual, or rectal routes. In one embodiment, the compound is selected from those compounds shown in Table 1.

[0247] 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 disclosure. The examples are typical of those that might be used, but other procedures, methods, or techniques known to those skilled in the art may be used instead. EXAMPLES

[0248] Example I compound synthesis TIFF0007676355000253.tif51155 Scheme 1 shows the synthesis of compound 02-1. 1 H 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) + .

[0249] TIFF0007676355000254.tif86150 Scheme 2 shows the synthesis of compound 02-2. 1 H 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) + .

[0250] TIFF0007676355000255.tif56149 Scheme 3 shows the synthesis of compound 02-3.

[0251] Step 1: Synthesis of 4-methyl-6-vinylpyridazin-3-amine. To a stirred solution of 6-chloro-4-methylpyridazin-3-amine (0.72 g, 5.01 mmol), potassium vinyl trifluoroborate (0.87 g, 6.51 mmol) and K2CO3 (2.07 g, 15.03 mmol) in dioxane / H2O (16 mL / 4 mL) was added Pd(dppf)2Cl2 (0.367 g, 0.501 mmol). The resulting mixture was purged with N2 and then heated to 85 °C for 12 h. 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 x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM / CH3OH (30 / 1 to 10 / 1) to give 4-methyl-6-vinylpyridazin-3-amine as a yellow solid (0.55 g, 82%). LC-MS: m / z 136.1 (M+1). + .

[0252] Step 2: Synthesis of 4-methyl-6-vinylpyridazine-3-N(Boc)2. To a stirred solution of 4-methyl-6-vinylpyridazin-3-amine (0.55 g, 4.1 mmol), di-tert-butyl dicarbonate (1.8 g, 8.2 mmol), and triethylamine (1.8 mL, 12.3 mmol) in dichloromethane (16 mL) was added DMAP (0.025 g, 0.21 mmol). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM / CH3OH (40 / 1 to 15 / 1) to give 4-methyl-6-vinylpyridazine-3-N(Boc)2 as a white solid (1 g, 73%). LC-MS: m / z 336.1 (M+1) + .

[0253] Step 3: Synthesis of 6-N(Boc)2-5-methylpyridazine-3-carbaldehyde. To a stirred solution of 4-methyl-6-vinylpyridazine-3-N(Boc)2 (0.5 g, 1.49 mmol) in acetone / HO (16 mL / 4 mL) was added NaIO4 (0.96 g, 4.47 mmol) and KO s O4.H2O (0.03 g, 0.075 mmol) was added. The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between EtOAc (30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with PE / EtOAc (30 / 1 to 2 / 1) to give 6-N(Boc)2-5-methylpyridazine-3-carbaldehyde (0.3 g, 59.7%). LC-MS: m / z 337.2 (M+1) + .

[0254] Step 4: Synthesis of 1-(6-N(Boc)2-5-methylpyridazin-3-yl)-2-(tert-butylamino)ethan-1-ol. tert-Butyl isocyanide (0.06 g, 0.70 mmol) was added to a stirred solution of 6-n(Boc)2-5-methylpyridazine-3-carbaldehyde (0.2 g, 0.58 mmol), hexamethylphosphoramide (0.012 g, 0.058 mmol) and SiCl4 (0.125 g, 0.66 mmol) in dichloromethane (4 mL) at -20°C. After stirring at -20°C for 4 hours, BH3NH3 (0.026 g, 0.88 mmol) was added. The mixture was stirred at room temperature for 3 hours and then diluted with dichloromethane (10 mL). The organic solution was added to an aqueous solution of Na2CO3 (10 wt%, 20 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and washed with DCM (10 mL). The aqueous layer was separated and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM / CH3OH (30 / 1 to 10 / 1) to give 1-(6-N(Boc)2-5-methylpyridazin-3-yl)-2-(tert-butylamino)ethan-1-ol (0.025 g, 10%). LC-MS: m / z 425.3 (M+1) + .

[0255] Step 5: Synthesis of 1-(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 (0.025 g, 0.058 mmol) in dichloromethane (3 mL) was added 4N HCl in dioxane (3 mL, 12 mmol). 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 (0.012 g, 59.7%). 1H NMR (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 / z 225.23(M+1) + .

[0256] TIFF0007676355000256.tif58150 Scheme 4 shows the synthesis of compound 02-4. 1 H NMR (400 MHz, chloroform-d) δ 7.83 (s, 1H), 4.45 (s, 2H), 3.88 (dd, J = 9.0, 4.9 Hz, 1H), 3.55 (dd, J = 10.4, 4.9 Hz, 1H), 3.32 (t, J = 9.7 Hz, 1H), 2.39 (d, J = 0.7 Hz, 3H), 1.06 (s, 9H), LC-MS: m / z 225.2 (M+1) + .

[0257] TIFF0007676355000257.tif75144 Scheme 5 shows the synthesis of compound 04-1.

[0258] Step 1: Synthesis of 5-bromoquinolin-2(1H)-one. (a) To a solution of 5-bromoquinoline (7.6 g, 36.5 mmol) in DCM (100 mL) was added m-CPBA (8.1 g, 47 mmol) in three portions at room temperature. Upon completion of the addition, the reaction mixture was stirred at room temperature for 3 h. After this, 1N aqueous NaOH solution (120 ml) was added to the reaction and the resulting mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give 5-bromoquinoline 1-oxide (5.1 g, 63%) as a pale yellow solid. LC-MS: m / z 223.9 (M+1) +(b) To a solution of 5-bromoquinoline 1-oxide (5.1 g, 23 mmol) in DMF (50 mL) at 0° C., trifluoroacetic anhydride (24 g, 115 mmol) was added in three portions. The reaction was then stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 (300 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give 5-bromoquinolin-2(1H)-one (4 g, 78%) as a yellow solid. LC-MS: m / z 223.9 (M+1) + .

[0259] Step 2: Synthesis of 5-acetylquinolin-2(1H)-one. To a stirred solution of 5-bromoquinolin-2(1H)-one and 1-ethoxyvinyltri-n-butyltin (1.1 eq.) in dioxane was added Pd(PPh3)4 (0.05 eq.). The resulting mixture was purged with N2 (3 times) and then heated to 120°C for 6 h. After cooling, 1.5 N HCl (2 eq.) was introduced into the flask and stirring was continued at room temperature overnight. The reaction was then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 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) + .

[0260] 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 AcOH was added pyridinium tribromide (1.2 equiv.). The resulting mixture was stirred at 40° C. overnight. After cooling to room temperature, the mixture was quenched with saturated aqueous NaHCO3. The reaction mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, 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) + .

[0261] Step 4: Synthesis of (R)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one. To a stirred solution of 5-(2-bromoacetyl)quinolin-2(1H)-one in toluene, (R)-2-methyl-CBS-oxazaborolidine (0.2 equiv.) was added at −35° C. The resulting mixture was stirred at −35° C. for 30 min. Then, BH3.THF (1N in THF, 1 equiv.) was introduced dropwise via syringe. After addition, the reaction was allowed to warm to −15° C. After 2 h, the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, 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) + .

[0262] Step 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 MeCN, tert-butylamine (60 equiv.) was added. The resulting mixture was stirred at 40° C. for 48 h. The reaction was concentrated and the residue was redissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The crude product was purified via HPLC (C18, MeCN / H2O (0.1% formic acid), (1%-100%)) to give (R)-5-(2-(tert-butylamino)-1-hydroxyethyl)quinolin-2(1H)-one (04-1) as a white solid (yield for 5 steps: 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, 1 H), 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) + .

[0263] TIFF0007676355000258.tif59154 Scheme 6 shows the synthesis of compound 04-5.

[0264] Step 1: Synthesis of 3-bromo-2-chloropyridin-4-amine. To a stirred solution of 2-chloropyridin-4-amine (10 g, 77.78 mmoL) in MeCN (250 mL) was added N-bromosuccinimide (13.8 g, 77.78 mmoL). The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, petroleum ether / EtOAc: 20 / 1 to 3 / 1) to give 3-bromo-2-chloropyridin-4-amine as a yellow solid (7.1 g, 43.9%). LC-MS: m / z 206.94, 208.97 (M+1, M+2) + .

[0265] Step 2: Synthesis of ethyl (E)-3-(4-amino-2-chloropyridin-3-yl)acrylate. To a stirred solution of 3-bromo-2-chloropyridin-4-amine (2 g, 9.6 mmol), ethyl acrylate (1.9 g, 19.3 mmol), Et3N (2.91 g, 28.8 mmol) and tricyclohexylphosphine (1.3 g, 4.8 mmol) in DMF (100 mL) was added Pd(OAc2) (431 mg, 1.9 mmol, 0.2 equiv). The resulting mixture was purged with N2 (3 times) and then heated to 100 °C for 24 h. After cooling, the reaction mixture was diluted with EtOAc (50 mL). The organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, petroleum ether / EtOAc: 30 / 1 to 1 / 1) to give (E)-ethyl 3-(4-amino-2-chloropyridin-3-yl)acrylate as a yellow solid (1.2 g, 55.3%). LC-MS: m / z 227.1, 229.1 (M+1, M+2). + .

[0266] 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 (2.5 g, 11.01 mmoL) in DIPEA (20 mL) was added DBU (3.3 g, 22.02 mmoL). The resulting mixture was stirred at 120° C. for 8 h. The reaction mixture was concentrated. The residue was purified by flash chromatography (silica, DCM / CH3OH: 40 / 1 to 15 / 1) to give 5-chloro-1,6-naphthyridin-2(1H)-one (1 g, 50.2%). LC-MS: m / z 181.0, 183.0 (M+1, M+2) + .

[0267] Steps 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 the starting material, the same procedure as in the synthesis of compound 04-1 was used to obtain (S)-5-(2-(tert-butylamino)-1-hydroxyethyl)-1,6-naphthyridin-2(1H)-one (04-5) as a white solid (12 mg, yield of 4 steps: 9.2%). 1 H 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=5.7 Hz, 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) + .

[0268] TIFF0007676355000259.tif64154 Scheme 7 shows the synthesis of compound 04-23.

[0269] 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 (2.5 g, 11.62 mmol) in DMF (20 mL) was added NaH (60%, 0.79 g, 19.75 mmol) portionwise at 0° C. The resulting mixture was stirred for 1 h, and then 2-(trimethylsilyl)ethoxymethyl chloride (3.1 mL, 2.92 g, 17.44 mmol) was added. The mixture was stirred at room temperature for 6 h. The reaction was quenched with saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with H2O (100 mL×3), 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 (1.9 g, 48%). LC-MS: m / z 346.3 M+1) + .

[0270] 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 (1.9 g, 5.51 mmol) in dioxane / HO (20 mL / 2 mL) was added potassium trifluoroborate (1.47 g, 11.01 mmol), Pd(dppf)Cl2·CH2Cl2 (0.45 g, 0.55 mmol), Cs2CO3 (5.38 g, 16.5 mmol) under N2. The mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with HO, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10% EtOAc in petroleum ether to give 7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-indazole as an oil (1.6 g, 99%). LCMS: m / z 293.3 (M+1). + .

[0271] Step 3: Synthesis of (R)-1-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)ethane-1,2-diol. To a stirred solution of 7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-indazole (1.6 g, 5.47 mmol) in tert-BuOH / H2O (20 mL / 20 mL) was added AD-mix-β (8.25 g) at 0° C., then stirred at room temperature for 16 h. After completion of the reaction, the mixture was quenched with saturated Na2SO3 solution (20 mL) 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 in 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 (2.1 g, 99%). LCMS: m / z 327.3 (M+1). + .

[0272] Step 4: Synthesis of (R)-7-fluoro-4-(oxiran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole. (i) To a stirred solution of (R)-1-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)ethane-1,2-diol (2.1 g, 6.4 mmol) in CHCl (20 mL), n-BuSnO (0.16 g, 0.64 mmol), p-TsCl (1.4 g, 7.1 mmol), and EtN (776 mg, 7.6 mmol) were added. The reaction mixture was then stirred at room temperature for 16 h. The reaction was quenched with water. The mixture was extracted with CHCl (50 mL×3). The combined organic layers were washed with water, 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 (R)-2-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-2-hydroxyethyl 4-methylbenzenesulfonate as a yellow oil (2.76 g, 90%). LCMS: m / z 481.3(M+1). + (ii) To a stirred solution of (R)-2-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-2-hydroxyethyl 4-methylbenzenesulfonate (2.76 g, 5.76 mmol) in MeOH (10 mL) was added K2CO3 (3.97 g, 28.8 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to provide a residue, which was redissolved in CHCl2. The organic layer was then washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-7-fluoro-4-(oxiran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole as an oil (2.1 g), which was used in the next step without further purification.

[0273] Step 5: Synthesis of (R)-2-(tert-butylamino)-1-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)ethan-1-ol. To a stirred solution of (R)-7-fluoro-4-(oxiran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.1 g, 6.48 mmol) in EtOH / H2O (4 mL / 8 mL) was added tert-BuNH2 (2.37 g, 32.42 mmol). The reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography eluting with 5% MeOH 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 (2 g, 81%). LCMS: m / z 382.3 (M+1). + .

[0274] Step 6: Synthesis of (R)-2-(tert-butylamino)-1-(7-fluoro-1H-indazol-4-yl)ethan-1-ol. To a stirred solution of (R)-2-(tert-butylamino)-1-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)ethan-1-ol (2 g, 5.24 mmol) in CHCl (8 mL) was added CFCOOH (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by column chromatography eluting with 10% MeOH in CHCl (containing 1% NHOH) to give (R)-2-(tert-butylamino)-1-(7-fluoro-1H-indazol-4-yl)ethan-1-ol (0.7 g, 90% purity by HPLC). The compound was further purified by reverse-phase HPLC (0.1% TFA in CHCN / HO) and lyophilized with 1N aqueous HCl (1 mL) to give (R)-2-(tert-butylamino)-1-(7-fluoro-1H-indazol-4-yl)ethan-1-ol HCl salt as a white solid (0.37 g, 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% at 254nM; LCMS: m / z 252.3(M+1) + SFC: 99% ee [AD-H column, mobile phase: HEP:IPA (0.1% DEA) = 95:5].

[0275] TIFF0007676355000260.tif72156 Scheme 8 shows the synthesis of compound 04-144 and compound 04-145.

[0276] Step 1: Synthesis of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine. To a stirred solution of 4-chloro-1H-pyrazolo[4,3-c]pyridine (4 g, 27.35 mmol) in DMF (25 mL) was added NaH (60%, 1.64 g, 41 mmol) at 0° C. The resulting mixture was stirred for 0.5 h and then SEMCl (5.93 g, 35.55 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with H2O (100 mL×3), 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 (3 g, 39%). LC-MS: m / z 284.2 M+1) + .

[0277] Step 2 - Synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrazolo[4,3-c]pyridine. To a stirred solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (3 g, 10.57 mmol) in dioxane / H2O (20 mL / 2 ml) was added potassium trifluoroborate (2.83 g, 21.14 mmol), Pd(dppf)Cl2·CH2Cl2 (856 mg, 1.05 mmol), Cs2CO3 (10.33 g, 31.71 mmol) under N2. The mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with H2O (20 mL x 2), brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10% EtOAc in petroleum ether to give 1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrazolo[4,3-c]pyridine as an oil (2.5 g, 81%). LC-MS: m / z 293.3 M+1). + .

[0278] Step 3: Synthesis of 4-(2-(tert-butylamino)-1-hydroxyethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide. To a stirred solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrazolo[4,3-c]pyridine (2.0 g, 7.26 mmol) in CHCl (10 mL) was added saturated NaHCO solution (10 mL) and mCPBA (3.76 g, 21.78 mmol) in portions. The resulting mixture was stirred for 10 min and then treated with t-BuNH 2 (2.5 g, 34.31 mmol) and EtOH (5 mL) were added. The resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography eluting with 10% CH3OH in CH2Cl2 to give 4-(2-(tert-butylamino)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide (1.2 g, 76% HPLC purity), which was used in the next step without further purification. LC-MS: m / z 381.2 M+1). + .

[0279] Step 4: Synthesis of (2-(tert-butylamino)-1-(-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol. 4-(2-(tert-butylamino)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide (0.6 g, 1.58 mmol) and 1H-pyrazolo[4,3-c]pyridine 5-oxide were reacted in EtOH (6 mL) under a hydrogen balloon. A mixture of Pd / C (10% on carbon, 0.06 g) was stirred at room temperature for 24 h and then at 60° C. for 48 h. 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 (0.3 g), which was used directly in the next step without further purification. LC-MS: m / z 365.2 M+1). +.

[0280] Step 5: Synthesis of (S)-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]pyridin-4-yl)ethan-1-ol. 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) and the mixture was stirred at 50°C for 48 hours. The mixture was purified by preparative TLC (10% CHOH in CHCl) 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 (0.11 g, 57%). LC-MS: m / z 235.2 M+1). + Racemic 2-(tert-butylamino)-1-(1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol (0.11 g, 0.47 mmol) was separated by SFC (column: IG-H; mobile phase: HEP / EtOH (0.1% DEA)=70 / 30) to give (R)-2-(tert-butylamino)-1-(1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol (0.02 g, 36%) and (S)-2-(tert-butylamino)-1-(1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol (0.02 g, 36%) as white solids. (R)-2-(tert-butylamino)-1-(1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol: 1 H 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: 98.7% ee. (S)-2-(tert-butylamino)-1-(1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol: 1 H NMR (400 MHz, 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.

[0281] Example 2 Evaluation of synthetic adrenergic receptor agonists cAMP Homogeneous Time-Resolved Fluorescence (HTRF): Experimental Methods. Compound potency was determined using the cAMP Gs Kinetic HTRF Assay (Cisbio, Cat. No. 62AM4PEC) primarily following the manufacturer's instructions and also detailed below.

[0282] Compound preparation: Candidate β-adrenergic compounds dissolved to 10 mM in DMSO are diluted in 1× Stimulation Buffer 1 (Cisbio part number 64SB1FDD) containing 1 mM 3-isobutyl-1-methylxanthene (IBMX; Cayman Chemical Company, catalog number 13347). Serially dilute to 2x the final desired concentration in 96-well V-bottom polypropylene compound microplates (Corning, catalog number 3363) in Stimulation Buffer containing 1 mM IBMX. The standard serial dilution curve is 10 points of 5-fold dilutions starting from a top concentration of 10 μM. Controls present on all assay plates are 0.1% DMSO (vehicle control), 1 μM isoproterenol (full β-adrenergic agonist control), and 15 μM xamoterol (partial β-adrenergic agonist control). Stamp 5 μL from the 2x compound plate into a white 384 round-hole well small volume HiBase assay plate (Greiner Bio-One; catalog no. 784075) to provide four technical replicates per compound, per concentration. Centrifuge the assay plate at 500 x g for 10 seconds. Prepare compounds and IBMX at 2x final doses to compensate for the addition of cells.

[0283] Cell preparation: Pre-warm 1x stimulation buffer, wash PBS (Dulbecco's phosphate buffered saline, -Mg-Ca; Caisson Labs, catalog number PBL01), assay PBS (Dulbecco's phosphate buffered saline, +Mg, +Ca+; Caisson Labs, catalog number PBL02), and Versene (0.02% EDTA disodium salt solution in PBS without calcium or magnesium, Caisson Labs, catalog number EDL01) to 37°C. Cells expressing β-adrenergic receptors were released from the surface by washing in wash PBS to remove growth medium, then incubating with Versene for 5-10 min at 37°C. Cells were harvested using assay PBS, counted manually by hemocytometer or by automated cell counter, pelleted by centrifugation (200 x g, 5 min), and resuspended to a final density of 1.5 x 10^6 cells / mL in 1x stimulation buffer at 37°C. 5 μL of the suspended cell solution (7500 cells total) was added to every well of a 384-well assay plate, the assay plate was covered with an Axygen® plate seal (Corning PCR-SP) and incubated for 30 minutes in a humidified 37° C. environment supplemented with 5% CO2.

[0284] HTRF Reagent Addition, Reading and Data Analysis: After 30 minutes of cell stimulation with test compounds, the assay plate was centrifuged at 500×g for 10 seconds and the incubation was stopped by adding 5 μL of cAMP-D2 acceptor, diluted 1:21 in Detection and Lysis Buffer 2 (Cisbio 62CL2FDF) and added to all cells. Subsequently, 5 μL of anti-cAMP-Eu donor, diluted 1:21 in Detection and Lysis Buffer 2, was added to the cells. The plate was sealed and the reaction was gently "vortexed" at 900 rpm on a Heidolph Titramax 1000 for at least 30 minutes at room temperature. The plate was centrifuged again at 500×g for 10 seconds and HTRF was measured using a Tecan Spark plate reader with 50 flashes per well. HTRF ratios (665 nm / 620 nm×10,000) were determined and plotted in GraphPad Prism to generate concentration-effect curves. Potency estimate (EC 50 and pEC 50 ) are derived from a four-parameter nonlinear regression of the concentration-effect curves, and estimates of relative efficacy are determined by comparing the size of the test compound HTRF signal window (min-max dose) to the signal window of the full agonist control, isoproterenol. Efficacy data are shown below in Tables 2 and 3.

[0285] Table 2: Pharmacological data for the compounds disclosed herein TIFF0007676355000261.tif30128EC 50 (nM): A<10nM, B=10-100nM, C=100nM-1μM, D>1μM

[0286] Table 3: Pharmacological data for compounds disclosed herein TIFF0007676355000262.tif181128TIFF0007676355000263.tif237128TIFF000767635500 0264.tif237128TIFF0007676355000265.tif237128TIFF0007676355000266.tif115128pEC 50:A>8;B=8-7;C=<7-6;D<6

[0287] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compositions and procedures described herein which are considered to be within the scope of this disclosure and covered by the following claims.

[0288] In addition to the various embodiments described in the specification above, the following additional embodiments are contemplated herein. Embodiment 1. A compound according to formula (I), or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof, comprising: TIFF0007676355000267.tif65128 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 CR2, Q is N, O, or CR2, G is NR5 or O, and / or Z is NR5, O, S, or CR3R4; R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R5 is 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; TIFF0007676355000268.tif55135, L is an optionally substituted C1-C5 alkyl linker; each X1, X2, X3, and X4 is independently a carbon, oxygen, or nitrogen substituted with a covalent bond, hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; Y is O or S; R6 and R7 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R6 and R7 are cyclically linked together with X2 to form an optionally substituted cycloalkyl or heterocycle; R8 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; R 10 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; The compound, or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. Embodiment 2. A compound according to formula (II), or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof, comprising: TIFF0007676355000269.tif65128 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 CR2, Q is N, O, or CR2, G is NR5 or O, and / or Z is NR5, O, S, or CR3R4; R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R5, R6, and R7 are independently 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; TIFF0007676355000270.tif61150; or or R5 and R6 together with the carbons form an unsubstituted or substituted 3-7 membered cycloalkyl or heterocycle, and L is an optionally substituted C1-C5 alkyl linker; each X1, X2, X3, and X4 is independently a carbon, oxygen, or nitrogen substituted with a covalent bond, 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 cyclically linked together with X2 to form an optionally substituted cycloalkyl or heterocycle; Each R 10 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R 11 is selected from the group consisting of hydrogen, halogen, cyano, nitro unsubstituted or substituted amino, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; R 12 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; The compound, or an optically pure stereoisomer, a pharma- ceutically acceptable salt, solvate, or prodrug thereof. Embodiment 3. The following structure: A compound having the formula: TIFF0007676355000271.tif46128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof. Embodiment 4. The following structure: A compound having the formula: TIFF0007676355000272.tif53128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof. Embodiment 5. The following structure: A compound having the formula: TIFF0007676355000273.tif53128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof. Embodiment 6. The following structure: A compound having the formula: TIFF0007676355000274.tif53128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof. Embodiment 7. The following structure: A compound having the formula: TIFF0007676355000275.tif46128, or an optically pure stereoisomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof. Embodiment 8. A pharmaceutical composition comprising a compound according to any one of embodiments 1-2 and a pharma- ceutically acceptable excipient. Embodiment 9. A compound according to any one of embodiments 1-7, wherein the compound is an agonist, partial agonist, or antagonist of an adrenergic receptor. Embodiment 10. A compound according to any one of embodiments 1 to 7, wherein the compound is a β1-adrenergic receptor agonist, a β2-adrenergic receptor agonist, or a non-selective β1 / β2-adrenergic receptor agonist. Embodiment 11. A compound according to any one of embodiments 1 to 7, wherein the compound is a β1-adrenergic receptor agonist. Embodiment 12. A compound according to any one of embodiments 1 to 7, wherein the compound is a β2-adrenergic receptor agonist. Embodiment 13. A compound according to any one of embodiments 1 to 7, wherein the compound is a non-selective β1 / β2-adrenergic agonist. Embodiment 14. A method for treating a subject having a disease, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 2. Embodiment 15. The method of embodiment 14, wherein the disease is an adrenergic receptor-related disease. Embodiment 16 The method of embodiment 14, wherein the disease is a neurodegenerative disease. Embodiment 17 The method of embodiment 14, wherein the subject is a human. Embodiment 18. The method according to embodiment 14, wherein the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementia, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia-telangiectasia, spinal dysmyopathy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis. Embodiment 19. The method of embodiment 14, wherein the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intraarachnoid, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, intravaginal, sublingual, or rectal routes. Embodiment 20. The disease is MCI (mild cognitive impairment), aMCI (amnestic mild cognitive impairment), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; alcohol-related 15. The method of embodiment 14, wherein the neurodegenerative disease is one or more selected from the group consisting of: dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (Parkinson's disease dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early Alzheimer's disease, and Down's syndrome (DS). Embodiment 21. The disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; The method of embodiment 14, wherein the neurodegenerative disease is one or more selected from the group consisting of: alcoholic dementia and thiamine deficiency, normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (Parkinson's disease 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's syndrome. Embodiment 23. The method of any one of embodiments 14-22, wherein administering to the subject further comprises a peripherally acting beta blocker (PABRA) along with the compound. Embodiment 24 The method of embodiment 23, wherein a peripherally acting beta blocker (PABRA) is administered to the subject prior to administration of the compound. Embodiment 25 The method of embodiment 23, wherein a peripherally acting beta blocker (PABRA) is administered to the subject simultaneously with administration of the compound. Embodiment 26 The method of any one of embodiments 14-22, wherein a β1 agonist, a β2 agonist, or a non-selective β1 / β2 agonist is administered to the patient in addition to the compound.

Claims

1. below:

1. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

2. 10. The compound of claim 1 which is an agonist, partial agonist, or antagonist of an adrenergic receptor.

3. The compound of claim 1 which is a β1-adrenergic receptor agonist, a β2-adrenergic receptor agonist, or a non-selective β1 / β2-adrenergic receptor agonist.

4. The compound of claim 1 which is a β1-adrenergic receptor agonist.

5. The compound of claim 1 which is a β2-adrenergic receptor agonist.

6. The compound of claim 1 which is a non-selective β1 / β2-adrenergic agonist.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharma- ceutically acceptable excipient.

8. A pharmaceutical composition for treating a subject having a disease, comprising a compound according to any one of claims 1 to 6.

9. The pharmaceutical composition according to claim 8, wherein the disease is an adrenergic receptor-related disease.

10. The pharmaceutical composition of claim 8, wherein the disease is a neurodegenerative disease.

11. The pharmaceutical composition of claim 8 , wherein the subject is a human.

12. 9. The pharmaceutical composition of claim 8, wherein the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia-telangiectasia, spinal dysmyopathy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis.

13. 9. The pharmaceutical composition of claim 8, which is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavernosal, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, intravaginal, sublingual, or rectal routes.

14. The disease may be MCI (mild cognitive impairment), aMCI (amnestic mild cognitive impairment), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; alcoholic dementia), and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (Parkinson's disease dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early Alzheimer's disease, and Down's syndrome (DS).

15. The disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome; Alcohol-Drug-Related Syndrome), and the like.

9. The pharmaceutical composition of claim 8, wherein the neurodegenerative disease is one or more selected from the group consisting of amyloidosis, rheumatoid arthritis ...

16. The pharmaceutical composition of any one of claims 8 to 15, wherein the subject does not have Down's syndrome.

17. The pharmaceutical composition according to any one of claims 8 to 16, which is administered to the subject in combination with a peripherally acting beta blocker (PABRA).

18. 18. The pharmaceutical composition of claim 17, wherein a peripherally acting beta blocker (PABRA) is administered to the subject prior to administration of the pharmaceutical composition.

19. 18. The pharmaceutical composition of claim 17, wherein a peripherally acting beta blocker (PABRA) is administered to the subject simultaneously with administration of the pharmaceutical composition.

20. The pharmaceutical composition of any one of claims 8 to 16, further comprising a β1 agonist, a β2 agonist, or a non-selective β1 / β2 agonist.

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