WO2021003161A1 - Agoniste bêta-adrénergique et procédés d'utilisation associés - Google Patents

Agoniste bêta-adrénergique et procédés d'utilisation associés Download PDF

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Publication number
WO2021003161A1
WO2021003161A1 PCT/US2020/040308 US2020040308W WO2021003161A1 WO 2021003161 A1 WO2021003161 A1 WO 2021003161A1 US 2020040308 W US2020040308 W US 2020040308W WO 2021003161 A1 WO2021003161 A1 WO 2021003161A1
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WIPO (PCT)
Prior art keywords
nitrogen
sulfur
oxygen
optionally substituted
independently selected
Prior art date
Application number
PCT/US2020/040308
Other languages
English (en)
Inventor
Anthony P. FORD
Jiaxin Yu
David Scott Carter
Wei Chen
Original Assignee
Curasen Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from US16/831,285 external-priority patent/US11040944B2/en
Application filed by Curasen Therapeutics, Inc. filed Critical Curasen Therapeutics, Inc.
Priority to MX2021015850A priority Critical patent/MX2021015850A/es
Priority to CN202080054317.7A priority patent/CN114340740A/zh
Priority to US17/620,065 priority patent/US20220315534A1/en
Priority to EP20835619.6A priority patent/EP3993878A4/fr
Priority to AU2020300999A priority patent/AU2020300999A1/en
Priority to JP2022500006A priority patent/JP2022538907A/ja
Priority to CA3144093A priority patent/CA3144093A1/fr
Publication of WO2021003161A1 publication Critical patent/WO2021003161A1/fr
Priority to IL289350A priority patent/IL289350A/en

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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present disclosure relates generally to chemical compounds and, in some embodiments, to beta adrenergic agonists and uses in the treatment of diseases associated with an adrenergic receptor.
  • PCT Application Publication Number WO2017197324 discloses “[a]drenergic receptor modulating compounds and methods of treating a subject for a disease or condition associated with an adrenergic receptor including administering a therapeutically effective amount of the subject compound.”
  • United States Patent Application Publication Number 20130096126 discloses“a method for enhancing learning or memory of both in a mammal having impaired learning or memory or both from a neuro-degenerative disorder, which entails the step of administering at least one compound or a salt thereof which is a b ⁇ -adrenergic receptor agonist, partial agonist or receptor ligand in an amount effective to improve the learning or memory or both of said mammal.”
  • United States Patent Application Publication Number 20140235726 discloses“a method of improving cognition in a patient with Down syndrome, which entails administering one or more b2 adrenergic receptor agonists to the patient in an amount and with a frequency effective to improve cognition of the patient as measured by contextual learning tests.”
  • United States Patent Application Publication Number 20160184241 discloses“a method of improving cognition in a patient with Down syndrome, which entails intranasally administering one or more b2-A ⁇ !1 agonists or pharmaceutically-acceptable salts of either or both to the patient in an amount and with a frequency effective to improve cognition of the patient as measured contextual learning tests.”
  • the present disclosure is based at least in part on the identification of compounds that modulate adrenergic receptor and methods of using the same to treat diseases associated with an adrenergic receptor.
  • Disclosed herein is a compound according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof
  • m is an integer selected from 0 to 3.
  • each A, B, and X is independently a nitrogen or carbon.
  • P is N, O, or CR2; Q is N, O, or CR2; G is NR5 or O; and/or Z is NR5, O, S, or CR3R4.
  • R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • R5 is one or more selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
  • L is a C1-C5 alkyl linker optionally substituted; each Xi, X2, X3, and X4 is independently a covalent bond, a carbon, an oxygen, or a nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; Y is O or S; R.6 and R.7 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R.6 and R.7 are cyclically linked and together with X2 to form an optionally substituted cycloalkyl or heterocycle; each Rs is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl,
  • m is an integer selected from 0 to 3.
  • each A, B, and X is independently a nitrogen or carbon.
  • P is N, O, or CR2; Q is N, O, or CR2; G is NR5 or O; and/or Z is NR5, O, S, or CR3R4.
  • R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • R5, R6, and R7 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
  • each Rio is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted
  • A’, B’, W’, and X’ are each independently a nitrogen atom or carbon atom;
  • Ring D’ is a fused ring selected from benzo, 5-9 membered monocyclic or bicycbc heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R 1 is independently hydrogen, halogen, R A , -CN, -NO2, -SFs, -O , -OR’, - NR’2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -C0 2 R’;
  • each R A is independently an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • rri is an integer selected from 0 to 3; R 2 ’ is selected from hydrogen, R A , -OR’,
  • L’ is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 , to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’2, or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 ’ is hydrogen, R A , or -CN;
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2;
  • R 7 ’ and R 8 ’ are each independently hydrogen or optionally substituted C1-2 aliphatic.
  • A’, B’, W’, and X’ are each independently a nitrogen atom or carbon atom;
  • Ring D’ is a fused ring selected from benzo, 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R 1 is independently hydrogen, halogen, R A , -CN, -NO2, -SFs, -O , -OR’, - NR’2, -SO2R’, -C(0)R’, -C(0)NR 2, -NRC(0)R, -NRCO2R, or -CO2R;
  • each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • n’ is an integer selected from 0 to 3;
  • R 4 ’, R 5 ’, and R 6 ’ are each independently selected from hydrogen, halogen, R A , -CN, -NO2,
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted ring selected from 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L’ is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 , to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -N0 2 , -NR’ 2 , or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 ’ is hydrogen, R A , or -CN;
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’ 2 ;
  • R 7 ’ and R 8 ’ are each independently hydrogen or optionally substituted Ci- 2 aliphatic.
  • A’, B’, and X’ are each independently a nitrogen atom or carbon atom;
  • G’ is -NR’- or -0-;
  • each R 1 ’ is independently hydrogen, halogen, R A , -CN, -NO2, -SFs, -OR’, -NR’ 2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -C0 2 R’; each R A is independently an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • n is an integer selected from 0 to 3;
  • R 4 ’, R 5 ’, and R 6 ’ are each independently selected from hydrogen, halogen, R A , -
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L’ is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 ’, to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’2, or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 ’ is hydrogen, R A , or -CN
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2.
  • A’, B’, and X’ are each independently a nitrogen atom or carbon atom;
  • each R 1 ’ is independently hydrogen, halogen, R A , -CN, -NO2, -SFs, -O , -OR’, - NR’2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -C0 2 R’;
  • each R A is independently an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • rri is an integer selected from 0 to 3;
  • R 3a ’ and R 3b ’ are independently hydrogen, R A , -OR’, -C(0)R’, -C(0)NR’2, or - CO2R’, or:
  • R 3a ’ and R 3b ’ are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the nitrogen from which R 3a ’ and R 3b ’ are attached, independently selected from nitrogen, oxygen, and sulfur;
  • R 4 ’, R 5 ’, and R 6 ’ are each independently selected from hydrogen, halogen, R A , -
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L’ is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 ’, to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’2, or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 ’ is hydrogen, R A , or -CN;
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2;
  • R 7 ’ and R 8 ’ are each independently hydrogen or optionally substituted C1-2 aliphatic.
  • each R 1 ’ is independently hydrogen, halogen, R A , -CN, -NO2, -SFs, -OR’, -NR’ 2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -C0 2 R’;
  • each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • rri is an integer selected from 0 to 3;
  • R 4 ’, R 5 ’, and R 6 ’ are each independently selected from hydrogen, halogen, R A , -
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y 1 ’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 ’, to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’2, or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 is hydrogen, R A , or -CN; and each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2.
  • a pharmaceutical composition including a compound as disclosed herein, i.e., a compound with a structure of Formula (I), Formula (F), Formula (II), Formula (IF), Formula (IIG), Formula (IV’), Formula (V’), Formula (VF), Formula (VIF), or a pharmaceutically acceptable excipient.
  • a compound as disclosed herein is an agonist, partial agonist or antagonist of an adrenergic receptor; in some embodiments the compound is a b ⁇ -adrenergic receptor agonist, 2-adrenertic receptor agonist or non-selective b l, ⁇ 2-adrenergic receptor agonist; in some embodiments the compound is a b ⁇ -adrenergic receptor agonist; in some embodiments the compound is a b2 ⁇ G6he3 ⁇ 4 ⁇ o receptor agonist; in some embodiments the compound is a compound is a non-selective b1/b2 ⁇ G6hb3 ⁇ 4 ⁇ o agonist.
  • a method of treating a subject with a disease including administering to the subject a therapeutically effective amount of a compound as disclosed herein, i.e., a compound with a structure of Formula (I), Formula (F), Formula (II), Formula (IF), Formula (III’), Formula (IV’), Formula (V’), Formula (VF), or Formula (VIF).
  • the disease is a disease associated with an adrenergic or receptor.
  • the disease is a neurodegenerative disease.
  • the subject is a human.
  • 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-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies, and neuronal ceroid lipofuscinosis
  • the compound is administered to the subject through oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavemous, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route.
  • the disease is a neurodegenerative disease that is one or more selected from the group consisting of MCI (mild cognitive impairment), aMCI (amnestic MCI), Vascular Dementia, Mixed Dementia, FTD (fronto-temporal dementia; Pick’s disease), HD (Huntington disease), Rett Syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (Multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wemicke-Korsakoff syndrome; alcoholic dementia & thiamine deficiency), normal pressure hydrocephalus, hypersomnia/narcolepsy, ASD (autistic spectrum disorders), FXS (fragile X syndrome), TSC (tuberous sclerosis complex),
  • MCI mimild
  • the disease is a neurodegenerative disease that is one or more selected from the group consisting of MCI, aMCI, Vascular Dementia, Mixed Dementia, FTD (fronto-temporal dementia; Pick’s disease), HD (Huntington disease), Rett Syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (Multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wemicke- Korsakoff syndrome; alcoholic dementia & thiamine deficiency), normal pressure hydrocephalus, hypersomnia/narcolepsy, ASD (autistic spectrum disorders), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (CJD etc.), depressive disorders, D
  • the methods include administering to the subject a compound as disclosed herein and a peripherally acting b-blocker (PABRA).
  • PABRA peripherally acting b-blocker
  • peripherally acting b-blocker means a b adrenergic receptor antagonist or simply a b 1-, b2- or non-selective b-blocker.
  • PABRA peripherally acting b-blockers
  • Examples of selective peripherally acting b-blockers (PABRA) that may in certain embodiments be used in the methods disclosed herein include nadolol, atenolol, sotalol and labetalol.
  • a b-blocker that can be used in the methods herein is one or more selected from the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol ad nevivolol; in other embodiments the methods do not use acebutolol, betaxolol, bisoprolol, celiprolol, esmolol, metaprolol or nevivolol as a b-blocker.
  • a peripherally acting b-blocker is administered to the subject prior to administration of a compound of the disclosure; in other embodiments a peripherally acting b-blocker (PABRA) is administered to the subject concurrently with the administration of a compound of the disclosure.
  • one or more peripherally acting b-blockers are administered prior to or concurrently with a compound of the disclosure in order to inhibit or preclude agonism of peripheral b ⁇ and/or b2 adrenergic receptors by a compound of the disclosure.
  • PABRA peripherally acting b-blockers
  • a b ⁇ agonist, a b2 agonist, or a non-selective b ⁇ / b2 agonist is administered to the patient in addition to a compound as disclosed herein.
  • the term“b 1 agonist” is used to mean b 1 -adrenergic receptor agonist or bI-ADR agonist.
  • the term b ⁇ agonist is understood to include compounds that are primarily b ⁇ agonists, but which may also exhibit some peripheral agonism for other adrenergic receptors, such as b2 ⁇ G6hb3 ⁇ 4K receptors.
  • the terms “b ⁇ -adrenergic receptor agonist”,“bI-ADR agonist”, b 1 AR agonist” and“b ⁇ agonist” may be used interchangeably.
  • the term bI-ADR agonist expressly includes both selective and partial agonists, as well as biased and non-biased agonists.
  • b ⁇ adrenergic agonists include, for example, xamoterol, noradrenalin, isoprenaline, dopamine, pindolol and dobutamine and the pharmaceutically-acceptable salts of any of the above.
  • Partial agonists and ligands of the bI-ADR are known. Further, using the methodology of Kolb et al, but for bI-ADR instead, one skilled in the art could determine new ligands by structure-based discovery. S QQ PTOC. Natl. Acad. Sci. USA 2009, 106, 6843-648.
  • the term b2 agonist is used to mean b2 ⁇ G6hb3 ⁇ 4 ⁇ o receptor agonist or b2-A ⁇ K agonist.
  • the term b2 agonist is understood to include compounds that are primarily b2 agonists, but which may also exhibit some peripheral agonism for other adrenergic receptors, such as b ⁇ -adrenergic receptors.
  • the terms ⁇ 2-adrenergic receptor agonist”,‘ ⁇ 2-ADR agonist”, b2AII agonist” and“b2 agonist” may be used interchangeably.
  • the term b2-A ⁇ K agonist expressly includes both selective and partial agonists.
  • b2 agonists that may be used in accordance with various aspects and embodiments of the present disclosure may be short-acting, long-acting or ultra long-acting.
  • short-acting b2 agonists that may be used are salbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol mesylate, oritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and isoetharine.
  • long-acting b2 agonists that may be used are salmeterol, bambuterol, formoterol and clenbuterol.
  • ultra long-acting b2 agonists include indacaterol, vilanterol and olodaterol.
  • compounds of the present disclosure exhibit unexpectedly beneficial properties, as demonstrated in the Examples section herein. For instance, it was surprisingly found that compounds of the present disclosure act as low nM ( ⁇ 10 nM) partial agonists of the b2 adrenergic receptor.
  • Alkyl groups refer to univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom, which include straight chain and branched chain with from 1 to 12 carbon atoms, and typically from 1 to about 10 carbons or in some embodiments, from 1 to about 6 carbon atoms, or in other embodiments having 1, 2, 3 or 4 carbon atoms.
  • straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups.
  • branched chain alkyl groups include, but are not limited to isopropyl, isobutyl, sec-butyl and tert-butyl groups.
  • Alkyl groups may be substituted or unsubstituted.
  • Representative substituted alkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted.
  • alkyl unless otherwise stated, refers to both cyclic and noncyclic groups.
  • cyclic alkyl or“cycloalkyl” refer to univalent groups derived from cycloalkanes by removal of a hydrogen atom from a ring carbon atom.
  • Cycloalkyl groups are saturated or partially saturated non-aromatic structures with a single ring or multiple rings including isolated, fused, bridged, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments, from 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6 or 7 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted.
  • Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted.
  • monocyclic cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • multi-cyclic ring systems include, but are not limited to, bicycle[4.4.0]decane, bicycle[2.2.1]heptane, spiro[2.2]pentane, and the like.
  • (Cycloalkyl)oxy refers to -O-cycloalkyl.
  • Cycloalkyl)thio refers to -S-cycloalkyl. This term also encompasses oxidized forms of sulfur, such as -S(O)- cycloalkyl, or— S(0)2-cycloalkyl.
  • Alkenyl groups refer to straight and branched chain and cycloalkyl groups as defined above, with one or more double bonds between two carbon atoms. Alkenyl groups may have 2 to about 12 carbon atoms, or in some embodiment from 1 to about 10 carbons or in other embodiments, from 1 to about 6 carbon atoms, or 1, 2, 3 or 4 carbon atoms in other embodiments. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted.
  • Alkynyl groups refer to straight and branched chain and cycloalkyl groups as defined above, with one or more triple bonds between two carbon atoms.
  • Alkynyl groups may have 2 to about 12 carbon atoms, or in some embodiment from 1 to about 10 carbons or in other embodiments, from 1 to about 6 carbon atoms, or 1, 2, 3 or 4 carbon atoms in other embodiments.
  • Alkynyl groups may be substituted or unsubstituted.
  • Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted.
  • Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and -CoC(CH3), among others.
  • Aryl groups are cyclic aromatic hydrocarbons that include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups.
  • Aryl groups may contain from 6 to about 18 ring carbons, or in some embodiments from 6 to 14 ring carbons or even 6 to 10 ring carbons in other embodiments.
  • Aryl group also includes heteroaryl groups, which are aromatic ring compounds containing 5 or more ring members, one or more ring carbon atoms of which are replaced with heteroatom such as, but not limited to, N, O, and S.
  • Aryl groups may be substituted or unsubstituted.
  • aryl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted.
  • Aryl groups include, but are not limited to, phenyl, biphenylenyl, triphenylenyl, naphthyl, anthryl, and pyrenyl groups.
  • Aryloxy refers to -O-aryl.
  • Arylthio refers to -S-aryl, wherein aryl is as defined herein. This term also encompasses oxidized forms of sulfur, such as -S(0)-aryl, or -S(0)2-aryl.
  • Heteroaryloxy refers to -O-heteroaryl.
  • Heteroarylthio refers to -S-heteroaryl. This term also encompasses oxidized forms of sulfur, such as -S(O)- heteroaryl, or -S(0)2-heteoaryl. N-oxides are also contemplated. In some embodiments, a compound of the present disclosure is in the form of an N-oxide.
  • Suitable heterocyclyl groups include cyclic groups with atoms of at least two different elements as members of its rings, of which one or more is a heteroatom such as, but not limited to, N, O, or S.
  • Heterocyclyl groups may include 3 to about 20 ring members, or 3 to 18 in some embodiments, or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members.
  • the ring systems in heterocyclyl groups may be unsaturated, partially saturated, and/or saturated.
  • Heterocyclyl groups may be substituted or unsubstituted.
  • Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di-, or tri-substituted.
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homo
  • Heterocyclyloxy refers to -O-heterocycyl.
  • Heterocyclylthio refers to -S-heterocycyl. This term also encompasses oxidized forms of sulfur, such as -S(0)-heterocyclyl, or -S(0)2-heterocyclyl.
  • Polycyclic or polycyclyl groups refer to two or more rings in which two or more carbons are common to the two adjoining rings, wherein the rings are“fused rings”; if the rings are joined by one common carbon atom, these are“spiro” ring systems. Rings that are joined through non-adjacent atoms are“bridged” rings. Polycyclic groups may be substituted or unsubstituted. Representative polycyclic groups may be substituted one or more times.
  • Halogen groups include F, Cl, Br, and I; nitro group refers to -NO2; cyano group refers to -CN; isocyano group refers to -NoC; epoxy groups encompass structures in which an oxygen atom is directly attached to two adjacent or non-adjacent carbon atoms of a carbon chain or ring system, which is essentially a cyclic ether structure.
  • An epoxide is a cyclic ether with a three-atom ring.
  • An alkoxy group is a substituted or unsubstituted alkyl group, as defined above, singular bonded to oxygen.
  • Alkoxy groups may be substituted or unsubstituted.
  • Representative substituted alkoxy groups may be substituted one or more times.
  • Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups.
  • Thiol refers to -SH.
  • Sulfonyl refers to -SC -alkyl, -SO2- substituted alkyl, -SC -cycloalkyl, -SCh-substituted cycloalkyl, -SCh-aryl, -SCh-substituted aryl, -SCh-heteroaryl, -SCh-substituted heteroaryl, -SCh-heterocyclyl, and -SCh-substituted heterocyclyl.
  • Sulfonylamino refers to -NR a SChalkyl, -NR a SCh-substituted alkyl, - NR a SChcycloalkyl,— NR a SChsubstituted cycloalkyl, -NR a SCharyl, -NR a SChsubstituted aryl, - -NR a SChheteroaryl, -NR a SCh substituted heteroaryl, -NR a SChheterocyclyl, -NR a SCh substituted heterocyclyl, wherein each R a independently is as defined herein.
  • Carboxyl refers to -COOH or salts thereof.
  • Carboxyester refers to -C(0)0-alkyl, - C(0)0- substituted alkyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0) -cycloalkyl, -C(0)0- substituted cycloalkyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl, -C(0)0- heterocyclyl, and -C(0)0-substituted heterocyclyl.
  • Carboxyesteramino refers to -NR a - C(0)0-alkyl, -NR a -C(0)0-substituted alkyl, -NR a -C(0)0-aryl, -NR a -C(0)0-substituted aryl, -NR a -C(0) -cycloalkyl,— NR a -C(0)0-substituted cycloalkyl, -NR a -C(0)0-heteroaryl, -NR a - C(0)0-substituted heteroaryl, -NR a -C(0)0-heterocyclyl, and -NR a -C(0)0-substituted heterocyclyl, wherein R a is as recited herein.
  • (Carboxyester)oxy refers to -0-C(0)0-alkyl, -O- C(0)0- substituted alkyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl, -0-C(0) -cycloalkyl, - 0-C(0)0-substituted cycloalkyl, -0-C(0)0-heteroaryl, -0-C(0)0-substituted heteroaryl, -O- C(0)0-heterocyclyl, and -0-C(0)0-substituted heterocyclyl.
  • amine and“amino” refer to derivatives of ammonia, wherein one of more hydrogen atoms have been replaced by a substituent which include, but are not limited to alkyl, alkenyl, aryl, and heterocyclyl groups.
  • substituted amino can include -NH-CO-R.
  • Aminocarbonyl refers to -C(0)N(R b )2, wherein each R b independently is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl. Also, each R b may optionally be joined together with the nitrogen bound thereto to form a heterocyclyl or substituted heterocyclyl group, provided that both R b are not both hydrogen.
  • Aminocarbonylalkyl refers to -alkylC(0)N(R b )2, wherein each R b independently is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl. Also, each R b may optionally be joined together with the nitrogen bound thereto to form a heterocyclyl or substituted heterocyclyl group, provided that both R b are not both hydrogen.
  • Aminocarbonylamino refes to -NR a C(0)N(R b )2, wherein R a and each R b are as defined herein.
  • Aminodicarbonylamino refers to -NR a C(0)C(0)N(R b )2, wherein R a and each R b are as defined herein.
  • Aminocarbonyloxy refers to -0-C(0)N(R b )2, wherein each R b independently is as defined herein.
  • Aminosulfonyl refers to -SC N(R b )2, wherein each R b independently is as defined herein.
  • compounds of the present disclosure may contain“optionally substituted” moieties.
  • the term“substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • the term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH 2 Ph, - 0(CH 2 )o-iPh, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicycl
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o 2 R*; -(haloR*); -(CH 2 )o 2 OH; -(CH 2 )o 2 OR*; -(CH 2 )o
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: -0(CR * 2)2-30-, wherein each independent occurrence of R * is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, - R ⁇ ; -(haloR*); -OH, -OR*; -0(haloR*); -CN; -C(0)OH; -C(0)OR*; -NH 2 ; -NHR*; -NR* 2 ; or -N0 2 ; wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently Ci ⁇ aliphatic, -CH 2 Ph; -0(CH 2 )o lPh; or a 5-6- membered saturated; partially unsaturated; or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include -R ⁇ ; -NR ⁇ 2 ; -C(0)Rt; -C(0)ORt; -C(0)C(0)Rt;
  • each R ⁇ is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, 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, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R*; -(haloR*); -OH; -OR*; -0(haloR*); -CN; -C(0)OH; -C(0)OR*; -NH 2 ; -NHR*; -NR* 2 ; or -N0 2 ; wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently Ci ⁇ aliphatic, -CH 2 Ph; -0(CH 2 )o lPh; or a 5-6- membered saturated; partially unsaturated; or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium (e.g., D or H 2 ) or tritium (e.g., T or H 3 ), or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are included and are within the scope of this disclosure.
  • deuterium e.g., D or H 2
  • tritium e.g., T or H 3
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure
  • compositions described herein include conventional nontoxic salts or quaternary ammonium salts of a compound, e.g., from non-toxic organic or inorganic acids.
  • conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • described compounds may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine
  • Prodrug refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In certain embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent. "Promoiety” refers to a form of protecting group that, when used to mask a functional group within an active agent, converts the active agent into a prodrug. In some cases, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo. Any convenient prodrug forms of the subject compounds can be prepared, e.g., according to the strategies and methods described by Rautio et al. ("Prodrugs: design and clinical applications", Nature Reviews Drug Discovery 7, 255-270 (February 2008)).
  • m is an integer selected from 0 to 3.
  • each A, B, and X is independently a nitrogen or carbon.
  • P is N, O, or CR2; Q is N, O, or CR2; G is NR5 or O; and/or Z is NR5, O, S, or CR3R4.
  • R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • R5 is one or more selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
  • L is a C1-C5 alkyl linker optionally substituted; each Xi, X2, X3, and X4 is independently a covalent bond, a carbon, an oxygen, or a nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl; Y is O or S; R.6 and R.7 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R.6 and R.7 are cyclically linked and together with X2 to form an optionally substituted cycloalkyl or heterocycle; each Rs is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl,
  • m is an integer selected from 0 to 3.
  • each A, B, and X is independently a nitrogen or carbon.
  • P is N, O, or CR2; Q is N, O, or CR2; G is NR5 or O; and/or Z is NR5, O, S, or CR3R4.
  • R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • R5, R6, and R7 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
  • each Rio is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted
  • A’, B’, W’, and X’ are each independently a nitrogen atom or carbon atom;
  • Ring D’ is a fused ring selected from benzo, 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R 1 is independently hydrogen, halogen, R A , -CN, -NO2, -SFs, -O , -OR’, - NR’2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -C0 2 R’;
  • each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • rri is an integer selected from 0 to 3; R 2 ’ is selected from hydrogen, R A , -OR’,
  • L’ is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 , to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’2, or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 ’ is hydrogen, R A , or -CN;
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2; and R 7 ’ and R 8 ’ are each independently hydrogen or optionally substituted C1-2 aliphatic.
  • R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2; and R 7 ’ and R 8 ’ are each independently hydrogen or optionally substituted C1-2 aliphatic.
  • A’, B’, W’, and X’ are each independently a nitrogen atom or carbon atom;
  • Ring D’ is a fused ring selected from benzo, 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R 1’ is independently hydrogen, halogen, R A , -CN, -NO2, -SFs, -O , -OR’, - NR’2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -C0 2 R’;
  • each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • rri is an integer selected from 0 to 3;
  • R 4 ’, R 5 ’, and R 6 ’ are each independently selected from hydrogen, halogen, R A , -
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted ring selected from 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L’ is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or: R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 , to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -N0 2 , -NR’ 2 , or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 ’ is hydrogen, R A , or -CN;
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’ 2 ;
  • R 7 ’ and R 8 ’ are each independently hydrogen or optionally substituted Ci- 2 aliphatic.
  • A’, B’, and X’ are each independently a nitrogen atom or carbon atom;
  • G’ is -NR’- or -0-;
  • each R 1 ’ is independently hydrogen, halogen, R A , -CN, -NO2, -SF5, -OR’, -NR’ 2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -C0 2 R’;
  • each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • n’ is an integer selected from 0 to 3;
  • R 4 ’, R 5 ’, and R 6 ’ are each independently selected from hydrogen, halogen, R A , -
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L’ is an optionally substituted C1-5 alkylene;
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 ’, to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’2, or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 ’ is hydrogen, R A , or -CN
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2.
  • A’, B’, and X’ are each independently a nitrogen atom or carbon atom;
  • each R 1 ’ is independently hydrogen, halogen, R A , -CN, -NO2, -SF5, -O , -OR’, - NR’2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -CO2R’;
  • each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • n’ is an integer selected from 0 to 3;
  • R 3a ’ and R 3b ’ are independently hydrogen, R A , -OR’, -C(0)R’, -C(0)NR’2, or - CO2R’, or:
  • R 3a ’ and R 3b ’ are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the nitrogen from which R 3a ’ and R 3b ’ are attached, independently selected from nitrogen, oxygen, and sulfur;
  • R 4 ’, R 5 ’, and R 6 ’ are each independently selected from hydrogen, halogen, R A , -
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L’ is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 ’, to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’2, or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 ’ is hydrogen, R A , or -CN;
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2;
  • R 7 ’ and R 8 ’ are each independently hydrogen or optionally substituted C1-2 aliphatic.
  • each R 1 ’ is independently hydrogen, halogen, R A , -CN, -NO2, -SFs, -OR’, -NR’ 2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR’C(0)R’, -NR’C0 2 R’, or -C0 2 R’;
  • each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur;
  • rri is an integer selected from 0 to 3;
  • R 4 ’, R 5 ’, and R 6 ’ are each independently selected from hydrogen, halogen, R A , -
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L’ is an optionally substituted C1-5 alkylene
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-;
  • X 2 ’ is a carbon atom or nitrogen atom
  • Y 1 ’ is O or S
  • R 9 ’ and R 10 ’ are each independently hydrogen or optionally substituted alkyl, or:
  • R 9 ’ and R 10 ’ are cyclically linked and, together with X 2 ’, to form an optionally substituted 3-7 membered saturated carbocyclic ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’2, or -OR’;
  • ri is an integer selected from 0 to 4.
  • R 12 is hydrogen, R A , or -CN; and each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, or -NR’2.
  • A’ is a nitrogen atom or a carbon atom.
  • A’ is a nitrogen atom. In some embodiments, A’ is a carbon atom.
  • A’ is selected from those depicted in Table 1, below.
  • B’ is a nitrogen atom or a carbon atom.
  • B’ is a nitrogen atom. In some embodiments, B’ is a carbon atom.
  • B’ is selected from those depicted in Table 1, below.
  • X’ is a nitrogen atom or a carbon atom.
  • X’ is a nitrogen atom. In some embodiments, X’ is a carbon atom.
  • X is selected from those depicted in Table 1, below.
  • W’ is a nitrogen atom or a carbon atom.
  • W’ is a nitrogen atom. In some embodiments, W’ is a carbon atom.
  • W’ is selected from those depicted in Table 1, below.
  • any of the nitrogen atoms mentioned above is optionally in the form of an N-oxide.
  • P’ and Q’ are selected from those depicted in Table 1, below.
  • G’ is -NR’- or -0-.
  • G’ is -NR’-. In some embodiments, G is -0-. In some embodiments, G is -NH-. In some embodiments, G is -NMe-.
  • G is selected from those depicted in Table 1, below.
  • Z NR’.
  • Z’ 0.
  • Z’ S.
  • Z’ CR’2.
  • Z’ is selected from those depicted in Table 1, below.
  • Ring D’ is a fused ring selected from benzo, 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring D’ is benzo. In some embodiments, Ring D’ is a 5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D’ is a 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D’ is . In some embodiments, Ring D’ is . In some embodiments,
  • Ring D’ is In some embodiments, Ring D’ is D’ is . In some embodiments, Ring D’ is In some embodiments,
  • Ring D’ is In some embodiments, Ring D’ is ⁇ In some
  • Ring D is (K V )J A V
  • Ring D i iss In
  • Ring D’ is In some embodiments, Ring D’ is . In some embodiments, Ring D’ is . In some embodiments, Ring D’ is . In some embodiments, Ring
  • Ring D’ is H In some embodiments, Ring D’ is H In some embodiments, Ring D’ is H In some embodiments, Ring D’ is H In some
  • Ring D’ is In some embodiments, Ring D’ is , some embodiments,
  • Ring D’ is in some embodiments, Ring In some embodiments, Ring D’ is
  • Ring D’ is selected from those depicted in Table 1, below.
  • each R 1 ’ is independently halogen, R A , -CN, -NO2, -Sri, -O , -OR’, -NR’2, -SO2R’, -C(0)R’, -C(0)NR’ 2, -NR'C(0)R’, -NR’C0 2 R’, or -CO2R’.
  • R 1 ’ is hydrogen. In some embodiments, R 1 ’ is halogen. In some embodiments, R 1 ’ is R A . In some embodiments, R 1 is -CN. In some embodiments, R 1 ’ is -NO2. In some embodiments, R 1 is -SF5. In some embodiments, R 1 ’ is -O . In some embodiments, R 1 ’ is -OR’. In some embodiments, R 1 ’ is -NR’2. In some embodiments, R 1 ’ is -SO2R’. In some embodiments, R 1 ’ is -C(0)R’. In some embodiments, R 1 is -C(0)NR’2.
  • R 1 ’ is -NR'C(0)R’. In some embodiments, R 1 is -NR’C02R’. In some embodiments, R 1 ’ is -CO2R’. In some embodiments, R 1 ’ is -Br. In some embodiments, R 1 ’ is -Cl. In some embodiments, R 1 ’ is -F. In some embodiments, R 1 ’ is - CFb. In some embodiments, R 1 ’ is -CH2CH3. In some embodiments, R 1 ’ is -CH(CH3)2. In some embodiments, R 1 ’ is -CF3. In some embodiments, R 1 ’ is -CF2H. In some embodiments, R 1 ’ is -CFH2.
  • R 1 ’ is -CF2CH3. In some embodiments, R 1 ’ is -CH2CF3. In some embodiments, R 1 ’ is -CoCCH. In some embodiments, R 1 ’ is vinyl. In some embodiments, R 1 ’ is -CoCCF3. In some embodiments, R 1 ’ is -CO2H. In some embodiments, R 1 ’ is -OH. In some embodiments, R 1 ’ is -OCH3. In some embodiments, R 1 ’ is -OCH2CH3. In some embodiments, R 1 ’ is -OCH(CH3)2. In some embodiments, R 1 is - OCF3. In some embodiments, R 1 is -NHCH3.
  • R 1 ’ is -NHCD3. In some embodiments, R 1 ’ is -N(CD3)C02tBu. In some embodiments, R 1 ’ is -NHCH2CH3. In some embodiments, R 1 ’ is -NHCH2(CH3)2. In some embodiments, R 1 ’ is -NHCH2CF3. In some embodiments, R 1 ’ is -NHPh. In some embodiments, R 1 ’ is -NHAc. In some
  • R 1 ’ is -N(CH3)2. In some embodiments, R 1 ’ is some O embodiments, R 1 ’ is . In some embodiments, R 1 ’ is In some embodiments,
  • R is / Tn some embodiment
  • R 1 ’ is ⁇ T Inn s soommee e emmbbooddiimmeennttss
  • R R 1 ’ i iss '—- ⁇
  • R 1 ’ is . In some embodiments, R 1 ’ is In some embodiments, R 1 ’ is O* . In some embodiments, R 1 ’ is in some rt-i
  • R 1 ’ is HN— . in some embodiments, R 1 ’ is . In some
  • R 1 ’ is . In some embodiments, R 1 ’ is / . In some embodiments, R 1 ’ is In some embodiments, R 1 ’ is In some embodiments, R 1 ’ is In some
  • R 1 ’ is N3 ⁇ 4/ . in some embodiments, R 1 ’ is H . In some -*
  • R 1 ’ is in some embodiments, R 1 ’ is H In some
  • R 1 ’ is HN « . In some N , embodiments, R 1 ’ is ⁇ In some embodiments, R 1 ’ is H in some H 2 N L
  • R 1 ’ is H . In some embodiments, R 1 ’ is / '
  • R 1 ’ is selected from those depicted in Table 1, below.
  • each R’ is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic partially unsaturated or heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen
  • R’ is hydrogen. In some embodiments, R’ is an optionally substituted Ci-6 aliphatic. For instance, in some embodiments, R’ is -CF3, -CF2H, or - CFFk. In some embodiments, R’ is an optionally substituted 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R’ is an optionally substituted 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R’ is an optionally substituted phenyl. In some embodiments, R’ is an optionally substituted 8- 10 membered bicyclic partially unsaturated carbocyclic ring.
  • R’ is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R’ is an optionally substituted 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R’ is an optionally substituted 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R’ is an optionally substituted 5- 6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R’ is an optionally substituted 8-10 membered bicyclic partially unsaturated ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R’ is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur. [00130] In some embodiments, R’ is selected from those depicted in Table 1, below.
  • m’ is an integer selected from 0 to 4.
  • m’ is 0. In some embodiments, m’ is 1. In some embodiments, m’ is 2. In some embodiments, m’ is 3. In some embodiments, m’ is 4.
  • m is selected from those depicted in Table 1, below.
  • each R A is independently an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R A groups on the same carbon or are optionally taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon from which the two R A groups are attached, independently selected from nitrogen, oxygen, and sulfur.
  • R A is an optionally substituted Ci-6 aliphatic. In some embodiments, R A is an optionally substituted 3-7 membered saturated monocyclic carbocyclic ring. In some embodiments, R A is an optionally substituted 3-7 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R A is an optionally substituted phenyl. In some embodiments, R A is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two R A groups on the same carbon or are optionally taken together with their intervening atoms to form an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon from which the two R A groups are attached, independently selected from nitrogen, oxygen, and sulfur.
  • R 2 ’ is hydrogen, R A , -OR’,
  • R 2 ’ is hydrogen. In some embodiments, R 2 ’ is R A . In some embodiments, R 2 ’ is -OR’. In some embodiments, some embodiments, R 2 ’ is In some embodiments, R 2 ’ is . , R V In some
  • R 2 ’ i iss h « ' A ? .
  • R 2 ’ is . , .
  • R 2 ’ is In some embodiments, R 2 ’ is . , In some embodiments, R 2 ’ is -CH3. In some embodiments, R 2 ’ is -CD3. In some embodiments, R 2 ’ is -C(CH3)3. In some embodiments, R 2 ’ is -C(CD3)3. In some embodiments, R 2 ’ is - C(CH3)2CH20R’. In some embodiments, R 2 ’ is -C(CH3)2CH20H. In some embodiments, R 2 ’ is -iPr. In some embodiments, R 2 ’ is -CPkiPr. In some embodiments, R 2 ’ is . , . In some embodiments, R 2 ’ is . , . In some embodiments, R 2 ’ is . In some embodiments, R 2 ’ is . In some embodiments, R 2
  • R 2 ’ is . In some embodiments, R 2 ’ is
  • R 2 ’ is selected from those depicted in Table 1, below.
  • R 3a ’ and R 3b ’ are independently hydrogen, R a , -OR’, -C(0)R’, -C(0)NR’2, or -CO2R’, or R 3a ’ and R 3b ’ are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the nitrogen from which R 3a ’ and R 3b ’ are attached, independently selected from nitrogen, oxygen, and sulfur.
  • R 3a ’ is hydrogen. In some embodiments, R 3a ’ is R A . In some embodiments, R 3a ’ is -OR’. In some embodiments, R 3a ’ is -C(0)R’. In some embodiments, R 3a ’ is -C(0)NR’2. In some embodiments, R 3a ’ is -CO2R’. In some embodiments, R 3b ’ is hydrogen. In some embodiments, R 3b ’ is R A . In some embodiments, R 3b ’ is -OR’. In some embodiments, R 3b ’ is -C(0)R’. In some embodiments, R 3b ’ is -C(0)NR’2.
  • R 3b ’ is - CO2R’.
  • R 3a ’ and R 3b ’ are optionally taken together with their intervening atoms to form an optionally substituted 4-10 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the nitrogen from which R 3a ’ and R 3b ’ are attached, independently selected from nitrogen, oxygen, and sulfur.
  • R 3a ’ and R 3b ’ are selected from those depicted in Table 1, below.
  • R 4 ’, R 5 ’, and R 6 ’ are each independently hydrogen, halogen,
  • an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 ’ is hydrogen. In some embodiments, R 2 ’ is R A . In some embodiments, R 2 ’ is -OR’. In some embodiments, R 2 ’ is -NR’ 2. In some embodiments, R 2 ’ ,
  • R 2’ is
  • R 2’ is In some embodiments, R 2 ’ is . , . In some
  • R 2 ’ is In some embodiments, R 2 ’ is . n some em o men s, s . In some
  • R 2 ’ is -CH3. In some embodiments, R 2 ’ is -CD3. In some embodiments, R 2 ’ is -C(CH3)3. In some embodiments, R 2 ’
  • R 4 ’ is hydrogen. In some embodiments, R 4 ’ is halogen. In some embodiments, R 4 ’ is R A . In some embodiments, R 4 ’ is -CN. In some embodiments, R 4 ’ is -NO2. In some embodiments, R 4 ’ is -OR’. In some embodiments, R 4 ’ is -CH2OR’. In some embodiments, R 4 ’ is -CPkiPr. In some embodiments, R 4 ’ is -NR’ 2. In some embodiments, R 4 ’ is hydrogen. In some embodiments, R 4 ’ is halogen. In some embodiments, R 4 ’ is R A . In some embodiments, R 4 ’ is -CN. In some embodiments, R 4 ’ is -NO2. In some embodiments, R 4 ’ is -OR’. In some embodiments, R 4 ’ is -CH2OR’. In some embodiments, R 4 ’ is -CPkiPr. In some embodiments, R 4 ’ is
  • R 4 ’ is In some embodiments, R 4 ’ is
  • R 4 ’ is . In some embodiments,
  • R 4 ’ is . In some embodiments, R 4 ’ is , . In some
  • R 4 ’ is In some embodiments, R 4 ’ is
  • R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 ’ and R 5 ’ are optionally taken together with the carbon to which they are attached to form an optionally substituted 3- 7 membered saturated or a partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 ’ is -CH3. In some embodiments, R 4 ’ is -CD3. In some embodiments, R 4 ’ is
  • R 5 ’ is hydrogen. In some embodiments, R 5 ’ is halogen. In some embodiments, R 5 ’ is R A . In some embodiments, R 5 ’ is -CN. In some embodiments, R 5 ’ is -NO2. In some embodiments, R 5 ’ is -OR’. In some embodiments, R 5 ’ is -NRi In some embodiments, R 5 ’ is . In some embodiments, R 5 ’ is , some embodiments, R 5 ’ is . In some embodiments,
  • R 5 ’ is . In some embodiments, R 5 ’ is , In some embodiments, R 5 ’ is In some embodiments, R 5 ’ is . n some em o mens, s . In some embodiments, some embodiments, R 5 ’ is -CH3. In some embodiments, R 5 ’ is -CD3. In some embodiments, R 5 ’ is [00146] In some embodiments, R 4 ’ and R 5 ’ are In some embodiments, R 4 ’ and R 5 ’ are . In some embodiments, R 4 ’ and R 5 ’ are . In some embodiments, R 4 ’ and R 5 ’ are . In some embodiments, R 4 ’ and R 5 ’ are . In some embodiments, R 4 ’ and R 5 ’ are . In some embodiments, R 4 ’ and
  • R 5 ’ are . In some embodiments, R 4 ’ and R 5 ’ are . In some embodiments,
  • R 4 ’ and R 5 ’ are
  • R 6 ’ is hydrogen. In some embodiments, R 6 ’ is halogen. In some embodiments, R 6 ’ is R A . In some embodiments, R 6 ’ is -CN. In some embodiments, R 6 ’ is -NO2. In some embodiments, R 6 ’ is -OR’. In some embodiments, R 6 ’ is -NR i In
  • R 6 ’ is . In some embodiments, R 6 ’ is
  • R 6 ’ is . In some embodiments,
  • R 6 ’ is . In some embodiments, R 6 ’ is . , . In some
  • R 6 ’ is In some embodiments, R 6 ’ is n some em o men s, s In some
  • R 6 ’ is -CH3. In some embodiments, R 6 ’ is -CD3. In some embodiments, R 6 ’ is
  • R 2 ’, R 4 ’, R 5 ’, and R 6 ’ are each selected from those depicted in Table 1, below.
  • L’ is an optionally substituted C 1-5 alkylene.
  • L’ is an optionally substituted C1-5 alkylene. In some embodiments, L’ is -CH2-.
  • L’ is selected from those depicted in Table 1, below.
  • X 1 ’, X 3 ’, and X 4 ’ are each independently a bivalent group selected from a covalent bond, -CRV, -0-, and -NR’-.
  • X 1 ’ is a covalent bond. In some embodiments, X 1 ’ is - CRV. In some embodiments, X 1 ’ is -0-. In some embodiments, X 1 ’ is -NR’-. In some embodiments, X 3 ’ is a covalent bond. In some embodiments, X 3 ’ is -CRV. In some embodiments, X 3 ’ is -0-. In some embodiments, X 3 is -NR’-. In some embodiments, X 4 ’ is a covalent bond. In some embodiments, X 4 ’ is -CRV. In some embodiments, X 4 ’ is - 0-. In some embodiments, X 4 ’ is -NR’-.
  • X 1 ’, X 3 ’, and X 4 ’ are selected from those depicted in Table 1, below.
  • X 2 ’ is a carbon atom or a nitrogen atom.
  • X 2 ’ is a carbon atom. In some embodiments, X 2 ’ is nitrogen atom.
  • X 2 ’ is selected from those depicted in Table 1, below.
  • Y’ is selected from those depicted in Table 1, below.
  • R 9 ’ and R 10 ’ are each independently hydrogen or an optionally substituted alkyl, or R 9 ’ and R 10 ’ are cyclically linked and together with X 2 ’, to form an optionally substituted ring selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 9 ’ is hydrogen. In some embodiments, R 9 ’ is an optionally substituted Ci-6 alkyl. In some embodiments, R 10 ’ is hydrogen. In some embodiments, R 10 ’ is an optionally substituted Ci-6 alkyl. In some embodiments, R 9 ’ and R 10 ’ are cyclically linked and together with X 2 ’ to form an optionally substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R 9 ’ and R 10 ’ are cyclically linked and together with X 2 ’ to form an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 9 ’ and R 10 ’ are cyclically linked and together with X 2 ’ to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 9 ’ and R 10 ’ are cyclically linked and together with X 2 ’ to form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 9 ’ and R 10 ’ are each selected from those depicted in Table 1, below.
  • each R 11 ’ is independently R A , halogen, -CN, -NO2, -NR’ 2 , or -OR’.
  • R 11 ’ is hydrogen. In some embodiments, R 11 ’ is halogen. In some embodiments, R 11 ’ is -CN. In some embodiments, R 11 ’ is -NO2. Some embodiments, R 11 ’ is -NR’2. In some embodiments, R 11 ’ is -OR’.
  • each R 11 ’ is independently selected from those depicted in Table 1, below.
  • n’ is an integer selected from 0 to 4. [00168] 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.
  • R 12 ’ is hydrogen, R A , or -CN.
  • R 12 ’ is hydrogen. In some embodiments, R 12 ’ is R A . In some embodiments, R 12 ’ is -CN.
  • R 12 ’ is selected from those depicted in Table 1, below.
  • each R 13 ’ is independently hydrogen, halogen, R A , -CN, -OR’, -NR’ 2 .
  • R 13 ’ is hydrogen. In some embodiments, R 13 ’ is halogen. In some embodiments, R 13 ’ is -CN. In some embodiments, R 13 ’ is -OR’. In some embodiments, R 13 ’ is -NR’2.
  • R 13 ’ is selected from those depicted in Table 1, below.
  • R 7 ’ and R 8 ’ are each independently hydrogen or optionally substituted C1-2 aliphatic.
  • R 7 ’ is hydrogen. In some embodiment, R 7 ’ is an optionally substituted Ci aliphatic. In some embodiment, R 7 ’ is methyl. In some embodiment, R 7 is an optionally substituted C2 aliphatic. In some embodiment, R 7 ’ is ethyl. In some embodiments, R 8 ’ is hydrogen. In some embodiment, R 8 ’ is an optionally substituted Ci aliphatic. In some embodiment, R 8 ’ is methyl. In some embodiment, R 8 ’ is an optionally substituted C2 aliphatic. In some embodiment, R 8 ’ is ethyl.
  • R 7 ’ and R 8 ’ are selected from those depicted in Table 1, below.
  • the present disclosure provides a compound of Formula (F), wherein Ring D’ is benzo, A’ is a carbon atom, and R 10 ’ and R 11 ’ are hydrogen as shown, to provide a compound of Formula (I’-a):
  • Ring D’ is a carbon atom, and R 10 ’ and R 11 ’ are hydrogen as shown, to provide a compound of Formula (I’-b):
  • the present disclosure provides a compound of Formula (F),
  • Ring D’ is , A A’ i iss a carbon atom, and R 10 ’ and R 11 ’ are hydrogen as shown, to provide a compound of Formula (I’-C):
  • the present disclosure provides a compound of Formula (F),
  • Ring D’ is , A’ is a carbon atom, and R 10 ’ and R 11 ’ are hydrogen as shown, to provide a compound of Formula (I’-d):
  • the present disclosure provides a compound of Formula (G),
  • Ring D’ is N A’ B’, W’, and X’ are a carbon atoms, and R 10 ’ and R 11 ’ are hydrogen as shown, to provide a compound of Formula (f-e):
  • R 1 ’, R 2 ’, and m’ is as defined above and described in embodiments herein, both singly and in combination.
  • treatment is used interchangeably herein with the term “therapeutic method” and refers to both 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions, disease or disorder, and 2) and prophylactic/ preventative measures.
  • Those in need of treatment may include individuals already having a particular medical disease or disorder as well as those who may ultimately acquire the disorder (i.e., those at risk or needing preventive measures).
  • subject refers to any individual or patient to which the subject methods are performed. Generally, the subject is human, although as will be appreciated by those in the art, the subject may be an animal.
  • the terms“therapeutically effective amount”,“effective dose”,“therapeutically effective dose”,“effective amount,” or the like refer to the amount of a subject compound that will elicit the biological or medical response in a tissue, system, animal or human that is being sought by administering said compound. Generally, the response is either amelioration of symptoms in a patient or a desired biological outcome. In some embodiments, such amount should be sufficient to modulate an adrenergic receptor.
  • an effective amount of an adrenergic receptor modulating compound is an amount that ranges from about 50 ng/ml to 50 pg/ml (e.g., from about 50 ng/ml to 40 pg/ml, from about 30 ng/ml to 20 pg/ml, from about 50 ng/ml to 10 pg/ml, from about 50 ng/ml to 1 pg/ml, from about 50 ng/ml to 800 ng/ml, from about 50 ng/ml to 700 ng/ml, from about 50 ng/ml to 600 ng/ml, from about 50 ng/ml to 500 ng/ml, from about 50 ng/ml to 400 ng/ml, from about 60 ng/ml to 400 ng/ml, from about 70 ng/ml to 300 ng/ml, from about 60 ng/ml to 100 ng/ml, from about 65 ng/m
  • an effective amount of an adrenergic receptor modulating compound is an amount that ranges from about 10 pg to 100 mg, e.g., from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1 ng, from about 1 ng to 10 ng, from about 10 ng to 50 ng, from about 50 ng to 150 ng, from about 150 ng to 250 ng, from about 250 ng to 500 ng, from about 500 ng to 750 ng, from about 750 ng to 1 mg, from about 1 pg to 10 pg, from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 100 mg, e.
  • compositions including compounds as disclosed herein e.g., with the structures of Formula (I), Formula (G), Formula (II), Formula (IF), Formula (III), Formula (IV) Formula (I), Formula (G), Formula (II), Formula (IF), Formula (III), Formula (IV), Formula (VF), and Formula (VIF).
  • pharmaceutically acceptable carrier refers to a non-toxic carrier that may be administered to a patient, together with a compound of this disclosure, and which does not destroy the pharmacological activity thereof.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glycer
  • compositions comprising only the compounds described herein as the active component
  • methods for administering these compositions may additionally comprise the step of administering to the subject an additional agent or therapy.
  • Such therapies include, but are not limited to, an anemia therapy, a diabetes therapy, a hypertension therapy, a cholesterol therapy, neuropharmacologic drugs, drugs modulating cardiovascular function, drugs modulating inflammation, immune function, production of blood cells; hormones and antagonists, drugs affecting gastrointestinal function, chemotherapeutics of microbial diseases, and/or chemotherapeutics of neoplastic disease.
  • Other pharmacological therapies can include any other drug or biologic found in any drug class.
  • other drug classes can comprise allergy/cold/ENT therapies, analgesics, anesthetics, anti-inflammatories, antimicrobials, antivirals, asthma/pulmonary therapies, cardiovascular therapies, dermatology therapies, endocrine/metabolic therapies, gastrointestinal therapies, cancer therapies, immunology therapies, neurologic therapies, ophthalmic therapies, psychiatric therapies or rheumatologic therapies.
  • agents or therapies that can be administered with the compounds described herein include a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.
  • the term“therapeutically effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) Preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or
  • a compound as disclosed herein may be an adrenergic receptor modulating compound (e.g., an agonist, partial agonist or antagonist of an adrenergic receptor).
  • the adrenergic receptor modulating compounds of the present disclosure can in some embodiments find use in modulating the activity of a target adrenergic receptor in vitro or in vivo. Aspects of the subject methods include contacting a sample with an effective amount of an adrenergic receptor modulating compound (e.g., as described herein) to determine whether the activity desired exists.
  • Adrenergic receptors are G-protein coupled receptors (GPCR) that are widely expressed throughout the body and play an important role in regulating multiple physiological processes including cognition, stress-related behavior, inflammation, and smooth muscle contraction/dilation, cardiac muscle contraction, airway reactivity and cognition. Adrenergic receptors mediate the central and peripheral effects of noradrenaline (NA) and adrenaline. Multiple subtypes of ADRs exist, including a-adrenergic receptors and b- adrenergic receptors. Each subtype is expressed in distinct patterns and involved in different physiological processes. Therefore, ligands that selectively target one subtype are valuable both as research tools to identify the roles of different ADR subtypes and as therapeutic agents for multiple diseases related to dysfunction of the NA and adrenaline systems.
  • GPCR G-protein coupled receptors
  • b-adrenergic receptors further include three sub-types: b ⁇ -adrenergic receptor (b ⁇ - ADR), b2 ⁇ G6hb3 ⁇ 4 ⁇ o receptor ⁇ 2-ADR), and b3 ⁇ G6hb3 ⁇ 4 ⁇ o receptor ⁇ 3-ADR). Because these subtypes are expressed in distinct patterns and involved in different physiological processes, ligands that can selectively target one subtype have therapeutic potential for multiple diseases. However, discovery of subtype-selective ligands has been challenging due to a high level of sequence homology shared by these subtypes. A lot of existing agonists for b- adrenergic receptors also exhibit inferior blood-brain-barrier (BBB) penetration, which is required in an effort for drug discovery for central nervous system (CNS) indications.
  • BBB blood-brain-barrier
  • adrenergic receptors signal via G protein- and b -arrestin-dependent pathways.
  • G protein- or b -arrestin signaling can mediate different physiological responses.
  • agonists can show biased activation of signaling pathways.
  • the ability of ligands to activate the receptor and produce responses in a pathway-dependent manner has been termed "signaling bias" or "functional selectivity”.
  • signal bias or “functional selectivity”.
  • biased agonists can provide improved therapeutic selectivity with reduced adverse effects.
  • BBB blood-brain-barrier
  • An adrenergic receptor modulating compound can be an agonist of the target adrenergic receptor.
  • an effective amount of an adrenergic receptor modulating compound is an amount sufficient to activate an activity related to the adrenergic receptor in a cell by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or or even more relative to a control, e.g., a control cell exhibiting a known activity level of the receptor.
  • the adrenergic receptor modulating compound can be a partial agonist of the target adrenergic receptor.
  • an effective amount of an adrenergic receptor modulating compound is an amount sufficient to achieve partially agonism of the adrenergic receptor in a cell, e.g., where the subject compound achieves 10% activation or more of the receptor, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, relative to a control, e.g., a receptor that is fully activated.
  • Partial agonism may be assessed using any convenient methods, such as a cell based assay using a known full agonist as a 100% activation control, where the relative maximum activation of the receptor can be measured relative to the full agonist.
  • the adrenergic receptor modulating compound can be an antagonist of the target adrenergic receptor.
  • an effective amount of an adrenergic receptor modulating compound is an amount sufficient to inhibit or decrease the activity of the target adrenergic receptor in a sample by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or even more relative to a control, e.g., a sample not contacted with the compound of interest.
  • the target adrenergic receptor is a b ⁇ - adrenergic receptor. In some embodiments of the method, the target adrenergic receptor is a b2 ⁇ G6hb3 ⁇ 4 ⁇ o receptor. In some embodiments of the method, the target adrenergic receptor is a b3 ⁇ G6hb3 ⁇ 4 ⁇ o receptor. In some embodiments, the compound is an agonist for both b ⁇ - adrenergic receptor and b2 ⁇ G6hb3 ⁇ 4 ⁇ o receptor. In certain cases, the compound is selective for the b2 ⁇ G6hb3 ⁇ 4 ⁇ o receptor over a b ⁇ -adrenergic receptor.
  • the target adrenergic receptor may be one that is responsible for a mediating an intracellular signal or pathway in a cell.
  • the sample includes a cell and modulating the adrenergic receptor modulates a physiological process in the cell. Any convenient physiological processes can be targeted for modulation in a cell using the subject methods.
  • the physiological process is one that is implicated in cardiac function, in certain instances, the physiological process is one that is implicated in cognitive function. In certain instances, the physiological process is one that is implicated in an inflammatory pathway or condition.
  • the subject methods can provide for mediation of the intracellular concentration of a signaling molecule in a cell, such as cAMP.
  • the subject methods can provide for partial or full blockage of the target adrenergic receptor to result in modulation (e.g., activation) of cAMP in a sample.
  • the method does not modulate b-arrestin pathways of the cell.
  • the cells are inflammatory cells and the function of the cells is regulated.
  • the subject methods can provide for inhibition of an inflammatory pathway in a cell.
  • TNF-alpha is inhibited in the cell, e.g., the concentration or production of TNF-alpha is reduced by practicing the subject method.
  • the cell is a neuron.
  • modulating the adrenergic receptor enhances neurogenesis.
  • the compounds of this disclosure may be employed in a conventional manner for controlling, preventing, treating a disease described herein, including, but not limited to, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral de
  • the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a described compound may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present disclosure provides a single unit dosage form comprising a described compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • Two or more agents are typically considered to be administered "in combination” when a patient or individual is simultaneously exposed to both agents.
  • two or more agents are considered to be administered "in combination” when a patient or individual simultaneously shows therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in brain, in serum, etc.).
  • compositions according to this disclosure comprise a combination of ivermectin, or any other compound described herein, and another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease, or condition, being treated.”
  • the subject method includes administering a therapeutically effective amount of one or more additional active agents.
  • combination therapy is meant that an adrenergic receptor modulating compound can be used in a combination with another therapeutic agent to treat a single disease or condition.
  • a compound of the present disclosure is administered concurrently with the administration of another therapeutic agent, which can be administered as a component of a composition including the compound of the present disclosure or as a component of a different composition.
  • the subject compounds can be administered in combination with other therapeutic agents in a variety of therapeutic applications.
  • Therapeutic applications of interest for combination therapy include those applications in which activity of a target adrenergic receptor is the cause or a compounding factor in disease progression.
  • the subject compounds find use in combination therapies in which the inhibition of a target adrenergic receptor in the subject is desired.
  • diseases which may be treated by a combination therapy including a subject compound include, but are not limited to, cardiac conditions or diseases, neurodegenerative or neurodevelopmental disease, respiratory disorders, asthma, memory impairment, depression, inflammatory diseases, stroke, ischemic brain or tissue injury and cancer.
  • Agents of interest which can be used in jointly with the subject adrenergic receptor modulating compounds include, but are not limited to, antidepressants, antipsychotics, beta- blockers, vasoconstrictors, antihypotensives, decongestants, chemotherapeutic agents, agents used in Alzheimer's disease, and anti-inflammatory agents.
  • the subject adrenergic receptor modulating compounds can be used jointly with any agent useful in the treatment of a cardiac condition, such as cardiogenic shock, hypertension, congestive heart failure, coronary heart disease, arrhythmias, myocardial infarction or ischemic heart diseases.
  • Agents of interest which can be used in jointly with the subject adrenergic receptor modulating compounds include, but are not limited to, denopamine, dobutamine, xamoterol, acebutolol, atenolol, betaxolol, bisoprolol, pindolol, esmolol, metoprolol, nebivolol, vortioxetine, Carvedilol, Labetalol, Phentolamine, Prazosin, Cirazoline, Methoxamine, Synephrine, Etilefrine, Metaraminol, Midodrine, and cumarin.
  • the subject adrenergic receptor modulating compounds can be used jointly with any agent useful in the treatment of a neurodegenerative or neurodevelopmental disease, such as such as Alzheimer's Disease, memory impairment, cognitive impairment, depression, stroke and ischemic brain or tissue injury, Down's syndrome or Autism.
  • Agents of interest which can be used in jointly with the subject adrenergic receptor modulating compounds include, but are not limited to, acepromazine.
  • the subject adrenergic receptor modulating compounds can be used in the treatment of a disease, such as a neurodegenerative or neurodevelopmental disease, in combination with a cholinesterase inhibitor or a NMDA receptor modulators.
  • Agents of interest include, but are not limited to, Donepezil, Aricept, Galantamine, Razadyne, Memantine, Namenda, Rivastigmine, Exelon, Tacrine and Cognex.
  • Other agents of interest which can be used in jointly with the subject adrenergic receptor modulating compounds include, but are not limited to, 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, Xylazine, Xylometazoline, Aripiprazole, Asenapine, Atipamezole,
  • agents of interest which can be used in jointly with the subject adrenergic receptor modulating compounds include, but are not limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline or isoproterenol, levosalbutamol or levalbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol, salbutamol or albuterol, terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, indacaterol, milveterol, olodaterol, vilanterol, fenoterol, hexoprenaline, isoxsuprine, ritodrine, salbutamol or albuterol, terbutaline, zilpaterol, ICI-118,551 and butoxamine.
  • compositions and methods of this disclosure may also be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those, which increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and/or alter rate of excretion.
  • compositions of this disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human being.
  • a subject or patient e.g., a mammal, preferably a human being.
  • Such pharmaceutical compositions are used to ameliorate, treat or prevent any of the diseases described herein in a subject.
  • Agents of the disclosure are often administered as pharmaceutical compositions comprising an active therapeutic agent, i.e., and a variety of other pharmaceutically acceptable components. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application.
  • the compositions can also include, depending on the formulation desired, pharmaceutically 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.
  • compositions or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of a described compound, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents for use in treating the diseases described herein, including, but not limited to stroke, ischemia, Alzheimer's, ankylosing spondylitis, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, asthma atherosclerosis, Crohn's disease, colitis, dermatitis diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, systemic lupus erythematous, nephritis, ulcerative colitis and Parkinson's disease.
  • pharmaceutically acceptable carriers additives
  • diluents for use in treating the diseases described herein, including, but not limited to stroke, ischemia, Alzheimer's, ankylosing spondylitis, arthritis, osteoarthritis, rheumatoid
  • Described compounds may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
  • compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly; transdermally; or nasally, pulmonary and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples 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 hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • 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 hydroxy toluene (BHT), lecithin
  • Formulations for use in accordance with the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient, which can be combined with a carrier material, to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material 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 active ingredient. In some embodiments, this amount will range from about 5% to about 70%, from about 10% to about 50%, or from about 20% to about 40%.
  • a formulation as described herein comprises an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and poly anhydrides; and a compound of the present disclosure.
  • an aforementioned formulation renders orally bioavailable a described compound of the present disclosure.
  • Methods of preparing formulations or compositions comprising described compounds include a step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients.
  • formulations may be prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed 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 pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as those described in Pharmacopeia Helvetica, or a similar alcohol.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • the absorption of the drug in order to prolong the effect of a drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the described compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. 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, which are compatible with body tissue.
  • compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • carriers which are commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a 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 pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
  • Compounds described herein may also be administered as a bolus, electuary or paste.
  • an active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made in a suitable machine in which a mixture of the powdered compound is moistened with an inert liquid diluent.
  • a solid carrier is used, the preparation can be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.
  • the amount of solid carrier will vary, e.g., from about 25 to 800 mg, preferably about 25 mg to 400 mg.
  • the preparation can be, e.g., in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • any routine encapsulation is suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.
  • Tablets and other solid dosage forms may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may alternatively or additionally be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze- dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of compounds of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of this disclosure may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this disclosure with a suitable non-irritating excipient, which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of this disclosure is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this disclosure may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-administered transdermal patches are also included in this disclosure.
  • compositions of this 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 solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. Dissolving or dispersing the compound in the proper medium can make such dosage forms. Absorption enhancers can also be used to increase the flux of the compound across the skin. Either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel can control the rate of such flux.
  • aqueous and nonaqueous carriers examples 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.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • 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.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • inclusion of one or more antibacterial and/orantifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like, may be desirable in certain embodiments.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, which delay absorption such as aluminum monostearate and gelatin.
  • a described compound or pharmaceutical preparation is administered orally. In other embodiments, a described compound or pharmaceutical preparation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administrations.
  • compounds described herein are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Preparations described herein may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for the relevant administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • Such compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracistemally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the disclosure may be varied so as 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.
  • kits that include the disclosed adrenergic receptor modulating compounds.
  • Systems of the present disclosure include collections of active agents brought together, e.g., by a health care practitioner, for administration to a subject, such as a patient. Such systems may include an adrenergic receptor modulating compound and one or more additional active agents disclosed herein.
  • Kits that include adrenergic receptor modulating compounds which are provided that may include one or more dosages of an adrenergic receptor modulating compound, and optionally one or more dosages of one or more additional active agents.
  • the formulations may be provided in a unit dosage format. In such kits, in addition to the containers containing the formulation(s), e.g.
  • unit doses is an informational package insert describing the use of the subject formulations in the methods of the as disclosed herein, e.g., instructions for using the subject unit doses to treat cellular proliferative disease conditions.
  • 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 as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, etc.
  • Yet another means would be a computer readable medium, e.g., diskette, CD, etc., on which the information has been recorded.
  • Y et another means that may be present is a website address which may be used via the internet to access the information at a removed site. Any convenient means may be present in the kits.
  • Table 1 below illustrates exemplary compounds of the instant disclosure. Table 1. The compounds in the instant disclosure.
  • a pharmaceutical composition including a compound with a structure of Formula (I), Formula (F), Formula (II), Formula (IF), Formula (III’), Formula (IV’), Formula (V’), Formula (VF), Formula (VIF), and a pharmaceutically acceptable excipient.
  • a method of treating a subject with a disease associated with an adrenergic receptor comprising or administering to the subject a therapeutically effective amount of a compound with a structure of Formula (I), Formula (F), Formula (II), Formula (IF), Formula (III’), Formula (IV’), Formula (V’), Formula (VF), or Formula (VIF), thereby treating the subject.
  • the disease is aneurodegenerative disease
  • the subject is a human.
  • the disease is selected from the group consisting of myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies, and neuronal ceroid
  • the compound is administered to the subject through oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavemous, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route.
  • the compound is selected from those compounds set forth in Table 1.
  • Scheme 1 illustrates the synthesis of compound 02-1.
  • Scheme 3 illustrates the synthesis of compound 02-3.
  • Step 1 Synthesis of 4-methyl-6-vinylpyridazin-3-amine.
  • 6- chloro-4-methylpyridazin-3-amine (0.72 g, 5.01 mmol)
  • potassium vinyltrifluoroborate (0.87 g, 6.51 mmol)
  • K2CO3 (2.07 g, 15.03 mmol) in dioxane/LhO (16 mL/4 mL)
  • Pd(dppf)2Cl2 0.367 g, 0.501 mmol.
  • the resulting mixture was purged with N2 before heating to 85 °C for 12 hrs. After cooled down, the reaction mixture was diluted with EtOAc.
  • Step 2 Synthesis of 4-methyl-6-vinylpyridazin-3-A r (5oc)2.
  • 4-methyl-6-vinylpyridazin-3-amine (0.55 g, 4.1 mmol
  • di-tert-butyl dicarbonate 1.8 g, 8.2 mmol
  • triethylamine 1.8 mL, 12.3 mmoL
  • dichloromethane 16 mL
  • DMAP 0.025 g, 0.21 mmol
  • Step 3 Synthesis of 6-A r (5oc)2-5-methylpyridazine-3-carbaldehyde.
  • 4-methyl-6-vinylpyridazin-3-A r (5oc)2 0.5 g, 1.49 mmol
  • acetone/LLO 16 mL/4 mL
  • NalCri 0.96 g, 4.47 mmol
  • K2O S O4.H2O 0.03 g, 0.075 mmol
  • Step 4 Synthesis of l-(6- /V(5oc)2-5-methylpyridazin-3-yl)-2-(tert- butylamino)ethan-l-ol.
  • Step 5 Synthesis of l-(6-amino-5-methylpyridazin-3-yl)-2-(tert-butylamino)ethan- l-ol.
  • l-(6-/V(5oc)2-5-methylpyridazin-3-yl)-2-(tert-butylamino)ethan- l-ol 0.025 g, 0.058 mmol
  • dichloromethane 3 mL
  • 4N HCI in dioxane 3 mL, 12 mmol
  • Scheme 5 illustrates the synthesis of compound 04-1.
  • Step 1 Synthesis of 5-bromoquinolin-2(lH)-one.
  • m-CPBA 8.1g, 47 mmol
  • the reaction mixture was stirred at room temperature for 3 hrs. After this time, IN NaOH aqueous solution (120 ml) was added to the reaction and the resulting mixture was extracted with DCM (100 mL x3).
  • Step 2 Synthesis of 5-acetylquinolin-2(lH)-one.
  • N2 N2
  • 1.5N HC1 2 eq.
  • Step 3 Synthesis of 5-(2-bromoacetyl)quinolin-2(lH)-one.
  • a stirred solution of 5-acetylquinolin-2(lH)-one and HBr (40%) in AcOH was added pyridinium tribromide (1.2 eq.).
  • the resulting mixture was stirred at 40 °C overnight. After cooling to rt the mixture was quenched with saturated NaHCCb aqueous solution.
  • the reaction mixture was subsequently extracted with EtOAc.
  • the combined organic layers were washed with brine, dried over Na2SC>4 and concentrated.
  • the crude product was purified via flash chromatography to afford 5-(2-bromoacetyl)quinolin-2(lH)-one.
  • LC-MS m/z 267.1 (M+l) + .
  • Step 4 Synthesis of (//)-5-(2-bromo- 1 -hydro ⁇ yethyl)quinolin-2( 1 H)-one.
  • To a stirred solution of 5-(2-bromoacetyl)quinolin-2(lH)-one in toluene was added (i?)-2-methyl- CBS-oxa/aborolidine (0.2 eq.) at -35 °C.
  • the resulting mixture was stirred at -35 °C for 30 minutes.
  • BEb.THF (IN in THF, 1 eq.) was then introduced dropwise via syringe. After addition, the reaction was warmed up to -15 °C.
  • Step 5 Synthesis of (//)-5-(2-(tert-butylamino)- 1 -hydro ⁇ yethyl)quinolin-2( 1 H)-one (Compound 04-1).
  • MeCN MeCN
  • /ert-butylamine 60 eq.
  • the resulting mixture was stirred at 40 °C for 48 hrs.
  • the reaction was concentrated, and the residue was re-dissolved with EtOAc.
  • the organic layer was washed with saturated NaHC03 aqueous solution and brine, dried over Na2S04 and concentrated.
  • Step 1 Synthesis of 3-bromo-2-chloropyridin-4-amine.
  • 2- chloropyridin-4-amine 10 g, 77.78 mmoL
  • MeCN 250 mL
  • N- Bromosuccinimide 13.8 g, 77.78 mmoL
  • the resulting mixture was stirred at room temperature for 12 hrs.
  • the reaction was concentrated.
  • the crude product was purified by purified via flash chromatography (silica, pet ether/EtOAc: 20/1 to 3/1) to afford 3-bromo-2- chloropyridin-4-amine as a yellow solid (7.1 g, 43.9%).
  • LC-MS m/z 206.94, 208.97 (M+l, M+2) + .
  • Step 2 Synthesis of ethyl (E)-3-(4-amino-2-chloropyridin-3-yl)acrylate.
  • 3-bromo-2-chloropyridin-4-amine (2 g, 9.6 mmoL)
  • ethyl acrylate (1.9 g, 19.3 mmoL)
  • Et3N (2.91 g, 28.8 mmoL)
  • tricyclohexyl phosphine 1.3 g, 4.8 mmol
  • DMF 100 mL
  • Pd(OAc2) 431 mg, 1.9 mmoL, 0.2 eq.
  • Step 3 Synthesis of Synthesis of 5-chloro- 1 6-naphthyridin-2( 1 //)-one.
  • ethyl (//)-3-(4-amino-2-chloropyridin-3-yl (acrylate (2.5 g, 11.01 mmoL) in DIPEA (20 mL) was added DBU (3.3 g, 22.02 mmoL).
  • DBU 3.3 g, 22.02 mmoL
  • Step 4-7 Synthesis of fV)-5-(2-(tert-butylamino)- 1 -hydroxy ethyl)- 1.6-naphthyridin- 2(lH)-one (Compound 04-5). Procedures similar to the synthesis of Compound 04-1 were employed using 5-chloro- 1 6-naphthy ridin-2( 1 //)-one instead of 5-bromoquinolin-2(lH)-one as starting material to obtain (5)-5-(2-(tert-butylamino)- 1 -hydroxy ethyl)- 1,6-naphthyri din- 2(lH)-one (04-5) as a white solid, 12 mg, 4-step yield: 9.2%).
  • Step 1 Synthesis of 4-bromo-7-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazole.
  • 4-bromo-7-fluoro-lH-indazolel 2.5 g, 11.62 mmol
  • DMF 20 mL
  • NaH 60%, 0.79 g, 19.75 mmol
  • 2-(trimethylsilyl)ethoxymethyl chloride 3.1 mL, 2.92 g, 17.44 mmol
  • Step 2 Synthesis of 7-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-lH- indazole.
  • 4-bromo-7-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazole 1.9 g, 5.51 mmol
  • dioxaneTLO 20 mL/2 mL
  • potassium vinyltrifluoroborate 1.47 g, 11.01 mmol
  • Pd(dppi)Cl2- CH2Cl2 (0.45 g, 0.55 mmol
  • CS2CO3 5.38 g, 16.5 mmol
  • Step 3 Synthesis of (R)- 1 -(7-fluoro- 1 -((2-(trimethylsilyl)etho ⁇ y)methyl)- 1 H- indazol-4-yl)ethane-l,2-diol. To a stirred solution of 7-fluoro- 1 -((2-(trimethylsilyl)etho ⁇ y)methyl)- 1 H- indazol-4-yl)ethane-l,2-diol. To a stirred solution of 7-fluoro- 1 -((2-(trimethylsilyl)etho ⁇ y)methyl)- 1 H- indazol-4-yl)ethane-l,2-diol. To a stirred solution of 7-fluoro- 1 -((2-(trimethylsilyl)etho ⁇ y)methyl)- 1 H- indazol-4-yl)ethane-l,2-diol. To a stirred solution of 7-fluoro
  • Step 4 Synthesis of (//)-7-fluoro-4-(oxiran-2-yl)- 1 -((2-
  • Step 5 Synthesis of (i?)-2-(tert-butylamino)- 1 -(7-fluoro- 1 -((2-
  • Step 6 Synthesis of (R)-2-(tert-butylamino)-l-(7-fluoro-lH-indazol-4-yl)ethan-l- ol.
  • (R)-2-(tert-butylamino)-l-(7-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-4-yl)ethan-l-ol (2 g, 5.24 mmol) in CH2CI2 (8 mL) at 0 °C was added CF3COOH (10 mL). The reaction mixture was stirred at room temperature for 2 hrs and then concentrated in vacuo.
  • This compound was further purified by reversed-phase HPLC (0.1% TFA in CH3CN/H2O) and lyophilized with 1 N aqueous HC1 (1 mL) to provide (R)-2-(tert-butylamino)-l-(7-fluoro-lH- indazol-4-yl)ethan-l-ol HC1 salt as a white solid (0.37 g, 25%).
  • Scheme 8 illustrates the synthesis of compound 04-144 and compound 04-145.
  • Step 1 Synthesis of 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[4,3-c]pyridine.
  • 4-chloro-lH-pyrazolo[4,3-c]pyridine 4 g, 27.35 mmol
  • DMF 25 mL
  • NaH 60%, 1.64 g, 41 mmol
  • SEMC1 5.93 g, 35.55 mmol
  • Step 2 Synthesis of l-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-lH-pyrazolo[4,3- c] pyridine.
  • 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[4,3-c]pyridine 3 g, 10.57 mmol
  • dioxane/EEO 20 mL/2 ml
  • potassium vinyltrifluoroborate 2.83 g, 21.14 mmol
  • Pd(dppf)Cl2-CH2Cl2 (856 mg, 1.05 mmol
  • CS2CO3 10.33 g, 31.71 mmol
  • Step 3 Synthesis of 4-(2-(tert-butylamino)- 1 -hydroxy ethyl)- 1 -((2-
  • Step 4 Synthesis of 2-(tert-butylamino)-l-(l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrazolo[4,3-c]pyridin-4-yl)ethan-l-ol.
  • Step 5 Synthesis of (S)-2-(tert-butylamino)-l-(lH-pyrazolo[4,3-c]pyridin-4- yl)ethan-l-ol and (//)-2-(tert-butylamino)- 1 -( 1 H-pyra/olo
  • cAMP homogeneous time-resolved fluorescence (HTRF): experimental methods. Compound efficacy is determined using the cAMP Gs dynamic HTRF assay (Cisbio, catalog # 62AM4PEC) largely following the manufacturer’s instructions, also detailed below.
  • Compound preparation Candidate beta-adrenergic compounds, dissolved to 10 mM in DMSO, are diluted in IX stimulation buffer 1 (Cisbio Part# 64SB1FDD) containing 1 mM 3-Isobutyl-l-methylxanthene (IBMX; Cayman Chemical Company, catalog # 13347). Serial dilutions are made in a 96 well V-bottom polypropylene compound microplate (Coming, catalog # 3363) in stimulation buffer containing 1 mM IBMX, to 2X of the final desired concentration. Standard serial dilution curves are 10-point, 5-fold dilutions starting from a highest concentration of 10 mM.
  • Controls present on every assay plate are 0.1% DMSO (vehicle control), 1 mM isoproterenol (full beta-adrenergic agonist control) and 15 mM xamoterol (partial beta-adrenergic agonist control).
  • 5 pL from the 2X compound plate is stamped into a white 384 round well small volume HiBase assay plate (Greiner Bio-One; catalog # 784075) to provide 4 technical replicates per concentration, per compound.
  • Assay plates are centrifuged at 500 x g for 10 seconds.
  • Compounds and IBMX are prepared at 2X final dose to compensate for addition of cells.
  • Cell preparation IX stimulation buffer, washing PBS (Dulbecco’s phosphate- buffered saline, -Mg -Ca; Caisson Labs, catalog # PBL01), assay PBS (Dulbecco’s phosphate- buffered saline, + Mg, + Ca; Caisson Labs, catalog # PBL02) and Versene (0.02% EDTA disodium salt solution in PBS without calcium or magnesium; Caisson Labs, catalog # EDL01) are pre-warmed to 37°C. Cells expressing beta-adrenergic receptor were washed in washing PBS to remove growth medium and then released from the surface by incubating with Versene for 5-10 minutes at 37°C.
  • PBS Dulbecco’s phosphate- buffered saline, -Mg -Ca
  • assay PBS Dulbecco’s phosphate- buffered saline, + Mg, + Ca
  • Cells are harvested using assay PBS, counted manually by hemocytometer or by an automated cell counter, pelleted by centrifugation (200 x g, 5 minutes) and resuspended in 37°C IX stimulation buffer to a final density of 1.5 x 10 L 6 cells/mL. 5 pL of the suspended cell solution (7500 cell total) are added to all wells of the 384 well assay plate, the assay plate was covered with an Axygen® plate seal (Coming PCR-SP) and incubated in a humidified 37°C environment supplemented with 5% CO2 for 30 minutes.
  • Axygen® plate seal Coming PCR-SP
  • HTRF reagent addition reading and data analysis After 30 minutes of cell stimulation with test compound, the assay plates are centrifuged at 500 x g for 10 seconds, and incubation was stopped with the addition of 5 pL cAMP-D2 acceptor, diluted 1 :21 in detection and lysis buffer 2 (Cisbio 62CL2FDF) was added to all cells. Subsequently, 5 pL Anti-cAMP- Eu Donor, diluted 1:21 in detection and lysis buffer 2, was added to cells. Plates were sealed and reactions gently‘vortexed’ at 900 rpm on aHeidolph Titramax 1000 for at least 30 minutes at room temperature.
  • HTRF ratios (665 nm / 620 nm x 10,000) are determined and plotted in GraphPad Prism to generate a concentration-effect curve.
  • Potency estimates (EC50 and pECso) are derived from the four-parameter nonlinear regression of the concentration-effect curve and an estimate of relative efficacy is determined by comparing the magnitude of the test compound HTRF signal window (min - max dose) with the signal window of the full agonist control, isoproterenol.
  • the potency data are shown in Table 2 and Table 3 below. Table 2.
  • Table 2 The pharmacological data of the chemical compounds disclosed herein.
  • Embodment 1 A compound according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
  • n is an integer selected from 0 to 3
  • each A, B, and X is independently a nitrogen or carbon
  • P is N, O, or CR.2
  • Q is N, O, or CR2
  • G is NR5 or O
  • Z is NR5, O, S, or
  • R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy,
  • each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy,
  • R5 is one or more selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
  • L is a C1-C5 alkyl linker optionally substituted
  • each Xi, X2, X3, and X4 is independently a covalent bond, a carbon, an oxygen, or a nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl,
  • Y is O or S
  • R.6 and R.7 are independently selected from hydrogen, unsubstituted or substituted alkyl, or R.6 and R7 are cyclically linked and together with X2 to form an optionally substituted cycloalkyl or heterocycle,
  • each Re is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
  • n is an integer selected from 0 to 4, and
  • R9 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino; and Rio is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • Embodiment 2 A compound according to Formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
  • n is an integer selected from 0 to 3
  • each A, B, and X is independently a nitrogen or carbon
  • P is N, O, or CR.2
  • Q is N, O, or CR2
  • G is NR5 or O
  • Z is NR5, O, S, or CR3R4
  • R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy,
  • each R3 and R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy,
  • R5, R6, and R7 are independently selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
  • L is a C1-C5 alkyl linker optionally substituted
  • each Xi, X2, X3, and X4 is independently a covalent bond, a carbon, an oxygen, or a nitrogen, optionally substituted with hydrogen, unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl,
  • Y is O or S
  • R.8 and R.9 are independently selected from hydrogen, unsubstituted or substituted alkyl, or Rx and R9 are cyclically linked and together with X2 to form an optionally substituted cycloalkyl or heterocycle,
  • each Rio is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl,
  • n is an integer selected from 0 to 4,
  • R11 is selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted amino, and
  • R12 is selected from the group consisting of hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
  • Embodiment 3 A compound with the following structure:
  • Embodiment 5 A compound with the following structure:
  • Embodiment 6 A compound with the following structure:
  • Embodiment 7 A compound with the following structure:
  • Embodiment 8 A pharmaceutical composition including the compound of any one of embodiments 1-2 and a pharmaceutically acceptable excipient.
  • Embodiment 9 The compound of any one of embodiments 1-7, wherein the compound is an agonist, partial agonist or antagonist of an adrenergic receptor;
  • Embodiment 10 The compound of any one of embodiments 1-7, wherein the compound is a b ⁇ -adrenergic receptor agonist, 2-adrenertic receptor agonist or non-selective b1/b2- adrenergic receptor agonist.
  • Embodiment 11 The compound of any one of embodiments 1-7, wherein the compound is a b ⁇ -adrenergic receptor agonist.
  • Embodiment 12 The compound of any one of embodiments 1-7, wherein the compound is a b2 ⁇ G6he3 ⁇ 4 ⁇ o receptor agonist.
  • Embodiment 13 The compound of any one of embodiments 1-7, wherein the compound is a non-selective b1/b2 ⁇ G6hb3 ⁇ 4 ⁇ o agonist.
  • Embodiment 14 A method of treating a subject with a disease, the method including administering to the subject a therapeutically effective amount of a compound of any one of claims 1-2.
  • Embodiment 15 The method according to embodiment 14, wherein the disease is a disease associated with an adrenergic receptor.
  • Embodiment 16 The method according to embodiment 14, wherein the disease is a neurodegenerative disease.
  • Embodiment 17 The method according to embodiment 14, wherein the subject is a human.
  • Embodiment 18 The method according to embodiment 14, wherein the disease is selected from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striato
  • Embodiment 19 The method according to embodiment 14, wherein the compound is administered to the subject through oral, enteral, topical, inhalation, transmucosal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, epidural, intracerebral, intracerebroventricular, epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac, intracavemous, intradermal, intralesional, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical, intravitreal, transdermal, perivascular, buccal, vaginal, sublingual, or rectal route.
  • Embodiment 20 The method according to embodiment 14, wherein the disease is a neurodegenerative disease that is one or more selected from the group consisting of MCI (mild cognitive impairment), aMCI (amnestic MCI), Vascular Dementia, Mixed Dementia, FTD (fronto-temporal dementia; Pick’s disease), HD (Huntington disease), Rett Syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (Multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wemicke-Korsakoff syndrome; alcoholic dementia & thiamine deficiency), normal pressure hydrocephalus, hypersomnia/narcolepsy, ASD (autistic spectrum disorders), FXS (fragile X syndrome), TSC (tuberous
  • Embodiment 21 The method according to embodiment 14, wherein the disease is a neurodegenerative disease that is one or more selected from the group consisting of MCI, aMCI, Vascular Dementia, Mixed Dementia, FTD (fronto-temporal dementia; Pick’s disease), HD (Huntington disease), Rett Syndrome, PSP (progressive supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (Multiple system atrophy), SDS (Shy-Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS (Wemicke-Korsakoff syndrome; alcoholic dementia & thiamine deficiency), normal pressure hydrocephalus, hypersomnia/narcolepsy, ASD (autistic spectrum disorders), FXS (fragile X syndrome), TSC (tuberous sclerosis complex), prion-related diseases (
  • Embodiment 22 The method according to any one of embodiments 14-21, wherein the subject does not have Down Syndrome
  • Embodiment 23 The method of any one of embodiments 14-22, wherein administering to the subject further includes a peripherally acting b-blocker (PABRA) along with the compound.
  • PABRA peripherally acting b-blocker
  • Embodiment 24 The method of embodiment 23, wherein a peripherally acting b-blocker (PABRA) is administered to the subject prior to administration of the compound.
  • PABRA peripherally acting b-blocker
  • Embodiment 25 The method of embodiment 23, wherein a peripherally acting b-blocker (PABRA) is administered to the subject concurrently with the administration of the compound.
  • Embodiment 26 The method of any one of embodiments 14-22, wherein a l agonist, a 2 agonist, or a non-selective b ⁇ / b2 agonist is administered to the patient in addition to the compound.
  • PABRA peripherally acting b-blocker

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Abstract

La présente invention concerne des composés chimiques et l'utilisation de tels composés dans le traitement de maladies associées à un récepteur adrénergique.
PCT/US2020/040308 2019-07-01 2020-06-30 Agoniste bêta-adrénergique et procédés d'utilisation associés WO2021003161A1 (fr)

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MX2021015850A MX2021015850A (es) 2019-07-01 2020-06-30 Agonista beta adrenergico y metodos de uso del mismo.
CN202080054317.7A CN114340740A (zh) 2019-07-01 2020-06-30 β肾上腺素能激动剂及其使用方法
US17/620,065 US20220315534A1 (en) 2019-07-01 2020-06-30 Beta adrenergic agonist and methods of using the same
EP20835619.6A EP3993878A4 (fr) 2019-07-01 2020-06-30 Agoniste bêta-adrénergique et procédés d'utilisation associés
AU2020300999A AU2020300999A1 (en) 2019-07-01 2020-06-30 Beta adrenergic agonist and methods of using the same
JP2022500006A JP2022538907A (ja) 2019-07-01 2020-06-30 βアドレナリンアゴニストおよびその使用方法
CA3144093A CA3144093A1 (fr) 2019-07-01 2020-06-30 Agoniste beta-adrenergique et procedes d'utilisation associes
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US16/831,285 US11040944B2 (en) 2019-03-27 2020-03-26 Beta adrenergic agonist and methods of using the same
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US16/831,370 US10947196B2 (en) 2019-03-27 2020-03-26 Beta adrenergic agonist and methods of using the same
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WO2022063889A1 (fr) 2020-09-23 2022-03-31 Atrogi Ab Dérivés d'hydroxylbenzyl azabicyclo[2.2.1] heptan-1-ane et leurs utilisations médicales
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WO2023046882A1 (fr) 2021-09-23 2023-03-30 Atrogi Ab Cyclohexyl bêta-hydroxy alkyl amines et leurs utilisations médicales
WO2023077678A1 (fr) * 2021-11-03 2023-05-11 中国药科大学 Composé à petites molécules ciblant la protéine srsf6 et son procédé de préparation et son utilisation
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Publication number Priority date Publication date Assignee Title
WO2022063895A1 (fr) 2020-09-23 2022-03-31 Atrogi Ab Dérivés d'arylazabicyclo[2,1,1]hexylméthanol et leurs utilisations médicales
WO2022063889A1 (fr) 2020-09-23 2022-03-31 Atrogi Ab Dérivés d'hydroxylbenzyl azabicyclo[2.2.1] heptan-1-ane et leurs utilisations médicales
CN115710158A (zh) * 2021-08-23 2023-02-24 凯特立斯（深圳）科技有限公司 一种不对称催化制备替格瑞洛中间体的方法
WO2023046885A1 (fr) 2021-09-23 2023-03-30 Atrogi Ab Hydroxyméthyl pyrrolidines substituées et leurs utilisations médicales
WO2023049290A1 (fr) * 2021-09-23 2023-03-30 Curasen Therapeutics, Inc. Agoniste bêta-adrénergique et ses méthodes d'utilisation
WO2023046882A1 (fr) 2021-09-23 2023-03-30 Atrogi Ab Cyclohexyl bêta-hydroxy alkyl amines et leurs utilisations médicales
WO2023077678A1 (fr) * 2021-11-03 2023-05-11 中国药科大学 Composé à petites molécules ciblant la protéine srsf6 et son procédé de préparation et son utilisation
WO2023180472A1 (fr) 2022-03-23 2023-09-28 Atrogi Ab Hydroxyméthyl azabicyclo[2.2.1]heptanes et leurs utilisations médicales
WO2023203223A1 (fr) 2022-04-22 2023-10-26 Atrogi Ab Combinaisons d'agonistes du récepteur bêta 2-adrénergique et d'agonistes du récepteur bêta 3-adrénergique et leurs utilisations médicales

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