β-adrenergic agonists and methods of use thereof

Abstract

The present disclosure relates to chemical compounds and the use of such compounds in the treatment of diseases associated with adrenergic receptors. The compounds provided herein have the advantage of being able to achieve a wide range of pharmacological activity consistent with the modulation of β-adrenergic receptors. In addition, the present disclosure provides a method of using the compounds described herein for the treatment of diseases associated with adrenergic receptors, including but not limited to neurodegenerative diseases and disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 247,727, filed September 23, 2021. The disclosure of said prior application is deemed to be part of the disclosure of this application and is incorporated by reference in its entirety into this application.

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

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

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

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

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

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

[0008] overview The present disclosure relates to small molecule compounds that modulate adrenergic receptors, methods for preparing said compounds, pharmaceutical compositions containing said compounds, and their use in medical therapy.In particular, the present disclosure provides compounds that find utility as β-adrenergic agonists.The compounds provided herein have the advantage that a broad range of pharmacological activity can be achieved, consistent with modulation of β-adrenergic receptors.In addition, the present disclosure provides methods of using the compounds described herein for the treatment of diseases associated with adrenergic receptors.

[0009] The compounds of the present disclosure, and pharma- ceutically acceptable compositions thereof, have been found to be effective as β-adrenergic agonists. Such compounds of the present disclosure have the general formula: TIFF2024536815000001.tif18128, or a pharma- ceutically acceptable salt thereof, wherein each variable is as defined and explained herein.

[0010] The disclosed compounds, and pharma- ceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with abnormal β-adrenergic receptor activity, including those described herein.

[0011] The compounds provided by the present disclosure are also useful for studying β-adrenergic receptors in biological and pathological phenomena and for the comparative in vitro or in vivo evaluation of new β-adrenergic agonists or other regulators of β-adrenergic receptors, signaling pathways, and neurotransmitter levels. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description In the following disclosure, certain specific details are described to provide a thorough understanding of various embodiments. However, one of ordinary skill in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout this specification and the claims that follow, the word "comprise" and variations thereof (such as "comprises" and "comprising") are to be construed in an inclusive and open-ended sense, i.e., "including, but not limited to." Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the disclosure herein.

[0013] Throughout this specification, references to "one embodiment" or "some embodiments" mean that a feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in some embodiments" in various places throughout this specification are not necessarily referring to the same embodiment. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in the sense of including "and / or" unless the context clearly dictates otherwise.

[0014] definition Compounds of the present disclosure include those generally described herein and are further described by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., General Principles of Organic Chemistry are also described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed., the entire contents of which are incorporated herein by reference. th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0015] The term "aliphatic" or "aliphatic group," as used herein, means a substituted or unsubstituted linear (i.e., unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl"), having a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0016] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is connected to three or more skeletal atoms (except hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group may be substituted with one or more substituents as described for the aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group may be substituted. Exemplary bridged bicyclic groups are the following: Includes TIFF2024536815000002.tif105128.

[0017] The term "lower alkyl" refers to C 1~4 It refers to a straight or branched chain alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0018] The term "lower haloalkyl" refers to a C substituted with one or more halogen atoms. 1~4 It refers to a straight or branched chain alkyl group.

[0019] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or an oxygen, sulfur, nitrogen, phosphorus, or silicon atom in a heterocyclic ring).

[0020] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0021] As used herein, the term "divalent C 1~8 (or C 1~6 )"saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene chains, alkenylene chains, and alkynylene chains as defined herein.

[0022] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0023] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0024] As used herein, the term "cyclopropylenyl" refers to a group having the following structure: TIFF2024536815000003.tif11128 refers to a divalent cyclopropyl group.

[0025] The term “halogen” means F, Cl, Br, or I.

[0026] The term "aryl" used alone or as part of a larger moiety in "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of 4 to 14 ring members, where at least one ring in the system is aromatic and where each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthaimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0027] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 pi-electrons shared in a cyclic array, and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" in the context of "heteroaryl" specifically includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroara-" also include groups in which the radical or point of attachment is on the aromatic heterocycle, where the aromatic heterocycle is fused to one or more aryl rings, alicyclic rings, or heterocyclyl rings. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl rings can contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0028] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, preferably 1 to 4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, a saturated or partially unsaturated ring may have 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen.

[0029] The heterocyclic ring can be attached to the compound provided at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. Heterocyclic rings can contain one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl moieties independently may be optionally substituted.

[0030] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0031] As described herein, the compounds of the present disclosure may include "substituted" moieties. In general, the term "substituted" means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituents may be the same or different at every position. The combinations of substituents contemplated by the present disclosure 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 substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more purposes disclosed herein.

[0032] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH) 0~6 R ○ , -(CH2) 0~6 OR ○ , -O(CH2) 0~6 R ○ , -O-(CH2) 0~6 C(O)OR ○ , -(CH2) 0~6 CH(OR ○ )2, -(CH2) 0~6 S.R. ○ , Ph is R ○ may be substituted with -(CH2) 0~6 Ph, Ph is substituted R ○ may be substituted with -(CH2) 0~6 O(CH2) 0~1Ph, Ph is substituted R ○ -CH=CHPh, pyridyl can be substituted with R ○ may be substituted with -(CH2) 0~6 O(CH2) 0~1 -Pyridyl, -NO2, -CN, -N3, -(CH2) 0~6 N(R ○ )2, -(CH2) 0~6 N(R ○ )C(O)R ○ , -N(R ○ )C(S)R ○ , -(CH2) 0~6 N(R ○ )C(O)NR ○ 2, -N(R ○ )C(S)NR ○ 2, -(CH2) 0~6 N(R ○ )C(O)OR ○ , -N(R ○ )N(R ○ )C(O)R ○ , -N(R ○ )N(R ○ )C(O)NR ○ 2, -N(R ○ )N(R ○ )C(O)OR ○ , -(CH2) 0~6 C(O)R ○ , -C(S)R ○ , -(CH2) 0~6 C(O)OR ○ , -(CH2) 0~6 C(O)SR ○ , -(CH2) 0~6 C(O)OSiR ○ 3. -(CH2) 0~6 O.C.(O)R ○ , -OC(O)(CH2) 0~6 S.R. ○ , -(CH2) 0~6 SC(O)R ○ , -(CH2) 0~6 C(O)NR ○ 2. -C(S)NR ○ 2. -C(S)SR ○ , -SC(S)SR ○ , -(CH2) 0~6 OC(O)NR○ 2. -C(O)N(OR ○ )R ○ , -C(O)C(O)R ○ , -C(O)CH2C(O)R ○ , -C(NOR ○ )R ○ , -(CH2) 0~6 SSR ○ , -(CH2) 0~6 S(O)2R ○ , -(CH2) 0~6 S(O)2OR ○ , -(CH2) 0~6 OS(O)2R ○ , -S(O)NR ○ 2, -(CH2) 0~6 S(O)R ○ , -N(R ○ )S(O)NR ○ 2, -N(R ○ )S(O)2R ○ , -N(OR ○ )R ○ , -C(NH)NR ○ 2. -P(O)2R ○ , -P(O)R ○ 2. -P(O)(OR ○ )2, -OP(O)(R ○ ) OR ○ , -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, where each R ○ may be substituted as defined below and are independently hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independently occurring R○ form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0033] R ○ (or two independently existing R ○ Preferred monovalent substituents on the ring (formed by -(CH) together with their intervening atoms) are independently halogen, -(CH) 0~2 R ● , -(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 S.R. ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0034] Preferred divalent substituents on a saturated carbon atom of an "optionally substituted" group are ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 S-, where each R * is hydrogen, C which may be substituted as defined below 1~6 The "optionally substituted" group is preferably a divalent substituent bonded to the adjacent substitutable carbon atom of the "optionally substituted" group, such as -O(CR * 2) 2~3 O-, wherein each R * is hydrogen, C which may be substituted as defined below 1~6 It is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] R * Preferred substituents on the aliphatic groups are halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ●2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] A preferred substituent on a substitutable nitrogen of an "optionally substituted" group is -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independently occurring R † form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] As used herein, the term "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of suitable salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.

[0039] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations, formed where appropriate using counterions such as, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0040] As used herein, a "prodrug" refers to a derivative of an active agent that requires conversion in the body to release the active agent. In certain embodiments, the conversion is an enzymatic conversion. A prodrug is pharmacologically inactive until, but not necessarily, converted to an active agent. A "promoiety" refers to a form of protecting group that, when used to mask a functional group in an active agent, converts the active agent into a prodrug. In some cases, the promoiety is attached to the drug via a bond that is cleaved by enzymatic or non-enzymatic means in vivo. Any convenient prodrug form of the subject compound can be prepared according to the strategies and methods described, for example, by Rautio et al. ("Prodrugs: design and clinical applications", Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0041] As used herein, the term "provided compounds" refers to any genus, subgenus, and / or species described herein.

[0042] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers and enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Unless otherwise stated, structures depicted herein are also intended to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, those in which a hydrogen has been replaced by deuterium or tritium, or a carbon has been replaced by an isotopically enriched atom. 13 C or 14 Compounds having the structures of the invention including those with C-enriched carbons substituted are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure.

[0043] Compounds of the Disclosure The disclosed compounds, and compositions thereof, are useful as β-adrenergic modulators. In some embodiments, provided compounds modulate the β-adrenergic receptor.

[0044] In certain embodiments, the compounds disclosed herein are agonists, partial agonists, or antagonists of adrenergic receptors. In some embodiments, the compounds are β1-adrenergic receptor agonists, β2-adrenergic receptor agonists, or non-selective β1 / β2-adrenergic receptor agonists. In some embodiments, the compounds are β1-adrenergic receptor agonists. In some embodiments, the compounds are β2-adrenergic receptor agonists. In some embodiments, the compounds are non-selective β1 / β2-adrenergic agonists.

[0045] As described herein, The structure represented by TIFF2024536815000004.tif14128 is, for example, the structure Includes TIFF2024536815000005.tif15128.

[0046] The present disclosure provides compounds of formula Ia: The present invention provides a compound of formula (TIFF2024536815000006.tif24128 or a pharma- ceutically acceptable salt thereof, During the ceremony, Each R 1 are independently hydrogen, halogen, or R A , -CN, -NO2, -SF5, -OR, -N(R)2, -SO2R, -C(O)R, -C(O)N(R) 2、 -NR(O)R, -NRCO2R, or -CO2R; Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen atom, optionally together with their intervening atoms, form an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring, said saturated or partially unsaturated heterocyclic ring having, in addition to the nitrogen atom to which the two R groups are attached, 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R A is independent, C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or 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 Two R on the same carbon atom Agroups, 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; R 2 and R 3 each independently represents hydrogen or an optionally substituted C 1~6 aliphatic, or R 2 and R 3 optionally, together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 is optionally substituted C 1~6 It is aliphatic, R 5 is hydrogen or optionally substituted C 1~6 It is aliphatic, R 6 is C 2~9 Aliphatic, Phenyl C 0~3 alkyl, heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0~3 alkyl and heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0~3 alkyl, Ring A and Ring B are independently fused rings selected from benzo, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0, 1, 2, 3, 4, 5, or 6.

[0047] In some embodiments, the disclosure provides a compound of formula Ia, wherein formula Ia-1: or a pharma- ceutically acceptable salt thereof, wherein ring A is pyrazolilenyl as shown, and ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0048] In some embodiments, the disclosure provides a compound of formula Ia, wherein the compound is represented by formula Ia-2: or a pharma- ceutically acceptable salt thereof, 2 and R 3 is hydrogen, where ring A, ring B, R 1 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0049] In some embodiments, the disclosure provides a compound of formula Ia, wherein the compound is represented by formula Ia-3: or a pharma- ceutically acceptable salt thereof, wherein ring A is pyrazolilenyl and R 2 and R 3 is hydrogen, where rings B, R 1 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0050] In some embodiments, the disclosure provides a compound of formula Ia, wherein the compound is represented by formula Ia-4: or a pharma- ceutically acceptable salt thereof, wherein ring B is benzo, and ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0051] In some embodiments, the disclosure provides a compound of formula Ia, wherein the compound is represented by formula Ia-5: or a pharma- ceutically acceptable salt thereof, wherein ring B is benzo and R 2 and R 3 is hydrogen, where rings A and R 1 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0052] In some embodiments, the disclosure provides a compound of formula Ia, wherein the compound is represented by formula Ia-6: or a pharma- ceutically acceptable salt thereof, wherein ring A is pyrazolilenyl, as shown below, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0053] In some embodiments, the disclosure provides a compound of formula Ia, wherein the compound is represented by formula Ia-7: or a pharma- ceutically acceptable salt thereof, wherein ring A is pyrazolilenyl, as shown below, where R 1 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0054] The present disclosure provides compounds of formula Ib: The present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof, During the ceremony, Each R 1 are independently hydrogen, halogen, or R A , -CN, -NO2, -SF5, -OR, -N(R)2, -SO2R, -C(O)R, -C(O)N(R) 2、 -NR(O)R, -NRCO2R, or -CO2R; Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen atom, optionally together with their intervening atoms, form an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring, said saturated or partially unsaturated heterocyclic ring having, in addition to the nitrogen atom to which the two R groups are attached, 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R A is independent, C 1~6an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or 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 Two R on the same carbon atom A groups, 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; R 2 and R 3 each independently represents hydrogen or an optionally substituted C 1~6 aliphatic, or R 2 and R 3 optionally, together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 and R 5 each independently represents hydrogen or an optionally substituted C 1~6 aliphatic, or R 4 and R 5 optionally, together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 is C 1~9 Aliphatic, Phenyl C 0~3 alkyl, heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0~3 alkyl and heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0~3alkyl, Ring A and Ring B are independently fused rings selected from benzo, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 2, 3, 4, 5, or 6; wherein when ring A is a 5-membered fused heterocyclic ring, it is not a 5-membered heterocyclic ring containing one nitrogen.

[0055] In some embodiments, the disclosure provides a compound of formula Ib, wherein Ib-1: or a pharma- ceutically acceptable salt thereof, wherein ring A is pyrazolilenyl, and ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0056] In some embodiments, the disclosure provides a compound of formula Ib, wherein the compound is represented by formula Ib-2: or a pharma- ceutically acceptable salt thereof, 2 and R 3 is hydrogen, where ring A, ring B, R 1 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0057] In some embodiments, the disclosure provides a compound of formula Ib, wherein the compound is represented by formula Ib-3: or a pharma- ceutically acceptable salt thereof, wherein ring A is pyrazolilenyl and R 2 and R 3 is hydrogen, where rings B, R 1 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0058] In some embodiments, the disclosure provides a compound of formula Ib, wherein the compound is represented by formula Ib-4: or a pharma- ceutically acceptable salt thereof, wherein ring B is benzo, and ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0059] In some embodiments, the disclosure provides a compound of formula Ib, wherein the compound is represented by formula Ib-5: or a pharma- ceutically acceptable salt thereof, wherein ring B is benzo and R 2 and R 3 is hydrogen, where rings A and R 1 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0060] In some embodiments, the disclosure provides a compound of formula Ib, wherein the compound is represented by formula Ib-6: or a pharma- ceutically acceptable salt thereof, wherein ring A is pyrazolilenyl, as shown below, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0061] In some embodiments, the disclosure provides a compound of formula Ib, wherein the compound is represented by formula Ib-7: or a pharma- ceutically acceptable salt thereof, wherein ring A is pyrazolilenyl, as shown below, where R 1 , R 4 , R 5 , R 6 Each of and n, both alone and in combination, is as defined above and described in embodiments herein.

[0062] As defined above and described herein, each R 1 are independently hydrogen, halogen, or R A , -CN, -NO2, -SF5, -OR, -N(R)2, -SO2R, -C(O)R, -C(O)N(R) 2、 -NR(O)R, -NRCO2R, or -CO2R.

[0063] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 1 is R A In some embodiments, R 1 In some embodiments, R 1is -NO2. In some embodiments, R 1 is -SF5. In some embodiments, R 1 In some embodiments, R 1 is -N(R). In some embodiments, R 1 is -SO2R. In some embodiments, R 1 is -C(O)R. In some embodiments, R 1 is -C(O)N(R). In some embodiments, R 1 is -NRC(O)R. In some embodiments, R 1 is -NRCO2R. In some embodiments, R 1 is -COR. In some embodiments, R 1 is chloro. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is methyl. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is -OCHF2.

[0064] In some embodiments, R 1 is selected from those shown in Tables 1A to C below.

[0065] As defined above and described herein, each R is independently hydrogen or C 1~6an optionally substituted group selected from aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen atom, optionally together with their intervening atoms, form an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring, said saturated or partially unsaturated heterocyclic ring having, in addition to the nitrogen atom to which the two R groups are bonded, 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C 1~6 It is aliphatic (e.g., methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, trifluoromethyl, etc.). In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen. In some embodiments, two R groups on the same nitrogen atom, optionally together with their intervening atoms, form an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring, said saturated or partially unsaturated heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen atom to which the two R groups are attached.

[0067] In some embodiments, R 1 is selected from those shown in Tables 1A to C below.

[0068] As defined above and described herein, each R A is independent, C 1~6 an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or 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 two R A The groups, 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.

[0069] In some embodiments, R A is an optionally substituted C 1~6 In some embodiments, R is an aliphatic group (e.g., methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, trifluoromethyl, etc.). A is optionally substituted phenyl. In some embodiments, R A is an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R A is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R A is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R A The groups, optionally taken together with their intervening atoms, form an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, two R AThe groups, optionally together with their intervening atoms, form an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0070] In some embodiments, R A is selected from those shown in Tables 1A to C below.

[0071] As defined above and described herein, R 2 and R 3 each independently represents hydrogen or an optionally substituted C 1~6 Aliphatic or R 2 and R 3 optionally, together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0072] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted C 1~6 It is aliphatic (eg, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, trifluoromethyl, etc.).

[0073] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C 1~6 It is aliphatic (eg, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, trifluoromethyl, etc.).

[0074] In some embodiments, R 2 and R 3optionally together with the carbon atom to which they are attached form an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic ring (e.g., cyclopropylenyl, cyclobutylenyl, etc.). 2 and R 3 optionally, together with the carbon atom to which they are attached, form an optionally substituted 3-6 membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., tetrahydrofuranylenyl, tetrahydro-2H-pyranylenyl, pyrrolidinylenyl, piperidinylenyl, etc.).

[0075] In some embodiments, R 2 and R 3 is selected from those shown in Tables 1A to C below.

[0076] As defined above and described herein, R 4 is hydrogen or optionally substituted C 1~6 It is aliphatic.

[0077] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is optionally substituted C 1~6 In some embodiments, R is an aliphatic group (e.g., methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, trifluoromethyl, etc.). 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is tert-butyl.

[0078] As defined above and described herein, R 5 is hydrogen or optionally substituted C 1~6 It is aliphatic.

[0079] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is an optionally substituted C 1~6 In some embodiments, R is an aliphatic group (e.g., methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, trifluoromethyl, etc.). 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is isopropyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is tert-butyl.

[0080] As defined above and described herein, R 4 and R 5 optionally, together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0081] In some embodiments, R 4 and R 5 optionally, together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] In some embodiments, R 4 and R 5 is selected from those shown in Tables 1A to C below.

[0083] As defined above and described herein, R6 is C 1~9 Aliphatic, Phenyl C 0~3 alkyl, heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0~3 alkyl and heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0~3 alkyl, and optionally substituted groups selected from the group consisting of aryl, aryl, aryl and alkyl.

[0084] In some embodiments, R 6 is an optionally substituted C 1~9 In some embodiments, R is an aliphatic group (e.g., methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, trifluoromethyl, etc.). 6 is an optionally substituted C 2~9 In some embodiments, R is an aliphatic group (e.g., ethyl, isopropyl, cyclopropyl, cyclobutyl, trifluoromethyl, etc.). 6 is an optionally substituted phenyl C 0~3 In some embodiments, R 6 is an optionally substituted heterocyclyl C having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0~3 In some embodiments, R 6 is an optionally substituted heteroaryl group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0~3 In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is cyclopropyl. In some embodiments, R 6 is tert-butyl. In some embodiments, R 6 is optionally substituted benzyl. In some embodiments, R 6is benzyl. In some embodiments, R 6 is para-methoxybenzyl.

[0085] In some embodiments, R 6 is selected from those shown in Tables 1A to C below.

[0086] As defined above and described herein, Ring A and Ring B are independently fused rings selected from benzo, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In some embodiments, ring A is benzo. In some embodiments, ring A is a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring A is a 5-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is pyrrolidinylenyl. In some embodiments, ring A is pyrazolyllenyl. In some embodiments, ring A is pyridinylenyl. In some embodiments, ring A is pyrimidinylenyl.

[0088] In some embodiments, ring B is benzo. In some embodiments, ring B is 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is 5-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, ring B is 5-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is pyridinylenyl.

[0089] In some embodiments, when ring A is a 5-membered fused heterocyclic ring, it is not a 5-membered heterocyclic ring containing one nitrogen.

[0090] In some embodiments, Ring A and Ring B are selected from those shown in Tables 1A-C below.

[0091] As defined above and described herein, n is 0, 1, 2, 3, 4, 5, or 6.

[0092] 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. In some embodiments, n is 5. In some embodiments, n is 6.

[0093] Exemplary compounds of the present disclosure are shown in the table below.

[0094] Table 1A: Exemplary Compounds TIFF2024536815000022.tif150128TIFF2024536815000023.tif202109TIFF2024536815000024.tif180128TIFF20245368150 00025.tif192109TIFF2024536815000026.tif202109TIFF2024536815000027.tif203109TIFF2024536815000028.tif173128 TIFF2024536815000029.tif201109TIFF2024536815000030.tif207109TIFF2024536815000031.tif191128TIFF20245368150 00032.tif172128TIFF2024536815000033.tif203109TIFF2024536815000034.tif168128TIFF2024536815000035.tif105128

[0095] In some embodiments, the disclosure provides a compound shown in Table 1A above, or a pharma- ceutically acceptable salt thereof.

[0096] Table 1B: Exemplary Compounds TIFF2024536815000036.tif57128TIFF2024536815000037.tif201109TIFF2024536815000038.tif144128

[0097] In some embodiments, the disclosure provides a compound shown in Table 1B above, or a pharma- ceutically acceptable salt thereof.

[0098] Table 1C: Exemplary Compounds TIFF2024536815000039.tif174128TIFF2024536815000040.tif206110TIFF2024536815000041.tif210110TIFF2024536815000042.tif211110TIFF2024536815000043.tif176128TIFF2024536815000044.tif161128TIFF2024536815000045.tif194110TIFF2024536815000046.tif187128TIFF2024536815000047.tif174128TIFF2024536815000048.tif187128TIFF2024536815000049.tif198110TIFF2024536815000050.tif184128TIFF2024536815000051.tif177128TIFF2024536815000052.tif203110TIFF2024536815000053.tif206110TIFF2024536815000054.tif175128TIFF2024536815000055.tif189128TIFF2024536815000056.tif179128TIFF2024536815000057.tif209110TIFF2024536815000058.tif193110TIFF2024536815000059.tif210110TIFF2024536815000060.tif190128TIFF2024536815000061.tif174128TIFF2024536815000062.tif170128TIFF2024536815000063.tif179128TIFF2024536815000064.tif190128TIFF2024536815000065.tif194110TIFF2024536815000066.tif205110TIFF2024536815000067.tif209110TIFF2024536815000068.tif185128TIFF2024536815000069.tif92128

[0099] In some embodiments, the disclosure provides a compound shown in Table 1C above, or a pharma- ceutically acceptable salt thereof.

[0100] General Methods for Providing Compounds of the Invention The compounds of the present disclosure may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art of similar compounds, and by the methods detailed in the Examples herein.

[0101] In the following schemes illustrating particular protecting groups, leaving groups, or transformation conditions, one of skill in the art will recognize that other protecting groups, leaving groups, and transformation conditions are suitable and contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 5th Edition, each of which is incorporated herein by reference in its entirety. th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, RC Larock, 2 nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd This is described in detail in the following edition, John Wiley & Sons, 1999.

[0102] As used herein, the expression "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference in its entirety. rdedition, John Wiley & Sons, 1999. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoylformate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl carbonate. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, β-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl ethers.

[0103] Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Huts, 3, incorporated herein by reference in its entirety. rd edition, John Wiley & Sons, 1999. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, etc. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0104] The compounds of the present disclosure can be prepared in a variety of ways. In some embodiments, the compounds of the present disclosure are generally prepared according to Scheme 1, shown below. Scheme 1 TIFF2024536815000070.tif40135

[0105] In some embodiments, compounds of the present disclosure are generally prepared according to Scheme 2, shown below. Scheme 2 TIFF2024536815000071.tif19160

[0106] In some embodiments, compounds of the present disclosure are generally prepared according to Scheme 3, shown below. Scheme 3 TIFF2024536815000072.tif19160

[0107] In some embodiments, compounds of the present disclosure are generally prepared according to Scheme 4, shown below. Scheme 4 TIFF2024536815000073.tif20160

[0108] In some embodiments, compounds of the present disclosure are generally prepared according to Scheme 5, shown below. Scheme 5 TIFF2024536815000074.tif21159

[0109] In some embodiments, compounds of the present disclosure are generally prepared according to Scheme 6, shown below. Scheme 6 TIFF2024536815000075.tif18156

[0110] In some embodiments, compounds of the present disclosure are generally prepared according to Scheme 7 below. Scheme 7 TIFF2024536815000076.tif23159

[0111] Those skilled in the art will appreciate that various functional groups present in the compounds of the present disclosure, such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles, can be interconverted by techniques well known in the art, including but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, March's Advanced Organic Chemistry, 5, incorporated herein by reference in its entirety. th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001. Such interconversions may require one or more of the techniques described above, and specific methods for synthesizing the compounds of the disclosure are described in the examples below.

[0112] Pharmaceutical Compositions of the Compounds of the Invention According to another embodiment, the present disclosure provides a composition comprising a compound of the present disclosure or a pharma- ceutically acceptable derivative thereof and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present disclosure is an amount effective to measurably agonize β-adrenergic receptors or variants thereof in a biological sample or in a subject. In certain embodiments, the amount of the compound in the composition of the present disclosure is an amount effective to measurably agonize β-adrenergic receptors or variants thereof in a biological sample or in a subject. In certain embodiments, the composition of the present disclosure is formulated for administration to a subject in need of such a composition. In a preferred embodiment, the composition of the present disclosure is formulated for oral administration to a subject.

[0113] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present disclosure 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, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0114] In some embodiments, the pharma- ceutically acceptable carrier, adjuvant, or vehicle comprises a granule, an enteric coating, a capsule, a conventional tablet, a multi-layer tablet, an extended release agent, an effervescent agent, an orally administered tablet, or an orally administered film, as described in the following sections.

[0115] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present disclosure which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present disclosure, or an inhibitory active metabolite or residue thereof.

[0116] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also a modulator of the β-adrenergic receptor or a variant thereof.

[0117] In certain embodiments, the compositions of the present disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human. Such pharmaceutical compositions are used to ameliorate, treat, or prevent any of the disorders described herein in the subject.

[0118] The agents of the present disclosure are often administered as pharmaceutical compositions containing an active therapeutic agent and various other pharma- ceutically acceptable ingredients. 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 contain pharma- ceutically acceptable non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, and the like.

[0119] In some embodiments, the present disclosure provides pharma- ceutically acceptable compositions comprising a therapeutically effective amount of one or more of the described compounds formulated with one or more pharma- ceutically acceptable carriers (additives) and / or diluents for use in 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, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, systemic lupus erythematosus, nephritis, ulcerative colitis, and Parkinson's disease. Although it is possible to administer the described compounds alone, it is preferred to administer the described compounds as a pharmaceutical formulation (composition) as described herein. The provided compounds may be formulated for administration in any convenient manner for use in human or veterinary medicine, by analogy with other pharmaceuticals.

[0120] As described in detail, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid forms, including forms adapted for oral administration, such as, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue, etc., for buccal, sublingual and systemic absorption; parenteral administration, for example, by sterile solutions or suspensions, or subcutaneous, intramuscular, intravenous or epidural injection as sustained release formulations; topical application, for example, as creams, ointments, or controlled release patches or sprays applied to the skin, lungs, or oral cavity; vaginal or rectal administration, for example, as pessaries, creams or foams; sublingual administration; ocular administration; transdermal administration; or administration to the nasal, pulmonary, and other mucosal surfaces.

[0121] Wetting agents, emulsifying agents, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0122] Examples of pharma- ceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0123] Formulations for use according to the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient. In some embodiments, this amount will range from about 5% to about 70%, about 10% to about 50%, or about 20% to about 40%.

[0124] In certain embodiments, the formulations described herein include an excipient selected from cyclodextrins, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides, and a provided compound. In certain embodiments, the formulations render a provided compound, or a pharma- ceutically acceptable salt thereof, orally bioavailable.

[0125] Methods for preparing formulations or compositions containing the provided compounds include the step of bringing the provided compounds into association with carriers and, optionally, one or more accessory ingredients. In general, the formulations can be prepared by uniformly and intimately bringing into association the provided compounds with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0126] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may be, for example, a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any smooth fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may contain long chain alcohol diluents or dispersants, such as those described in the Pharmacopeia Helvetica, or similar alcohols. For formulation purposes, other commonly used surfactants may also be used, such as Tweens, Spans and other emulsifiers or bioavailability enhancers that are commonly used in the manufacture of pharma- ceutically acceptable solid, liquid, or other dosage forms.

[0127] In some cases, it may be desirable to delay the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous substances that are poorly water-soluble.The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the size and crystalline system of the crystals.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0128] Injectable depot forms are made by forming microencapsule matrices of the provided compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0129] The pharmaceutical composition of the present disclosure may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. For oral administration of aqueous suspensions and solutions, and propylene glycol, the provided compound may be combined with emulsifying and suspending agents. If necessary, certain sweetening and / or flavoring and / or coloring agents may be added.

[0130] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each containing a predetermined amount of a provided compound or a pharma-ceutically acceptable salt thereof as the active ingredient. A provided compound may also be administered as a bolus, electuary, or paste.

[0131] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be mixed with sodium citrate or dicalcium phosphate and / or with fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid, binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, wetting agents, such as glycerol, disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, humectants, such as glycerol, disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, gelatin, polyvinylpyrrolidone, sucrose, gelatin, polyvinylpyrrolidone, sucrose, gelatin, polyvinylpyrrolidone, alginates ... Mix with one or more pharma- ceutically acceptable carriers, such as any of the following: glyceryl stearate, certain silicates, and sodium carbonate, solution retarders, such as paraffin, absorption enhancers, such as quaternary ammonium compounds, wetting agents, such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, absorbents, such as kaolin and bentonite clay, lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and coloring agents.In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents.Similar types of solid compositions may also be used as fillers in soft and hard shell gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0132] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made in a suitable machine by moistening a mixture of powdered compounds with an inert liquid diluent. When a solid carrier is used, the preparation can be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier varies, for example, from about 25 to 800 mg, preferably from about 25 mg to 400 mg. When a liquid carrier is used, the preparation can be in the form of a sterile injectable liquid, such as, for example, a syrup, emulsion, soft gelatin capsule, ampoule, or non-aqueous liquid suspension. When the composition is in the form of a capsule, any of the conventional encapsulation methods are suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.

[0133] Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They can alternatively or additionally be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres to provide the desired release profile. They can be formulated for rapid release, for example, lyophilized. They can be sterilized, for example, by filtration through a bacterial retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or any other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can optionally be of a composition that releases the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0134] Liquid dosage forms for oral administration of the provided compounds include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the provided compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0135] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0136] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and the like, and mixtures thereof.

[0137] The pharmaceutical composition of the present disclosure may also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the provided compound with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0138] Topical administration of the pharmaceutical composition of the present disclosure is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated into a suitable ointment containing the active component suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present disclosure may also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present disclosure.

[0139] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0140] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0141] Transdermal patches have the added advantage of providing controlled delivery of the compound provided to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0142] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure 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 the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0143] Such compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents, 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 in the composition, such as sugars, sodium chloride, and the like. In addition, prolonged absorption of the injectable pharmaceutical form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0144] In certain embodiments, the described compounds or pharmaceutical preparations are administered orally. In other embodiments, the described compounds or pharmaceutical preparations are administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0145] When the compounds described herein are administered to humans and animals as pharmaceuticals, they may be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0146] The preparations described herein may be given orally, parenterally, topically, or rectally. They are, of course, given in a form suitable for the relevant route of administration. For example, they are given in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by administration by injection, infusion or inhalation, topically by lotion or ointment, and rectally by suppositories. Oral administration is preferred.

[0147] Such compounds may be administered to humans and other animals for treatment by any suitable route of administration, including, for example, orally by spray, nasally, rectally by powders, ointments, or drops, intravaginally, parenterally, intracisternally, and topically (including buccal and sublingual).

[0148] Regardless of the route of administration selected, the compounds described herein, which may be used in a suitable hydrated form, and / or pharmaceutical compositions of the disclosure, are formulated into pharma- ceutical acceptable dosage forms by conventional methods known to those of skill in the art.

[0149] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0150] Kits are also provided that include the provided adrenergic receptor modulating compounds. The systems of the present disclosure include a collection of active agents that are assembled for administration to a subject, such as a patient, for example, by a medical professional. Such systems may include the provided adrenergic receptor modulating compounds and one or more additional active agents disclosed herein. Kits are provided that include the provided adrenergic receptor modulating compounds, which may include one or more doses of the provided adrenergic receptor modulating compounds, and optionally one or more doses of one or more additional active agents. Conveniently, the formulations may be provided in unit dosage form. In such kits, in addition to the containers that include the formulations, e.g., unit doses, there is an information insert that describes the use of the subject formulations in the methods as disclosed herein, e.g., instructions for using the subject unit doses for CNS pathologies. These instructions may be present in the subject systems and kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is information printed on a suitable medium or substrate, e.g., one or more sheets of paper on which the information is printed, the kit packaging, the insert, etc. Another means is a computer readable medium having the information recorded thereon, such as a diskette, CD, etc. Yet another means that may be present is a website address that may be used to access the information at a remote site via the Internet. Any convenient means may be present in the kit.

[0151] Most preferably, the pharma- ceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharma- ceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharma- ceutically acceptable compositions of the present disclosure are administered with food.

[0152] The amount of the compounds of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host used, the particular mode of administration. Preferably, the compositions provided will be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compounds can be administered to a patient receiving these compositions.

[0153] The compounds used in the compositions and methods of the present disclosure may be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include those that enhance biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), enhance oral availability, enhance solubility to allow administration by injection, alter metabolism, and / or alter excretion rate.

[0154] It should be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, biology, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a compound of the present disclosure in a composition will also depend on the particular compound in the composition.

[0155] Therapeutic Uses of Pharmaceutical Compositions and Compounds of the Invention The compounds and compositions described herein are generally useful for modulating adrenergic receptors.

[0156] As used herein, the term "adrenergic receptor-mediated" disorder, disease, and / or condition refers to any disease or other deleterious condition in which an adrenergic receptor is known to be involved. Accordingly, another embodiment of the present disclosure relates to treating or reducing the severity of one or more diseases in which an adrenergic receptor or a variant thereof is known to be involved.

[0157] In some embodiments, the disclosure provides a method of treating a subject having an adrenergic receptor-mediated disorder, disease, and / or condition, the method comprising administering to the subject a therapeutically effective amount of a provided compound or a pharma- ceutically acceptable salt thereof. In some embodiments, the adrenergic receptor-mediated disorder, disease, and / or condition is a disease associated with a β-adrenergic receptor. In some embodiments, the adrenergic receptor-mediated disorder, disease, and / or condition is a neurodegenerative disease. In some embodiments, the subject is a human.

[0158] In some embodiments, the compounds disclosed herein can be adrenergic receptor modulating compounds (e.g., adrenergic receptor agonists, partial agonists, or antagonists). The adrenergic receptor modulating compounds of the present disclosure are useful in some embodiments for modulating the activity of a target adrenergic receptor in vitro or in vivo. Aspects of the subject methods include contacting a sample with an adrenergic receptor modulating compound (e.g., as described herein) to determine whether a desired activity is present.

[0159] Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the body and play an important role in controlling multiple physiological processes, including cognition, stress-related behavior, inflammation, and smooth muscle contraction / dilation, myocardial contraction, airway reactivity, and cognition. Adrenergic receptors mediate the central and peripheral actions of noradrenaline (NA) and adrenaline. There are multiple subtypes of ADRs, including α-adrenergic receptors and β-adrenergic receptors. Each subtype is expressed in a different pattern and is involved in different physiological processes. Thus, ligands that selectively target one subtype are highly useful both as research tools to distinguish the role of different ADR subtypes and as therapeutic agents for multiple diseases associated with dysfunction of NA and the adrenergic system.

[0160] β-adrenergic receptors further include three subtypes: β1-adrenergic receptors (β1-ADR), β2-adrenergic receptors (β2-ADR), and β3-adrenergic receptors (β3-ADR). These subtypes are expressed in different patterns and are involved in different physiological processes, so ligands that can selectively target one subtype have therapeutic potential for multiple diseases. However, the discovery of subtype-selective ligands is difficult due to the high level of sequence homology shared by these subtypes. Many of the existing agonists for β-adrenergic receptors also show poor blood-brain barrier (BBB) ​​penetration, a property that is necessary for drug discovery for central nervous system (CNS) indications.

[0161] As a class of G protein-coupled receptors, adrenergic receptors transmit signals through G protein and β-arrestin-dependent pathways. G protein or β-arrestin signaling can mediate different physiological responses. Recently, it has been found that agonists can exhibit biased activation of signaling pathways. The ability of a ligand to activate a receptor and generate a response in a pathway-dependent manner is called "signaling bias" or "functional selectivity." Because G protein and β-arrestin mediate different physiological processes, biased agonists can provide improved therapeutic selectivity with reduced side effects. Thus, in some embodiments, the present disclosure relates to β-adrenergic receptor subtype selective agonists with improved blood-brain barrier (BBB) ​​penetration.

[0162] In some embodiments, the provided compound is an adrenergic receptor modulating compound and can be an agonist of the target adrenergic receptor.In some cases, the effective amount of the provided adrenergic receptor modulating compound is sufficient to activate the activity associated with the adrenergic receptor in cells by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, or even 200% or more, compared to a control, for example, a control cell that shows a known level of activity of the receptor.

[0163] In some embodiments, the provided compound is an adrenergic receptor modulating compound and can be a partial agonist of the target adrenergic receptor.In some cases, the effective amount of the provided adrenergic receptor modulating compound is sufficient to achieve partial agonism of the adrenergic receptor in cells, for example, the amount of the subject compound achieves 10% or more activation of the receptor, for example 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more activation compared to a control, for example, a fully activated receptor.Partial agonism can be evaluated using any convenient method, such as, for example, 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 compared to the full agonist.

[0164] In some embodiments, the provided compound is an adrenergic receptor modulating compound and can be an antagonist of the target adrenergic receptor.In some cases, the effective amount of the provided adrenergic receptor modulating compound is sufficient to inhibit or reduce the activity of the adrenergic receptor in a sample by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or even 90% or more, compared to a control, for example, a sample not contacted with the target compound.

[0165] In some embodiments, provided compounds act as low nM partial agonists of the β2-adrenergic receptor. For example, in some embodiments, provided compounds have an EC of less than about 1 nM, less than about 5 nM, less than about 10 nM, less than about 15 nM, less than about 20 nM, less than 25 nM, less than 30 nM, less than 35 nM, less than 40 nM, less than 45 nM, less than 50 nM, less than 55 nM, less than 60 nM, less than 65 nM, less than 70 nM, less than 75 nM, less than 80 nM, less than 85 nM, less than 90 nM, less than 95 nM, or less than 100 nM. 50In some embodiments, provided compounds act as low nM partial agonists of β2-adrenergic receptors and have an EC of about 0.001 nM to about 200 nM, 0.001 nM to about 150 nM, about 0.001 nM to about 100 nM, 0.01 nM to about 100 nM, 0.1 nM to about 100 nM, or about 0.1 nM to about 80 nM, or about 0.1 nM to about 60 nM, or about 0.1 nM to about 40 nM, or about 0.1 nM to about 30 nM, or about 0.1 nM to about 20 nM, or about 0.1 nM to about 10 nM. 50 has.

[0166] In some embodiments, provided compounds act as low μM partial agonists of the β2-adrenergic receptor. For example, in some embodiments, provided compounds have an EC of less than about 0.1 μM, less than about 0.5 μM, less than about 1.0 μM, less than about 1.5 μM, less than about 2.0 μM, less than about 2.5 μM, less than about 3.0 μM, less than about 3.5 μM, less than about 4.0 μM, less than about 4.5 μM, less than about 5.0 μM, less than about 5.5 μM, less than about 6.0 μM, less than about 6.5 μM, less than about 7.0 μM, less than about 7.5 μM, less than about 8.0 μM, less than about 8.5 μM, less than about 9.0 μM, less than about 9.5 μM, or less than about 10.0 μM. 50 has.

[0167] In some embodiments, provided compounds act as low μM partial agonists of β2-adrenergic receptors, with an EC of about 0.01 μM to about 10 μM, about 0.01 μM to about 9.0 μM, about 0.01 μM to about 8.0 μM, about 0.01 μM to about 7.0 μM, about 0.01 μM to about 6.0 μM, about 0.01 μM to about 5.0 μM, about 0.01 μM to about 4.0 μM, about 0.01 μM to about 3.0 μM, about 0.01 μM to about 2.0 μM, about 0.01 μM to about 1.0 μM, about 0.01 μM to about 9.0 μM, about 0.1 μM to about 1.0 μM. 50 has.

[0168] In some embodiments, the present disclosure provides a method for treating a subject having an adrenergic receptor-mediated disorder, disease, and / or condition, wherein the target adrenergic receptor is a β1-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β2-adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a β3-adrenergic receptor. In some embodiments, the compound is an agonist for both the β1-adrenergic receptor and the β2-adrenergic receptor. In certain cases, the compound is selective for the β2-adrenergic receptor over the β1-adrenergic receptor.

[0169] In some embodiments, the target adrenergic receptor may be one responsible for mediating an intracellular signal or pathway in the cell. In some embodiments, the sample comprises a cell, and modulation of the adrenergic receptor modulates a physiological process in the cell. Any convenient physiological process may be targeted for modulation in the cell using the subject methods. In some embodiments, the physiological process is a process involved in cardiac function, and in certain cases, the physiological process is a process involved in cognitive function. In certain cases, the physiological process is a process involved in an inflammatory pathway or condition. The subject methods may provide for mediation of intracellular concentrations of signaling molecules, such as cAMP, in the cell. The subject methods may provide for partial or complete blocking of the target adrenergic receptor to result in modulation (e.g., activation) of cAMP in the sample. In some embodiments, the method does not modulate the β-arrestin pathway of the cell. In some cases, the cell is an inflammatory cell, and the function of the cell is controlled. The subject methods may provide for inhibition of an inflammatory pathway in the cell. In some cases, TNF-α is inhibited in the cell, e.g., the concentration or production of TNF-α is reduced by performing the subject methods. In certain embodiments of the method, the cell is a neuron. In some embodiments, modulation of adrenergic receptors enhances neurogenesis.

[0170] In some embodiments, provided compounds or pharma- ceutically acceptable salts thereof are useful in treating myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedreich's ataxia, ataxia-telangiectasia, spinal muscular dystrophy, The therapeutic methods may be used in conventional manner to control, prevent, or treat the diseases described herein, including but not limited to cerebral autosomal dominant arteriopathy with subcortical infarctions (CADASIL), progressive supranuclear palsy, dystonia, muscle spasms, tremors, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis, cerebral autosomal dominant arteriopathy with subcortical infarctions (CADASIL), and diabetic retinopathy. Such therapeutic methods, their dosage levels, and requirements may be selected by the skilled artisan from available methods and techniques.

[0171] In some embodiments, the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedreich's ataxia, ataxia-telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscinosis.

[0172] In some embodiments, the disease is MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia, Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke's syndrome), or other conditions. and neurodegenerative diseases, which are one or more selected from Korsakoff's syndrome, alcoholic dementia and thiamine deficiency), normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis), prion-related diseases (CJD, etc.), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down's syndrome (DS). In some embodiments, the disease is MCI, aMCI, vascular dementia, mixed dementia, FTD (frontotemporal dementia, Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Welsh syndrome), or other conditions. The neurodegenerative disease is one or more selected from the group consisting of rheumatoid arthritis, ...

[0173] In some embodiments, the disclosure provides a method of treating a subject having a β-adrenergic receptor mediated disorder, disease, and / or condition, the method comprising administering to the subject a provided compound or a pharma- ceutically acceptable salt thereof and a peripherally acting β-blocker (PABRA).

[0174] As used herein, the term "peripherally acting beta blocker (PABRA)" refers to a beta-adrenergic receptor antagonist, or simply a beta 1, beta 2, or non-selective beta blocker. Examples of selective peripherally acting beta blockers (PABRA) that can be used in the methods disclosed herein in certain embodiments include nadolol, atenolol, sotalol, and labetalol. In certain embodiments, the beta blocker that can be used in the methods herein is one or more selected from acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, and nebivolol, and in other embodiments, the method does not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol, and nebivolol as a beta blocker.

[0175] In certain embodiments, a peripherally acting beta blocker (PABRA) is administered to a subject prior to administration of a provided compound or a pharma- ceutically acceptable salt thereof. In other embodiments, a peripherally acting beta blocker (PABRA) is administered to a subject simultaneously with administration of a provided compound or a pharma- ceutically acceptable salt thereof.

[0176] In certain embodiments of the compositions and methods provided herein, one or more peripherally acting beta blockers (PABRA) are administered prior to or simultaneously with the provided compounds or pharma- ceutically acceptable salts thereof to inhibit or eliminate peripheral beta1 and / or beta2-adrenergic receptor agonism by the disclosed compounds. In some embodiments, it is preferred to block peripheral beta1 and / or beta2-adrenergic receptors according to the disclosed compositions and methods to eliminate or at least minimize any adverse peripheral, cardiac, metabolic or muscular effects on the treated human.

[0177] In some embodiments of the methods provided herein, in addition to a provided compound or a pharma- ceutically acceptable salt thereof, a beta1 agonist and / or a beta2 agonist, or a non-selective beta1 / beta2 agonist is administered to the patient.

[0178] As used herein, the term "β1 agonist" is used to mean a β1-adrenergic receptor agonist or a β1-ADR agonist. In certain embodiments, the term β1 agonist includes compounds that are, of course, primarily β1 agonists, but may also exhibit some peripheral agonism at other adrenergic receptors, such as the β2-adrenergic receptor. In this application, the terms "β1-adrenergic receptor agonist", "β1-ADR agonist", "β1AR agonist" and "β1 agonist" may be used interchangeably. In certain embodiments, the term β1-ADR agonist explicitly includes both selective and partial agonists, and biased and unbiased agonists. Examples of β1-adrenergic agonists include, for example, xamoterol, noradrenaline, isoprenaline, dopamine, pindolol and dobutamine, and pharma- ceutically acceptable salts of any of the above. Partial agonists and ligands of β1-ADR are known. In addition, using the methodology of Kolb et al., but instead for β1-ADR, those skilled in the art can determine new ligands by structure-based discovery. See Proc.Natl.Acad.Sci.USA 2009,106,6843-648.

[0179] As used herein, the term "β2 agonist" is used to mean a β2-adrenergic receptor agonist or a β2-ADR agonist. In certain embodiments, the term β2 agonist includes compounds that are, of course, primarily β2 agonists, but may also exhibit peripheral agonism at other adrenergic receptors, such as the β1-adrenergic receptor. As used herein, the terms "β2-adrenergic receptor agonist", "β2-ADR agonist", "β2AR agonist" and "β2 agonist" may be used interchangeably. In some embodiments, the term β2-ADR agonist explicitly includes both selective agonists and partial agonists. The β2 agonists that may be used according to various aspects and embodiments of the present disclosure may be short-acting, long-acting or ultra-long-acting. Examples of short-acting β2 agonists that can be used are salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, oritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and isoetharin.Examples of long-acting β2 agonists that can be used are salmeterol, bambuterol, formoterol, and clenbuterol.Examples of ultra-long-acting β2 agonists that can be used include indacaterol, vilanterol, and olodaterol.

[0180] Surprisingly, it has been discovered that the compounds of the present disclosure exhibit unexpected beneficial properties, as demonstrated in the Examples section of this specification.For example, it has been surprisingly discovered that the compounds of the present disclosure act as low nM (<10 nM) partial agonists of β2-adrenergic receptors.Furthermore, the compounds of the present disclosure exhibit unexpectedly high ability to penetrate the blood-brain barrier and accumulate in cerebrospinal fluid.In addition, the compounds of the present disclosure exhibit excellent oral bioavailability and stability, while at the same time exhibiting low toxicity and low potential for drug-drug interactions.

[0181] It is believed that the provided compounds or pharma- ceutically acceptable salts thereof may have good pharmacological profiles and promising biopharmaceutical properties, such as toxicological profiles, metabolic and pharmacokinetic properties, solubility, and permeability. It will be understood that determining the appropriate biopharmaceutical properties, such as determining cytotoxicity in cells, or determining inhibition of a particular target or channel to determine potential toxicity, is within the knowledge of one of ordinary skill in the art.

[0182] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of symptoms and / or genetic or other susceptibility factors). Treatment may also be continued after resolution of symptoms, e.g., to prevent or delay recurrence.

[0183] The terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0184] The term "therapeutically effective amount" as used herein refers to an amount of an active compound or pharmaceutical agent that elicits a biological or pharmacological response in a tissue, system, animal, individual or human as desired by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of: (1) preventing a disease, e.g., preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but has not yet experienced or exhibited the pathology or symptomology of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, condition or disorder (i.e., halting further development of the pathology and / or symptomology); and (3) ameliorating a disease, e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomology).

[0185] In some embodiments, the compounds of the present disclosure are useful for preventing or reducing the risk of developing any of the diseases mentioned herein, for example, for preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but has not yet experienced or exhibited the pathology or symptomology of that disease.

[0186] Co-administration with one or more other therapeutic agents Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, can also be present in the compositions of the present disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0187] In some embodiments, the disclosure provides a method for treating a disclosed disease or condition, the method comprising administering to a patient in need thereof an effective amount of a provided compound or a pharma- ceutically acceptable salt thereof, either simultaneously or sequentially, an effective amount of one or more additional therapeutic agents, such as those described herein.

[0188] As used herein, the terms "concomitant," "concomitant," and related terms refer to simultaneous or sequential administration of a therapeutic agent according to the present disclosure. For example, the described compounds may be administered simultaneously or sequentially with another therapeutic agent, in separate unit dosage forms or in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form that includes the described compounds, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "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., in the brain, in serum, etc.).

[0189] In some embodiments, when a provided compound or a pharma- ceutically acceptable salt thereof is administered in combination therapy with other agents, they may be administered to a patient sequentially or simultaneously. In some embodiments, the combination is administered sequentially. In some embodiments, the combination is administered simultaneously.

[0190] The amount of additional therapeutic agent present in the compositions of the present disclosure is equal to or less than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0191] One or more other therapeutic agents may be administered separately from the compound or composition of the present disclosure as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed with the compound of the present disclosure in a single composition. When administered as a multiple dose regimen, one or more other therapeutic agents and the compound or composition of the present disclosure may be administered simultaneously, sequentially, or at intervals from each other, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from each other. In some embodiments, one or more other therapeutic agents and the compound or composition of the present disclosure are administered as a multiple dose regimen at intervals of more than 24 hours.

[0192] In one embodiment, the present disclosure provides a composition comprising a provided compound and one or more additional therapeutic agents. The therapeutic agent may be administered together with the provided compound, or before or after administration of the provided compound. Suitable therapeutic agents are described in further detail below. In certain embodiments, the provided compound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before administration of the therapeutic agent. In other embodiments, provided compounds may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after administration of the therapeutic agent.

[0193] The provided compounds can be administered in combination with other therapeutic agents in a variety of therapeutic applications. Target therapeutic applications of combination therapy include applications in which the activity of the target adrenergic receptor is a causative or compounding factor in disease progression. Thus, the subject compounds are useful in combination therapy where inhibition of the target adrenergic receptor in a subject is desired. Pathologies that may be treated by combination therapy with the subject compounds include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental diseases, respiratory disorders, asthma, memory disorders, depression, inflammatory diseases, stroke, ischemic brain or tissue damage, and cancer. Drugs of interest that can be used with the subject adrenergic receptor modulating compounds include, but are not limited to, antidepressants, antipsychotics, beta-blockers, vasoconstrictors, antihypertensives, decongestants, chemotherapeutic agents, agents used in Alzheimer's disease, and anti-inflammatory agents.

[0194] In some embodiments, the provided adrenergic receptor modulating compounds can be used with any agent that is useful in treating cardiac conditions such as cardiogenic shock, hypertension, congestive heart failure, coronary heart disease, arrhythmias, myocardial infarction or ischemic heart disease, etc. Agents of interest that can be used with a subject adrenergic receptor modulating compound include, but are not limited to, denopamine, dobutamine, xamoterol, acebutolol, atenolol, betaxolol, bisoprolol, pindolol, esmolol, metoprolol, nebivolol, vortioxetine, carvedilol, labetalol, phentolamine, prazosin, cirazoline, methoxamine, synephrine, etilefrine, metaraminol, midrine, and coumarin.

[0195] In some embodiments, the provided adrenergic receptor modulating compounds can be used with any drug that is useful for treating neurodegenerative or neurodevelopmental diseases, such as Alzheimer's disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue injury, Down's syndrome, or autism. Drugs of interest that can be used with the provided adrenergic receptor modulating compounds include, but are not limited to, acepromazine. In some embodiments, the provided adrenergic receptor modulating compounds can be used in combination with a cholinesterase inhibitor or an NMDA receptor modulating agent to treat diseases, such as neurodegenerative or neurodevelopmental diseases. Drugs of interest include, but are not limited to, donepezil, aricept, galantamine, razadyne, memantine, namenda, rivastigmine, exelon, tacrine, and cognex. Other drugs of interest that can be used in conjunction with the subject adrenergic receptor modulating compounds are 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tiamenidine, tizanidine, tolonidine, xylazidine, and talipexole. These include, but are not limited to, phenoxybenzamine, phentolamine, piribedil, rauwolscine, risperidone, rotigotine, quetiapine, norquetiapine, setiptiline, tolazoline, yohimbine, ziprasidone, and zotepine.Other agents of interest that can be used in conjunction with a subject adrenergic receptor modulating compound include, but are not limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levosalbutamol or levalbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol, salbutamol or albuterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, mirveterol, olodaterol, vilanterol, fenoterol, hexoprenaline, isoxsuprine, ritodrine, salbutamol or albuterol, terbutaline, zilpaterol, ICI-118, 551, and butoxamine.

[0196] The following examples are provided to further illustrate the advantages and features of the present disclosure, but they are not intended to limit the scope of the disclosure. The examples are typical of those that may be used, but other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used. EXAMPLES

[0197] Example 1 Synthesis of (R)-2-(((S)-3,3-dimethylbutan-2-yl)amino)-1-(1H-indazol-4-yl)ethan-1-ol TIFF2024536815000077.tif24128 Step 1 To solution 1 (410 g, 2.092 mol) in DMF (4 L) was added NaH (60%, 125.5 g, 3.138 mmol) at 0° C. for 0.5 h, then SEMCl (418.5 g, 2.51 mol) was added to the above solution at 0° C. and warmed to room temperature for 2 h. The reaction mixture was quenched with water (2.5 L) at 0° C. The mixture was heated to room temperature and stirred for 0.5 h. The mixture was extracted three times with dichloromethane (3*10 L) at room temperature. The combined organic phase was washed with water (2*10 L) and brine (10 L), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (1% EtOAc in PE) to give compound 2 (377 g, 55.4% yield).

[0198] TIFF2024536815000078.tif29128 Step 2 To a stirred solution of compound 2 (475 g, 1.45 mol) in dioxane (4.7 L) / H2O (950 ml) was added potassium trifluoro(vinyl)borate (389 g, 2.90 mol), Pd(dppf)Cl2 (59.35 g, 72.56 mmol), Cs2CO3 (1416 g, 4.354 mmol) under N2, then heated to 80 °C and stirred for 2 h. The reaction mixture was filtered and the filtrate was extracted with EtOAc (2 L * 4). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (5% EtOAc in PE) to give compound 3 (351 g, 88.1% yield).

[0199] TIFF2024536815000079.tif29128 Step 3 To a solution of compound 3 (306 g, 1.115 mmol) in t-BuOH / H2O (5508 mL / 5508 mL) was added AD-mix-β (1563 g, 2.007 mol) at 0° C. Stirred at room temperature for 24 h. The reaction mixture was filtered and the filtrate was washed with EtOAc (2 L*3). The combined organic phase was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuum to give compound 4 (350 g) as an oil, which was used directly in the next step.

[0200] TIFF2024536815000080.tif31128Step 4 To a solution of 4 (348g, 1.128mol) in CH2Cl2 (3.5L) was added nBu2SnO (14g, 0.0564mol), TsCl (258g, 1.35mol), Et3N (136.7g, 1.35mol) at room temperature for 16h. The reaction solution was quenched with water (3L). The mixture was extracted with CH2Cl2 (1.5L*2). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (25% EtOAc in PE) to give compound 5 (250g & 95g, 57.5% yield).

[0201] TIFF2024536815000081.tif28128Step 5 To a solution of compound 5 (30 g, 0.065 mol) in toluene (150 mL) was added DIPEA (16.8 g, 0.13 mmol) and the reaction mixture was heated to 65° C. for 64 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL*3). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give compound 8 (25 g) as an oil, which was used directly in the next step.

[0202] TIFF2024536815000082.tif33128To a solution of compound 8 (25 g) in CH2Cl2 (125 ml) was added TFA (125 ml) at 0-20 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuum to remove CH2Cl2. THF (125 ml) and ammonia hydroxide (300 ml) were added in sequence at 0-20 °C. The reaction mixture was stirred for 12 h. After LCMS showed the reaction mixture was complete. The reaction mixture was quenched with water (100 mL) and extracted with CH2Cl2 (200 mL*4). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (3% MeOH in DCM) to give (R)-2-(((S)-3,3-dimethylbutan-2-yl)amino)-1-(1H-indazol-4-yl)ethan-1-ol (9, 6.8 g).

[0203] Example 2 Evaluation of synthetic adrenergic receptor agonists The experimental method is cAMP homogeneous time-resolved fluorescence (HTRF) method. Compound potency is primarily measured using the cAMP Gs dynamic HTRF assay (Cisbio, Cat. No. 62AM4PEC) according to the manufacturer's instructions (also detailed below).

[0204] Compound preparation: Candidate β-adrenergic compounds dissolved at 10 mM in DMSO were diluted in 1× Stimulation Buffer 1 (Cisbio, Part #64SB1FDD) containing 1 mM 3-isobutyl-1-methylxanthene (IBMX, Cayman Chemical Company, Cat #13347). Serial dilutions were performed in Stimulation Buffer containing 1 mM IBMX to 2× the final desired concentration in 96-well V-bottom polypropylene compound microplates (Corning, Cat #3363). Standard step curves were 10-point, 5-fold dilutions starting from a top concentration of 10 μM. Controls present on all assay plates were 0.1% DMSO (vehicle control), 1 μM isoproterenol (full β-adrenergic agonist control), and 15 μM xamoterol (partial β-adrenergic agonist control). 5 μL from the 2× compound plate was stamped into a white 384 round well small volume HiBase assay plate (Greiner Bio-One, Catalog No. 784075) to give 4 technical replicates per compound at each concentration. Assay plates were centrifuged at 500×g for 10 seconds. Compounds and IBMX are prepared at 2× final volumes to compensate for the addition of cells.

[0205] Cell preparation: 1x stimulation buffer, wash PBS (Dulbecco's Phosphate Buffered Saline, -Mg, -Ca. Caisson Labs, Cat. No. PBL01), assay PBS (Dulbecco's Phosphate Buffered Saline, +Mg, +Ca. Caisson Labs, Cat. No. PBL02) and Versene (0.02% EDTA disodium salt solution in PBS without calcium or magnesium. Caisson Labs, Cat. No. EDL01) were pre-warmed to 37°C. Cells expressing β-adrenergic receptors were washed with wash PBS to remove growth medium and then detached from the surface by incubation with Versene for 5-10 min at 37°C. Cells were harvested using assay PBS, counted manually with a hemocytometer or automated cell counter, pelleted by centrifugation (200×g, 5 min) and resuspended in 1x 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, the assay plate was covered with an Axygen® plate seal (Corning PCR-SP) and incubated for 30 minutes at 37° C. in a humidified environment supplemented with 5% CO2.

[0206] HTRF Reagent Addition, Reading and Data Analysis: After 30 minutes of cell stimulation with test compounds, the assay plate was centrifuged at 500×g for 10 seconds and the incubation was stopped by the addition of 5 μL of cAMP-D2 acceptor diluted 1:21 in detection and lysis buffer 2 (Cisbio 62CL2FDF) and added to all cells. Subsequently, 5 μL of anti-cAMP-Eu donor diluted 1:21 in detection and lysis buffer 2 was added to the cells. The plate was sealed and the reaction was gently "vortexed" at 900 rpm on a Heidolph Titramax1000 for at least 30 minutes at room temperature. The plate was again centrifuged at 500×g for 10 seconds and HTRF was measured using a Tecan Spark plate reader with 50 flashes per well. HTRF ratios (665 nM / 620 nM x 10,000) were determined and plotted in GraphPad Prism to generate concentration-effect curves. Potency estimates (EC 50 and pEC 50 ) was obtained from a four-parameter nonlinear regression of the concentration-effect curves and an estimate of relative efficacy was determined by comparing the magnitude of the test compound HTRF signal window (minimum-maximum dose) with the signal window of the full agonist control, isoproterenol.

[0207] Potency and efficacy data in CHO-K1 cells are shown in Table 2 below. Potency (pEC 50 ) Letter codes include: A=>8, B=>7~8, C=>6~7, D=<6. Effectiveness (Emax) letter codes include: A=>90%, B=>70~90%, C=>50~70%, D=<50%.

[0208] Table 2: Pharmacological data for certain chemical compounds disclosed herein TIFF2024536815000083.tif212161TIFF2024536815000084.tif212161TIFF2024536815000085.tif212161

[0209] All publications, patents, patent applications, and other documents cited in this application are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, and other document was individually indicated to be incorporated by reference in its entirety for all purposes.

[0210] While various specific embodiments have been illustrated and described, it will be understood that various modifications can be made without departing from the spirit and scope of the disclosure and claims.

Claims

1. Formula Ia or Formula Ib: or a pharmaceutically acceptable salt thereof, During the ceremony, Each R １ are independently hydrogen, halogen, R Ａ , -CN, -NO ２ , -SF ５ , -OR, -N(R) ２ , -SO ２ R, -C(O)R, -C(O)N(R) ２、 -NRC(O)R, -NRCO ２ R, or -CO ２ R, Each R is independently hydrogen or C １～６ an optionally substituted group selected from aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen atom, optionally together with their intervening atoms, form an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring, said saturated or partially unsaturated heterocyclic ring having, in addition to the nitrogen atom to which the two R groups are attached, 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R Ａ is independent, C １～６ an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or 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 Two R on the same carbon atom Ａ groups optionally taken 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; R ２ and R ３ are each independently hydrogen or optionally substituted C １～６ aliphatic, or R ２ and R ３ optionally, together with the carbon atoms to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; In the compound of formula Ia, R ４ is an optionally substituted C １～６ aliphatic, and R ５ is hydrogen or optionally substituted C １～６ is aliphatic, or In compounds of formula Ib, R 4 and R 5 are each independently hydrogen or an optionally substituted C 1-6 aliphatic; or R 4 and R 5 optionally together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; In the compound of formula Ia, R ６ is C ２～９ Aliphatic, phenyl C ０～３ alkyl, heterocyclyl C having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ０～３ alkyl and heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ０～３ alkyl, or In compounds of formula Ib, R 6 is an optionally substituted group selected from C 1-9 aliphatic, phenylC 0-3 alkyl, heterocyclylC 0-3 alkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and heteroaraC 0-3 alkyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A and ring B are independently fused rings selected from benzo, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and In the compounds of formula Ia, n is 0, 1, 2, 3, 4, 5, or 6; In compounds of formula Ib, n is 2, 3, 4, 5, or 6; wherein in compounds of formula Ib, when ring A is a fused 5-membered heterocyclic ring, it is not a 5-membered heterocyclic ring containing one nitrogen; the compound, or below: or a pharmaceutically acceptable salt thereof.

2. Formula Ia: or a pharmaceutically acceptable salt thereof, During the ceremony, each R 1 is independently hydrogen, halogen, R A , —CN, —NO 2 , —SF 5 , —OR, —N(R) 2 , —SO 2 R, —C(O)R, —C(O)N(R) 2 , —NRC(O)R, —NRCO 2 R, or —CO 2 R; each R is independently hydrogen or an optionally substituted group selected from a C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen atom, optionally together with their intervening atoms, form an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring, said saturated or partially unsaturated heterocyclic ring having, in addition to the nitrogen atom to which the two R groups are attached, 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R A groups on the same carbon atom, optionally together with their intervening atoms, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 2 and R 3 are each independently hydrogen or an optionally substituted C 1-6 aliphatic; or R 2 and R 3 optionally together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 is an optionally substituted C 1-6 aliphatic; R 5 is hydrogen or an optionally substituted C 1-6 aliphatic; R 6 is an optionally substituted group selected from C 2-9 aliphatic, phenylC 0-3 alkyl, heterocyclylC 0-3 alkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and heteroaraC 0-3 alkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A and ring B are independently fused rings selected from benzo, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0, 1, 2, 3, 4, 5, or 6; The compound.

3. (a) R ２ and R ３ are each hydrogen, and / or (b) R ６ But C ２～９ Aliphatic and phenyl C ０～３ and / or an optionally substituted group selected from alkyl (c) Ring A is a 5-6 membered fused heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or (d) Ring B is benzo or a 5-6 membered fused heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound of claim 2.

4. (a) A compound of the following formula: or a pharmaceutically acceptable salt thereof; below: or a pharmaceutically acceptable salt thereof; The compound of claim 2.

5. Formula Ib: or a pharmaceutically acceptable salt thereof, During the ceremony, Each R １ are independently hydrogen, halogen, R Ａ , -CN, -NO ２ , -SF ５ , -OR, -N(R) ２ , -SO ２ R, -C(O)R, -C(O)N(R) ２、 -NRC(O)R, -NRCO ２ R, or -CO ２ R, Each R is independently hydrogen or C １～６ an optionally substituted group selected from aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen atom, optionally together with their intervening atoms, form an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring, said saturated or partially unsaturated heterocyclic ring having, in addition to the nitrogen atom to which the two R groups are attached, 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R Ａ is independent, C １～６ an optionally substituted group selected from aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic or 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 Two R on the same carbon atom Ａ groups optionally taken 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; R ２ and R ３ are each independently hydrogen or optionally substituted C １～６ aliphatic, or R ２ and R ３ optionally, together with the carbon atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring or an optionally substituted heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ４ and R ５ are each independently hydrogen or optionally substituted C １～６ aliphatic, or R ４ and R ５ optionally, together with the carbon atoms to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ６ is C １～９ Aliphatic, phenyl C ０～３ alkyl, heterocyclyl C having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ０～３ alkyl and heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ０～３ alkyl, and Ring A and ring B are independently fused rings selected from benzo, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 2, 3, 4, 5, or 6; wherein, when ring A is a fused 5-membered heterocyclic ring, it is not a 5-membered heterocyclic ring containing one nitrogen; The compound.

6. (a) R ２ and R ３ are each hydrogen, and / or (b) Ring A is a 5-6 membered fused heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or (c) Ring B is benzo or a 5-6 membered fused heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound of claim 5. (a) a compound of the following formula: or a pharmaceutically acceptable salt thereof; below: or a pharmaceutically acceptable salt thereof; The compound of claim 5.

8. The following: or a pharmaceutically acceptable salt thereof. (a) an agonist, partial agonist, or antagonist of an adrenergic receptor; or (b) a β1-adrenergic receptor agonist, a β2-adrenergic receptor agonist, or a non-selective β1 / β2-adrenergic receptor agonist; or (c) a β1-adrenergic receptor agonist; or (d) a β2-adrenergic receptor agonist; or (e) is a non-selective β1 / β2-adrenergic agonist; A compound according to any one of claims 1 to 8.

10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

11. A pharmaceutical composition for modulating adrenergic receptors in a subject, comprising a compound according to any one of claims 1 to 8.

12. An in vitro method for modulating adrenergic receptors in a biological sample, the method comprising contacting a compound described in any one of claims 1 to 8 with the biological sample.

13. A pharmaceutical composition for treating an adrenergic receptor-mediated disorder, disease, and / or condition in a subject, comprising a compound according to any one of claims 1 to 8.

14. the adrenoceptor-mediated disorder, disease, and / or condition is a neurodegenerative disease; Optionally, the disease is MCI (mild cognitive impairment), aMCI (amnestic MCI), vascular dementia, mixed dementia, FTD (frontotemporal dementia, Pick's disease), HD (Huntington's disease), Rett's syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome), 14. The pharmaceutical composition of claim 13, wherein the disease is one or more selected from the group consisting of thiamine deficiency, alcoholic dementia and thiamine deficiency, normal pressure hydrocephalus, hypersomnia / narcolepsy, ASD (autism spectrum disorder), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (such as CJD), depressive disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD), early AD, and Down's syndrome (DS). (a) the subject is a human, and / or (b) the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavity, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal routes; The pharmaceutical composition of claim 11. (a) the subject is a human; and / or (b) the compound is administered to the subject via oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intraventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavity, intradermal, intralesional, intraocular, intraosseous injection, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal routes; The pharmaceutical composition of claim 13.

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