Beta adrenergic agonist and methods of using the same

Abstract

This invention relates to compounds and their use in the treatment of diseases related to adrenaline receptors.

Description

Technical Field

[0001] The present invention generally relates to compounds, and in some embodiments, to beta adrenergic agonists and their use in treating diseases associated with adrenergic receptors. Prior Art

[0002] PCT application publication No. WO2017197324 discloses “[Adrenergic] receptor modulating compounds and methods for treating a disease or condition associated with an adrenergic receptor in a subject, the methods comprising administering a therapeutically effective amount of a compound of the present invention.”

[0003] U.S. Patent Application Publication No. 20130096126 discloses a method for enhancing learning or memory, or both, in a mammal having impaired learning or memory, or both, due to a neurodegenerative disorder, the method comprising administering at least one compound or a salt thereof in an amount effective to improve learning or memory, or both, in the mammal, wherein the compound or salt thereof is a β1-adrenergic receptor agonist, partial agonist, or receptor ligand.

[0004] U.S. Patent Application Publication No. 20140235726 discloses a method for improving cognition in a patient with Down 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).

[0005] U.S. Patent Application Publication No. 20160184241 discloses "a method for improving cognition in a patient with Down syndrome, the method comprising administering to the patient intranasally one or more β2-ADR agonists or pharmaceutically acceptable salts thereof, or both, in an amount and frequency effective to improve the patient's cognition (as measured by a contextual learning test)." Summary of the Invention

[0006] The present invention is based, at least in part, on the identification of compounds that modulate adrenaline receptors and methods of using the same to treat diseases associated with adrenaline receptors. Disclosed herein are compounds according to formula (I) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. Formula (I)

[0007] In some embodiments of Formula (I), each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amine, pentafluorosulfenyl, 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.

[0008] In some embodiments of Formula (I), m is an integer selected from 0 to 3.

[0009] In some embodiments of Formula (I), each A, B, and X is independently nitrogen or carbon.

[0010] 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 of 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.

[0011] In some embodiments of Formula (I), R 5 is one or more selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, L is an optionally substituted C1-C5 alkyl linker; each of X1, X2, X3 and X4 is independently a covalent bond, carbon, oxygen or nitrogen, which is optionally substituted with 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 linked in a ring and together with X2 form an optionally substituted cycloalkyl or heterocycle; each R8 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R R is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and R is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0012] Also disclosed herein are compounds according to formula (II) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. Formula (II)

[0013] In some embodiments of Formula (II), each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amine, pentafluorosulfenyl, 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.

[0014] In some embodiments of formula (II), m is an integer selected from 0 to 3.

[0015] In some embodiments of Formula (II), each A, B, and X is independently nitrogen or carbon.

[0016] In some embodiments of Formula (II), P is N, O, or CR 2; Q is N, O, or CR 2; G is NR 5 or O; and / or Z is NR 5, O, S, or CR 3R 4.

[0017] In some embodiments of Formula (II), R 2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0018] In some embodiments of Formula (II), each of R 3 and R 4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0019] In some embodiments of Formula (II), R 5, R 6, and R 7 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, , or R 5 and R 6 together with carbon form an unsubstituted or substituted 3-7 membered cycloalkyl or heterocycle; L is an optionally substituted C1-C5 alkyl linker; each X 1, X 2, X 3 and X 4 is independently a covalent bond, carbon, oxygen or nitrogen, which is optionally substituted with hydrogen, unsubstituted or substituted alkyl or unsubstituted or substituted cycloalkyl; Y is O or S; R 8 and R 9 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R 8 and R 9 are linked in a ring and together with X 2 form an optionally substituted cycloalkyl or heterocycle; each R R 10 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; 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; and R 12 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0020] Also disclosed herein is a compound according to formula (I'): Formula (I') or a pharmaceutically 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 the group consisting of: benzo; a 5- to 9-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and a 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -O -, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the group consisting of: a C 1-6 aliphatic; a phenyl group; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: The two RA groups on the same carbon, optionally together with their intervening atoms, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon to which the two RA groups are attached; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 2' is selected from hydrogen, RA, -OR', 、 ; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and together with X 2 form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12 'is hydrogen, RA or -CN; Each R 13' is independently hydrogen, halogen, RA, -CN, -OR' or -NR' 2; and R 7′ and R 8′ are each independently hydrogen or an optionally substituted C 1-2 aliphatic.

[0021] As described herein, the structure is depicted as , including structures such as .

[0022] Also disclosed herein is a compound according to formula (II'): Formula (II') or a pharmaceutically 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 the group consisting of: benzo; a 5- to 9-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and a 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -O -, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the group consisting of: a C 1-6 aliphatic; a phenyl group; a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: The two RA groups on the same carbon, optionally together with their intervening atoms, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon to which the two RA groups are attached; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 4', R 5' and R 6' are each independently selected from hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, and ,or: R 4' and R 5' optionally form, together with the carbon atoms to which they are attached, an optionally substituted ring selected from: a 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and together with X 2 form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12 'is hydrogen, RA or -CN; Each R 13' is independently hydrogen, halogen, RA, -CN, -OR' or -NR' 2; and R 7′ and R 8′ are each independently hydrogen or an optionally substituted C 1-2 aliphatic.

[0023] Also disclosed herein is a compound according to formula (III'): Formula (III') or a pharmaceutically acceptable salt thereof, wherein: A', B' and X' are each independently a nitrogen atom or a carbon atom; P' and Q' are each independently -N=, -NR'-, -CR'= or -CR' 2-; G' is -NR'- or -O-; Z' is =NR', =O, =S or =CR' 2; is a single bond or a double bond; Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the following: C 1-6 aliphatic; phenyl; a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 4', R 5' and R 6' are each independently selected from hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, ,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 carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and, together with X 2', form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12′ is hydrogen, RA or -CN; and Each R 13′ is independently hydrogen, halogen, RA, —CN, —OR′, or —NR′ 2 .

[0024] This article further discloses a compound having the following structure: Compound 04-1 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

[0025] This article further discloses a compound having the following structure: Compound 04-2 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

[0026] This article further discloses a compound having the following structure: Compound 04-3 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

[0027] This article further discloses a compound having the following structure: Compound 04-4 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

[0028] This article further discloses a compound having the following structure: Compound 04-5 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

[0029] Also disclosed herein is a compound according to formula (IV'): Formula (IV') or a pharmaceutically acceptable salt thereof, wherein: A', B' and X' are each independently a nitrogen atom or a carbon atom; Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -O -, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the following: C 1-6 aliphatic; phenyl; a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 3a' and R 3b' are independently hydrogen, RA, -OR', -C(O)R', -C(O)NR' 2 or -CO 2R', or: R 3a' and R 3b' optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, which, in addition to the nitrogen to which R 3a' and R 3b' are attached, has 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 4', R 5' and R 6' are each independently selected from hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, ,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 carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and, together with X 2', form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12 'is hydrogen, RA or -CN; Each R 13' is independently hydrogen, halogen, RA, -CN, -OR' or -NR' 2; and R 7′ and R 8′ are each independently hydrogen or an optionally substituted C 1-2 aliphatic.

[0030] Also disclosed herein is a compound according to formula (V'): Formula (V') [] or a pharmaceutically acceptable salt thereof, wherein: Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the following: C 1-6 aliphatic; phenyl; a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 4', R 5' and R 6' are each independently selected from hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, ,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 carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and, together with X 2', form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12 is hydrogen, RA or -CN; and Each R 13′ is independently hydrogen, halogen, RA, —CN, —OR′, or —NR′ 2 .

[0031] This article further discloses a compound having the following structure: or a pharmaceutically acceptable salt thereof.

[0032] This article further discloses a compound having the following structure: or a pharmaceutically acceptable salt thereof.

[0033] Further disclosed herein is a compound according to formula (VI'): Formula (VI'), or a pharmaceutically acceptable salt thereof, wherein each of A', B', X', R1', R3a', R3b', R4', R5', R6' and m' is as defined above and as described in the Examples provided herein, used both alone and in combination.

[0034] Further disclosed herein is a compound according to formula (VII'): Formula (VII'), or a pharmaceutically acceptable salt thereof, wherein each of A', B', X', R 1', R 4', R 5', R 6' and m' is as defined above and as described in the Examples provided herein, used both alone and in combination.

[0035] Also disclosed herein is a pharmaceutical composition comprising a compound as 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'), and a pharmaceutically acceptable excipient.

[0036] In certain embodiments, the compounds disclosed herein are agonists, partial agonists, or antagonists of adrenaline receptors; in some embodiments, the compounds are β1-adrenaline receptor agonists, β2-adrenaline receptor agonists, or non-selective β1 / β2-adrenaline receptor agonists; in some embodiments, the compounds are β1-adrenaline receptor agonists; in some embodiments, the compounds are β2-adrenaline receptor agonists; in some embodiments, the compounds are non-selective β1 / β2-adrenaline agonists.

[0037] Further disclosed is a method of treating a subject suffering from a disease, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, i.e., a compound having the structure of Formula (I), (I'), (II), (II'), (III'), (IV'), (V'), (VI'), or (VII'). In some embodiments, the disease is an adrenaline receptor-related disease. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the subject is human.

[0038] In some embodiments, the disease is selected from the group: myocardial infarction, stroke, focal ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (muscular dystrophic lateral sclerosis), Huntington's disease disease), multiple sclerosis, senile dementia, subcortical dementia, atherosclerotic dementia, AIDS-related dementia, other dementia, cerebrovascular inflammation, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease disease), encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia capillary dilatation, spinal muscular dystrophy, progressive supranuclear palsy, muscle hypotonia, muscle spasm, tremor, retinal amelanosis, striatum. In some embodiments, the compound is via oral, enteral, topical, inhaled, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, superior epidermis, epiamniotic, intraarterial, intraarticular, intracardiac, penile corpus cavernosum ( intracavernous), intracutaneous, intrafocal, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, percutaneous, perivascular, intrachial, transvaginal, sublingual, or transrectal routes were administered to the individual.

[0039] In some embodiments, the disease is a neurodegenerative disease selected from the group consisting of MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Pick's disease), HD (Huntington's disease), Rett syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar ataxia, 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 Complex), prion-related diseases (CJD, etc.), depression, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (Parkinson's dementia), ADHD (Attention Deficit Hyperactivity Disorder), Alzheimer's disease (AD), early AD and Down syndrome (DS). In some embodiments, the disease is a neurodegenerative disease, and the neurodegenerative disease is one or more selected from the group consisting of: 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 (Schay-Dauer syndrome), olivopontocerebellar ataxia, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wei Kerr syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (CJD, etc.), depression, DLB (Lewy body dementia), PD In some embodiments, the subject does not have Parkinson's disease, PDD (Parkinson's disease), and ADHD (Attention Deficit Hyperactivity Disorder). In some embodiments, the subject does not have Alzheimer's disease (AD). In some embodiments, the subject does not have Down syndrome.

[0040] In certain embodiments of the methods disclosed herein, the methods comprise administering to the subject a compound as disclosed herein and a peripherally acting beta-blocker (PABRA).

[0041] As used herein, the term "peripherally acting beta-blocker (PABRA)" means a beta-adrenergic receptor antagonist or a beta-only, beta-only, or non-selective beta-blocker. Examples of selective peripherally acting beta-blockers (PABRAs) that can be used in the methods disclosed herein in certain embodiments include nadolol, atenolol, sotalol, and labetalol. In certain embodiments, the beta-blocker useful in the methods herein is one or more selected from the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, and nebivolol; in other embodiments, the methods do not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, or nebivolol as a beta-blocker.

[0042] In certain embodiments, a peripherally acting beta-blocker (PABRA) is administered to the subject prior to administration of the compound of the invention; in other embodiments, a peripherally acting beta-blocker (PABRA) is administered to the subject concurrently with administration of the compound of the invention.

[0043] In certain embodiments of the compositions and methods provided herein, one or more peripherally acting beta-blockers (PABRAs) are administered prior to or concurrently with the compounds of the invention to inhibit or eliminate peripheral β1 and / or β2 adrenergic receptor agonism by the compounds of the invention. In various embodiments, it is preferred to block peripheral β1 and / or β2 adrenergic receptors according to the compositions and methods of the invention to eliminate or at least minimize any adverse peripheral cardiac, metabolic, or muscular effects on the human being treated.

[0044] In some embodiments of the methods provided herein, a β1 agonist, a β2 agonist, or a non-selective β1 / β2 agonist other than a compound as disclosed herein is administered to the patient.

[0045] As used herein, the term "β1-agonist" is used to refer to β1-adrenergic receptor agonists or β1-ADR agonists. In certain embodiments, the term β1-agonist is understood to include compounds that are primarily β1-agonists, but may also exhibit some peripheral agonism at other adrenergic receptors (such as β2-adrenergic receptors). In this application, the terms "β1-adrenergic receptor agonist," "β1-ADR agonist," "β1AR agonist," and "β1-agonist" are used interchangeably. In certain embodiments, the term β1-ADR agonist explicitly includes both selective and partial agonists, as well as biased and unbiased agonists. Examples of β1-adrenergic agonists include xamoterol, noradrenalin, isoprenaline, dopamine, pindolol, and dobutamine, and pharmaceutically acceptable salts of any of these. Partial agonists and ligands for β1-ADR are known. Furthermore, using the method of Kolb et al., new ligands for β1-ADR can be identified by those skilled in the art through structure-based discovery. See Proc. Natl. Acad. Sci. USA 2009, 106, 6843-648.

[0046] As used herein, the term β2-agonist is used to refer to β2-adrenergic receptor agonists or β2-ADR agonists. In certain embodiments, the term β2-agonist is understood to include compounds that are primarily β2-agonists, but may also exhibit some peripheral agonism at other adrenergic receptors (such as the β1-adrenergic receptor). In this application, the terms "β2-adrenergic receptor agonist," "β2-ADR agonist," "β2AR agonist," and "β2 agonist" are used interchangeably. In some embodiments, the term β2-ADR agonist explicitly includes both selective and partial agonists. β2-agonists useful in accordance with various aspects and embodiments of the present invention may have short-acting, long-acting, or ultra-long-acting properties. Examples of short-acting β2 agonists that can be used are salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, oritodrine, isoproterenol, salmefamol, fenoterol, albuterol, and isoetharine. Examples of long-acting β2 agonists that can be used are salmeterol, bambuterol, formoterol, and clenbuterol. Examples of ultralong-acting beta2 agonists include indacaterol, vilanterol, and olodaterol.

[0047] It was unexpectedly discovered that, as demonstrated in the Examples section herein, the compounds of the present invention unexpectedly exhibit beneficial properties. For example, it was unexpectedly discovered that the compounds of the present invention act as low nM (<10 nM) partial agonists of the β2 adrenergic receptor. Implementation Method

[0048] [Cross-reference to related applications] This application claims the benefit of U.S. Provisional Application No. 62 / 869,448, filed on July 1, 2019, U.S. Provisional Application No. 62 / 934,482, filed on November 12, 2019, U.S. Provisional Application No. 63 / 018,431, filed on April 30, 2020, U.S. Serial No. 16 / 831,285, filed on March 26, 2020, and U.S. Serial No. 16 / 831,370, filed on March 26, 2020, the contents of each of which are hereby incorporated by reference in their entirety.

[0049] In the following detailed description of embodiments of the present invention, 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 embodiments of the present invention can be practiced without these specific details. In other instances, well-known methods, procedures, components, and cycles have not been described in detail to avoid unnecessarily obscuring aspects of the embodiments of the present invention.

[0050] The following explanations of terms and methods are provided to better describe the present invention and guide those of ordinary skill in the art to practice the present invention. Unless the context clearly indicates otherwise, the singular terms "a," "an," and "the" include plural referents. Similarly, the word "or" is intended to include "and," unless the context clearly indicates otherwise. The term "comprising" means "including." Thus, "comprising A or B" means "comprising A, B, or A and B" without excluding additional elements. Those of ordinary skill in the art will understand the term "about." Regardless of whether the term "about" is used explicitly or implicitly, each quantity given herein refers to the actual given value and is also intended to refer to an approximation of such a given value that would be reasonably inferred based on the context of one of ordinary skill in the art.

[0051] It should be further understood that all base sizes or amino acid sizes and all molecular weight or molecular mass values given for nucleic acids or polypeptides are approximate and are provided for descriptive purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

[0052] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the art to which the present invention belongs. Definitions of common 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).

[0053] Unless otherwise indicated, nomenclature for substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group followed by the adjacent functional groups toward the point of attachment. One of ordinary skill in the art will recognize that the above definitions are not intended to include impermissible substitution patterns (e.g., a methyl group, a pentavalent carbon, and the like substituted with five different groups). One of ordinary skill in the art readily recognizes such impermissible substitution patterns. 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 the event of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0054] An alkyl group refers to a monovalent group derived from an alkane by removing a hydrogen atom from any carbon atom, and includes straight and branched chains having 1 to 12 carbon atoms, and typically 1 to about 10 carbon atoms, or in some embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. As used herein, unless otherwise specified, the term alkyl refers to both cyclic and acyclic groups.

[0055] 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. A cycloalkyl group is a saturated or partially saturated non-aromatic structure having a single ring or multiple rings, including separated, fused, bridged, and spiro ring systems, with 3 to 14 carbon atoms, or in some embodiments, 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted. Representative substituted cycloalkyl groups can be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic ring systems include, but are not limited to, bicyclo[4.4.0]decane, bicyclo[2.2.1]heptane, spiro[2.2]pentane, and the like. (Cycloalkyl)oxy refers to -O-cycloalkyl. (Cycloalkyl)thio refers to -S-cycloalkyl. This term also encompasses oxidized forms of sulfur, such as -S(O)-cycloalkyl or -S(O)2-cycloalkyl.

[0056] Alkenyl refers to straight-chain, branched, and cyclic alkyl groups, as defined above, in which one or more double bonds are between two carbon atoms. Alkenyl groups may have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbon atoms, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH₃), -CH=C(CH₃)₂, -C(CH₃)=CH₂, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0057] Alkynyl refers to straight-chain, branched, and cyclic alkyl groups, as defined above, in which one or more triple bonds are between two carbon atoms. Alkynyl groups may have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbon atoms, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 1, 2, 3, or 4 carbon atoms. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and -C≡C(CH3), among others.

[0058] Aryl groups are cyclic aromatic hydrocarbons, including single and multiple ring compounds (including multiple ring compounds containing separate and / or fused aromatic groups). Aryl groups may contain 6 to about 18 ring carbon atoms, or in some embodiments, 6 to 14 ring carbon atoms, or even 6 to 10 ring carbon atoms 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 by heteroatoms (such as, but not limited to, N, O, and S). Aryl groups may be substituted or unsubstituted. Representative substituted aryl groups may be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Aryl groups include, but are not limited to, phenyl, biphenylene, triphenylene, naphthyl, anthracenyl, and pyrenyl. Aryloxy refers to an -O-aryl group. Arylthio refers to an -S-aryl group, where aryl is as defined herein. The term also encompasses oxidized forms of sulfur, such as -S(O)-aryl or -S(O)2-aryl. 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 invention are in the form of N-oxides.

[0059] Suitable heterocyclyl groups include cyclic groups having atoms of at least two different elements as ring members, one or more of which is a heteroatom, such as, but not limited to, N, O, or S. Heterocyclyl groups may include 3 to about 20 ring members, or in some embodiments, 3 to 18 ring members, or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring system in a heterocyclyl group may be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups may be substituted or unsubstituted. Representative substituted heterocyclyl groups may be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted. Exemplary heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxanyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl, Examples of the following include oxazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, diazepanyl, thiazepanyl, 1,2,3,6-tetrahydropyridinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolizinyl, cinnolinyl, phthalazinyl, pteridinyl, and benzothiazolyl. Heterocyclyloxy refers to an -O-heterocyclyl group. Heterocyclylthio refers to an -S-heterocyclyl group. This term also encompasses oxidized forms of sulfur, such as -S(O)-heterocyclyl or -S(O)2-heterocyclyl.

[0060] A polycyclic or polycyclic group refers to two or more rings in which two or more carbon atoms are common to two adjacent rings, in which case the rings are "fused"; if the rings are joined through a common carbon atom, they are "spiro" ring systems. Rings joined through non-adjacent atoms are "bridged." Polycyclic groups may be substituted or unsubstituted. Representative polycyclic groups may be substituted one or more times.

[0061] Halogen includes F, Cl, Br, and I; nitro refers to -NO2; cyano refers to -CN; isocyano refers to -N≡C; and epoxy encompasses structures in which an oxygen atom is directly attached to two adjacent or non-adjacent carbon atoms of a carbon chain or ring system, where the carbon chain or ring system is essentially a cyclic ether structure. Epoxides are cyclic ethers with a three-atom ring.

[0062] Alkoxy is a substituted or unsubstituted alkyl group, as defined above, singly bonded to an oxygen group. Alkoxy groups may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0063] 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 SO 2 alkyl, -NR a SO 2-substituted alkyl, -NR a SO 2 cycloalkyl, -NR a SO 2 substituted cycloalkyl, -NR a SO 2 aryl, -NR a SO 2 substituted aryl, -NR a SO 2 heteroaryl, -NR a SO 2 substituted heteroaryl, -NR a SO 2 heterocyclyl, -NR a SO 2 substituted heterocyclyl, wherein each Ra is independently as defined herein.

[0064] Carboxyl refers to -COOH or a salt thereof. Carboxyl 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. (Carboxyl ester)amino refers to -NR a C(O)O-alkyl, -NR a C(O)O-substituted alkyl, -NR a C(O)O-aryl, -NR a C(O)O-substituted aryl, -NR a C(O)β-cycloalkyl, --NR a C(O)O-substituted cycloalkyl, -NR a C(O)O-heteroaryl, --NR a C(O)O-substituted heteroaryl, -NR a C(O)O-heterocyclyl, and -NR a C(O)O-substituted heterocyclyl, where R a is as described herein. (Carboxyl 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. Pendant oxy refers to (=O).

[0065] The terms "amine" and "amino" refer to derivatives of amino in which one or more hydrogen atoms have been replaced by substituents including, but not limited to, alkyl, alkenyl, aryl, and heterocyclic groups. In some embodiments, the substituted amino group may include -NH-CO-R. A carbamate group refers to -O(C=O)NR1R2, where R1 and R2 are independently hydrogen, aliphatic, aryl, or heterocyclic.

[0066] Aminocarbonyl refers to -C(O)N(R b) 2, where each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. Furthermore, each R b may optionally be joined with the nitrogen to which it is attached to form a heterocyclyl or substituted heterocyclyl, provided that both R b are not hydrogen. Aminocarbonylalkyl refers to -alkylC(O)N(R b) 2, where each R b is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl. Furthermore, each R b may optionally be joined with the nitrogen to which it is attached to form a heterocyclyl or substituted heterocyclyl, provided that both R b are not hydrogen. Aminocarbonylamino refers to -NR a C(O)N(R b) 2, where Ra and each R b are as defined herein. Aminodicarboxy refers to -OC(O)N(R b) 2, where each R b is independently defined herein. Aminosulfonyl refers to -SO 2N(R b) 2, where each R b is independently defined herein.

[0067] Imino refers to -N=R c , wherein R c can be selected from hydrogen, aminocarbonylalkoxy, substituted aminocarbonylalkoxy, aminocarbonylalkylamino, and substituted aminocarbonylalkylamino.

[0068] As described herein, compounds of the present invention may contain "optionally substituted" moieties. Generally, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogen atoms of the designated 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 multiple positions in any given structure are substituted with multiple substituents selected from the designated group, the substituents at each position may be the same or different. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are not substantially altered when subjected to conditions that allow their production, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0069] Suitable monovalent substituents on the substitutable carbon atom of the "optionally substituted" group are independently: halogen; -(CH 2) 0-4R°; -(CH 2) 0-4OR°; -O(CH 2) 0-4R°, -O-(CH 2) 0-4C(O)OR°; -(CH 2) 0-4CH(OR°) 2; -(CH 2) 0-4SR°; -(CH 2) 0-4Ph, which may be substituted by R°; -(CH 2) 0-4O(CH 2) 0-1Ph, which may be substituted by R°; -CH=CHPh, which may be substituted by R°; -(CH 2) 0-4O(CH 2) 0-1-pyridyl, which may be substituted by R°; -NO 2; -CN; -N 3; -(CH 2) 0-4N(R°) 2; -(CH 2) 0-4N(R°)C(O)R°;-N(R°)C(S)R°;-(CH 2) 0-4N(R°)C(O)NR° 2;-N(R°)C(S)NR° 2;-(CH 2) 0-4N(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°;-(CH 2) 0-4C(O)R°;-C(S)R°;-(CH 2) 0-4C(O)OR°;-(CH 2) 0-4C(O)SR°;-(CH 2) 0-4C(O)OSiR° 3;-(CH 2) 0-4OC(O)R°;-OC(O)(CH 2) 0-4SR o;SC(S)SR°;-(CH 2) 0-4SC(O)R°;-(CH 2) 0-4C(O)NR° 2;-C(S)NR° 2;-C(S)SR°;-SC(S)SR°;-(CH 2) 0-4OC(O)NR° 2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH 2C(O)R°;-C(NOR°)R°;-(CH 2) 0-4SSR°; [-](CH 2) 0-4S(O) 2R°;-(CH 2) 0-4S(O) 2OR°;-(CH 2) 0-4OS(O) 2R°;-S(O) 2NR° 2; [-]S(O)(NR°)R°; -S(O) 2N=C(NR° 2) 2; -(CH 2) 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°) 2, wherein each R° may be substituted as defined below and is independently: hydrogen, C 1-6 aliphatic, -CH 2Ph, -O(CH 2) 0- 1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two independent occurrences of R° together with their intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below. []

[0070] -(CH 2) 0 - 2C(O)R 1; -(CH 2) 0 - 2C(O)OH; -(CH 2) 0 - 2C(O)OR 1; -(CH 2) 0 - 2SR 1; -(CH 2) 0 - 2SH; -(CH 2) 0 - 2NH 2; -(CH 2) 0 - 2NHR 1; -(CH 2) 0 - 2NR 1 2; -NO 2, -SiR 1 3; -OSiR 1 3; -C(O)SR 1; -(C 1-4 straight or branched alkylene)C(O)OR 1 or -SSR 1, wherein each R 1 is unsubstituted or, if preceded by "halo," substituted only with one or more halogens, and is independently selected from a C 1-4 aliphatic, -CH 2Ph, -O(CH 2) 0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R include =O and =S. []

[0071] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O; =S; =NNR*2; =NNHC(O)R*; =NNHC(O)OR*; =NNHS(O)2R*; =NR*; =NOR*; -O(C(R*2))2-3O-; or -S(C(R*2))2-3S-, wherein each individual occurrence of R* is selected from hydrogen, a C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bound to an adjacent substitutable carbon of an "optionally substituted" group include: -O(CR*2)2-3O-, wherein each individual occurrence of R* is selected from hydrogen, a C1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. []

[0072] Suitable substituents on the aliphatic radical of R* include: halogen; -Rl; -(haloRl); -OH, -ORl; -O(haloRl); -CN; -C(O)OH; -C(O)ORl; -NH2; -NHRl; -NRl2; or -NO2, wherein each Rl is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. []

[0073] Suitable substituents on the 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)2NR†2; -C(S)NR†2; -C(NH)NR†2; or -N(R†)S(O)2R†, wherein each R† is independently hydrogen, a C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 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, two independent occurrences of R †Together with its intervening atoms, it forms a 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. []

[0074] Suitable substituents on the aliphatic radical of R† are independently: halogen, -Rl; -(haloRl); -OH; -ORl; -O(haloRl); -CN; -C(O)OH; -C(O)ORl; -NH2; -NHRl; -NRl2; or -NO2, wherein each Rl is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. []

[0075] Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures include and are within the scope of the present invention those compounds that include the replacement of a hydrogen by a deuterium (e.g., D or H 2 ) or tritium (e.g., T or H 3 ) or the replacement of a carbon by a C- or C-enriched carbon. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0076] Pharmaceutically acceptable salts of the compounds described herein include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochlorides, hydrobromides, sulfates, sulfonates, phosphates, nitrates, and the like; and salts prepared from organic acids such as acetates, propionates, succinates, glycolates, stearates, lactates, malates, tartrates, citrates, ascorbates, palmitates, maleates, hydroxymaleates, phenylacetates, glutamate, benzoates, salicylates, p-aminobenzenesulfonates, 2-acetyloxybenzoates, fumarates, toluenesulfonates, methanesulfonates, edisylate, oxalates, isothiosulfonates, and the like. In other cases, the compounds described may contain one or more acidic functional groups and, therefore, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. Such salts can also be prepared in situ during the administration vehicle or dosage form manufacturing process, or by reacting the purified compound in its free acid form with a suitable base (such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali metal or alkaline earth metal 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.

[0077] A "prodrug" refers to a derivative of an active agent that requires a transformation in vivo to release the active agent. In certain embodiments, the transformation is enzymatic. Prodrugs are often, though not necessarily, pharmacologically inactive until converted to the active agent. A "promoiety" refers to a protective group that, when used to mask a functional group within the active agent, converts the active agent into a prodrug. In some cases, the promoiety will be bound to the drug via a bond that is cleaved enzymatically or non-enzymatically in vivo. Any suitable prodrug form of the compounds of the invention can be prepared, for example, according to the strategies and methods described by Rautio et al. ("Prodrugs: design and clinical applications," Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0078] Disclosed herein are compounds according to formula (I) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof. Formula (I)

[0079] In some embodiments of Formula (I), each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amine, pentafluorosulfenyl, 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.

[0080] In some embodiments of Formula (I), m is an integer selected from 0 to 3.

[0081] In some embodiments of Formula (I), each A, B, and X is independently nitrogen or carbon.

[0082] In some embodiments of Formula (I), P is 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 of 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.

[0083] In some embodiments of Formula (I), R 5 is one or more selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, L is an optionally substituted C1-C5 alkyl linker; each of X1, X2, X3 and X4 is independently a covalent bond, carbon, oxygen or nitrogen, which is optionally substituted with 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 linked in a ring and together with X2 form an optionally substituted cycloalkyl or heterocycle; each R8 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; R R is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and R is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0084] Also disclosed herein are compounds according to formula (II) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. Formula (II)

[0085] In some embodiments of Formula (II), each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amine, pentafluorosulfenyl, 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.

[0086] In some embodiments of formula (II), m is an integer selected from 0 to 3.

[0087] In some embodiments of Formula (II), each A, B, and X is independently nitrogen or carbon.

[0088] In some embodiments of Formula (II), P is N, O, or CR 2; Q is N, O, or CR 2; G is NR 5 or O; and / or Z is NR 5, O, S, or CR 3R 4.

[0089] In some embodiments of Formula (II), R 2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0090] In some embodiments of Formula (II), each of R 3 and R 4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0091] In some embodiments of Formula (II), R 5, R 6, and R 7 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, , or R 5 and R 6 together with carbon form an unsubstituted or substituted 3-7 membered cycloalkyl or heterocycle; L is an optionally substituted C1-C5 alkyl linker; each X 1, X 2, X 3 and X 4 is independently a covalent bond, carbon, oxygen or nitrogen, which is optionally substituted with hydrogen, unsubstituted or substituted alkyl or unsubstituted or substituted cycloalkyl; Y is O or S; R 8 and R 9 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R 8 and R 9 are linked in a ring and together with X 2 form an optionally substituted cycloalkyl or heterocycle; each R R 10 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4; 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; and R 12 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.

[0092] Also disclosed herein is a compound according to formula (I'): Formula (I') or a pharmaceutically 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 the group consisting of: benzo; a 5- to 9-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and a 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -O -, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the group consisting of: a C 1-6 aliphatic; a phenyl group; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: The two RA groups on the same carbon, optionally together with their intervening atoms, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon to which the two RA groups are attached; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 2' is selected from hydrogen, RA, -OR', 、 ; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and together with X 2 form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12 'is hydrogen, RA or -CN; Each R 13' is independently hydrogen, halogen, RA, -CN, -OR' or -NR' 2; and R 7′ and R 8′ are each independently hydrogen or an optionally substituted C 1-2 aliphatic.

[0093] Also disclosed herein is a compound according to formula (II'): Formula (II') or a pharmaceutically 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 the group consisting of: benzo; a 5- to 9-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and a 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -O -, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the group consisting of: a C 1-6 aliphatic; a phenyl group; a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: The two RA groups on the same carbon, optionally together with their intervening atoms, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon to which the two RA groups are attached; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 4', R 5' and R 6' are each independently selected from hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, ,or: R 4' and R 5' optionally form, together with the carbon atoms to which they are attached, an optionally substituted ring selected from: a 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and together with X 2 form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12 'is hydrogen, RA or -CN; Each R 13' is independently hydrogen, halogen, RA, -CN, -OR' or -NR' 2; and R 7′ and R 8′ are each independently hydrogen or an optionally substituted C 1-2 aliphatic.

[0094] Also disclosed herein is a compound according to formula (III'): Formula (III') or a pharmaceutically acceptable salt thereof, wherein: A', B' and X' are each independently a nitrogen atom or a carbon atom; P' and Q' are each independently -N=, -NR'-, -CR'= or -CR' 2-; G' is -NR'- or -O-; Z' is =NR', =O, =S or =CR' 2; is a single bond or a double bond; Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the following: C 1-6 aliphatic; phenyl; a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 4', R 5' and R 6' are each independently selected from hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, ,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 carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and, together with X 2', form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12′ is hydrogen, RA or -CN; and Each R 13′ is independently hydrogen, halogen, RA, —CN, —OR′, or —NR′ 2 .

[0095] Also disclosed herein is a compound according to formula (IV'): Formula (IV') or a pharmaceutically acceptable salt thereof, wherein: A', B' and X' are each independently a nitrogen atom or a carbon atom; Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -O -, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the following: C 1-6 aliphatic; phenyl; a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 3a' and R 3b' are independently hydrogen, RA, -OR', -C(O)R', -C(O)NR' 2 or -CO 2R', or: R 3a' and R 3b' optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, which, in addition to the nitrogen to which R 3a' and R 3b' are attached, has 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 4', R 5' and R 6' are each independently selected from hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, ,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 carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and, together with X 2', form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12 'is hydrogen, RA or -CN; Each R 13' is independently hydrogen, halogen, RA, -CN, -OR' or -NR' 2; and R 7′ and R 8′ are each independently hydrogen or an optionally substituted C 1-2 aliphatic.

[0096] Also disclosed herein is a compound according to formula (V'): Formula (V') [] or a pharmaceutically acceptable salt thereof, wherein: Each R 1' is independently hydrogen, halogen, RA, -CN, -NO 2, -SF 5, -OR', -NR' 2, -SO 2R', -C(O)R', -C(O)NR' 2, -NR'C(O)R', -NR'CO 2R' or -CO 2R'; Each RA is independently an optionally substituted group selected from the following: C 1-6 aliphatic; phenyl; a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R′ is independently hydrogen or an optionally substituted group selected from the following: C 1-6 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 heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and an 8- to 10-membered bicyclic partially unsaturated or heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: The two R' groups on the same carbon or nitrogen optionally form together with their intervening atoms an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached; m 'is an integer selected from 0 to 3; R 4', R 5' and R 6' are each independently selected from hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, ,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 carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 'is optionally substituted C 1 - 5 stretching alkyl; X 1 ', X 3 'and X 4 'are each 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, or: R 9' and R 10' are linked in a ring and, together with X 2', form an optionally substituted 3- to 7-membered saturated carbocyclic ring; 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 heterocyclic ring 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 heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 11 'is independently RA, halogen, -CN, -NO 2, -NR '2 or -OR '; n 'is an integer selected from 0 to 4; R 12 is hydrogen, RA or -CN; and Each R 13′ is independently hydrogen, halogen, RA, —CN, —OR′, or —NR′ 2 .

[0097] As defined above and described herein, A' is a nitrogen atom or a carbon atom.

[0098] In some embodiments, A' is a nitrogen atom. In some embodiments, A' is a carbon atom.

[0099] In some embodiments, A' is selected from the following [surface] Those described in [1].

[0100] As defined above and described herein, B' is a nitrogen atom or a carbon atom.

[0101] In some embodiments, B' is a nitrogen atom. In some embodiments, B' is a carbon atom.

[0102] In some embodiments, B' is selected from the following [surface] Those described in [1].

[0103] As defined above and described herein, X' is a nitrogen atom or a carbon atom.

[0104] In some embodiments, X' is a nitrogen atom. In some embodiments, X' is a carbon atom.

[0105] In some embodiments, X' is selected from the following [surface] Those described in [1].

[0106] As defined above and described herein, W' is a nitrogen atom or a carbon atom.

[0107] In some embodiments, W' is a nitrogen atom. In some embodiments, W' is a carbon atom.

[0108] In some embodiments, W' is selected from the following [surface] Those described in [1].

[0109] In some embodiments, any of the above-mentioned nitrogen atoms is optionally in the form of an N-oxide.

[0110] As defined above and described herein, P' and Q' are each independently -N=, -NR'-, -CR'=, or -CR' 2-.

[0111] 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=.

[0112] In some embodiments, P' and Q' are selected from the following [surface] Those described in [1].

[0113] As defined above and described herein, G' is -NR'- or -O-.

[0114] In some embodiments, G' is -NR'-. In some embodiments, G' is -O-. In some embodiments, G' is -NH-. In some embodiments, G' is -NMe-.

[0115] In some embodiments, G' is selected from those described in Table 1 below.

[0116] As defined above and described herein, Z' is =NR', =O, =S or =CR'2.

[0117] 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.

[0118] In some embodiments, Z' is selected from the following [surface] Those described in [1].

[0119] As defined above and described herein, It is a single bond or a double bond.

[0120] In some embodiments, is a single bond. In some embodiments, For double bonds.

[0121] In some embodiments, Selected from the following [surface] Those described in [1].

[0122] As defined above and described herein, Ring D' is a fused ring selected from the group consisting of benzo; a 5- to 9-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and a 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0123] In some embodiments, Ring D' is benzo. In some embodiments, Ring D' is a 5-9 membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D' is a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic group containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is In some embodiments, ring D' is .

[0124] In some embodiments, ring D' is selected from the following [surface] Those described in [1].

[0125] As defined above and described herein, each R 1′ is independently halogen, R A, —CN, —NO 2 , —SF 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′.

[0126] In some embodiments, R 1' is hydrogen. In some embodiments, R 1' is halogen. In some embodiments, R 1' is RA. In some embodiments, R 1' is -CN. In some embodiments, R 1' is -NO 2. In some embodiments, R 1' is -SF 5. In some embodiments, R 1' is -O -. In some embodiments, R 1' is -OR'. In some embodiments, R 1' is -NR' 2. In some embodiments, R 1' is -SO 2R'. In some embodiments, R 1' is -C(O)R'. In some embodiments, R 1' is -C(O)NR' 2. In some embodiments, R 1' is -NR'C(O)R'. In some embodiments, R 1' is -NR'CO 2R'. In some embodiments, R 1' is -CO 2R'. In some embodiments, R 1' is -Br. In some embodiments, R 1' is -Cl. In some embodiments, R 1' is -F. In some embodiments, R 1' is -CH 3. In some embodiments, R 1' is -CH 2CH 3. In some embodiments, R 1' is -CH(CH 3) 2. In some embodiments, R 1' is -CF 3. In some embodiments, R 1' is -CF 2H. In some embodiments, R 1' is -CF 2CH 3. In some embodiments, R 1' is -CH 2CF 3. In some embodiments, R 1' is -C≡CCH. In some embodiments, R 1' is vinyl. In some embodiments, R 1' is -C≡CCF 3. In some embodiments, R 1' is -CO 2H. In some embodiments, R 1' is -OH. In some embodiments, R 1' is -OCH 3. In some embodiments, R 1' is -OCH 2CH 3. In some embodiments, R 1' is -OCH(CH 3) 2. In some embodiments, R 1' is -OCF 3. In some embodiments, R 1' is -NHCH 3. In some embodiments, R 1' is -NHCD 3. In some embodiments, R 1' is -N(CD 3)CO 2tBu. In some embodiments, R 1' is -NHCH 2CH 3. In some embodiments, R 1' is -NHCH 2(CH 3) 2. In some embodiments, R 1' is -NHCH 2CF 3. In some embodiments, R 1' is -NHPh. In some embodiments, R 1' is -NHAc. In some embodiments, R 1' is -N(CH 3) 2. In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1 ' is In some embodiments, R 1' is In some embodiments, R 1 ' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1 ' is In some embodiments, R 1' is In some embodiments, R 1 ' is In some embodiments, R 1 ' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1' is In some embodiments, R 1 ' is .

[0127] In some embodiments, R 1' is selected from the following [surface] Those described in [1].

[0128] As defined above and described herein, each R' is independently hydrogen or an optionally substituted group selected from the following: C1-6 aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocycle; a phenyl group; 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 heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the 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 carbocycle or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached.

[0129] In some embodiments, R' is hydrogen. In some embodiments, R' is an optionally substituted C 1-6 aliphatic. For example, in some embodiments, R' is -CF 3, -CF 2H, or -CFH 2. In some embodiments, R' is an optionally substituted 3- to 8-membered saturated monocyclic carbocycle. In some embodiments, R' is an optionally substituted 3- to 8-membered partially unsaturated monocyclic carbocycle. In some embodiments, R' is an optionally substituted phenyl group. In some embodiments, R' is an optionally substituted 8- to 10-membered bicyclic partially unsaturated carbocycle. In some embodiments, R' is an optionally substituted 8- to 10-membered bicyclic aromatic carbocycle. In some embodiments, R' is an optionally substituted 4- to 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- to 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- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R' is an optionally substituted 8- to 10-membered bicyclic partially unsaturated ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R' is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, the two R' groups on the same carbon or nitrogen optionally form, together with their intervening atoms, an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the carbon or nitrogen to which the two R' groups are attached.

[0130] In some embodiments, R' is selected from the following [surface] Those described in [1].

[0131] As defined above and described herein, m' is an integer selected from 0 to 4.

[0132] 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.

[0133] In some embodiments, m' is selected from the following [surface] Those described in [1].

[0134] As defined above and described herein, each RA is independently an optionally substituted group selected from the group consisting of a C1-6 aliphatic; a phenyl group; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or the two RA groups on the same carbon optionally together with their intervening atoms form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the carbon to which the two RA groups are attached.

[0135] In some embodiments, RA is an optionally substituted C 1-6 aliphatic. In some embodiments, RA is an optionally substituted 3- to 7-membered saturated monocyclic carbocyclic ring. In some embodiments, RA is an optionally substituted 3- to 7-membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, RA is an optionally substituted phenyl ring. In some embodiments, RA is a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the two RA groups on the same carbon, optionally together with their intervening atoms, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the carbon atoms to which the two RA groups are attached.

[0136] As defined above, R 2' is hydrogen, RA, -OR', 、 .

[0137] In some embodiments, R 2' is hydrogen. In some embodiments, R 2' is RA. In some embodiments, R 2' is -OR'. In some embodiments, R 2' is In some embodiments, R 2' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2' is -CH 3. In some embodiments, R 2' is -CD 3. In some embodiments, R 2' is -C(CH 3) 3. In some embodiments, R 2' is -C(CD 3) 3. In some embodiments, R 2' is -C(CH 3) 2CH 2OR'. In some embodiments, R 2' is -C(CH 3) 2CH 2OH. In some embodiments, R 2' is -iPr. In some embodiments, R 2' is -CH 2iPr. In some embodiments, R 2' is In some embodiments, R 2' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is .

[0138] In some embodiments, R 2' is selected from the following [surface] Those described in [1].

[0139] As defined above and described herein, 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 'are optionally taken together with their intervening atoms to form an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen to which R 3a 'and R 3b 'are attached.

[0140] In some embodiments, R 3a' is hydrogen. In some embodiments, R 3a' is RA. In some embodiments, R 3a' is -OR'. In some embodiments, R 3a' is -C(O)R'. In some embodiments, R 3a' is -C(O)NR' 2. In some embodiments, R 3a' is -CO 2R'. In some embodiments, R 3b' is hydrogen. In some embodiments, R 3b' is RA. In some embodiments, R 3b' is -OR'. In some embodiments, R 3b' is -C(O)R'. In some embodiments, R 3b' is -C(O)NR' 2. In some embodiments, R 3b' is -CO 2R'. In some embodiments, R 3a' and R 3b' optionally, together with their intervening atoms, form an optionally substituted 4- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having, in addition to the nitrogen to which R 3a' and R 3b' are attached, 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0141] In some embodiments, R 3a' and R 3b' are selected from the following [surface] Those described in [1].

[0142] As defined above, R 4', R 5' and R 6' are each independently hydrogen, halogen, RA, -CN, -NO 2, -OR', -NR' 2, , 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 carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0143] In some embodiments, R 2' is hydrogen. In some embodiments, R 2' is RA. In some embodiments, R 2' is -OR'. In some embodiments, R 2' is -NR' 2. In some embodiments, R 2' is In some embodiments, R 2' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2 ' is In some embodiments, R 2' is -CH 3. In some embodiments, R 2' is -CD 3. In some embodiments, R 2' is -C(CH 3) 3. In some embodiments, R 2' is -C(CD 3) 3. In some embodiments, R 2' is .

[0144] In some embodiments, R 4' is hydrogen. In some embodiments, R 4' is halogen. In some embodiments, R 4' is RA. In some embodiments, R 4' is -CN. In some embodiments, R 4' is -NO 2. In some embodiments, R 4' is -OR'. In some embodiments, R 4' is -CH 2OR'. In some embodiments, R 4' is -CH 2iPr. In some embodiments, R 4' is -NR' 2. In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' is In some embodiments, R 4' and R 5' are optionally taken together with the carbon to which they are attached to form an optionally substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R 4' and R 5' are optionally taken together with the carbon to which they are attached to form an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4' and R 5' are optionally taken together with the carbon to which they are attached to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4' is -CH 3. In some embodiments, R 4' is -CD 3. In some embodiments, R 4' is .

[0145] In some embodiments, R 5' is hydrogen. In some embodiments, R 5' is halogen. In some embodiments, R 5' is RA. In some embodiments, R 5' is -CN. In some embodiments, R 5' is -NO 2. In some embodiments, R 5' is -OR'. In some embodiments, R 5' is -NR' 2. In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is In some embodiments, R 5' is -CH 3. In some embodiments, R 5' is -CD 3. In some embodiments, R 5' is .

[0146] In some embodiments, R 4' and R 5' are In some embodiments, R 4' and R 5' are In some embodiments, R 4' and R 5' are In some embodiments, R 4' and R 5' are In some embodiments, R 4' and R 5' are In some embodiments, R 4' and R 5' are .

[0147] In some embodiments, R 6' is hydrogen. In some embodiments, R 6' is halogen. In some embodiments, R 6' is RA. In some embodiments, R 6' is -CN. In some embodiments, R 6' is -NO 2. In some embodiments, R 6' is -OR'. In some embodiments, R 6' is -NR' 2. In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is In some embodiments, R 6' is -CH 3. In some embodiments, R 6' is -CD 3. In some embodiments, R 6' is .

[0148] In some embodiments, R 2', R 4', R 5' and R 6' are each selected from the following [surface] Those described in [1].

[0149] As defined above and described herein, L' is an optionally substituted C 1-5 alkylene group.

[0150] In some embodiments, L' is optionally substituted C 1-5 alkylene. In some embodiments, L' is -CH 2 -.

[0151] In some embodiments, L' is selected from the following [surface] Those described in [1].

[0152] As defined above and described herein, X 1′, X 3′, and X 4′ are each independently a divalent group selected from a covalent bond, —CR′ 2—, —O—, and —NR′—.

[0153] In some embodiments, X 1' is a covalent bond. In some embodiments, X 1' is -CR' 2-. In some embodiments, X 1' is -O-. In some embodiments, X 1' is -NR'-. In some embodiments, X 3' is a covalent bond. In some embodiments, X 3' is -CR' 2-. In some embodiments, X 3' is -O-. In some embodiments, X 3' is -NR'-. In some embodiments, X 4' is a covalent bond. In some embodiments, X 4' is -CR' 2-. In some embodiments, X 4' is -O-. In some embodiments, X 4' is -NR'-.

[0154] In some embodiments, X1', X3' and X4' are selected from the following [surface] Those described in [1].

[0155] As defined above and described herein, X 2′ is a carbon atom or a nitrogen atom.

[0156] In some embodiments, X 2' is a carbon atom. In some embodiments, X 2' is a nitrogen atom.

[0157] In some embodiments, X 2' is selected from the following [surface] Those described in [1].

[0158] As defined above and described herein, Y' is ═O or ═S.

[0159] In some embodiments, Y' is =0. In some embodiments, Y' is =S.

[0160] In some embodiments, Y' is selected from the following [surface] Those described in [1].

[0161] As defined above and described herein, R 9′ and R 10′ are each independently hydrogen or optionally substituted alkyl, or R 9′ and R 10′ are linked in a ring and, together with X 2′, form an optionally substituted ring selected from: a 3- to 7-membered saturated carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0162] In some embodiments, R 9′ is hydrogen. In some embodiments, R 9′ is optionally substituted C 1-6 alkyl. In some embodiments, R 10′ is hydrogen. In some embodiments, R 10′ is optionally substituted C 1-6 alkyl. In some embodiments, R 9′ and R 10′ are linked in a ring and, together with X 2′, form an optionally substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R 9′ and R 10′ are linked in a ring and, together with X 2′, form an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 9′ and R 10′ are linked in a ring and, together with X 2′, form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 9′ and R 10′ are linked in a ring and, together with X 2′, form an optionally substituted 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0163] In some embodiments, R 9' and R 10' are each selected from the following [surface] Those described in [1].

[0164] As defined above and described herein, each R 11′ is independently RA, halogen, —CN, —NO 2 , —NR′ 2 , or —OR′.

[0165] In some embodiments, R 11′ is hydrogen. In some embodiments, R 11′ is halogen. In some embodiments, R 11′ is -CN. In some embodiments, R 11′ is -NO 2. In some embodiments, R 11′ is -NR' 2. In some embodiments, R 11′ is -OR'.

[0166] In some embodiments, each R 11' is independently selected from the following [surface] Those described in [1].

[0167] As defined above, n' is an integer selected from 0 to 4.

[0168] 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.

[0169] As defined above and described herein, R 12′ is hydrogen, RA or —CN.

[0170] In some embodiments, R 12′ is hydrogen. In some embodiments, R 12′ is RA. In some embodiments, R 12′ is -CN.

[0171] In some embodiments, R 12′ is selected from the following [surface] Those described in [1].

[0172] As defined above and described herein, each R 13′ is independently hydrogen, halogen, RA, —CN, —OR′, —NR′ 2 .

[0173] In some embodiments, R 13′ is hydrogen. In some embodiments, R 13′ is halogen. In some embodiments, R 13′ is -CN. In some embodiments, R 13′ is -OR′. In some embodiments, R 13′ is -NR′ 2.

[0174] In some embodiments, R 13' is selected from the following [surface] Those described in [1].

[0175] As defined above and described herein, R 7′ and R 8′ are each independently hydrogen or an optionally substituted C 1-2 aliphatic.

[0176] In some embodiments, R 7′ is hydrogen. In some embodiments, R 7′ is an optionally substituted C 1 aliphatic. In some embodiments, R 7′ is methyl. In some embodiments, R 7′ is an optionally substituted C 2 aliphatic. In some embodiments, R 7′ is ethyl. In some embodiments, R 8′ is hydrogen. In some embodiments, R 8′ is an optionally substituted C 1 aliphatic. In some embodiments, R 8′ is methyl. In some embodiments, R 8′ is an optionally substituted C 2 aliphatic. In some embodiments, R 8′ is ethyl.

[0177] In some embodiments, R 7' and R 8' are selected from the following [surface] Those described in [1].

[0178] In some embodiments, the present invention provides a compound of formula (I'), wherein, as shown, ring D' is benzo, A' is a carbon atom, and R 10' and R 11' are hydrogen, to provide a compound of formula (I'-a): Formula (I'-a) [] or a pharmaceutically acceptable salt thereof, wherein each of B', W', X', R 1', R 2' and m' is as defined above and described in the embodiments herein, both individually and in combination.

[0179] In some embodiments, the present invention provides a compound of formula (I'), wherein, as shown, ring D' is , A' is a carbon atom, and R 10' and R 11' are hydrogen, to provide a compound of formula (I'-b): Formula (I'-b) [] or a pharmaceutically acceptable salt thereof, wherein each of B', W', X', R 1', R 2' and m' is as defined above and described in the embodiments herein, both individually and in combination.

[0180] In some embodiments, the present invention provides a compound of formula (I'), wherein, as shown, ring D' is , A' is a carbon atom, and R 10' and R 11' are hydrogen, to provide a compound of formula (I'-c): Formula (I'-c) or a pharmaceutically acceptable salt thereof, wherein each of B', W', X', R 1', R 2' and m' is as defined above and described in the embodiments herein, both individually and in combination.

[0181] In some embodiments, the present invention provides a compound of formula (I'), wherein, as shown, ring D' is , A' is a carbon atom, and R 10' and R 11' are hydrogen, to provide a compound of formula (I'-d): Formula (I'-d) [] or a pharmaceutically acceptable salt thereof, wherein each of B', W', X', R 1', R 2' and m' is as defined above and described in the embodiments herein, both individually and in combination.

[0182] In some embodiments, the present invention provides a compound of formula (I'), wherein, as shown, ring D' is , A', B', W' and X' are carbon atoms, and R 10' and R 11' are hydrogen, to provide a compound of formula (I'-e): Formula (I'-e) [] or a pharmaceutically acceptable salt thereof, wherein each of R 1', R 2' and m' is as defined above and described in the Examples herein, both individually and in combination.

[0183] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to: 1) therapeutic treatment or measures that cure, alleviate, lessen the symptoms of, and / or halt the progression of a diagnosed pathological condition, disease, or disorder; and 2) prophylactic / preventative measures. Those in need of treatment may include those already suffering from a particular medical disease or disorder as well as those who may eventually develop the disorder (i.e., those who are at risk or in need of preventative measures).

[0184] As used herein, the term "subject" refers to any individual or patient who performs the methods of the present invention. Generally, the subject is a human, but as will be appreciated by those skilled in the art, the subject may be an animal.

[0185] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," or the like, refer to an amount of a compound of the invention that will elicit the biological or medical response in a tissue, system, animal, or human being for which the compound is administered. Generally, the response is an improvement in a patient's symptoms or a desired biological outcome. In some embodiments, such an amount is sufficient to modulate adrenaline receptors.

[0186] In some embodiments, the effective amount of the adrenaline receptor modulating compound is an amount ranging from about 50 ng / ml to 50 pg / ml (e.g., about 50 ng / ml to 40 pg / ml, about 30 ng / ml to 20 pg / ml, about 50 ng / ml to 10 μg / ml, about 50 ng / ml to 1 μg / ml, about 50 ng / ml to 800 ng / ml, about 50 ng / ml to 700 ng / ml, about 50 ng / ml to 600 ng / ml, about 50 ng / ml to 500 ng / ml, about 50 ng / ml to 400 ng / ml, about 60 ng / ml to 400 ng / ml, about 70 ng / ml to 300 ng / ml, about 60 ng / ml to 100 ng / ml, about 65 ng / ml to 85 ng / ml, about 70 ng / ml to 90 ng / ml, about 200 ng / ml to 900 ng / ml, about 200 ng / ml to 800 ng / ml, about 200 ng / ml to 700 ng / ml, about 200 ng / ml to 600 ng / ml, about 200 ng / ml to 500 ng / ml, about 200 ng / ml to 400 ng / ml, or about 200 ng / ml to about 300 ng / ml).

[0187] In some embodiments, an effective amount of an adrenaline receptor modulating compound is an amount ranging from about 10 pg to 100 mg, for example, 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, from about 250 ng to 500 ng, from about 500 ng to 750 ng, from about 750 ng to 1 mg, from about 1 pg to 10 pg, 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 ng The amount may be from about 10 pg to about 100 mg, from about 100 pg to about 500 pg, from about 750 pg to about 1 mg, from about 1 mg to about 50 mg, from about 1 mg to about 100 mg, or from about 50 mg to about 100 mg. The amount may be a single dose amount or a total daily amount. The total daily amount may range from about 10 pg to about 100 mg, or from about 100 mg to about 500 mg, or from about 500 mg to about 1000 mg.

[0188] Also disclosed herein are pharmaceutical compositions comprising compounds disclosed herein, for example, having structures of Formula (I), (I'), (II), (II'), (III'), (IV'), (V'), (VI'), and (VII'), and a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be administered to a patient with the compound of the present invention without destroying its pharmacological activity. Pharmaceutically acceptable carriers that can be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, ammonium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin).

[0189] In pharmaceutical compositions comprising only a compound described herein as an active ingredient, methods of administering such compositions may further comprise the step of administering an additional agent or therapy to the subject. Such therapies include, but are not limited to, anemia therapies, diabetes therapies, hypertension therapies, cholesterol therapies, neuropharmacological agents, drugs that modulate cardiovascular function, drugs that modulate inflammation, immune function, blood cell production, hormones and antagonists, drugs that affect gastrointestinal function, chemotherapeutic agents for microbial diseases, and / or chemotherapeutic agents for neoplastic diseases. Other pharmacological therapies may include any other drug or biologic agent found in any drug class. For example, other drug classes may include allergy / cold / ENT therapies, analgesics, anesthetics, anti-inflammatory agents, antibacterial agents, antiviral agents, asthma / pulmonary therapies, cardiovascular therapies, dermatological therapies, endocrine / metabolic therapies, gastrointestinal therapies, cancer therapies, immunological therapies, neurological therapies, ophthalmic therapies, psychiatric therapies, or rheumatological therapies. Other examples of agents or therapies that can be administered with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-angiogenic compounds.

[0190] As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, subject, or human that is being sought by the researcher, veterinarian, physician, or other clinician, including one or more of the following: (1) preventing disease, e.g., preventing the disease, condition, or disorder in a subject that may be susceptible to the disease, condition, or disorder but does not yet experience or display the signs or symptoms of the disease; (2) inhibiting disease, e.g., inhibiting the disease, condition, or disorder in a subject that is experiencing or displaying the signs or symptoms of the disease, condition, or disorder (i.e., arresting the further development of the signs and / or symptoms); and (3) ameliorating disease, e.g., ameliorating the disease, condition, or disorder in a subject that is experiencing or displaying the signs or symptoms of the disease, condition, or disorder (i.e., reversing the signs and / or symptoms).

[0191] In some embodiments, the compounds disclosed herein may be adrenergic receptor modulating compounds (e.g., agonists, partial agonists, or antagonists of adrenergic receptors). In some embodiments, the adrenergic receptor modulating compounds of the present invention may be useful for modulating the activity of a target adrenergic receptor in vitro or in vivo. Aspects of the methods of the present invention include contacting a sample with an effective amount of an adrenergic receptor modulating compound (e.g., as described herein) to determine whether the desired activity is present.

[0192] Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCRs) that are ubiquitously expressed throughout the body and play a crucial role in regulating numerous physiological processes, including cognition, stress-related behaviors, inflammation, and smooth muscle contraction / dilation, cardiac contraction, and airway reactivity. ADRs mediate the central and peripheral actions of norepinephrine (NA) and epinephrine. There are multiple ADR subtypes, including α-adrenergic receptors and β-adrenergic receptors. Each subtype expresses in distinct patterns and participates in different physiological processes. Therefore, ligands that selectively target a subtype are valuable as research tools to characterize the roles of different ADR subtypes and as therapeutic agents for various diseases associated with dysfunction of the NA and adrenergic systems.

[0193] β-adrenergic receptors further comprise three subtypes: β1-adrenergic receptor (β1-ADR), β2-adrenergic receptor (β2-ADR), and β3-adrenergic receptor (β3-ADR). Because these subtypes express distinct patterns and participate in different physiological processes, ligands that selectively target a subtype have therapeutic potential for a variety of diseases. However, due to the high level of sequence homology shared by these subtypes, the discovery of subtype-selective ligands has been challenging. Many existing β-adrenergic receptor agonists also exhibit poor blood-brain barrier (BBB) penetration, which is crucial for drug discovery efforts for central nervous system (CNS) indications.

[0194] As a type of G protein-coupled receptor, adrenergic receptors signal via G protein- and β-arrestin-dependent pathways. G protein- or β-arrestin signaling can modulate diverse physiological responses. Recently, it has become apparent that agonists can exhibit biased activation of signaling pathways. The ability of a ligand to activate a receptor and produce a response in a pathway-dependent manner has been termed "signaling bias" or "functional selectivity." Because G proteins and β-arrestins regulate distinct physiological processes, biased agonists may offer improved therapeutic selectivity and reduced adverse effects. Therefore, the present invention is directed to β-adrenergic receptor subtype-selective agonists with improved blood-brain barrier (BBB) penetration.

[0195] Adrenoceptor modulating compounds can be agonists of the target adrenoceptor. In some cases, an effective amount of an adrenoceptor modulating compound is an amount sufficient to activate adrenoceptor-associated activity in a cell by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or even more, relative to a control (e.g., a control cell exhibiting a known level of activity for the receptor).

[0196] Adrenoceptor modulating compounds can be partial agonists of the target adrenoceptor. In some cases, an effective amount of an adrenoceptor modulating compound is an amount sufficient to achieve partial agonism of an adrenoceptor in a cell, for example, wherein the compound of the invention achieves 10% or greater activation of the receptor relative to a control (e.g., a fully activated receptor), such as 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater. Partial agonism can be assessed using any suitable method, such as a cell-based assay using a known full agonist as a 100% activation control, where the relative maximum activation of the receptor can be measured relative to the full agonist.

[0197] Adrenoceptor modulating compounds can be antagonists of the target adrenoceptor. In some cases, an effective amount of an adrenoceptor modulating compound is an amount sufficient to inhibit or reduce the activity of the target adrenoceptor in a sample by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or even more, relative to a control (e.g., a sample not contacted with the compound of interest).

[0198] In some embodiments of the methods, the target adrenergic receptor is the β1-adrenergic receptor. In some embodiments of the methods, the target adrenergic receptor is the β2-adrenergic receptor. In some embodiments of the methods, the target adrenergic receptor is the β3-adrenergic receptor. In some embodiments, the compound is an agonist for both the β1-adrenergic receptor and the β2-adrenergic receptor. In certain instances, the compound is selective for the β2-adrenergic receptor over the β1-adrenergic receptor.

[0199] The target adrenergic receptors may be receptors responsible for regulating intracellular signals or pathways in the cell. In some embodiments, the sample comprises a cell and modulates a physiological process in an adrenergic receptor regulatory cell. Any indicated physiological process may be targeted for regulation in the cell using the methods of the invention. In some embodiments, physiological processes are processes involving cardiac function, and in some cases, physiological processes are processes involving cognitive function. In some cases, physiological processes are those involving inflammatory pathways or disease conditions. The method of the invention may provide modulation of the intracellular concentration of signaling molecules (such as cAMP) in a cell. The method of the invention may provide partial or complete blockade of the adrenergic receptor of interest such that cAMP in a sample is modulated (e.g., activated). In some embodiments, the method does not regulate the β-arrestin pathway of the cell. In some cases, the cells are inflammatory cells and regulate the function of the cells. The method of the invention may provide inhibition of the inflammatory route in the cell. In some cases, inhibition of TNF-α in cells, for example, by practicing the methods of the invention to reduce the concentration or yield of TNF-α. In certain embodiments of the method, the cell is a neuron. In some embodiments, modulation of adrenergic receptors promotes neurogenesis.

[0200] Compounds of the invention may be adopted in a habitual manner for use in the control, prevention, treatment of the diseases described herein, including (but not limited to) myocardial infarction, stroke, focal ischemia, Alzheimer's disease, Parkinson's disease, Greck's disease (muscular dystrophy) lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, atherosclerotic dementia, AIDS-related dementia, other dementia, cerebrovascular inflammation, epilepsy, Tourette syndrome, Wilson's disease, Picker's disease, brain inflammation, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia Capillary dilatation, spinal muscular dystrophy, progressive supranuclear palsy, muscle hypotonia , muscle spasms, tremor, retinal pigmentation, striatal substantia nigra degeneration, mitochondrial encephalomyopathy, neuronal waxy lipofuscin storage disease, autosomal dominant hereditary cerebral artery disease with subcortical infarction (CADASIL) and diabetic retinopathy. Such treatments, their dosage levels and needs may be selected from the self-available methods and techniques of those generally familiar with the technology.

[0201] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a described compound can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a described compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are generally considered to be administered "in combination" when a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "in combination" when a patient or individual simultaneously exhibits therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., brain, serum, etc.).

[0202] When a compound of the present invention is administered in combination therapy with another agent, they may be administered to the patient sequentially or simultaneously. Alternatively, a pharmaceutical or prophylactic composition according to the present invention comprises ivermectin or any other compound described herein in combination with another therapeutic or prophylactic agent. Additional therapeutic agents typically administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0203] In some embodiments, the methods of the present invention comprise administering a therapeutically effective amount of one or more additional active agents. Combination therapy means that an adrenergic receptor modulating compound can be used in combination with another therapeutic agent to treat a single disease or condition. In certain embodiments, a compound of the present invention is administered concurrently with another therapeutic agent, which can be administered as a component of a composition comprising the compound of the present invention or as a component of a separate composition.

[0204] The compounds of the present invention can be administered in combination with other therapeutic agents in a variety of therapeutic applications. Combination therapy-related therapeutic applications include those in which activity of the target adrenergic receptor is a causal or contributing factor to disease progression. Thus, the compounds of the present invention find use in combination therapies where inhibition of a subject's target adrenergic receptor is desired. Examples of disease conditions that can be treated by combination therapies comprising the compounds of the present invention include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental diseases, respiratory disorders, asthma, memory impairment, depression, inflammatory diseases, stroke, ischemic brain or tissue damage, and cancer. Related agents that can be used in combination with the adrenergic receptor modulating compounds of the present invention include, but are not limited to, antidepressants, antipsychotics, beta-blockers, vasoconstrictors, antihypotensives, decongestants, chemotherapeutic agents, agents used for Alzheimer's disease, and anti-inflammatory agents.

[0205] The adrenaline receptor modulating compounds of the present invention may be used in combination with any agent useful in treating a cardiac condition such as cardiogenic shock, hypertension, congestive heart failure, coronary artery disease, arrhythmia, myocardial infarction, or ischemic heart disease. Related agents that can be used in combination with the adrenoceptor modulating compounds of the present invention 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, metaminol, midodrine, and coumarin.

[0206] Adrenoceptor modulating compounds of the present invention can be used in combination with any agent 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 syndrome, or autism. Related agents that can be used in combination with adrenoceptor modulating compounds of the present invention include, but are not limited to, acepromazine. In some embodiments, adrenoceptor modulating compounds of the present invention can be used in combination with cholinesterase inhibitors or NMDA receptor modulators to treat diseases such as neurodegenerative or neurodevelopmental diseases. Related agents include, but are not limited to, Donepezil, Aricept, Galantamine, Razadyne, Memantine, Namenda, Rivastigmine, Exelon, Tacrine, and Cognex.Other related agents that can be used in combination with the adrenaline receptor modulating compounds of the present invention include, but are not limited to, 4-NEMD, 7-Me-marsanidine, Agmatine, Apraclonidine, Brimonidine, Cannabigerol, Clonidine, Detomidine, Dexmedetomidine, Fadolmidine, Guanabenz, Guanfacine, Lofexitin, and dapoxetine. dine), Marsanidine, Medetomidine, Methamphetamine, Mivazerol, Rilmenidine, Romifidine, Talipexole, Tiamenidine, Tizanidine, Tolonidine, Xylazine, Xylometazol ine), Aripiprazole, Asenapine, Atipamezole, Cirazoline, Clozapine, Efaroxan, Idazoxan, Lurasidone, Melperone, Mianserin, Mirtazapine, Napitane, Olanzapine, Paliperidone ne), Phenoxybenzamine, Phentolamine, Piribedil, Rauwolscine, Risperidone, Rotigotine, Quetiapine, Norquetiapine, Setiptiline, Tolazoline, Yohimbine, Ziprasidone, and Zotepine.Other related agents that can be used in combination with the adrenaline receptor modulating compounds of the present invention include, but are not limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol (levalbuterol), orciprenaline (metaproterenol), pirbuterol, procaterol, salbutamol (albuterol), terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, milveterol, olodaterol, vilanterol, isoxsuprine, ritodrine, zilpaterol, ICI-118,551, and butoxamine.

[0207] The compounds used in the compositions and methods of the present invention 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 increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and / or alter secretion rate.

[0208] According to a preferred embodiment, the compositions of the present invention are formulated for pharmaceutical administration to an individual or patient (e.g., a mammal, preferably a human). Such pharmaceutical compositions are used to improve, treat, or prevent any of the diseases described herein in the individual.

[0209] The agents of the present invention are typically administered as pharmaceutical compositions comprising an active therapeutic agent and various other pharmaceutically acceptable components. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application. Depending on the desired formulation, the composition may also include a pharmaceutically acceptable nontoxic carrier or diluent, which is defined as a vehicle commonly used to formulate pharmaceutical compositions for administration to animals or humans. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, non-therapeutic, non-immunogenic stabilizers and the like.

[0210] In some embodiments, the present invention provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described herein, formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents for the treatment of diseases described herein, including but not limited to stroke, ischemia, Alzheimer's disease, ankylosing spondylitis, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma, atherosclerosis, Crohn's disease, colitis, diverticulitis, myalgia, 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 in the form of a pharmaceutical formulation (composition). The compounds described can be formulated for administration in any suitable manner for use in human or veterinary medicine, similar to other pharmaceutical agents.

[0211] As described in detail, the pharmaceutical compositions of the present invention can be specifically formulated for administration in solid or liquid form, including those suitable for the following: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), lozenges (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses for application to the tongue, powders, granules, pastes; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, for example, in the form of a sterile solution or suspension or sustained-release formulation; topical application, such as a cream, ointment, or controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, in the form of a pessary, cream, or foam; sublingually; ophthalmically; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0212] Wetting agents, emulsifiers 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 compositions.

[0213] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0214] The formulations used according to the present invention include formulations suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations can be suitably presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the individual being treated and the specific mode of administration. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally speaking, 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%.

[0215] In certain embodiments, the formulations described herein comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle formers (e.g., bile acids), and polymeric carriers (e.g., polyesters and polyanhydrides), and a compound of the invention. In certain embodiments, the formulations described herein render the compounds described herein orally bioavailable.

[0216] Methods for preparing formulations or compositions comprising the described compounds include the step of bringing into association a compound of the invention with a carrier and, optionally, one or more accessory ingredients. In general, the formulations can be prepared by uniformly and intimately bringing into association a compound of the invention with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0217] Pharmaceutical compositions may be in the form of sterile injectable preparations, for example, sterile injectable aqueous or oily suspensions. Such suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting agents (such as Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among acceptable vehicles and solvents, mannitol, water, Ringer's solution, and isotonic sodium chloride solution may be used. Sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as those described in Pharmacopeia Helvetica, or similar alcohols. Other commonly used surfactants (such as Tween, Span and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

[0218] In some cases, to prolong the effect of a drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The rate of absorption of the drug then depends on its rate of dissolution, which in turn depends on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oily vehicle.

[0219] Injectable depot forms are prepared by forming microencapsule matrices of the described compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the properties of the specific polymer used, the rate of drug release can be controlled. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0220] The pharmaceutical compositions of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions and solutions, as well as propylene glycol, are administered orally, the active ingredient is combined with an emulsifier and suspending agent. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added.

[0221] The formulations described herein suitable for oral administration can be in the form of capsules, cachets, pills, lozenges, buccal lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or in the form of a solution or suspension in an aqueous or non-aqueous liquid, or in the form of an oil-in-water or water-in-oil liquid emulsion, or in the form of an elixir or syrup, or in the form of a tablet (using an inert base such as gelatin and glycerin, or sucrose and acacia) and / or in the form of a mouthwash and the like, each containing a predetermined amount of a compound of the invention as the active ingredient. The compounds described herein can also be administered in the form of a bolus, elixir, or paste.

[0222] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, such as carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; Humectants such as glycerol; disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarder such as paraffin; absorption promoters such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glyceryl monostearate, and nonionic surfactants; adsorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffering agent. Solid compositions of a similar type may also be used as fillers in soft-shell and hard-shell gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0223] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant, or a dispersing agent. Molded tablets can be made in a suitable machine by moistening a mixture of the powdered compound with an inert liquid diluent. If a solid carrier is used, the preparation can be in the form of a tablet, placed in a hard gelatin capsule as a powder or agglomerate, or as a sugar-coated lozenge or buccal 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, for example, a syrup, an emulsion, a soft gelatin capsule, a sterile injectable liquid (such as an ampoule), or a non-aqueous liquid suspension. When the composition is in the form of a capsule, any conventional encapsulation is suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.

[0224] Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may alternatively or additionally be formulated using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, and / or microspheres to provide slow or controlled release of the active ingredient therein. They may be formulated for rapid release, for example, by freeze-drying. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium prior to use. These compositions may also optionally contain opacifying agents and may be compositions that release the active ingredient only or preferentially in a certain portion of the gastrointestinal tract in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be microencapsulated, where appropriate, with one or more of the above-mentioned excipients.

[0225] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0226] Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0227] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0228] The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0229] Topical administration of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application to the skin, the pharmaceutical compositions are formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical compositions may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention may also be topically applied to the lower intestinal tract via rectal suppository formulations or in a suitable enema formulation. Transdermal patches for topical administration are also encompassed by the present invention.

[0230] The pharmaceutical compositions of the present invention can be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions in physiological 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.

[0231] For ophthalmic use, the pharmaceutical composition can 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 benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated in the form of an ointment such as paraffin.

[0232] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel can control the rate of such flux.

[0233] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials (such as lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0234] Such compositions may also 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 parabens, chlorobutanol, phenol, sorbic acid, and the like. Alternatively or additionally, it may be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the composition. Furthermore, prolonged absorption of the injectable pharmaceutical form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0235] 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.

[0236] When the compounds described herein are administered as pharmaceuticals to humans and animals, they can be administered per se or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of active ingredient and a pharmaceutically acceptable carrier.

[0237] The formulations described herein can be administered orally, parenterally, topically, or rectally. They are, of course, administered in a form suitable for the respective route of administration. For example, they can be administered in the form of tablets or capsules, by injection, inhalation, eye lotions, ointments, suppositories, etc., by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppository. Oral administration is preferred.

[0238] The compounds can be administered to humans and other animals for therapeutic use by any suitable route of administration, including oral, nasal (e.g., by spray), rectal, vaginal, parenteral, intracisternal, and topical (e.g., by powders, ointments, or drops, including buccal and sublingual).

[0239] Regardless of the route of administration chosen, the compounds described herein and / or pharmaceutical compositions of the present invention, which may be used in a suitably hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0240] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so that an amount of the active ingredient is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0241] Also provided are kits comprising the disclosed adrenergic receptor modulating compounds. Systems of the present invention include, for example, a collection of active agents assembled by a healthcare provider for administration to an individual (such as a patient). Such systems may include adrenergic receptor modulating compounds and one or more additional active agents disclosed herein. Kits comprising adrenergic receptor modulating compounds may include one or more doses of the adrenergic receptor modulating compound and, optionally, one or more doses of one or more additional active agents. Suitably, the formulations may be provided in unit dosage form. Such kits may include, in addition to the container containing the formulation (e.g., a unit dose), an informational package insert describing the use of the formulations of the present invention in the methods disclosed herein, such as instructions for using the unit doses of the present invention to treat a cell proliferative disorder. These instructions may be present in various formats in the systems and kits of the present invention, one or more of which may be present in the kit. One possible form of these instructions is printed information on a suitable medium or substrate (e.g., one or more sheets of paper with information printed thereon), within the packaging of the kit, within a package insert, etc. Another form is computer-readable media with information recorded thereon, such as a disk, CD, etc. Still another possible form is a website address where information can be accessed remotely via the internet. Any suitable form may be present in the kit.

[0242] the following [surface] [1] Exemplary compounds of the present invention are described. [surface] [1]. The compounds of the present invention.

[0243] Also disclosed herein is a pharmaceutical composition comprising a compound as disclosed herein, namely, a compound having a structure of formula (I), formula (I'), formula (II), formula (II'), formula (III'), formula (IV'), formula (V'), formula (VI'), formula (VII'), and a pharmaceutically acceptable excipient. Further elucidating methods of treating an individual suffering from a disease associated with adrenergic receptors comprising or administering to the individual a therapeutically effective amount of a compound having a structure of formula (I), formula (I'), formula (II), formula (II'), formula (III'), formula (IV'), formula (V'), formula (VI'), formula (VII'), thereby treating the individual. In some embodiments, the disease is a neurodegenerative disease and the individual is a human.

[0244] In some embodiments, the disease is selected from the group consisting of: myocardial infarction, stroke, focal ischemia, Alzheimer's disease, Parkinson's disease, Greck's disease (muscular dystrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, atherosclerotic dementia, AIDS-related dementia, other dementia, cerebral vasculitis, epilepsy disease, Picker's disease, encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia Capillary dilatation, spinal muscular dystrophy, progressive supranuclear palsy, muscle hypotonia, muscle spasm, tremor, retinal pigmentation, striatal reservoir encephalomyelosis and granulometriosis. In some embodiments, the compound is via oral, enteral, topical, aspirated, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, superior epidermis, extraamniotic, intraarterial, intraarticular, cardiac Intra-, penile spongy intracorporeal, intradermal, intrafocal, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, percutaneous, perivascular, intrachial, transvaginal, sublingual, or transrectal routes are administered to the individual. In one embodiment, the compounds are selected from those compounds described in Table 1 .

[0245] The following examples are provided to further illustrate the advantages and features of the invention, but they are not intended to limit the scope of the invention. Notwithstanding the fact that the instances are typical of those instances that may be used, alternative steps, methods, or techniques known to those familiar with this technology may be used alternatively. [instance] [] [instance] [1] [Compound Synthesis] [process] [1] [.] Compound

[02] [-] [1] synthesis.

[0246] [process] [1] Description of the compound

[02] [-] [1] Synthesis. 1H NMR (400 MHz, DMSO- d 6) δ 7.86 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 1.6 Hz, 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) +. [process] [2] [.] Compound

[02] [-] Synthesis of [2]

[0247] [process] [2] Description of the compound

[02] [-] [2] Synthesis. 1H NMR (400 MHz, DMSO- d 6) δ 8.37 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 6.77 (s, 2H), 4.48 (d, J = 4.9 Hz, 1H), 3.86 - 3.79 (m, 1H), 3.69 (dd, J = 11.5, 5.1 Hz, 1H), 1.25 (s, 9H); LC-MS: m / z 278.2 (M+1) +. [process] [3] [.] Compound

[02] [-] [3] synthesis.

[0248] [process] [3] Description of the compound

[02] [-] [3] synthesis.

[0249] 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 vinyltrifluoroborate (0.87 g, 6.51 mmol), and KCO (2.07 g, 15.03 mmol) in dioxane / HO (16 mL / 4 mL) was added Pd(dppf)Cl (0.367 g, 0.501 mmol). The resulting mixture was purged with N before being heated to 85°C for 12 hours. After cooling, the reaction mixture was diluted with EtOAc. The organic layer was separated and washed with brine (30 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using DCM / CH3OH (30 / 1 to 10 / 1) to afford 4-methyl-6-vinylpyridazin-3-amine (0.55 g, 82%) as a yellow solid. LC-MS: m / z 136.1 (M+1) +.

[0250] 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 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography using DCM / CH3OH (40 / 1 to 15 / 1) to afford 4-methyl-6-vinylpyridazine-3-N(Boc)2 (1 g, 73%) as a white solid. LC-MS: m / z 336.1 (M+1).

[0251] 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 / H2O (16 mL / 4 mL) was added NaIO4 (0.96 g, 4.47 mmol) and K2OsO4.H2O (0.03 g, 0.075 mmol). The resulting mixture was stirred at room temperature for 24 hours. 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) +.

[0252] Step 4: Synthesis of 1-(6-N(Boc)2-5-methylpyridazin-3-yl)-2-(tert-butylamino)ethan-1-ol. tert-Butyl isocyanate (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), hexamethylphosphamidone (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 minutes. 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 NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using DCM / CHOH (30 / 1 to 10 / 1) to afford 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).

[0253] 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 (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 8.65 (s, 1H), 8.47 (s, 2H), 7.90 (d, J= 1.3 Hz, 1H), 6.74 (s, 1H), 5.06 - 4.96 (m, 1H), 3.21 - 3.13 (m, 2H), 2.31 (d, J= 1.2 Hz, 3H), 1.32 (s, 9H). LC-MS: m / z225.23(M+1)+. [process] [4] [.] Compound

[02] [-] Synthesis of [4]

[0254] [process] [4] Description of compounds

[02] [-] [4] Synthesis. 1H 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) +. [process] [5] [.] Compound

[04] [-] Synthesis of [1]

[0255] [process] [5] Description of compounds

[04] [-] [1] Synthesis.

[0256] 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 hours. A 1N aqueous NaOH solution (120 mL) was then 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 afford 5-bromoquinoline 1-oxide (5.1 g, 63%) as a light 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 was added trifluoroacetic anhydride (24 g, 115 mmol) 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 x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated to afford 5-bromoquinolin-2(1H)-one (4 g, 78%) as a yellow solid. LC-MS: m / z 223.9 (M+1) +.

[0257] 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(PPh) (0.05 eq). The resulting mixture was purged with N (3×) before being heated to 120°C for 6 hours. After cooling, 1.5N HCl (2 eq.) was added to the flask, and stirring was continued at room temperature overnight. The reaction solution was then quenched with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated. The crude product was purified by flash chromatography to obtain 5-acetylquinolin-2(1H)-one. LC-MS: m / z 188.1 (M+1).

[0258] 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 eq.). The resulting mixture was stirred at 40°C overnight. After cooling to rt, 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 obtain 5-(2-bromoacetyl)quinolin-2(1H)-one. LC-MS: m / z 267.1 (M+1)⁺.

[0259] 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 at -35°C was added (R)-2-methyl-CBS-oxazaboridine (0.2 eq.). The resulting mixture was stirred at -35°C for 30 minutes. BH3 / THF (1N / THF, 1 eq.) was then introduced dropwise via syringe. After the addition, the reaction was allowed to warm to -15°C. After 2 hours, 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 obtain (R)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one. LC-MS: m / z 269.1 (M+1) +.

[0260] Step 5: (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 was added tert-butylamine (60 eq.). The resulting mixture was stirred at 40°C for 48 hours. The reactants were concentrated, and the residue was redissolved with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated. The crude product was purified by HPLC (C18, MeCN / H2O (0.1% formic acid), (1%~100%)) to obtain (R)-5-(2-(tert-butylamino)-1-hydroxyethyl)quinolin-2(1H)-one (

[04] [-] [1]) (5-step yield: 12%). 1H NMR (400 MHz, DMSO- d 6) δ 11.82 (br,1H), 8.21 (d, J= 9.9 Hz, 1H), 7.52 (t, J= 7.9 Hz, 1H), 7.36 (dd, J= 7.6, 1.1 Hz, 1H), 7.28 (d, J= 8.5 Hz, 1H), 6.57 (d, J= 9.9 Hz, 1H), 5.38 (dd, J= 9.6, 2.8 Hz, 1H), 3.00 - 2.85 (m, 2H), 1.24 (s, 9H). LC-MS: m / z261.2 (M+1) +. [process] [6]. Compounds

[04] [-] [5] synthesis.

[0261] [process] [6] Description of compounds

[04] [-] [5] synthesis.

[0262] 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 hours. The reaction was concentrated. The crude product was purified by flash chromatography (silica, petroleum ether / EtOAc: 20 / 1 to 3 / 1) to obtain 3-bromo-2-chloropyridin-4-amine (7.1 g, 43.9%) as a yellow solid. LC-MS: m / z 206.94, 208.97 (M+1, M+2).

[0263] 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 eq). The resulting mixture was purged with N2 (3×) before being heated to 100°C for 24 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL). The organic layer was washed with brine (30 mL×3), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica, petroleum ether / EtOAc: 30 / 1 to 1 / 1) to obtain ethyl (E)-3-(4-amino-2-chloropyridin-3-yl)acrylate (1.2 g, 55.3%) as a yellow solid. LC-MS: m / z 227.1, 229.1 (M+1, M+2).

[0264] 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 hours. 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).

[0265] Step 4-7: (S)-5-(2-tert-butylamino)-1-hydroxyethyl)-1,6-naphthyridin-2(1H)-one (Compound

[04] [-] [5]) was synthesized by using the compound

[04] [-] [1], using 5-chloro-1,6-naphthyridin-2(1H)-one instead of 5-bromoquinolin-2(1H)-one as the starting material to obtain (S)-5-(2-(tert-butylamino)-1-hydroxyethyl)-1,6-naphthyridin-2(1H)-one (

[04] [-] [5]) (12 mg, 9.2% yield over 4 steps). 1H NMR (400 MHz, DMSO- d 6) δ 12.03 (br, 1H), 8.42 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 9.9 Hz, 1H), 7.21 (d, J = 5.7 Hz, 1H), 6.63 (d, J = 9.9 Hz, 1H), 5.25 (t, J = 6.3 Hz, 1H), 3.16 (d, J = 6.7 Hz, 2H), 1.22 (d, J = 12.6 Hz, 9H). LC-MS: m / z 262.2. (M+1) +. [process] [7]. Compounds

[04] [-]

[23] synthesis.

[0266] [process] [7] Description of compounds

[04] [-]

[23] synthesis.

[0267] 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) at 0°C was added NaH (60%, 0.79 g, 19.75 mmol) portionwise. The resulting mixture was stirred for 1 h, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (3.1 mL, 2.92 g, 17.44 mmol). 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 x 3). The combined organic layers were washed with H₂O (100 mL x 3), brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 20% EtOAc / petroleum ether to give 4-bromo-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.9 g, 48%) as a yellow oil. LC-MS: m / z 346.3 M+1).

[0268] 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) under N2 was added potassium vinyl trifluoroborate (1.47 g, 11.01 mmol), Pd(dppf)Cl2·CH2Cl2 (0.45 g, 0.55 mmol), and Cs2CO3 (5.38 g, 16.5 mmol). 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, brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10% EtOAc / petroleum ether to afford 7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-indazole (1.6 g, 99%) as an oil. LCMS: m / z 293.3 (M+1).

[0269] 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 a third BuOH / H₂O (20 mL / 20 mL) at 0°C was added AD-mix-β (8.25 g) and then stirred at room temperature for 16 hours. After the reaction was complete, 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 using 50% EtOAc / petroleum ether to afford (R)-1-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)ethane-1,2-diol (2.1 g, 99%) as a yellow oil. LCMS: m / z 327.3 (M+1).

[0270] 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) were added n-BuSnO (0.16 g, 0.64 mmol), p-TsCl (1.4 g, 7.1 mmol), and EtN (776 mg, 7.6 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction was quenched with water. The mixture was extracted with CHCl (50 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30% EtOAc / petroleum ether to afford (R)-2-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-2-hydroxyethyl 4-methylbenzenesulfonate (2.76 g, 90%) as a yellow oil. 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 KCO (3.97 g, 28.8 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give a residue that was redissolved in CH2Cl2. 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 (2.1 g) as an oil, which was used in the next step without further purification.

[0271] 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 using 5% MeOH / dichloromethane to provide (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).

[0272] 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 CH2Cl2 (8 mL) at 0°C was added CF3COOH (10 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by column chromatography eluting with 10% MeOH / CH2Cl2 (containing 1% NH4OH) to give (R)-2-(tert-butylamino)-1-(7-fluoro-1H-indazol-4-yl)ethan-1-ol (0.7 g, 90% HPLC purity). This compound was further purified by reverse phase HPLC (0.1% TFA / CH3CN / H2O) and lyophilized from 1 N 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 (400 MHz, CD 3OD) δ 8.39 - 9.33 (m, 1H), 7.22 - 7.17 (m, 1H), 7.12 (dd, J = 10.3, 8.0 Hz, 1H), 5.31 - 5.25 (m, 1H), 3.22 (d, J = 9.1 Hz, 2H), 1.39 (s, 9H); HPLC: 99.2 % @254 nM; LCMS: m / z 252.3 (M+1) +; SFC: 99% ee [AD-H column, mobile phase: HEP: IPA (0.1% DEA) = 95:5]. [] [process] [8]. Compounds

[04] [-]

[0144] and compounds

[04] [-]

[0145] The synthesis of.

[0273] [process] [8] Description of compounds

[04] [-] and compounds

[04] [-]

[0145] Synthesis.

[0274] 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) at 0°C was added NaH (60%, 1.64 g, 41 mmol). The resulting mixture was stirred for 0.5 h, followed by the addition of SEMCl (5.93 g, 35.55 mmol). 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 x 3). The combined organic layers were washed with H2O (100 mL x 3), brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30% EtOAc / petroleum ether to give 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (3 g, 39%) as a yellow oil. LC-MS: m / z 284.2 (M+1).

[0275] 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 / H 2 O (20 mL / 2 ml) under N 2 was added potassium vinyl trifluoroborate (2.83 g, 21.14 mmol), Pd(dppf)Cl 2 · CH 2 Cl 2 (856 mg, 1.05 mmol), and Cs 2 CO 3 (10.33 g, 31.71 mmol). The mixture was stirred at 100° C. for 16 hours. 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) and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10% EtOAc / petroleum ether to provide 1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrazolo[4,3-c]pyridine (2.5 g, 81%) as an oil. LC-MS: m / z 293.3 (M+1).

[0276] 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 CH2Cl2 (10 mL) at room temperature were added saturated NaHCO3 solution (10 mL) and mCPBA (3.76 g, 21.78 mmol) portionwise. The resulting mixture was stirred for 10 min before adding t-BuNH2 (2.5 g, 34.31 mmol) and EtOH (5 mL). The resulting mixture was stirred at 60°C for 16 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography eluting with 10% CH3OH / 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).

[0277] Step 4: Synthesis of 2-(tert-butylamino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol. A mixture of 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 Pd / C (10% carbon, 0.06 g) in EtOH (6 mL) under a hydrogen balloon was stirred at room temperature for 24 hours and then at 60° C. for 48 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to give 2-(tert-butylamino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol (0.3 g), which was used directly in the next step without further purification. LC-MS: m / z 365.2 (M+1).

[0278] 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 (1 M in THF, 4 mL, 4 mmol) was added to 2-(tert-butylamino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol (0.3 g, 0.82 mmol), and the mixture was stirred at 50° C. for 48 hours. The mixture was purified by preparative TLC (10% CH 3 OH / CH 2 Cl 2) and further purified via reverse phase chromatography to give 2-(tert-butylamino)-1-(1H-pyrazolo[4,3-c]pyridin-4-yl)ethan-1-ol (0.11 g, 57%) as a colorless oil. 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: 1H NMR (400 MHz, CD 3OD) δ 9.03 (s, 1H), 8.45 (d, J= 6.9 Hz, 1H), 8.08 (d, J= 6.4 Hz, 1H), 5.95 (d, J= 9.4 Hz, 1H), 3.58 (d, J= 12.9 Hz, 1H), 3.39 (t, J= 11.5 Hz, 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: 1H NMR (400 MHz, CD 3OD) δ 9.03 (s, 1H), 8.45 (d, J = 6.9 Hz, 1H), 8.08 (d, J = 6.4 Hz, 1H), 5.95 (d, J = 9.4 Hz, 1H), 3.58 (d, J = 12.9 Hz, 1H), 3.39 (t, J = 11.5 Hz, 1H), 1.43 (s, 9H); LC-MS: m / z 235.3 (M+1) +; SFC: 98.3% ee. [Example] [2] [Evaluation of synthetic adrenaline receptor agonists]

[0279] cAMP Homogeneous Time-Fall Fluorescence (HTRF): Experimental Methods Compound efficacy was determined using a cAMP Gs kinetic HTRF assay (Cisbio, Cat. No. 62AM4PEC) largely following the manufacturer's instructions, also described in detail below.

[0280] [Compound Preparation] Candidate β-adrenergic compounds dissolved in DMSO to 10 mM were diluted in 1× stimulation buffer 1 (Cisbio part number 64SB1FDD) containing 1 mM 3-isobutyl-1-methyldibenzopyran (IBMX; Cayman Chemical Company, catalog number 13347). Serial dilutions were made in 96-well V-bottom polypropylene compound microtiter plates (Corning, catalog number 3363) in stimulation buffer containing 1 mM IBMX to a 2× final desired concentration. A standard serial dilution curve consisted of 10 points of 5-fold dilutions starting at a peak concentration of 10 μM. Controls present on each assay plate were 0.1% DMSO (vehicle control), 1 μM isoproterenol (full β-adrenergic agonist control), and 15 μM xamoterol (partial β-adrenergic agonist control). Punch 5 μL from the 2× compound plates into white 384-round-well, low-volume HiBase assay plates (Greiner Bio-One; Catalog No. 784075) to provide four technical replicates at each concentration of each compound. Centrifuge the plates at 500 × g for 10 seconds. Compounds and IBMX were prepared at 2× the final dose to compensate for the addition of cells.

[0281] [Cell Preparation] Prewarm 1× 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 (PBS containing 0.02% EDTA disodium salt without calcium or magnesium; Caisson Labs, catalog number EDL01) to 37°C. Cells expressing β-adrenergic receptors were washed in wash PBS to remove growth medium and then released from the surface by incubation with Versene at 37°C for 5-10 minutes. Cells were harvested using analytical PBS, counted manually using a hemocytometer or an automated cell counter, pelleted by centrifugation (200 × g, 5 minutes), and resuspended in 1× stimulation buffer at 37°C to a final density of 1.5 × 10^6 cells / mL. 5 μL of the suspended cell solution (7500 cells total) was added to all wells of a 384-well assay plate, covered with an Axygen® plate seal (Corning PCR-SP), and incubated in a humidified 37°C environment supplemented with 5% CO2 for 30 minutes.

[0282] [HTRF] [Reagent addition, reading and data analysis] After 30 minutes of cell stimulation with the test compound, the assay plate was centrifuged at 500 × g for 10 seconds, and the incubation was stopped by adding 5 µL of cAMP-D2 receptor, diluted 1:21 in detection buffer, and Lysis Buffer 2 (Cisbio 62CL2FDF) to all cells. Subsequently, 5 µL of anti-cAMP-Eu donor, diluted 1:21 in detection buffer 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. The HTRF ratio (665 nm / 620 nm × 10,000) was determined and plotted in GraphPad Prism to generate concentration-effect curves. Potency estimates (EC50 and pEC50) were derived from four-parameter nonlinear regression of the concentration-effect curves, and estimates of relative efficacy were determined by comparing the magnitude (minimum-maximum dose) of the HTRF signal window for the test compound to the signal window for the full agonist control (isoproterenol). [surface] [2] and [surface] [3] Chinese. [surface] [2]. Pharmacological data of the compounds disclosed herein. [Compound] [β1] [β2] [EC , 50 , (nM) ] [EC , 50 , (nM) ] [02-1] C B [02-2] D D EC 50(nM):A < 10 nM;B = 10-100 nM;C = 100 nM-1 µM;D > 1 µM [surface] [3]. Pharmacological data of the compounds disclosed herein. [Compound] [average value] [pEC, 50 , ] [[] [Receptor subtype] [:] [B1] [-] [AR] [;] [Cell Type] [:] [CHO] [-] [K1] [(] [HitHunter] [)]] [average value] [pEC, 50 , ] [[] [Receptor subtype] [:] [B2] [-] [AR] [;] [Cell Type] [:] [CHO] [-] [K1] [(] [HitHunter] [)]] [average value] [pEC, 50 , ] [[] [Receptor subtype] [:] [Endogenous] [;] [Cell Type] [:] [1321N1] []] [02-1] C B C [02-2] D D - [02-3] D C - [02-4] C D - [02-6] C B C [02-7] D D D [02-8] D D D [02-9] C B - [02-10] D C - [02-11] D D - [02-12] D D - [02-13] B B - [02-14] B A - [04-1] A A - [04-2] B A - [04-3] D C - [04-4] A A - [04-5] D D - [04-6] B A - [04-7] B B - [04-8] B A - [04-9] C B - [04-10] B B - [04-11] B B - [04-12] C B - [04-13] B A - [04-14] C A - [04-15] D C - [04-16] C B - [04-17] C D - [04-18] A B - [04-19] A A - [04-24] B B - [04-25] A A - [04-26] B B - [04-27] A B - [04-28] C D - [04-29] C D - [04-30] D - - [04-36] A A - [04-38] C A - [04-39] A A - [04-40] B B - [04-41] A A - [04-42] C C - [04-43] A A - [04-44] C A - [04-45] A A - [04-46] C C - [04-48] D D - [04-49] D D - [04-50] C B - [04-51] D D - [04-52] C B - [04-54] D C - [04-55] B A - [04-56] A A - [04-57] A A - [04-67] D D - [04-68] D D - [04-69] B C - [04-70] - A - [04-71] C C - [04-72] A A - [04-73] B B - [04-74] D D - [04-75] A A - [04-76] A A - [04-77] - D - [04-78] C - - [04-79] C C - [04-80] A A - [04-81] C C - [04-82] A A - [04-83] C C - [04-84] A B - [04-85] A A - [04-86] C C - [04-87] C C - [04-88] A A - [04-89] D - - [04-90] C D - [04-91] D - - [04-92] D D - [04-93] C C - [04-94] A A - [04-96] B B - [04-97] D D - [04-98] A B - [04-102] C C - [04-103] C C - [04-104] C A - [04-105] D D - [04-106] C C - [04-107] D C - [04-108] A A - [04-109] B A - [04-110] D D - [04-111] D D - [04-112] A A - [04-113] A A - [04-114] D D - [04-115] C B - [04-116] A A - [04-117] C A - [04-118] D D - [04-119] A A - [04-120] D C - [04-121] - D - [04-122] A A - [04-123] D C - [04-124] B A - [04-125] B A - [04-126] D D - [04-127] B A - [04-128] D C - [04-129] D B - [04-130] A A - [04-131] A A - [04-133] A A - [04-134] B C - [04-135] A A - [04-136] D C - [04-137] C B - [04-138] D C - [04-139] D D - [04-140] D C - [04-141] B A - [04-142] A A - [04-143] B B - [04-144] D D - [04-145] D D - [04-146] A A - [04-147] A A - [04-148] A A - [04-149] A A - [04-150] B A - [04-151] A B - [04-152] A A - [04-153] D B - [04-154] C A - [04-155] D C - [04-156] B A - [04-157] C B - [04-158] B A - pEC 50:A > 8;B = 8-7;C = <7-6;D < 6

[0283] Using no more than routine experimentation, those skilled in the art will recognize or be able to ascertain several equivalents to the specific compositions and procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.

[0284] In addition to the various embodiments described in the above specification, the following additional embodiments are contemplated herein. [Example] [1.] A compound according to formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Formula (I) each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amino, pentafluorothio, 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 CR 2, Q is N, O or CR 2, G is NR 5 or O, and / or Z is NR 5, O, S or CR 3R 4, R 2 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 of R 3 and R 4 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. R 5 is one or more selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, , L is an optionally substituted C1-C5 alkyl linking group, Each of X 1 , X 2 , X 3 and X 4 is independently a covalent bond, carbon, oxygen or nitrogen, which is optionally substituted with 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 linked in a ring and together with X2 form an optionally substituted cycloalkyl or heterocycle, each R 8 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, n is an integer selected from 0 to 4, and R 9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and R 10 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy. [Example] [2] A compound according to formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Formula (II) each R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or substituted amino, pentafluorothio, 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 CR 2, Q is N, O or CR 2, G is NR 5 or O, and / or Z is NR 5, O, S or CR 3R 4, R 2 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 of R 3 and R 4 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. R 5, R 6 and R 7 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, , or R 5 and R 6 together with carbon form an unsubstituted or substituted 3-7 membered cycloalkyl or heterocyclic ring; L is an optionally substituted C1-C5 alkyl linking group, Each of X 1 , X 2 , X 3 and X 4 is independently a covalent bond, carbon, oxygen or nitrogen, which is optionally substituted with hydrogen, unsubstituted or substituted alkyl or unsubstituted or substituted cycloalkyl, Y is O or S, R 8 and R 9 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R 8 and R 9 are linked in a ring and together with X 2 form an optionally substituted cycloalkyl or heterocycle, each R 10 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, n is an integer selected from 0 to 4, 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, and R 12 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy. [Example] [3.] A compound having the following structure: Compound 04-1 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof. [Example] [4.] A compound having the following structure: Compound 04-2 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof. [Example] [5]. A compound having the following structure: Compound 04-3 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof. [Example] [6]. A compound having the following structure: Compound 04-4 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof. [Example] [7.] A compound having the following structure: Compound 04-5 or an optically pure stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof. [Example] [8.] A pharmaceutical composition comprising the compound of any one of Examples 1 to 2 and a pharmaceutically acceptable excipient. [Example] [9.] The compound of any one of Examples 1 to 7, wherein the compound is an agonist, partial agonist or antagonist of an adrenaline receptor. [Example] [10.] The compound of any one of Examples 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. [Example] [11.] The compound of any one of Examples 1 to 7, wherein the compound is a β1-adrenergic receptor agonist. [Example] [12.] The compound of any one of Examples 1 to 7, wherein the compound is a β2-adrenergic receptor agonist. [Example]

[13] A compound according to any one of Examples 1 to 7, wherein the compound is a non-selective β1 / β2-adrenergic agonist. [Example] [14.] A method for treating a subject suffering from a disease, the method comprising administering to the subject a therapeutically effective amount of a compound as described in any one of Examples 1 to 2. [Example] [15.] The method of Example 14, wherein the disease is a disease associated with adrenaline receptors. [Example]

[16] The method of Example 14, wherein the disease is a neurodegenerative disease. [Example] [17.] The method of Example 14, wherein the individual is a human. [Example]

[18] .The method of Example 14, wherein the disease is selected from the following: myocardial infarction, stroke, focal ischemia, Alzheimer's disease, Parkinson's disease, Greck's disease (muscular dystrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, atherosclerotic dementia, cerebral dementia, dementia-related dementia, dementia, dementia-related dementia, dementia Mori's disease, Picker's disease, encephalitis, encephalomyelitis, meningitis, prion disease, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia Capillary dilatation, spinal muscular dystrophy, progressive supranuclear palsy, muscle hypotonia, muscle spasm, tremor, retinal degeneration, striatal reservoir encephalomyopathy. [Example] [19.] The method of embodiment 14, wherein the compound is via oral, enteral, topical, aspirated, via mucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, epidermal, epiamniotic, intraarterial, guanosine Intranodal, intracardiac, intracorporeal penile spongy, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, percutaneous, perivascular, intrachural, transvaginal, sublingual, or transrectal routes were administered to the individual. [Example]

[20] .The method of embodiment 14, wherein the disorder is a neurodegenerative disorder, the neurodegenerative disorder is selected from one or more of the following group consisting of: MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Picker's disease), HD (Huntington's disease), Retttome Syndrome, Retttome Syndrome (progressive supranuclear palsy), CBD (corticobasal nucleus degeneration), SCA (spinocerebellar ataxia), MSA (multiple systemic atrophy), SDS (Shay-Delger syndrome), oligopoon cerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic brain lesion), stroke, WKS (Wein-Collard syndrome; alcoholic dementia and thiamine deficiency), normotensive hydrocephalus, hypersomnia / narcolepsy, ASD (autistic series disorder), FXS (X fragile fold syndrome), TSC (tuberous sclerosis), prion-related diseases (CJD, etc.), depression, DLB (lewy body dementia), PD (Parkinson's disease), PDAD (dementia), PD (attention deficit hyperactivity disorder), Alzheimer’s disease (AD), early AD and Down syndrome (DS). [Example]

[21] The method of Example 14, wherein the disease is a neurodegenerative disease, and the neurodegenerative disease is one or more selected from the group consisting of: 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 (Schay-Dauer syndrome), olivopontocerebellar ataxia, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wei Kerr syndrome; alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (CJD, etc.), depression, DLB (Lewy body dementia), PD (Parkinson's disease), PDD (PD dementia) and ADHD (Attention Deficit Hyperactivity Disorder). In some embodiments, the individual does not have Alzheimer's disease (AD). [Example] [22.] The method of any one of Examples 14 to 21, wherein the individual does not have Down syndrome. [Example] [23.] The method of any one of embodiments 14 to 22, wherein the subject is administered a peripherally acting beta-blocker (PABRA) along with the compound. [Example]

[24] The method of embodiment 23, wherein a peripherally acting beta-blocker (PABRA) is administered to the subject prior to administering the compound. [Example]

[25] The method of Example 23, wherein a peripherally acting beta-blocker (PABRA) is administered to the subject concurrently with the administration of the compound. [Example] [26.] The method of any one of embodiments 14 to 22, wherein in addition to the compound, a β1 agonist, a β2 agonist, or a non-selective β1 / β2 agonist is administered to the patient.

Claims

1. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

2. A compound having the following structure: , wherein X is selected from H, F, Cl, Br and I; R1 and R2 are methyl; R3 is methyl, ethyl, hydroxymethyl or hydroxyethyl, or R2 and R3, depending on the case, together with the inserted atom, form a 4-membered carbon ring or a 3-membered carbon ring.

3. The compound of claim 2, wherein R1, R2 and R3, together with their attached methylamine groups, form groups selected from the following:

4. A compound of any one of claims 1 to 3, wherein the compound is an agonist, partial agonist or antagonist of an adrenergic receptor.

5. The compound of any one of claims 1 to 3, wherein the compound is a β1-adrenergic receptor agonist, a β2-adrenergic receptor agonist or a nonselective β1 / β2-adrenergic receptor agonist.

6. The compound of any one of claims 1 to 3, wherein the compound is a β1-adrenergic receptor agonist.

7. The compound of any one of claims 1 to 3, wherein the compound is a β2-adrenergic receptor agonist.

8. The compound of any one of claims 1 to 3, wherein the compound is a nonselective β1 / β2-adrenergic receptor agonist.

9. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 8 and a pharmaceutically acceptable excipient.

10. Use of a compound as claimed in any one of claims 1 to 8 or a pharmaceutical composition as claimed in claim 9, for the manufacture of a medicament for treating an individual suffering from a disease related to adrenergic receptors.

11. As claimed in claim 10, wherein the disease is a disease associated with β1 or β2 adrenergic receptors.

12. As requested in claim 10, wherein the disease is a neurodegenerative disease.

13. As used in claim 10, wherein the individual is a human being.

14. The use as claimed in claim 10, wherein the compound is administered to the individual via oral, enteric, local, inhalation, mucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intravenous, upper epidermal, extraamniotic, intraarticular, intraarticular, intracardiac, intracavernous, intradermal, intralesional, intraocular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intrabladder, intravitreal, percutaneous, perivascular, buccal, vaginal, sublingual, or rectal routes.

15. As claimed in claim 10, wherein the disease is one or more neurodegenerative diseases selected from the group consisting of: MCI (mild cognitive impairment), aMCI (amnesic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia; Picker's disease), Rett syndrome, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, TSC (tuberous sclerosis), DLB (dementia with Lewy body), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down syndrome (DS).

16. As claimed in claim 10, wherein the disease is one or more neurodegenerative diseases selected from the group consisting of: MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia; Picker's disease), Rett syndrome, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, TSC (tuberous sclerosis), DLB (Lewy body dementia), PDD (PD dementia), and ADHD (attention deficit hyperactivity disorder).

17. For any of the uses of items 10 to 16, wherein the individual does not have Down syndrome.

18. The use of any one of claims 10 to 16, wherein the drug further comprises a peripheral beta-blocker (PABRA).

19. The use of any of claims 10 to 16, wherein a peripherally acting beta-blocker (PABRA) is administered to the individual prior to administration of the drug.

20. The use of any of claims 10 to 16, wherein a peripherally acting beta-blocker (PABRA) is administered to the individual concurrently with the administration of the drug.

21. The use of any one of claims 10 to 16, wherein the drug further comprises a β1 agonist, a β2 agonist, or a non-selective β1 / β2 agonist.