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WO2025038987A2 - Agents de dégradation de protéine pde4, compositions pharmaceutiques et applications thérapeutiques - Google Patents

Agents de dégradation de protéine pde4, compositions pharmaceutiques et applications thérapeutiques Download PDF

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WO2025038987A2
WO2025038987A2 PCT/US2024/042843 US2024042843W WO2025038987A2 WO 2025038987 A2 WO2025038987 A2 WO 2025038987A2 US 2024042843 W US2024042843 W US 2024042843W WO 2025038987 A2 WO2025038987 A2 WO 2025038987A2
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compound
mixture
pyrimidin
certain embodiments
piperidin
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WO2025038987A3 (fr
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Eduardo Torres
Kyle W.H. Chan
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Katalytic Therapeutics Inc
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Katalytic Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This application claims the benefit of the priority of U.S. Provisional Application No.63/520,297, filed August 17, 2023; the disclosure of which is incorporated herein by reference in its entirety.
  • FIELD [0002] Provided herein are PDE4 protein degraders and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PDE4.
  • Phosphodiesterase 4 is a key enzyme in the degradation of cyclic adenosine monophosphate (cAMP), which regulates the cytokine production in inflammatory cells. Li et al., Front. Pharmacol.2018, 9, 1048. PDE4 has therefore become an attractive therapeutic target for inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, and inflammatory bowel disease. Id.; Baillie et al., Nat. Rev.
  • COPD chronic obstructive pulmonary disease
  • PDE4 inhibitors are encoded by four genes that encode approximately 25 different isoforms.
  • members of the PDE4 family are classified into four categories: (i) long isoforms (“longforms”), which possess both of the regulatory upstream conserved region 1 (UCR1) and upstream conserved region 2 (UCR2) domains; (ii) short forms (“shortforms”), which lack UCR1; (iii) supershort forms, which both lack UCR1 and have a truncated UCR2; and (iv) dead-short forms, which lack both UCR1 and UCR2 as well as have a truncated catalytic unit that renders them catalytically inactive.
  • longforms which possess both of the regulatory upstream conserved region 1 (UCR1) and upstream conserved region 2 (UCR2) domains
  • short forms (“shortforms”), which lack UCR1
  • supershort forms which both lack UCR1 and have a truncated UCR2
  • dead-short forms which lack both UCR1 and UCR2 as well as have a truncated
  • PDE4 shortforms are also upregulated in response to chronic PDE4 inhibition in the treatment of COPD. Susuki-Miyata et al., Proc. Natl. Acad. Sci. U.S.A.2015, 112, E1800-8. Therefore, there is a need for small molecule modulators specific to a PDE4 isoform. Li et al., Front. Pharmacol.2018, 9, 1048; Peng et al., J. Med. Chem.2022, 63, 10594-617.
  • R 1 and R 2 are: (i) R 1 is –L–R e ; and R 2 is (i) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; (ii) –C(O)R 1a , –C(O)OR 1a , –C(O)NR 1b R 1c
  • a pharmaceutical composition comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a phosphodiesterase 4 (PDE4) in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • PDE4 phosphodiesterase 4
  • a method of treating, preventing, or ameliorating one or more symptoms of an inflammatory disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating one or more symptoms of cancer in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inhibiting the activity of a PDE4 comprising contacting the PDE4 with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inducing degradation of a PDE4 comprising contacting the PDE4 with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • FIG.1 is an immunoblot showing the degradation of PDE4D and PDE4B isoforms in A549 cells treated with PDE4 degrader A001 for 24 h. Nerandomilast was used as a control (Ctrl), demonstrating that a PDE4 inhibitor by itself did not induce PDE4 protein degradation.
  • FIG.2 shows the effects of PDE4 degrader A001 on PDE4D longforms and shortforms. ****p ⁇ 0.0001.
  • FIG.3 shows the effects of PDE4 degrader A001 on PDE4B longforms and shortforms.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • patient e.g., cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
  • the terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
  • the terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
  • contacting or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo.
  • a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule.
  • a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell.
  • the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.
  • therapeutically effective amount or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • terapéuticaally effective amount or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a biological molecule e.g., a protein, enzyme, RNA, or DNA
  • IC50 or “EC50” refers to an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such a response.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • linear C 1-6 and branched C 3-6 alkyl groups are also referred as “lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).
  • alkylene and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally substituted with one or more substituents Q as described herein.
  • C 1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C 1-30 ), 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • linear C 1-6 and branched C 3-6 alkanediyl groups are also referred as “lower alkanediyl.”
  • alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane-1,1-diyl and ethane-1,2- diyl), propanediyl (including all isomeric forms, e.g., propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomeric forms, e.g., butane-1,1-diyl, butane-1,2- diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane-1,
  • substituted alkanediyl groups include, but are not limited to, –C(O)CH 2 –, –C(O)(CH 2 ) 2 –, –C(O)(CH 2 ) 3 –, –C(O)(CH 2 ) 4 –, –C(O)(CH 2 ) 5 –, –C(O)(CH 2 ) 6 –, –C(O)(CH 2 ) 7 –, –C(O)(CH 2 ) 8 –, –C(O)(CH 2 ) 9 –, –C(O)(CH 2 ) 10 –, –C(O)CH 2 C(O)–, –C(O)(CH 2 ) 2 C(O)–, –C(O)(CH 2 ) 3 C(O)–, –C(O)(CH 2 ) 4 C(O)–, or –C(O)(CH 2 ) 5 C(O)–.
  • heteroalkyl refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N.
  • the heteroalkyl is optionally substituted with one or more substituents Q as described herein.
  • C 1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • linear C 1-6 and branched C 3-6 heteroalkyl groups are also referred as “lower heteroalkyl.”
  • heteroalkyl groups include, but are not limited to, –OCH 3 , –OCH 2 CH 3 , –CH 2 OCH 3 , –NHCH 3 , –ONHCH 3 , –NHOCH 3 , –SCH 3 , –CH 2 NHCH 2 CH 3 , and –NHCH 2 CH 2 CH 3 .
  • substituted heteroalkyl groups include, but are not limited to, –CH 2 NHC(O)CH 3 and –NHC(O)CH 2 CH 3 .
  • heteroalkylene and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N.
  • the heteroalkylene is optionally substituted with one or more substituents Q as described herein.
  • C 1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • linear C 1-6 and branched C 3-6 heteroalkylene groups are also referred as “lower heteroalkylene.”
  • heteroalkylene groups include, but are not limited to, –CH 2 O–, –CH 2 CH 2 O–, –CH 2 CH 2 CH 2 O–, –(CH 2 ) 4 O–, –(CH 2 ) 5 O–, –(CH 2 ) 6 O–, –(CH 2 )7O–, –(CH 2 )8O–, –(CH 2 )9O–, –(CH 2 )10O—, –CH 2 OCH 2 –, –CH 2 CH 2 O–, –(CH 2 CH 2 O) 2 –, –(CH 2 CH 2 O) 3 –, –(CH 2 CH 2 O) 4 –, –(CH 2 CH 2 O) 5 –, –CH 2 NH—, –CH 2 NHCH 2 –, –CH 2 CH 2 NH–, –
  • substituted heteroalkylene groups include, but are not limited to, –C(O)CH 2 O–, –C(O)(CH 2 ) 2 O–, –C(O)CH 2 CH 2 CH 2 O–, –C(O)CH 2 CH 2 CH 2 CH 2 O–, –C(O)(CH 2 ) 5 O–, –C(O)(CH 2 ) 6 O–, –C(O)(CH 2 ) 7 O–, –C(O)(CH 2 ) 8 O–, –C(O)(CH 2 ) 9 O–, –C(O)(CH 2 ) 10 O–, –C(O)CH 2 OCH 2 CH 2 O–, –C(O)CH 2 O(CH 2 CH 2 O) 2 –, –C(O)CH 2 O(CH 2 CH 2 O) 3 –, –C(O)CH 2 O(CH 2 CH 2 O) 4 , –C(O)CH 2 O(CH 2 CH 2 O)
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s).
  • the alkenyl is optionally substituted with one or more substituents Q as described herein.
  • alkenyl embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “ ” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C 2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g., buten- 1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).
  • alkenylene and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s).
  • alkenediyl is optionally substituted with one or more substituents Q as described herein.
  • alkenediyl embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C 2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g., ethene-1,1- diyl and ethene-1,2-diyl), propenediyl (including all isomeric forms, e.g., 1-propene-1,1-diyl, 1- propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomeric forms, e.g., 1- butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomeric forms, e
  • heteroalkenylene and “heteroalkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain.
  • the heteroalkenylene is optionally substituted with one or more substituents Q as described herein.
  • heteroalkenylene embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C 2-6 heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carbon- carbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein.
  • C 2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4 -20 ), 4 to 15 (C4 -15 ), 4 to 10 (C 4-10 ), or 4 to 6 (C 4-6 ) carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (–C ⁇ CH), propynyl (including all isomeric forms, e.g., 1-propynyl (–C ⁇ CCH 3 ) and propargyl (–CH 2 C ⁇ CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn- 1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).
  • alkynylene and alkynediyl are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s).
  • An alkynylene group does not contain a carbon-carbon double bond.
  • the alkynediyl is optionally substituted with one or more substituents Q as described herein.
  • C 2-6 alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ), or 4 to 6 (C 4- 6) carbon atoms.
  • alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), butynediyl (including all isomeric forms, e.g., 1-butyne-1,3-diyl, 1-butyne-1,4-diyl, and 2- butyne-1,1-diyl), pentynediyl (including all isomeric forms, e.g., 1-pentyne-1,3-diyl, 1-pentyne- 1,4-diyl, and 2-pentyne-1,1-diyl), and hexynediyl (including all isomeric forms, e.g., 1-hexyne- 1,3-diyl, 1-
  • heteroalkynylene and “heteroalkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s), and which contains one or more heteroatoms in its main chain, each independently selected from O, S, and N.
  • a heteroalkynylene group does not contain a carbon-carbon double bond.
  • the heteroalkynylene is optionally substituted with one or more substituents Q as described herein.
  • C 2-6 heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the heteroalkynylene is a linear divalent hydrocarbon radical of 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2- 6 ) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 (C4 -15 ), 4 to 10 (C4 -10 ), or 4 to 6 (C4 -6 ) carbon atoms.
  • heteroalkynylene groups include, but are not limited to, –C ⁇ CCH 2 O–, –C ⁇ CCH 2 S–, or –C ⁇ CCH 2 NH–.
  • cycloalkyl refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein.
  • the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group.
  • the cycloalkyl has from 3 to 20 (C 3-20 ), from 3 to 15 (C 3-15 ), from 3 to 10 (C 3-10 ), or from 3 to 7 (C 3-7 ) carbon atoms.
  • the cycloalkyl is monocyclic.
  • the cycloalkyl is bicyclic.
  • the cycloalkyl is tricyclic.
  • the cycloalkyl is polycyclic.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.
  • cycloalkylene and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein.
  • cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups.
  • the cycloalkanediyl has from 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), from 3 to 15 (C 3-15 ), from 3 to 10 (C 3-10 ), or from 3 to 7 (C 3-7 ) carbon atoms.
  • cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane-1,1-diyl, cyclo
  • aryl refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C 6-20 ), from 6 to 15 (C 6-15 ), or from 6 to 10 (C6 -10 ) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • the aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • the aryl is monocyclic.
  • the aryl is bicyclic.
  • the aryl is tricyclic.
  • the aryl is polycyclic.
  • the aryl is optionally substituted with one or more substituents Q as described herein.
  • arylene and “arenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic hydrocarbon ring.
  • the arylene has from 6 to 20 (C6 -20 ), from 6 to 15 (C6 -15 ), or from 6 to 10 (C6 -10 ) ring atoms.
  • arylene groups include, but are not limited to, phenylene (including all isomeric forms, e.g., phen-1,2-diyl, phen-1,3-diyl, and phen-1,4-diyl), naphthylene (including all isomeric forms, e.g., naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorenylene (including all isomeric forms, e.g., fluoren-1,2-diyl, fluoren-1,3-diyl, and fluoren-1,8-diyl), azulenylene (including all isomeric forms, e.g., azulen-1,2-diyl, azulen-1,3-diyl, and azulen-1,8- diyl), anthrylene (including all isomeric forms, e.g., an
  • Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth-1,2-diyl and dihydronaphth-1,8-diyl), indenylene (including all isomeric forms, e.g., inden-1,2-diyl, inden-1,5-diyl, and inden-1,7-diyl), indanylene (including all isomeric forms, e.g., indan-1,2-diyl, indan-1,5-diyl, and indan-1,7-diyl), or tetrahydronaphthylene (tetralinylene) (including all isomeric forms, e.g., tetrahydronaphth-1,2- diyl, te
  • arylene is optionally substituted with one or more substituents Q as described herein.
  • the term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7 -30 ), from 7 to 20 (C 7-20 ), or from 7 to 16 (C 7-16 ) carbon atoms.
  • aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2- phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2- phenylpropyl, and 3-phenylpropyl).
  • the aralkyl is optionally substituted with one or more substituents Q as described herein.
  • the term “aralkylene” or “arylalkylene” refers to a divalent alkyl group substituted with one or more aryl groups.
  • the aralkylene has from 7 to 30 (C 7-30 ), from 7 to 20 (C 7-20 ), or from 7 to 16 (C 7-16 ) carbon atoms.
  • aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethdiyl), phenylethylene (including all isomeric forms, e.g., 2-phenyl-ethan-1,1-diyl and 2-phenyl-ethan-1,2-diyl), and phenylpropylene (including all isomeric forms, e.g., 3-phenyl- propan-1,1-diyl, 3-phenyl-propan-1,2-diyl, and 3-phenyl-propan-1,3-diyl).
  • the aralkylene is optionally substituted with one or more substituents Q as described herein.
  • heteroaryl refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring.
  • heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • the heteroaryl is monocyclic.
  • heteroaryl groups examples include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • the heteroaryl is bicyclic.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridinyl, imidazo[4,5- b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothi
  • the heteroaryl is tricyclic.
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7- phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl is optionally substituted with one or more substituents Q as described herein.
  • the terms “heteroarylene” and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N.
  • the heteroarylene group is not bonded to the rest of a molecule via its nonaromatic heterocyclic ring.
  • Each ring of a heteroarylene group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrroldiyl, thiadiazoldiyl, thiazoldiyl, thiendiyl, tetrazoldiyl, triazinediyl, and triazoldiyl.
  • bicyclic heteroarylene groups include, but are not limited to, benzofurandiyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadiazoldiyl, benzothiazoldiyl, benzothiendiyl, benzotriazoldiyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g., furo[2,3-b]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2-b]pyridindiyl, furo[3,2-c]- pyridindiyl, furo[3,4-b]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridindiyl,
  • tricyclic heteroarylene groups include, but are not limited to, acridindiyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5-phenanthrolindiyl, 1,6- phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl.
  • heteroarylene is optionally substituted with one or more substituents Q as described herein.
  • heterocyclyl or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non- aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydro- benzisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4- dihydrobenzo[c][1,2]-oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydro- pyranyl, dihydropyrazoly
  • heterocyclylene refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms.
  • the heterocyclylene group For a heterocyclylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclylene group has at least one bond to the rest of a molecule via its nonaromatic heterocyclic ring.
  • the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclylene groups include, but are not limited to, azepindiyl, benzodioxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazindiyl, 3,4-dihydrobenzo[c][1,2]oxazindiyl, and 3,4-dihydrobenzo[d][1,2]oxazindiyl), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydroisoindold
  • the heterocyclylene is optionally substituted with one or more substituents Q as described herein.
  • halogen refers to fluoro, chloro, bromo, and/or iodo.
  • each Q a is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)R e , –C(O)OR e , –C(O)NR f R g , –C(O)SR e , –C(NR e )NR f R g , –C(S)R e , –C(S)OR e , –C(S)NR f R g , –OR e , –OC(O)R e
  • optically active and ”enantiomerically active refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
  • an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. [0050] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the compound, R and S.
  • isotopically enriched refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35
  • an isotopically enriched compound is in a stable form, that is, non-radioactive.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur- 33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), and iodine-127 ( 127 I).
  • an isotopically enriched compound is in an unstable form, that is, radioactive.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 Cl), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I), and iodine-131 ( 131 I).
  • any hydrogen can be 2 H, as example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, or any oxygen can be 18 O, as example, where feasible according to the judgment of one of ordinary skill in the art.
  • isotopic enrichment refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope (e.g., for protium or hydrogen-1) of the element.
  • isotopic enrichment factor refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.
  • hydrogen or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium ( 1 H), deuterium ( 2 H or D), and tritium ( 3 H), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%.
  • Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.
  • the term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average.
  • carbon refers to the composition of naturally occurring carbon isotopes, which include carbon-12 ( 12 C) and carbon-13 ( 13 C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.
  • carbon-13 enrichment or “ 13 C enrichment” refers to the percentage of incorporation of carbon-13 at a given position in a molecule in the place of carbon.
  • carbon-13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon-13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average.
  • when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
  • substantially pure and substantially homogeneous mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • substantially pure or substantially homogeneous refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods.
  • a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable.
  • the complex or aggregate is in a crystalline form.
  • the complex or aggregate is in a noncrystalline form.
  • the solvent is water
  • the solvate is a hydrate.
  • examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
  • an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof” has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a diastereomer,
  • a compound of Formula (II) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R e , A, E, L, and a are each as defined herein.
  • a compound of Formula (III) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R e , A, E, L, and a are each as defined herein.
  • A is a bond.
  • A in any one of Formulae (I) to (III), A is bridged, fused, or spiro C 4-10 cycloalkylene, each optionally substituted with one, two, or three substituents Q.
  • A in any one of Formulae (I) to (III), A is heterocyclylene, optionally substituted with one or more substituents Q.
  • A in any one of Formulae (I) to (III), A is monocyclic heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A in any one of Formulae (I) to (III), A is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (III), A is 3-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (III), A is 4-membered heterocyclylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (III), A is 5-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is 6- membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is 7-membered heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is azetidindiyl, piperidindiyl, or piperazindiyl, each optionally substituted with one, two, or three substituents Q.
  • A is azetidin-1,3-diyl, piperidin-1-4-diyl, or piperazin-1,4-diyl, each optionally substituted with one, two, or three substituents Q.
  • A is bicyclic heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is bridged, fused, or spiro heterocyclylene, each optionally substituted with one, two, or three substituents Q.
  • A is bridged heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is fused heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is spiro heterocyclylene, optionally substituted with one, two, or three substituents Q.
  • A is 3,9-diazaspiro[5.5]undecandiyl, optionally substituted with one, two, or three substituents Q.
  • A is 3,9- diazaspiro[5.5]undecan-3,9-diyl, optionally substituted with one, two, or three substituents Q.
  • a compound of Formula (IV) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R e , E, L, and a are each as defined herein.
  • a compound of Formula (V) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R e , E, L, and a are each as defined herein.
  • a compound of Formula (VI) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: U is C(R 4 ) or N; R 4 is hydrogen or R 4a ; each R 4a is independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(O
  • a compound of Formula (VII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R 4a , R e , E, L, a, b, c, and d are each as defined herein.
  • E is a bond.
  • E in any one of Formulae (I) to (VII), E is C 6-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is phendiyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is phen-1,4-diyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is bicyclic C8-14 arylene, optionally substituted with one, two, or three substituents Q.
  • E in any one of Formulae (I) to (VII), E is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is monocyclic heteroarylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is 5- or 6- membered heteroarylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is 5-membered heteroarylene, optionally substituted with one, two, or three substituents Q.
  • E in any one of Formulae (I) to (VII), E is 6-membered heteroarylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is pyridindiyl or pyrimidindiyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is pyridin-2,5-diyl or pyrimidin- 2,5-diyl, each optionally substituted with one, two, or three substituents Q.
  • E in any one of Formulae (I) to (VII), E is bicyclic heteroarylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (VII), E is 5,5-fused heteroarylene, optionally substituted with one, two, or three substituents Q.
  • E is 5,6-fused heteroarylene, optionally substituted with one, two, or three substituents Q.
  • E is 6,6-fused heteroarylene, optionally substituted with one, two, or three substituents Q.
  • a compound of Formula (VIII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R e , L, and a are each as defined herein.
  • a compound of Formula (IX) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R e , L, and a are each as defined herein.
  • a compound of Formula (X) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R e , L, U, a, b, c, and d are each as defined herein.
  • a compound of Formula (XI) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R 4a , R e , L, U, a, b, c, and d are each as defined herein.
  • a compound of Formula (XII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: X and Y are each independently C(R 5 ) or N; each R 5 is independently hydrogen or R 5a ; each R 5a is independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or
  • a compound of Formula (XIII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R 4a , R 5a , R e , L, U, X, Y, a, b, c, d, and e are each as defined herein.
  • a compound of Formula (XIV) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R 5a , R e , L, U, X, Y, a, b, c, d, and e are each as defined herein.
  • a compound of Formula (XV) is provided herein:
  • the sulfoxide group of the compound in any one of Formulae (I) to (XV), is in the S-configuration.
  • a compound of Formula (XVII) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R e , L, and a are each as defined herein.
  • a compound of Formula (XVIII) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4 , R e , L, U, a, b, c, and d are each as defined herein.
  • a compound of Formula (XIX) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R 4 , R e , L, U, a, b, c, and d are each as defined herein.
  • a compound of Formula (XX) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4 , R 5 , R e , L, U, X, Y, a, b, c, d, and e are each as defined herein.
  • a compound of Formula (XXI) is a compound of Formula (XXI):
  • R 1 , R 3 , R 4 , R 5 , R e , L, U, X, Y, a, b, c, d, and e are each as defined herein.
  • a compound of Formula (XXII) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4 , R 5 , R e , L, U, X, Y, a, b, c, d, and e are each as defined herein.
  • a compound of Formula (XXIII) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R 4 , R 5 , R e , L, U, X, Y, a, b, c, d, and e are each as defined herein.
  • R 1 is hydrogen.
  • R 1 is deuterium.
  • R 1 is cyano. In certain embodiments, in any one of the formulae described herein, R 1 is halo. In certain embodiments, in any one of the formulae described herein, R 1 is fluoro, chloro, or bromo. In certain embodiments, in any one of the formulae described herein, R 1 is nitro. [0093] In certain embodiments, in any one of the formulae described herein, R 1 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
  • R 1 is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R 1 is C 2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 1 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is C 6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is C 7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 1 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is heterocyclyl, optionally substituted with one or more substituents Q. [0094] In certain embodiments, in any one of the formulae described herein, R 1 is –C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –C(O)OR 1a , wherein R 1a is as defined herein.
  • R 1 is –C(O)OR 1a , wherein R 1a is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is methoxycarbonyl. In certain embodiments, in any one of the formulae described herein, R 1 is –C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –C(O)SR 1a , wherein R 1a is as defined herein.
  • R 1 is –C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 1 is –C(S)R 1a , wherein R 1a is as defined herein.
  • R 1 is –C(S)OR 1a , wherein R 1a is as defined herein.
  • R 1 is –C(S)NR 1b R 1c , wherein R 1b and R 1c are each defined herein.
  • R 1 is –OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is hydroxyl. In certain embodiments, in any one of the formulae described herein, R 1 is C 1-6 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is methoxy. In certain embodiments, in any one of the formulae described herein, R 1 is –OC(O)R 1a , wherein R 1a is as defined herein.
  • R 1 is –OC(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –OC(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –OC(O)SR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –OC(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 1 is –OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –OC(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –OS(O)R 1a , wherein R 1a is as defined herein.
  • R 1 is –OS(O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –OS(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –OS(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. [0096] In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 1 is –NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1a C(O)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 1 is –NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1a C(NR 1d )NR 1b R 1c , wherein R 1a , R 1b , R 1c , and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1a C(S)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 1 is –NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1a C(S)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 1 is –NR 1a S(O) 2 R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1a S(O)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –NR 1a S(O) 2 NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 1 is –SR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –S(O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 1 is –S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 1 is –S(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 1 is (i) cyano or halo; (ii) C 1-6 alkyl or C 1-6 heteroalkyl, each optionally substituted with one or more substituents Q; or (iii) –C(O)OR 1a or –OR 1a , wherein each R 1a is as defined herein.
  • R 1 is cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, isopropyl, methoxycarbonyl, hydroxyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R 1 is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 1 is chloro. [0099] In certain embodiments, in any one of the formulae described herein, R 2 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is C 1-6 alkyl substituted with hydroxyl.
  • R 2 is 1-hydroxy-3-methylbut-2-yl or 1-hydroxylpent-2-yl. In certain embodiments, in any one of the formulae described herein, R 2 is C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is C 2-6 alkynyl, optionally substituted with one or more substituents Q.
  • R 2 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is monocyclic C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more substituents Q.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with hydroxylmethyl.
  • R 2 is 1-methylcyclobutyl, 1-(2-hydroxylprop-2-yl)cyclopropyl, 1-hydroxymethyl- cyclopropyl, or 1-hydroxymethylcyclobutyl.
  • R 2 is bicyclic C4 -10 cycloalkyl, optionally substituted with one or more substituents Q.
  • R 2 is bridged, fused, or spiro C 4-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is bridged C5 -10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is fused C 4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is spiro C4 -10 cycloalkyl, optionally substituted with one or more substituents Q.
  • R 2 is bicyclo[1.1.1]pentan-1-yl. [00101] In certain embodiments, in any one of the formulae described herein, R 2 is C 6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is phenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is 3- fluorophenyl. In certain embodiments, in any one of the formulae described herein, R 2 is C 7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 2 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is bicyclic heteroaryl, optionally substituted with one or more substituents Q.
  • R 2 is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q.
  • R 2 is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 2 is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.
  • R 2 is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q.
  • R 2 is 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is 6-membered heterocyclyl, optionally substituted with one or more substituents Q.
  • R 2 is 7-membered heterocyclyl, optionally substituted with one or more substituents Q.
  • R 2 is thietanyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, or thianyl, each optionally substituted with one or more substituents Q.
  • R 2 is thietan-3-yl, pyrrolidin-3-yl, tetrahydropyran-4- yl, piperidin-3-yl, or thian-4-yl, each optionally substituted with one or more substituents Q.
  • R 2 is 1,1-dioxothietan-3-yl, 1- methoxycarbonyl-pyrrolidin-3-yl, tetrahydropyran-4-yl, 1-methoxycarbonylpiperidin-3-yl, 1- methyl-2-oxo-piperidin-5-yl, or 1,1-dioxothian-4-yl.
  • R 2 is bicyclic heterocyclyl, optionally substituted with one or more substituents Q.
  • R 2 is bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2 is spiro heterocyclyl, optionally substituted with one or more substituents Q.
  • R 2 is –C(O)R 1a , wherein R 1a is as defined herein.
  • R 2 is –C(O)OR 1a , wherein R 1a is as defined herein.
  • R 2 is –C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 2 is –C(O)SR 1a , wherein R 1a is as defined herein.
  • R 2 is –C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 2 is –C(S)R 1a , wherein R 1a is as defined herein.
  • R 2 is –C(S)OR 1a , wherein R 1a is as defined herein.
  • R 2 is –C(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 2 is –S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 2 is –S(O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 2 is –S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 2 is –S(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 2 is C 1-6 alkyl, C 1-6 heteroalkyl, C 3-10 cycloalkyl, C 6-14 aryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
  • R 2 is C 1-6 alkyl, C 1-6 heteroalkyl, C 3-10 cycloalkyl, or heterocyclyl, each optionally substituted with one or more substituents Q.
  • R 2 is 1-hydroxy-3-methylbut-2-yl, 1-hydroxylpent-2-yl, 1-methylcyclobutyl, 1- (2-hydroxylprop-2-yl)cyclopropyl, 1-hydroxymethylcyclopropyl, 1-hydroxymethylcyclobutyl, bicyclo[1.1.1]pentan-1-yl, 3-fluorophenyl, 1,1-dioxothietan-3-yl, 1-methoxycarbonylpyrrolidin- 3-yl, tetrahydropyran-4-yl, 1-methoxycarbonylpiperidin-3-yl, 1-methyl-2-oxopiperidin-5-yl, or 1,1-dioxothian-4-yl.
  • R 2 is 1-hydroxymethylcyclopropyl or 1-hydroxymethylcyclobutyl. In certain embodiments, in any one of the formulae described herein, R 2 is 1-hydroxymethylcyclobutyl.
  • R 3 is deuterium. In certain embodiments, in any one of the formulae described herein, R 3 is cyano. In certain embodiments, in any one of the formulae described herein, R 3 is halo. In certain embodiments, in any one of the formulae described herein, R 3 is fluoro, chloro, or bromo. In certain embodiments, in any one of the formulae described herein, R 3 is nitro.
  • R 3 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R 3 is C 2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 3 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is C 6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is C 7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 3 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is heterocyclyl, optionally substituted with one or more substituents Q. [00108] In certain embodiments, in any one of the formulae described herein, R 3 is –C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –C(O)OR 1a , wherein R 1a is as defined herein.
  • R 3 is –C(O)OR 1a , wherein R 1a is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is –C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –C(O)SR 1a , wherein R 1a is as defined herein.
  • R 3 is –C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 3 is –C(S)R 1a , wherein R 1a is as defined herein.
  • R 3 is –C(S)OR 1a , wherein R 1a is as defined herein.
  • R 3 is –C(S)NR 1b R 1c , wherein R 1b and R 1c are each defined herein.
  • R 3 is –OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is hydroxyl. In certain embodiments, in any one of the formulae described herein, R 3 is C 1-6 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is methoxy. In certain embodiments, in any one of the formulae described herein, R 3 is –OC(O)R 1a , wherein R 1a is as defined herein.
  • R 3 is –OC(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is —OC(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –OC(O)SR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –OC(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 3 is –OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is —OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –OC(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –OS(O)R 1a , wherein R 1a is as defined herein.
  • R 3 is –OS(O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –OS(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –OS(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. [00110] In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 3 is –NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1a C(O)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 3 is –NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1a C(NR 1d )NR 1b R 1c , wherein R 1a , R 1b , R 1c , and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1a C(S)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3 is –NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1a C(S)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3 is –NR 1a S(O) 2 R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1a S(O)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –NR 1a S(O) 2 NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 3 is –SR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is —S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –S(O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3 is –S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 3 is –S(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 4 is hydrogen.
  • R 4 is R 4a , which is as defined herein.
  • R 4 is –C(O)OR 1a , wherein R 1a is as defined herein.
  • R 4 is –C(O)OR 1a , wherein R 1a is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4 is methoxycarbonyl. [00113] In certain embodiments, in any one of the formulae described herein, R 4a is deuterium. In certain embodiments, in any one of the formulae described herein, R 4a is cyano. In certain embodiments, in any one of the formulae described herein, R 4a is halo. In certain embodiments, in any one of the formulae described herein, R 4a is fluoro, chloro, or bromo.
  • R 4a is nitro.
  • R 4a is C 1-6 alkyl, optionally substituted with one or more substituents Q.
  • R 4a is methyl, optionally substituted with one or more substituents Q.
  • R 4a is C 1-6 heteroalkyl, optionally substituted with one or more substituents Q.
  • R 4a is trifluoromethyl.
  • R 4a is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is C 6-14 aryl, optionally substituted with one or more substituents Q.
  • R 4a is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is heterocyclyl, optionally substituted with one or more substituents Q. [00115] In certain embodiments, in any one of the formulae described herein, R 4a is –C(O)R 1a , wherein R 1a is as defined herein.
  • R 4a is –C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –C(O)OR 1a , wherein R 1a is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is –C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –C(O)SR 1a , wherein R 1a is as defined herein.
  • R 4a is –C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 4a is –C(S)R 1a , wherein R 1a is as defined herein.
  • R 4a is –C(S)OR 1a , wherein R 1a is as defined herein.
  • R 4a is –C(S)NR 1b R 1c , wherein R 1b and R 1c are each defined herein. [00116] In certain embodiments, in any one of the formulae described herein, R 4a is –OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is hydroxyl. In certain embodiments, in any one of the formulae described herein, R 4a is C 1-6 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is methoxy.
  • R 4a is –OC(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –OC(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –OC(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 4a is –OC(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 4a is –OC(S)R 1a , wherein R 1a is as defined herein.
  • R 4a is –OC(S)OR 1a , wherein R 1a is as defined herein.
  • R 4a is –OC(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 4a is –OS(O)R 1a , wherein R 1a is as defined herein.
  • R 4a is –OS(O) 2 R 1a , wherein R 1a is as defined herein.
  • R 4a is –OS(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 4a is –OS(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. [00117] In certain embodiments, in any one of the formulae described herein, R 4a is –NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is –NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –NR 1a C(O)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is –NR 1a C(NR 1d )NR 1b R 1c , wherein R 1a , R 1b , R 1c , and R 1d are each as defined herein.
  • R 4a is –NR 1a C(S)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is –NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is –NR 1a C(S)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 4a is –NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is –NR 1a S(O) 2 R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is –NR 1a S(O)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –NR 1a S(O) 2 NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. [00118] In certain embodiments, in any one of the formulae described herein, R 4a is –SR 1a , wherein R 1a is as defined herein.
  • R 4a is –S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –S(O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is –S(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 5 is hydrogen. In certain embodiments, in any one of the formulae described herein, R 5 is R 5a , which is as defined herein. [00120] In certain embodiments, in any one of the formulae described herein, R 5a is deuterium. In certain embodiments, in any one of the formulae described herein, R 5a is cyano. In certain embodiments, in any one of the formulae described herein, R 5a is halo. In certain embodiments, in any one of the formulae described herein, R 5a is fluoro, chloro, or bromo. In certain embodiments, in any one of the formulae described herein, R 5a is nitro.
  • R 5a is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 5a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 5a is C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 5a is trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R 5a is C 2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 5a is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 5a is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 5a is C 6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 5a is C 7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 5a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 5a is heterocyclyl, optionally substituted with one or more substituents Q. [00122] In certain embodiments, in any one of the formulae described herein, R 5a is –C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –C(O)OR 1a , wherein R 1a is as defined herein.
  • R 5a is –C(O)OR 1a , wherein R 1a is C 1-6 alkyl, optionally substituted with one or more substituents Q.
  • R 5a is –C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 5a is –C(O)SR 1a , wherein R 1a is as defined herein.
  • R 5a is –C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 5a is –C(S)R 1a , wherein R 1a is as defined herein.
  • R 5a is –C(S)OR 1a , wherein R 1a is as defined herein.
  • R 5a is –C(S)NR 1b R 1c , wherein R 1b and R 1c are each defined herein. [00123] In certain embodiments, in any one of the formulae described herein, R 5a is –OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is hydroxyl. In certain embodiments, in any one of the formulae described herein, R 5a is C 1-6 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is methoxy.
  • R 5a is –OC(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –OC(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –OC(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 5a is –OC(NR 1a )NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 5a is –OC(S)R 1a , wherein R 1a is as defined herein.
  • R 5a is –OC(S)OR 1a , wherein R 1a is as defined herein.
  • R 5a is –OC(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 5a is –OS(O)R 1a , wherein R 1a is as defined herein.
  • R 5a is –OS(O) 2 R 1a , wherein R 1a is as defined herein.
  • R 5a is –OS(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • R 5a is –OS(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. [00124] In certain embodiments, in any one of the formulae described herein, R 5a is –NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 5a is –NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 5a is –NR 1a C(O)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 5a is –NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 5a is –NR 1a C(NR 1d )NR 1b R 1c , wherein R 1a , R 1b , R 1c , and R 1d are each as defined herein.
  • R 5a is –NR 1a C(S)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 5a is –NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 5a is –NR 1a C(S)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R 5a is –NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 5a is –NR 1a S(O) 2 R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 5a is –NR 1a S(O)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –NR 1a S(O) 2 NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein. [00125] In certain embodiments, in any one of the formulae described herein, R 5a is –SR 1a , wherein R 1a is as defined herein.
  • R 5a is –S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –S(O) 2 R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 5a is –S(O) 2 NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.
  • U is C(R 4 ), wherein R 4 is as defined herein. In certain embodiments, in any one of the formulae described herein, U is CH. In certain embodiments, in any one of the formulae described herein, U is C(R 4 ), wherein R 4 is –C(O)OR 1a and R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, U is C(R 4 ), wherein R 4 is –C(O)OR 1a and R 1a is C 1-6 alkyl, optionally substituted with one or more substituents Q.
  • U is C(R 4 ), wherein R 4 is methoxycarbonyl. In certain embodiments, in any one of the formulae described herein, U is N.
  • X is C(R 5 ), wherein R 5 is as defined herein. In certain embodiments, in any one of the formulae described herein, X is CH. In certain embodiments, in any one of the formulae described herein, X is N. [00128] In certain embodiments, in any one of the formulae described herein, Y is C(R 5 ), wherein R 5 is as defined herein.
  • Y is CH. In certain embodiments, in any one of the formulae described herein, Y is N. [00129] In certain embodiments, in any one of the formulae described herein, X and Y are each independently C(R 5 ), wherein R 5 is as defined herein. In certain embodiments, in any one of the formulae described herein, X and Y are each CH. In certain embodiments, in any one of the formulae described herein, X is C(R 5 ), wherein R 5 is as defined herein; and Y is N. In certain embodiments, in any one of the formulae described herein, X is CH and Y is N.
  • X and Y are each N.
  • a is an integer of 0. In certain embodiments, in any one of the formulae described herein, a is an integer of 1. In certain embodiments, in any one of the formulae described herein, a is an integer of 2. In certain embodiments, in any one of the formulae described herein, a is an integer of 3. In certain embodiments, in any one of the formulae described herein, a is an integer of 4. [00131] In certain embodiments, in any one of the formulae described herein, b is an integer of 0.
  • b is an integer of 1. In certain embodiments, in any one of the formulae described herein, b is an integer of 2. In certain embodiments, in any one of the formulae described herein, b is an integer of 3. In certain embodiments, in any one of the formulae described herein, b is an integer of 4. In certain embodiments, in any one of the formulae described herein, b is an integer of 5. In certain embodiments, in any one of the formulae described herein, b is an integer of 6. In certain embodiments, in any one of the formulae described herein, b is an integer of 7. In certain embodiments, in any one of the formulae described herein, b is an integer of 8.
  • c is an integer of 0. In certain embodiments, in any one of the formulae described herein, c is an integer of 1. In certain embodiments, in any one of the formulae described herein, c is an integer of 2. [00133] In certain embodiments, in any one of the formulae described herein, d is an integer of 0. In certain embodiments, in any one of the formulae described herein, d is an integer of 1. In certain embodiments, in any one of the formulae described herein, d is an integer of 2. [00134] In certain embodiments, in any one of the formulae described herein, c and d are each an integer of 0.
  • c and d are each an integer of 1.
  • U is C(R 4 ), wherein R 4 is as defined herein; and c and d are each an integer of 0.
  • U is CH; and c and d are each an integer of 0.
  • U is C(R 4 ), wherein R 4 is as defined herein; and c and d are each an integer of 1.
  • U is C(R 4 ), wherein R 4 is –C(O)OR 1a and R 1a is as defined herein; and c and d are each an integer of 1.
  • U is C(R 4 ), wherein R 4 is –C(O)OR 1a and R 1a is C 1-6 alkyl, optionally substituted with one or more substituents Q; c and d are each an integer of 1.
  • U is C(R 4 ), wherein R 4 is methoxycarbonyl; c and d are each an integer of 1.
  • U is CH; and c and d are each an integer of 1. In certain embodiments, in any one of the formulae described herein, U is N; and c and d are each an integer of 1. [00136] In certain embodiments, in any one of the formulae described herein, e is an integer of 0. In certain embodiments, in any one of the formulae described herein, e is an integer of 1. In certain embodiments, in any one of the formulae described herein, e is an integer of 2.
  • R e is a moiety of an E3 ubiquitin ligase ligand that binds to an E3 ubiquitin ligase reversibly.
  • R e is a moiety of an E3 ubiquitin ligase ligand that binds to an E3 ubiquitin ligase irreversibly.
  • R e is a moiety of a cereblon (CRBN) E3 ligand.
  • R e is a moiety of a CRBN E3 ligand that binds to an E3 ubiquitin ligase reversibly.
  • R e is a moiety of a CRBN E3 ligand that binds to an E3 ubiquitin ligase irreversibly.
  • R e is a moiety having the structure of Formula (EI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein: A e is a bond, –O–, –N(R 1b )–, –S–, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, C 2-6 heteroalkenylene, C 2-6 alkynylene, C 2-6 heteroalkynylene, C 3-10 cycloalkylene, C 6-14
  • R e is a moiety having the structure of Formula (EII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein: each R e4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(O)R 1a , –C(O)OR 1a , –C(O)NR
  • R e is a moiety having the structure of Formula (EIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e3 is hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EIV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e3 is hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e3 is hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EVI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A e , E e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • EVI Formula
  • R e is a moiety having the structure of Formula (EVII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e3 is hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EVIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein. In one embodiment, R e3 is hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EIX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A e , E e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e3 is hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EXI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e3 is hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EXII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A e , E e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EXIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e3 is hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EXIV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , E e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e3 is hydrogen or fluoro.
  • each E e is O. In certain embodiments, in any one of Formulae (EI) to (EXIV), two E e are each O and one E e is S. In certain embodiments, in any one of Formulae (EI) to (EXIV), one E e is O and two E e are each S. In certain embodiments, in any one of Formulae (EI) to (EXIV), each E e is S.
  • R e is a moiety having the structure of Formula (EXV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein: R e5 is (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; or (iii) –C(O)R 1a , –C(O)OR 1a , –C(O)
  • R e is a moiety having the structure of Formula (EXVI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXVII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXVIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXIX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e4 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e4 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e4 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein: Y e is a bond, C 1-6 alkylene, –O–, –S–, –S(O)–, –S(O2)–, or –N(R e6 )–; R e6 is hydrogen or C 1-6 alkyl; and A e , R e2 , R e4 , X e , m, and n are each as defined herein.
  • Formula (EXXII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a
  • R e is a moiety having the structure of Formula (EXXIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e4 , X e , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXIV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXVI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXVII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e4 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXVIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e4 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXIX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e4 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , R e6 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXXI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , R e6 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXXII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , R e6 , m, and n are each as defined herein.
  • a e is a bond, –O–, –N(R 1b )–, C 2-6 alkynylene, heterocyclylene, C 1-6 heteroalkylene-C 6-14 arylene, or C 2-6 alkynylene-heterocyclylene, where each heteroalkylene, alkynylene, arylene, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; wherein R 1b is as defined herein; Z, if present, is –CH 2 – or –C(O)–; m is an integer of 0, 1, or 2; R e1 , if present, is hydrogen; R e2 is hydrogen; and R e3 , if present, is independently hydrogen or fluoro.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidindiyl, piperazindiyl, (phendiyl)oxymethanediyl, or (piperidindiyl)ethynediyl;
  • Z if present, is –CH 2 – or –C(O)–;
  • m is an integer of 0, 1, or 2;
  • R e1 if present, is hydrogen;
  • R e2 is hydrogen; and
  • R e3 if present, is independently hydrogen or fluoro.
  • a e is a bond, –NH–, piperidin-1,3-diyl, piperidin-1,4-diyl, piperaz-1,4-diyl, (phen-1,4-diyl)oxymethanediyl, or (piperidin-1,4-diyl)ethynediyl;
  • Z if present, is –CH 2 – or –C(O)–;
  • m is an integer of 0, 1, or 2;
  • R e1 if present, is hydrogen;
  • R e2 is hydrogen; and
  • R e3 if present, is independently hydrogen or fluoro.
  • R e is a moiety having the structure of Formula (EXXXIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein: R e7 and R e8 are each independently (i) hydrogen, deuterium, or halo; or (ii) C 1-6 alkyl, optionally substituted with one or more substituents Q; and R e9a , R e9b , R e9c , R e9d , and R e9e are each independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C
  • R e7 and R e8 are each independently (i) hydrogen, deuterium, or halo; or (ii) C 1-6 alkyl, optionally substituted with one or more substituents Q; and R e9a , R e9b , R e9c , R e9d , and R e9e are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) –OR 1a , wherein R 1a is as defined herein.
  • R e7 and R e8 are each independently (i) hydrogen, deuterium, or halo; or (ii) C 1-6 alkyl, optionally substituted with one or more substituents Q; and R e9a , R e9b , R e9c , R e9d , and R e9e are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C 1-6 alkoxy, optionally substituted with one or more substituents Q.
  • R e7 and R e8 are each independently hydrogen, deuterium, fluoro, methyl, or trifluoromethyl; and R e9a , R e9b , R e9c , R e9d , and R e9e are each independently hydrogen, deuterium, cyano, fluoro, chloro, bromo, nitro, or methoxy.
  • R e is a moiety having the structure of Formula (EXXXIV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein: R e10a , R e10b , R e10c , and R e10d are each independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) –C(
  • R e10a , R e10b , R e10c , and R e10d are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) –OR 1a , wherein R 1a is as defined herein; and R e11 , R e12 , R e13 , and R e14 are each independently (i) hydrogen, deuterium, or halo; or (ii) C 1-6 alkyl, optionally substituted with one or more substituents Q.
  • R e10a , R e10b , R e10c , and R e10d are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C 1-6 alkoxy, optionally substituted with one or more substituents Q; and R e11 , R e12 , R e13 , and R e14 are each independently (i) hydrogen, deuterium, or halo; or (ii) C 1-6 alkyl, optionally substituted with one or more substituents Q.
  • R e10a , R e10b , R e10c , and R e10d are each independently hydrogen, deuterium, cyano, fluoro, chloro, bromo, nitro, or methoxy; and R e11 , R e12 , R e13 , and R e14 are each independently hydrogen, deuterium, fluoro, methyl, or trifluoromethyl; and [00184]
  • R e is a moiety having the structure of Formula (EI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXXIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of:
  • R e is a moiety having the structure of: , or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e is as defined herein.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidindiyl, piperazindiyl, (phendiyl)oxymethanediyl, or (piperidindiyl)- ethynediyl.
  • a e is a bond.
  • a e is –O–.
  • a e is —NH–.
  • a e is ethynediyl. In yet another embodiment, in any one of Formulae E1 to E11, A e is piperidindiyl. In yet another embodiment, in any one of Formulae E1 to E11, A e is piperazindiyl. In yet another embodiment, in any one of Formulae E1 to E11, A e is (phendiyl)oxymethanediyl. In still another embodiment, in any one of Formulae E1 to E11, A e is (piperidindiyl)ethynediyl.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidin-1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, (phen-1,4-diyl)- oxymethanediyl, or (piperidin-1,4-diyl)ethynediyl.
  • a e is piperidin-1,3-diyl.
  • a e is piperidin-1,4-diyl. In yet another embodiment, in any one of Formulae E1 to E11, A e is piperazin-1,4-diyl. In yet another embodiment, in any one of Formulae E1 to E11, A e is (phen-1,4-diyl)oxymethanediyl. In still another embodiment, in any one of Formulae E1 to E11, A e is (piperidin-1,4-diyl)ethynediyl. [00192] In certain embodiments, in any one of the formulae described herein, R e is a moiety having the structure of:
  • R e is a moiety having the structure of:
  • R e is a moiety having the structure of: ; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A E is as defined herein.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidindiyl, piperazindiyl, (phendiyl)oxymethanediyl, or (piperidindiyl)ethynediyl.
  • a e is a bond.
  • a e is –O–.
  • a e is —NH–.
  • a e is ethynediyl.
  • a e is piperidindiyl. In yet another embodiment, in Formula E12 or E13, A e is piperazindiyl. In yet another embodiment, in Formula E12 or E13, A e is (phendiyl)oxymethanediyl. In still another embodiment, in Formula E12 or E13, A e is (piperidindiyl)ethynediyl.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidin-1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, (phen-1,4-diyl)oxy- methanediyl, or (piperidin-1,4-diyl)ethynediyl.
  • a e is piperidin-1,3-diyl.
  • a e is piperidin-1,4- diyl.
  • a e is piperazin-1,4-diyl. In yet another embodiment, in Formula E12 or E13, A e is (phen-1,4-diyl)oxy-methanediyl. In still another embodiment, in Formula E12 or E13, A e is (piperidin-1,4-diyl)ethynediyl.
  • R e is a moiety having the structure of Formula E12, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E13, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of: ; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e is as defined herein.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidindiyl, piperazindiyl, or (phendiyl)oxymethanediyl.
  • a e is a bond.
  • a e is –O–. In yet another embodiment, in Formula E14 or E15, A e is –NH–. In yet another embodiment, in Formula E14 or E15, A e is ethynediyl. In yet another embodiment, in Formula E14 or E15, A e is piperidindiyl. In yet another embodiment, in Formula E14 or E15, A e is piperazindiyl. In still another embodiment, in Formula E14 or E15, A e is (phendiyl)oxy- methanediyl.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidin-1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, or (phen-1,4-diyl)oxy- methanediyl.
  • a e is piperidin-1,3-diyl.
  • a e is piperidin-1,4-diyl.
  • a e is piperazin-1,4-diyl.
  • a e is (phen-1,4-diyl)oxymethanediyl.
  • R e is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e is as defined herein.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidindiyl, piperazindiyl, or (phendiyl)oxymethanediyl.
  • a e is a bond.
  • a e is –O–. In yet another embodiment, in any one of Formulae E16 to E21, A e is –NH–. In yet another embodiment, in any one of Formulae E16 to E21, A e is ethynediyl. In yet another embodiment, in any one of Formulae E16 to E21, A e is piperidindiyl. In yet another embodiment, in any one of Formulae E16 to E21, A e is piperazindiyl. In still another embodiment, in any one of Formulae E16 to E21, A e is (phendiyl)oxymethanediyl.
  • a e is a bond, –O–, –NH–, ethynediyl, piperidin-1,3-diyl, piperidin-1,4-diyl, piperazin-1,4-diyl, or (phen-1,4-diyl)- oxymethanediyl.
  • a e is piperidin- 1,3-diyl.
  • a e is piperidin-1,4- diyl.
  • a e is piperazin-1,4-diyl. In still another embodiment, in any one of Formulae E16 to E21, A e is (phen-1,4-diyl)oxy- methanediyl. [00206] In certain embodiments, in any one of the formulae described herein, R e is a moiety having the structure of:
  • R e is a moiety having the structure of: or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of: or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of: or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • provided herein is a compound of Formula (XXIV):
  • R 2 , R 3 , R 4a , R 5a , R e1 , R e2 , R e3 , A e , E e , L, U, X, Y, Z, a, b, c, d, e, and m are each as defined herein.
  • a compound of Formula (XXV) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R 5a , R e1 , R e2 , R e3 , A e , E e , L, U, X, Y, Z, a, b, c, d, e, and m are each as defined herein.
  • a compound of Formula (XXVI) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R 5a , R e1 , R e2 , R e4 , R e5 , A e , L, U, X, Y, a, b, c, d, e, m, and n are each as defined herein.
  • a compound of Formula (XXVII) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R 5a , R e1 , R e2 , R e4 , A e , L, U, X, Y, a, b, c, d, e, m, and n are each as defined herein.
  • a compound of Formula (XXVIII) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R 5a , R e1 , R e2 , R e4 , A e , L, U, X, Y, a, b, c, d, e, m, and n are each as defined herein.
  • a compound of Formula (XXIX) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R 5a , R e2 , R e4 , A e , L, U, X, Y, a, b, c, d, e, m, and n are each as defined herein.
  • a compound of Formula (XXX) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R 5a , R e2 , R e4 , A e , L, U, X, Y, a, b, c, d, e, m, and n are each as defined herein.
  • a compound of Formula (XXXI) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R 4a , R 5a , R e2 , R e4 , A e , L, U, X, Y, a, b, c, d, e, m, and n are each as defined herein.
  • a compound of Formula (XXXII) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R e7 , R e8 , R e9a , R e9b , R e9c , R e9d , R e9e , L, and a are each as defined herein.
  • a compound of Formula (XXXIII) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R e7 , R e8 , R e9a , R e9b , R e9c , R e9d , R e9e , L, U, a, b, c, and d are each as defined herein.
  • a compound of Formula (XXXIV) or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 2 , R 3 , R 4a , R 5a , R e7 , R e8 , R e9a , R e9b , R e9c , R e9d , R e9e , L, U, X, Y, a, b, c, d, and e are each as defined herein.
  • a compound of Formula (XXXV) is a compound of Formula (XXXV):
  • a e is a bond, –NH–, piperidin-1,3-diyl, piperidin-1,4-diyl, piperaz-1,4-diyl, (phen-1,4-diyl)oxymethanediyl, or (piperidin-1,4-diyl)ethynediyl.
  • a e is a bond.
  • a e is –NH–.
  • a e is piperidin-1,3- diyl.
  • a e is piperidin-1,4- diyl. In certain embodiments, in any one of the formulae described herein, A e is piperaz-1,4- diyl. In certain embodiments, in any one of the formulae described herein, A e is (phen-1,4-diyl)- oxymethanediyl. In certain embodiments, in any one of the formulae described herein, A e is (piperidin-1,4-diyl)ethynediyl. [00222] In certain embodiments, in any one of the formulae described herein, each E e is O.
  • E e in any one of the formulae described herein, two E e are each O and one E e is S. In certain embodiments, in any one of the formulae described herein, one E e is O and two E e are each S. In certain embodiments, in any one of the formulae described herein, each E e is S. [00223] In certain embodiments, in any one of the formulae described herein, Z is –CH 2 –. In certain embodiments, in any one of the formulae described herein, Z is –C(O)–. [00224] In certain embodiments, in any one of the formulae described herein, R e1 is hydrogen, fluoro, or methyl.
  • R e1 is hydrogen.
  • R e2 is hydrogen.
  • R e3 is hydrogen or halo.
  • R e3 is hydrogen, fluoro, or chloro.
  • R e3 is hydrogen.
  • R e3 is fluoro.
  • R e5 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e5 is methyl.
  • m is an integer of 0 or 1. In certain embodiments, in any one of the formulae described herein, m is an integer of 0. In certain embodiments, in any one of the formulae described herein, m is an integer of 1. [00229] In certain embodiments, in any one of the formulae described herein, n is an integer of 0.
  • R e7 is hydrogen or fluoro. In certain embodiments, in any one of the formulae described herein, R e7 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e7 is fluoro. [00231] In certain embodiments, in any one of the formulae described herein, R e8 is hydrogen or fluoro. In certain embodiments, in any one of the formulae described herein, R e8 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e8 is fluoro. [00232] In certain embodiments, in any one of the formulae described herein, R e9a is hydrogen or methoxy.
  • R e9a is hydrogen. In certain embodiments, in any one of the formulae described herein, R e9a is methoxy. [00233] In certain embodiments, in any one of the formulae described herein, R e9b is hydrogen or methoxy. In certain embodiments, in any one of the formulae described herein, R e9b is hydrogen. In certain embodiments, in any one of the formulae described herein, R e9b is methoxy. [00234] In certain embodiments, in any one of the formulae described herein, R e9c is hydrogen or methoxy. In certain embodiments, in any one of the formulae described herein, R e9c is hydrogen.
  • R e9c is methoxy.
  • R e9d is hydrogen or methoxy. In certain embodiments, in any one of the formulae described herein, R e9d is hydrogen. In certain embodiments, in any one of the formulae described herein, R e9d is methoxy. [00236] In certain embodiments, in any one of the formulae described herein, R e9e is hydrogen or methoxy. In certain embodiments, in any one of the formulae described herein, R e9e is hydrogen. In certain embodiments, in any one of the formulae described herein, R e9e is methoxy.
  • R e9a , R e9b , R e9c , R e9d , and R e9e are hydrogen; and one of R e9a , R e9b , R e9c , R e9d , and R e9e is methoxy.
  • R e9a , R e9b , R e9c , R e9d , and R e9e are hydrogen; and two of R e9a , R e9b , R e9c , R e9d , and R e9e are methoxy.
  • R e9a , R e9b , R e9c , R e9d , and R e9e are hydrogen; and three of R e9a , R e9b , R e9c , R e9d , and R e9e are methoxy.
  • R e10a is hydrogen or methoxy.
  • R e10a is hydrogen.
  • R e10a is methoxy.
  • R e10b is hydrogen or methoxy. In certain embodiments, in any one of the formulae described herein, R e10b is hydrogen. In certain embodiments, in any one of the formulae described herein, R e10b is methoxy. [00240] In certain embodiments, in any one of the formulae described herein, R e10c is hydrogen or methoxy. In certain embodiments, in any one of the formulae described herein, R e10c is hydrogen. In certain embodiments, in any one of the formulae described herein, R e10c is methoxy.
  • R e10d is hydrogen or methoxy. In certain embodiments, in any one of the formulae described herein, R e10d is hydrogen. In certain embodiments, in any one of the formulae described herein, R e10d is methoxy. [00242] In certain embodiments, in any one of the formulae described herein, three of R e10a , R e10b , R e10c , and R e10d are hydrogen; and one of R e10a , R e10b , R e10c , and R e10d is methoxy.
  • R e10a , R e10b , R e10c , and R e10d are hydrogen; and two of R e10a , R e10b , R e10c , and R e10d are methoxy.
  • R e11 is hydrogen or fluoro. In certain embodiments, in any one of the formulae described herein, R e11 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e11 is fluoro.
  • R e12 is hydrogen or fluoro. In certain embodiments, in any one of the formulae described herein, R e12 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e12 is fluoro. [00245] In certain embodiments, in any one of the formulae described herein, R e13 is hydrogen or fluoro. In certain embodiments, in any one of the formulae described herein, R e13 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e13 is fluoro. [00246] In certain embodiments, in any one of the formulae described herein, R e14 is hydrogen or fluoro.
  • R e14 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e14 is fluoro. [00247] In certain embodiments, in any one of the formulae described herein, U is C(H) or N. In certain embodiments, in any one of the formulae described herein, U is C(H). In certain embodiments, in any one of the formulae described herein, U is N. [00248] In certain embodiments, in any one of the formulae described herein, b is an integer of 0. [00249] In certain embodiments, in any one of the formulae described herein, c is an integer of 0.
  • c is an integer of 1.
  • d is an integer of 0. In certain embodiments, in any one of the formulae described herein, d is an integer of 1.
  • U is C(H) or N; b is an integer of 0 or 1; and c and d are each an integer of 0 or 1. In certain embodiments, in any one of the formulae described herein, U is C(H) or N; b is an integer of 0; and c and d are each an integer of 0.
  • U is C(H) or N; b is an integer of 0; and c and d are each an integer of 1.
  • U is C(H) or N; b is an integer of 0; and c and d are each an integer of 0.
  • U is C(H); b is an integer of 0; and c and d are each an integer of 0.
  • U is N; b is an integer of 0; and c and d are each an integer of 0.
  • U is C(H); b is an integer of 0; and c and d are each an integer of 1. In certain embodiments, in any one of the formulae described herein, U is N; b is an integer of 0; and c and d are each an integer of 1. [00253] In certain embodiments, in any one of the formulae described herein, X is C(H) or N. In certain embodiments, in any one of the formulae described herein, X is C(H). In certain embodiments, in any one of the formulae described herein, X is N. [00254] In certain embodiments, in any one of the formulae described herein, Y is C(H) or N.
  • Y is C(H). In certain embodiments, in any one of the formulae described herein, Y is N. [00255] In certain embodiments, in any one of the formulae described herein, e is an integer of 0. [00256] In certain embodiments, in any one of the formulae described herein, X and Y are each independently C(H) or N; and e is an integer of 0. In certain embodiments, in any one of the formulae described herein, X and Y are C(H) or N; and e is an integer of 0. In certain embodiments, in any one of the formulae described herein, X is C(H); Y is N; and e is an integer of 0.
  • L is a linker having the structure of –Z k –(R k –Z k )z–, wherein: each R k is independently C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, C 3-10 cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Z k is independently a bond, –C(O)–, –C(O)O–, –C(O)NR 1b –, –C(O)S–, –C(NR 1a )NR 1b –, –C(S)–, –C(S)O—,
  • each R k is independently C 1-10 alkylene, C 2-10 alkynylene, C 3-10 cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Z k is independently a bond, –C(O)–, –C(O)NR 1b –, –C(NR 1a )NR 1b –, –O–, –OC(O)NR 1b –, –NR 1b –, –NR 1a C(O)NR 1b –, –NR 1a C(NR 1d )NR 1b –, –NR 1a S(O)NR 1b –, –NR 1a S(O)NR 1b –, –NR 1a S(O) 2 NR 1b –, –S–, –S(O)–, –S(O) 2 –, –S(
  • each R k is independently C 1-10 alkylene, C 2-10 alkynylene, C 3-10 cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Z k is independently a bond, –C(O)–, –C(O)NR 1b –, –O–, –OC(O)NR 1b –, –NR 1b –, –NR 1a C(O)NR 1b –, –NR 1a C(NR 1d )NR 1b –, or –S–; and z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; where each R 1a , R 1b , and R 1d is as defined herein.
  • each R k is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, ethynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, phendiyl, pyrazoldiyl, imidazoldiyl, tetrazoldiyl, pyrimidindiyl, 5,6,7,8,9,10-hexahydrocycloocta[d]-pyridazindiyl, aze
  • each R k is independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane- 1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, ethyne-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane- 1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,3- diyl, cycloheptane-1,4-d
  • L is: wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–. [00263] In certain embodiments, in any one of the formulae described herein, L is: , wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–. [00264] In certain embodiments, in any one of the formulae described herein, L is: wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–.
  • L is: wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–; and wherein each amino (NH) group is optionally substituted with methyl.
  • L is: , wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–; and wherein each amino (NH) group is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–; and wherein each amino (NH) group is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–. [00270] In certain embodiments, in any one of the formulae described herein, L is:
  • each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: ; wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–.
  • L is:
  • each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is:
  • each A k is independently a bond, –O–, –NH–, or –N(CH 3 )–.
  • L is:
  • L is:
  • a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon-14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to, 15 N for nitrogen; 17 O or 18 O for oxygen, and 34 S, 35 S, or 36 S for sulfur.
  • a compound provided herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 50, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000.
  • an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope.
  • the maximum isotopic enrichment factor is different for different isotopes.
  • a compound provided herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about
  • the deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
  • at least one of the atoms of a compound provided herein, as specified as deuterium-enriched has deuterium enrichment of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • a compound provided herein is isolated or purified.
  • a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
  • the compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified.
  • a compound provided herein contains an alkenyl group
  • the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers.
  • structural isomers are interconvertible
  • the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • a compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers.
  • a compound in its (R) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its (S) form.
  • a pharmaceutically acceptable salt of a compound provided herein is a solvate.
  • a pharmaceutically acceptable salt of a compound provided herein is a hydrate.
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentis
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethyl- amino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl- glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)morpholine, methylamine, piperidine, piperazine, prop
  • a compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound and is readily convertible into the parent compound in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
  • compositions comprising a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition provided herein can be formulated in various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration.
  • the pharmaceutical composition can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra; Modified- Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008. [00299]
  • the pharmaceutical composition provided herein is formulated in a dosage form for oral administration.
  • the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration. In still another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for topical administration. [00300] The pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form.
  • a unit-dosage form refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of a unit-dosage form include, but are not limited to, an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form.
  • Examples of a multiple-dosage form include, are not limited to, a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • the pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. A.
  • oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • binders fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500®); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, Ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), VEEGUM®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pre-gelatinized starch.
  • the amount of a binder or filler in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical composition provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and VEEGUM® HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross- linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre- gelatinized starch; clays; and algins.
  • the amount of a disintegrant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical composition provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; and silica or silica gels, such as AEROSIL ® 200 and CAB-O-SIL ® .
  • a lubricant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O- SIL ® , and asbestos-free talc.
  • Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes.
  • a color lake is a combination by absorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80), and triethanolamine oleate.
  • Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, VEEGUM®, acacia, sodium carboxymethyl- cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, and sodium benzoate and alcohol.
  • Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
  • Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.
  • Suitable organic acids include, but are not limited to, citric and tartaric acid.
  • Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
  • Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
  • the pharmaceutical composition provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredient(s) from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • the tablet dosage forms can be prepared from an active ingredient(s) in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical composition provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient(s). [00312]
  • the pharmaceutical composition provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • a pharmaceutically acceptable liquid carrier e.g., water
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient(s), and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350- dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • These dosage forms can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • propyl gallate vitamin E
  • hydroquinone hydroxycoumarins
  • ethanolamine lecithin
  • cephalin cephalin
  • ascorbic acid malic acid
  • sorbitol phosphoric acid
  • bisulfite sodium metabisulfite
  • thiodipropionic acid and its esters and dithiocarbamates.
  • the pharmaceutical composition provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the dosage forms described herein.
  • the pharmaceutical composition provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • B. Parenteral Administration [00318] The pharmaceutical composition provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • the pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, e.g., Remington: The Science and Practice of Pharmacy, supra.
  • the pharmaceutical composition provided herein for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer’s injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer’s injection.
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium- chain triglycerides of coconut oil, and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to, EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including ⁇ - cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® ).
  • cyclodextrins including ⁇ - cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® ).
  • cyclodextrins including ⁇ - cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextr
  • the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution.
  • the pharmaceutical composition is provided as a sterile dry soluble product, including a lyophilized powder and hypodermic tablet, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical composition is provided as a ready-to-use sterile suspension.
  • the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use.
  • the pharmaceutical composition is provided as a ready-to-use sterile emulsion.
  • the pharmaceutical composition provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • the pharmaceutical composition provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical composition provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient(s) in the pharmaceutical composition to diffuse through.
  • Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross- linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • Topical Administration [00329]
  • the pharmaceutical composition provided herein can be administered topically to the skin, orifices, or mucosa.
  • the topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
  • the pharmaceutical composition provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches.
  • the topical formulations of the pharmaceutical composition provided herein can also comprise liposomes, micelles, microspheres, and nanosystems.
  • Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non- aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • the pharmaceutical composition can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM and BIOJECTTM.
  • the pharmaceutical composition provided herein can be provided in the forms of ointments, creams, and gels.
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water- soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid.
  • emulsifiable or absorption vehicles such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin
  • water-removable vehicles such as hydrophilic o
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier.
  • Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL ® ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • crosslinked acrylic acid polymers such as carbomers, carboxypolyalkylenes, and CARBOPOL ®
  • hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol
  • cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose
  • the pharmaceutical composition provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
  • These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
  • Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
  • Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with an active ingredient(s); and antioxidants as described herein, including bisulfite and sodium metabisulfite.
  • Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
  • the pharmaceutical composition provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants. [00339] The pharmaceutical composition provided herein can be administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical composition can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane.
  • atomizer such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer
  • a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane.
  • the pharmaceutical composition can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • the powder can comprise a bioadhesive agent, including chitosan or cyclodextr
  • Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of an active ingredient(s); a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the pharmaceutical composition provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less.
  • Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the pharmaceutical composition provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
  • the pharmaceutical composition provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
  • D. Modified Release [00344]
  • the pharmaceutical composition provided herein can be formulated as a modified release dosage form.
  • modified release refers to a dosage form in which the rate or place of release of an active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • the pharmaceutical composition in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s).
  • Matrix Controlled Release Devices [00345]
  • the pharmaceutical composition provided herein in a modified release dosage form can be fabricated using a matrix-controlled release device known to those skilled in the art. See, e.g., Takada et al.
  • the pharmaceutical composition provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum Ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose
  • the pharmaceutical composition provided herein is formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • the pharmaceutical composition provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression. 2.
  • the pharmaceutical composition provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • an osmotic controlled release device including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.”
  • Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic mono
  • PEO polyethylene oxide
  • PEG polyethylene
  • the other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, ed
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEM TM EZ can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No.5,798,119.
  • Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core.
  • delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.5,612,059 and 5,698,220.
  • the total amount of the active ingredient(s) released and the release rate can substantially be modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • the pharmaceutical composition in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.
  • the pharmaceutical composition provided herein is formulated as an AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, e.g., U.S. Pat. No.5,612,059 and WO 2002/17918.
  • the AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • the pharmaceutical composition provided herein is formulated as an ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers. 3.
  • the pharmaceutical composition provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ m to about 3 mm, about 50 ⁇ m to about 2.5 mm, or from about 100 ⁇ m to about 1 mm in diameter.
  • Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry- granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores.
  • compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a PDE4 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutical
  • the disorder, disease, or condition is mediated by a PDE4 shortform. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4 longform. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4A. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4A shortform. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4A longform. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4B. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4B shortform.
  • the disorder, disease, or condition is mediated by a PDE4B longform. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4C. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4C shortform. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4C longform. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4D. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4D shortform. In certain embodiments, the disorder, disease, or condition is mediated by a PDE4D longform.
  • the disorder, disease, or condition mediated by a PDE4 is an inflammatory disease.
  • a method of treating, preventing, or ameliorating one or more symptoms of an inflammatory disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or
  • the inflammatory disease is arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet’s disease, an inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, or COPD.
  • the inflammatory disease is psoriasis.
  • the inflammatory disease is psoriatic arthritis.
  • the inflammatory disease is atopic dermatitis.
  • the inflammatory disease is contact dermatitis.
  • the disorder, disease, or condition mediated by a PDE4 is cancer.
  • a method of treating, preventing, or ameliorating one or more symptoms of cancer in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof
  • the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the subject is a mammal. In certain embodiments, the subject is a human.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 60 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 25 mg/kg/day, from about 0.1 to about 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1 to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day. In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 60 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 25 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 20 mg/kg/day.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 15 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 10 mg/kg/day. In still another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 5 mg/kg/day. [00377] It is understood that the administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m 2 /day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m 2 /day to given either the height or weight of a subject or both.
  • a dose of 1 mg/m 2 /day for a 65 kg human is approximately equal to 58 mg/kg/day.
  • a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • a compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for each route of administration.
  • a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered parenterally. In yet another embodiment, a compound provided herein is administered intravenously. In yet another embodiment, a compound provided herein is administered intramuscularly. In yet another embodiment, a compound provided herein is administered subcutaneously. In still another embodiment, a compound provided herein is administered topically.
  • a compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time.
  • a compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity.
  • a compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • the administration can be continuous, i.e., every day, or intermittently.
  • the term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals.
  • intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
  • a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
  • a compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a condition, disorder, or disease described herein.
  • the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound provided herein
  • a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject.
  • a second therapy e.g., a prophylactic or therapeutic agent
  • Triple therapy is also contemplated herein.
  • the route of administration of a compound provided herein is independent of the route of administration of a second therapy.
  • a compound provided herein is administered orally.
  • a compound provided herein is administered topically.
  • a compound provided herein is administered orally or topically, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • a compound provided herein and a second therapy are administered by the same mode of administration, orally or topically.
  • a compound provided herein is administered by one mode of administration, e.g., topically, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally.
  • a method of inhibiting the activity of a PDE4 comprising contacting the PDE4 with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inducing degradation of a PDE4 comprising contacting the PDE4 with an effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PDE4 is a PDE4 shortform.
  • the PDE4 is a PDE4 longform.
  • the PDE4 is a PDE4A.
  • the PDE4 is a PDE4A shortform. In certain embodiments, the PDE4 is a PDE4A longform. In certain embodiments, the PDE4 is a PDE4B. In certain embodiments, the PDE4 is a PDE4B shortform. In certain embodiments, the PDE4 is a PDE4B longform. In certain embodiments, the PDE4 is a PDE4C. In certain embodiments, the PDE4 is a PDE4C shortform. In certain embodiments, the PDE4 is a PDE4C longform. In certain embodiments, the PDE4 is a PDE4D. In certain embodiments, the PDE4 is a PDE4D shortform.
  • the PDE4 is a PDE4D longform.
  • a compound provided herein is specific for a PDE4 shortform.
  • a compound provided herein is specific for a PDE4 longform.
  • a compound provided herein is specific for a PDE4A.
  • a compound provided herein is specific for a PDE4A shortform.
  • a compound provided herein is specific for a PDE4A longform.
  • a compound provided herein is specific for a PDE4B.
  • a compound provided herein is specific for a PDE4B shortform.
  • a compound provided herein is specific for a PDE4B longform. In certain embodiments, a compound provided herein is specific for a PDE4C. In certain embodiments, a compound provided herein is specific for a PDE4C shortform. In certain embodiments, a compound provided herein is specific for a PDE4C longform. In certain embodiments, a compound provided herein is specific for a PDE4D. In certain embodiments, a compound provided herein is specific for a PDE4D shortform. In certain embodiments, a compound provided herein is specific for a PDE4D longform. [00390] A compound provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art.
  • kits which, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject.
  • the kit provided herein includes a container and a dosage form of a compound provided herein.
  • Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle- less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients. [00393] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • aqueous vehicles including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’s injection
  • water-miscible vehicles including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • non-aqueous vehicles including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • g grams
  • mg milligrams
  • mL milliliters
  • ⁇ L microliters
  • mM millimolar
  • ⁇ M micromolar
  • mmol millimoles
  • min minute or minutes
  • h hour or hours
  • ACN acetonitrile
  • AcOH acetic acid
  • Boc tert-butoxycarbonyl
  • DCM diichloromethane
  • DIEA or DIPEA N,N-diisopropylethylamine
  • DMF dimethylformamide
  • DMP Dess-Martin periodinane
  • DMSO dimethyl sulfoxide
  • EDCI (1-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide
  • FA formic acid
  • HOBt hydroxybenzotriazole
  • EtOAc ethyl acetate
  • HATU hexafluoride
  • Example B1 Inhibition of LPS-induced TNF- ⁇ production [00456] Normal human peripheral blood mononuclear cells (PBMCs) from a commercial source were thawed and resuspended in RPMI supplemented with 10% FBS and 1% penicillin- streptomycin. The cells (100 ⁇ L per well, 1 x 10 6 cells/mL) were plated in 96-well plates. Lipopolysaccharide (LPS) (100 ng/mL) and a compound in a serial dilution were then added to the cells in 100 ⁇ L volume of the complete media. The plates were incubated for 6 h at 37 °C/5% CO2, followed by centrifugation at 1,200 rpm for 5 min.
  • LPS Lipopolysaccharide
  • the media was decanted and the plates were washed with 200 ⁇ L of the complete media. The plates were then added with 100 ⁇ L of a fresh media. The wash out plates were added another 100 ⁇ L of the media + LPS. The non- wash out plates were added with 100 ⁇ L of media + LPS + the compound. The plates were incubated for 18 h at 37 °C/5% CO2. The next day, the plates were centrifuged at 1,200 rpm for 5 min. The cell culture supernatant was collected and an LPS-induced TNF- ⁇ production assay was performed using a U-PLEX Human TNF- ⁇ assay kit according to the manufacturer's instructions.
  • the A549 cells were cultured in DMEM with 2 mM L-glutamine supplemented with 10% fetal bovine serum and 1% streptomycin and penicillin at 37 °C/5% CO2.
  • the cells were plated in a 12-well plate at 100,000 cells/well. After overnight incubation, the cells were treated with nerandomilast (control) or a compound for 24 h at 37 °C/5% CO 2 . The media were then removed and the cells were washed once with 1 x cold PBS.
  • the cells were scraped on ice with 120 ⁇ L/well of a cold lysis buffer (25 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1% NP-40, 1 mM EDTA, 5% glycerol) containing a COMPLETETM EDTA-free protease inhibitor tablet. After incubation for 1 h with gentle agitation in a cold room, cellular lysates were collected by centrifugation and stored at -20 or -80 oC. [00459] The protein concentrations of the lysates were determined using the Bradford assay and all samples were equalized for protein concentration.
  • Proteins were separated by SDS/PAGE (4–12% Bis-Tris gels) and transferred onto nitrocellulose membranes for Western blotting.
  • the membranes were blocked in INTERCEPT (TBS) Blocking Buffer for 1 h at room temperature, followed by incubation with primary antibody dilution in INTERCEPT T20 (TBS) Antibody Diluent overnight at 4 °C with gentle shaking.
  • Primary antibodies used were rabbit anti-PDE4D, sheep anti-PDE4D, sheep anti-PDE4B, mouse anti-GAPDH, rabbit anti-GAPDH, mouse anti-ubiquitin, rabbit anti-phospho-(Ser/Thr) PKA substrate, rabbit anti-phospho-ERK, mouse anti-total ERK, rabbit anti-PARP1, mouse anti-Ki67, and rabbit anti-VSV-G.
  • Membranes were washed with TBST and then incubated with fluorescently labeled secondary antibodies (1:20,000) for 1 h at room temperature.
  • the secondary antibodies used were ALEXA FLUOR 680 donkey anti-goat IgG, IRDYE 680RD donkey anti-mouse IgG, IRDYE 800CW donkey anti- mouse IgG, and IRDYE 800CW donkey anti-rabbit IgG. Images were acquired using a LI-COR ODYSSEY CLX Imaging System and signals was detected at 700 and 800 nm channels. All densitometry analyses were done using Image Studio and normalized to GAPDH.
  • PDE4 inhibitor with 9-fold preference for PDE4B (an IC 50 of 10 nM) over PDE4D (an IC 50 of 91 nM), was used a control (Ctrl) to demonstrate that a PDE4 inhibitor does not induce PDE4 protein degradation by itself.
  • Herrmann et al. Front. Pharmacol.2022, 13, 838449; Richeldi et al., N. Engl. J. Med.2022, 386, 2178-87.
  • PDE4 degrader A001 unexpectedly degraded over 50% of PDE4D shortforms at 10 pM and over 50% of the PDE4B shortforms at 400 pM.
  • PDE4 degrader A001 was highly selective for PDE4 shortforms over longforms as PDE4D longforms were not significantly degraded at any of the concentrations tested, whereas PDE4B longforms were significantly degraded to less than 50% of control levels at 10 nM.
  • the PDE4 degraders provided herein, including A002, A003, A005, A011 to A016, A101 to A103, A301 to A303, A305 to A313, B002, and B101 were found to be highly selective for the degradation of PDE4 shortforms over longforms.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des agents de dégradation de protéine PDE4, par exemple, un composé de formule : (I), et des compositions pharmaceutiques associées. L'invention concerne également des procédés d'utilisation de ceux-ci pour traiter, prévenir ou atténuer un ou plusieurs symptômes d'un trouble, d'une maladie ou d'un état à médiation par un PDE4.
PCT/US2024/042843 2023-08-17 2024-08-19 Agents de dégradation de protéine pde4, compositions pharmaceutiques et applications thérapeutiques Pending WO2025038987A2 (fr)

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WO2025245178A1 (fr) * 2024-05-21 2025-11-27 Innovo Therapeutics, Inc. Agents de dégradation de protéine pak4, cstf2 ou cstf2t, compositions pharmaceutiques et applications thérapeutiques

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WO2009050236A1 (fr) * 2007-10-19 2009-04-23 Boehringer Ingelheim International Gmbh Nouveaux dérivés de pipérazino-dihydrothiénopyrimidine
WO2009050248A1 (fr) * 2007-10-19 2009-04-23 Boehringer Ingelheim International Gmbh Pipéridino-dihydrothiénopyrimidines substituées
EP2400962B1 (fr) * 2009-02-27 2017-11-08 Boehringer Ingelheim International GmbH Combinaisons de médicaments contenant des inhibiteurs PDE4 et NSAID
KR102438072B1 (ko) * 2012-01-12 2022-08-31 예일 유니버시티 E3 유비퀴틴 리가아제에 의한 표적 단백질 및 다른 폴리펩티드의 증진된 분해를 위한 화합물 및 방법
CN111712502B (zh) * 2017-12-15 2023-10-27 联合疗法公司 取代的氮杂环丁烷二氢噻吩并嘧啶类化合物及其作为磷酸二酯酶抑制剂的用途
KR20230157936A (ko) * 2020-12-14 2023-11-17 바이오테릭스, 인코포레이티드 Pde4 분해인자, 약제학적 조성물, 및 치료학적 적용

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