EP4598905A2 - Agents de dégradation doubles de bcl-xl/bcl-2 de recrutement de céréblon - Google Patents

Agents de dégradation doubles de bcl-xl/bcl-2 de recrutement de céréblon

Info

Publication number
EP4598905A2
EP4598905A2 EP23875719.9A EP23875719A EP4598905A2 EP 4598905 A2 EP4598905 A2 EP 4598905A2 EP 23875719 A EP23875719 A EP 23875719A EP 4598905 A2 EP4598905 A2 EP 4598905A2
Authority
EP
European Patent Office
Prior art keywords
substituted
unsubstituted
compound
alkylene
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23875719.9A
Other languages
German (de)
English (en)
Other versions
EP4598905A4 (fr
Inventor
Wanyi HU
Peiyi Zhang
Guangrong Zheng
Daohong Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Florida
University of Texas System
University of Florida Research Foundation Inc
University of Texas at Austin
Original Assignee
University of Florida
University of Texas System
University of Florida Research Foundation Inc
University of Texas at Austin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Florida, University of Texas System, University of Florida Research Foundation Inc, University of Texas at Austin filed Critical University of Florida
Publication of EP4598905A2 publication Critical patent/EP4598905A2/fr
Publication of EP4598905A4 publication Critical patent/EP4598905A4/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • ABT-737 (US20070072860), navitoclax (ABT-263, W02009155386), venetoclax (ABT-199, W02010138588), obatoclax (GX 15-070, W02004106328), (-)-gossypol (AT-101, W02002097053), sabutoclax (BI-97C1, W02010120943), TW-37 (W02006023778), BM-1252 (APG-1252), and A-1155463 (VV02010080503).
  • Venetoclax a selective Bcl-2 inhibitor, was approved by the FDA in 2016 for the treatment of chronic lymphocytic leukemia (CLL) with 17-p deletion. Venetoclax was designed to have high selectivity for Bcl-2 over Bcl-xL to avoid the on-target platelet toxicity (Souers et al., Nat Med 19: 202-208, 2013).
  • Platelets depend on Bcl-xL to maintain their viability, therefore dose-limiting thrombocytopenia has been observed in animals and/or humans treated with ABT- 737 (Schoenwaelder et al., Blood 118: 1663-1674, 2011), ABT-263 (Tse et al., Cancer Res 68: 3421-3428, 2008; Roberts et al., Bri J Haematol 170: 669-678, 2015), BM-1197 (Bai et al., PLoS ONE 9:e99404, 2014), or A-1155463 (Tao et al., ACS Med Chem Lett 5:1088-1093,2014), due to their inhibition of Bcl-xL.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof:
  • the compounds include a Bcl-xL and/or Bcl-2 binding moiety cereblon (CRBN) binding moiety ( linker (e.g., –L 3 –L 2 –L 1 –) connecting the Bcl- xL and/or Bcl-2 binding moiety and the CRBN binding moiety.
  • CRBN Bcl-xL and/or Bcl-2 binding moiety cereblon
  • the compounds may be Bcl-xL/Bcl-2 dual inhibitors.
  • the compounds may connect a Bcl-2 or Bcl-xL small molecule inhibitor or ligand to an E3 ligase binding moiety, such as CRBN.
  • CRBN is a protein encoded by the CRBN gene (Ensembl: ENSG00000113851).
  • CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1).
  • DDB1 DNA binding protein 1
  • CUL4A Cullin-4A
  • ROC1 regulator of cullins 1
  • the compounds may actively recruit anti-apoptotic Bcl-2 family of proteins to E3 ligase, resulting in their degradation by ubiquitin proteasome system.
  • Platelets depend on Bcl-xL protein for survival.
  • inhibition of Bcl-xL protein in platelets causes thrombocytopenia which limits the use of Bcl-xL inhibitors as cancer therapeutic agents.
  • strategies devised to minimize the on-target platelet toxicity associated with the inhibition of Bcl-xL could boost the therapeutic applications of drugs like ABT-263, a dual Bcl- 2/Bcl-xL inhibitor, in cancer.
  • the present disclosure provides compounds, pharmaceutical compositions, kits, and methods for at least selectively degrading anti-apoptotic Bcl-2 family of proteins.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a kit comprising a provided compound or pharmaceutical composition, and instructions for using the compound or pharmaceutical composition.
  • the present disclosure provides a method of degrading a Bcl-2 protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition provided herein.
  • the present disclosure provides a method of degrading a Bcl-xL protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition provided herein.
  • the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.
  • the present disclosure provides a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.
  • the present disclosure provides a method of selectively killing one or more cancer cells in a tissue or biological sample, the method comprising contacting the tissue or biological sample with an effective amount of a compound or pharmaceutical composition of the present disclosure
  • the present disclosure provides a method of selectively killing one or more cancer cells in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the present disclosure.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • the bond is a single bond
  • the dashed line is a single bond or absent
  • formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • isotopes refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.
  • range range of values
  • C 1-6 alkyl encompasses, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1– 2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1– 9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1–6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), n-dodecyl (C 12 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1–12 alkyl (such as unsubstituted C 1–6 alkyl, e.g., ⁇ CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t- Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)).
  • unsubstituted C 1–12 alkyl such as unsubstituted C 1–6 alkyl, e.g.
  • the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., – CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 20 carbon atoms (“C 1–20 haloalkyl”).
  • the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10 haloalkyl”).
  • the haloalkyl moiety has 1 to 9 carbon atoms (“C 1–9 haloalkyl”).
  • haloalkyl groups include –CHF2, ⁇ CH2F, ⁇ CF3, ⁇ CH2CF3, ⁇ CF2CF3, ⁇ CF2CF2CF3, ⁇ CCl3, ⁇ CFCl2, ⁇ CF2Cl, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC 1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1–3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12 alkenyl”).
  • an alkenyl group has 1 to 11 carbon atoms (“C 1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C 1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6 alkenyl”).
  • an alkenyl group has 1 to 5 carbon atoms (“C 1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C 1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C 1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 alkenyl”). In some embodiments, the one or more carbon-carbon double bonds is internal (such as in 2-butenyl) or terminal (such as in 1- butenyl).
  • Examples of C1–4 alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C 1–6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C1-20 alkenyl.
  • the alkenyl group is a substituted C1-20 alkenyl.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkenyl”).
  • a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkenyl”).
  • a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–7 alkenyl”).
  • a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–4 alkenyl”).
  • a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 1–3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6 alkenyl”).
  • each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.
  • the heteroalkenyl group is an unsubstituted heteroC 1–20 alkenyl.
  • the heteroalkenyl group is a substituted heteroC1–20 alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”).
  • an alkynyl group has 1 to 10 carbon atoms (“C 1-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C 1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C 1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”).
  • an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C 1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1 alkynyl”). In some embodiments, the one or more carbon-carbon triple bonds is internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 1-4 alkynyl groups include, without limitation, methylidynyl (C 1 ), ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C4), and the like.
  • Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
  • the alkynyl group is an unsubstituted C 1-20 alkynyl.
  • the alkynyl group is a substituted C 1-20 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkynyl”).
  • a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkynyl”).
  • a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkynyl”).
  • a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC 1–4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkynyl”).
  • a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1– 6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 1–20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 1–20 alkynyl.
  • carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”).
  • a carbocyclyl group has 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”).
  • a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”).
  • Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H- indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • Exemplary C3-8 carbocyclyl groups include the aforementioned C 3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C 14 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and is saturated or contains one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C3-14 cycloalkyl.
  • the cycloalkyl group is a substituted C 3-14 cycloalkyl.
  • heterocyclyl or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”).
  • the point of attachment is a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group is either monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and is either saturated or contains one or more carbon-carbon double or triple bonds.
  • heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3– 14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3–14 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]di
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1– naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
  • the point of attachment is a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • the point of attachment is on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroe
  • each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • Oxygen protecting wherein X ⁇ , R aa , R bb , and R cc are as defined herein.
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • each oxygen protecting group is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohex
  • each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.
  • at least one sulfur atom substituent is oxo.
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.
  • a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • an anionic counterion is monovalent (e.g., including one formal negative charge).
  • An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ), NO3 – , ClO4 – , OH – , H2PO4 – , HCO3 ⁇ , HSO4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–
  • halo or “halogen” refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • hydroxyl or “hydroxy” refers to the group ⁇ OH.
  • thiol refers to the group –SH.
  • amino refers to the group ⁇ NH2.
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from ⁇ N(R bb )3 and ⁇ N(R bb )3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
  • sulfonyl refers to a group selected from –SO 2 N(R bb ) 2 , –SO 2 R aa , and – SO2OR aa , wherein R aa and R bb are as defined herein.
  • sil refers to the group –Si(R aa )3, wherein R aa is as defined herein.
  • Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances.
  • a “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base.
  • a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge).
  • Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4 alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C1-4 alkyl)4 ⁇ salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction.
  • This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds provided herein are prepared, e.g., in crystalline form.
  • the compounds provided herein are prepared, e.g., in crystalline form, and are solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • Solidvate encompasses both solution-phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound, or a salt thereof, that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound, or a salt thereof is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, in some embodiments, a hydrate of a compound, or a salt thereof, is represented, for example, by the general formula R ⁇ x H2O, wherein R is the compound, or a salt thereof, and x is a number greater than 0.
  • a given compound, or a salt thereof may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H2O) and hexahydrates (R ⁇ 6 H2O)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H2O) and hexahydrates (R ⁇ 6 H2O)
  • tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to- imine, and enamine-to-(a different enamine) tautomerizations. It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • co-crystal refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent.
  • a co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature.
  • co-crystal In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. In some embodiments, co-crystals are useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof).
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • C 1 -C 8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein are preferred.
  • composition and “formulation” are used interchangeably.
  • a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • primate e.g., cynomolgus monkey or rhesus monkey
  • commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
  • bird e.g., commercially relevant bird, such as
  • the non-human animal is a fish, reptile, or amphibian. In some embodiments, the non-human animal is a male or female at any stage of development. In some embodiments, the non-human animal is a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disease.
  • tissue refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels. In some embodiments, “tissue” is the object to which a compound, particle, and/or composition of the disclosure is delivered. In some embodiments, a tissue is an abnormal or unhealthy tissue, which may need to be treated.
  • a tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented.
  • biological sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centr
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • administered refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound provided herein, a compound useful in a provided method, or a pharmaceutical composition provided herein, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment is administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment is administered in the absence of signs or symptoms of the disease.
  • treatment is administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • prevent refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease.
  • the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.
  • An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • prophylactically effective amount can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease.
  • Bcl-2 family refers to a family consists of a number of evolutionarily- conserved proteins that share Bcl-2 homology (BH) domains.
  • the Bcl-2 family may be able to regulate apoptosis at the mitochondrion.
  • the Bcl-2 family may promote or inhibit apoptosis, or control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis.
  • MOMP mitochondrial outer membrane permeabilization
  • the Bcl-2 family is a human Bcl-2 family.
  • the term “Bcl-2” refers to a protein of the Bcl-2 family and, when in humans, is encoded by the BCL2 gene.
  • Bcl-xL refers to a protein of the Bcl-2 family and, when in humans, is encoded by the BCL2-like 1 gene.
  • a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990).
  • Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF).
  • angiogenic proteins such as growth factors (e.g., VEGF).
  • VEGF growth factors
  • neoplasm and tumor are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
  • a neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
  • a “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
  • a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
  • Exemplary benign neoplasms include lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • metastasis refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
  • a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
  • cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues.
  • the cancer may be a solid tumor.
  • the cancer may be a hematological malignancy.
  • Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordom
  • Wilms tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g.,bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • genetic disease refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and/or RNAs of the subject. In such cases, the genetic disease will be heritable if it occurs in the germline.
  • Exemplary genetic diseases include Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adreno- leukodystrophy, albinism, ablepharon-macrostomia syndrome, alagille syndrome, alkaptonuria, alpha-1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith-Wiedemann syndrome, Best disease, bipolar disorder, brachydactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia
  • inflammatory disease refers to a disease caused by, resulting from, or resulting in inflammation.
  • inflammatory disease may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non- infectious causes.
  • Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia
  • An ocular inflammatory disease includes post-surgical inflammation.
  • An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney).
  • the treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response.
  • Exemplary autoimmune diseases include glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.
  • a “hematological disease” includes a disease which affects a hematopoietic cell or tissue.
  • Hematological diseases include diseases associated with aberrant hematological content and/or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute non- lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), poly
  • Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease.
  • neurological diseases include headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro- ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions.
  • Addiction and mental illness include bipolar disorder and schizophrenia, are also included in the definition of neurological diseases.
  • neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch
  • a “painful condition” includes neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post–operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre–operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and/or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre–term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rhe
  • One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.
  • the term “metabolic disease” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof.
  • a metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and/or carbohydrates.
  • Factors affecting metabolism include the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like.
  • Examples of metabolic disorders include diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.
  • the term “psychiatric disorder” refers to a condition or disorder relating to the functioning of the brain and the cognitive processes or behavior.
  • Psychiatric disorders may be further classified based on the type of neurological disturbance affecting the mental faculties. Psychiatric disorders are expressed primarily in abnormalities of thought, feeling, emotion, and/or behavior producing either distress or impairment of function (for example, impairment of mental function such with dementia or senility).
  • the term “psychiatric disorder” is, accordingly, sometimes used interchangeably with the term “mental disorder” or the term “mental illness”.
  • a psychiatric disorder is often characterized by a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as part of normal development or culture.
  • Definitions, assessments, and classifications of mental disorders can vary, but guideline criteria listed in the International Classification of Diseases and Related Health Problems (ICD, published by the World Health Organization, WHO), or the Diagnostic and Statistical Manual of Mental Disorders (DSM, published by the American Psychiatric Association, APA) and other manuals are widely accepted by mental health professionals.
  • Individuals may be evaluated for various psychiatric disorders using criteria set forth in these and other publications accepted by medical practitioners in the field and the manifestation and severity of a psychiatric disorder may be determined in an individual using these publications. Categories of diagnoses in these schemes may include dissociative disorders, mood disorders, anxiety disorders, psychotic disorders, eating disorders, developmental disorders, personality disorders, and other categories.
  • psychiatric disorders encompass schizophrenia, delirium, attention deficit disorder (ADD), schizoaffective disorder, depression (e.g., lithium-resistant depression), mania, attention deficit disorders, drug addiction, dementia, agitation, apathy, anxiety, psychoses, personality disorders, bipolar disorders, unipolar affective disorder, obsessive-compulsive disorders, eating disorders, post-traumatic stress disorders, irritability, adolescent conduct disorder and disinhibition.
  • Some diseases classified as neurodegenerative diseases for example Alzheimer’s disease, also sometimes show aspects of psychiatric disorders as listed herein, for example disorders of memory or dementia.
  • Some neurodegenerative diseases or manifestations thereof can, accordingly, also be referred to as psychiatric disorders.
  • the state of anxiety or fear can become disordered, so that it is unusually intense or generalized over a prolonged period of time.
  • anxiety disorders include specific phobia, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder.
  • Relatively long lasting affective states can also become disordered.
  • Mood disorder involving unusually intense and sustained sadness, melancholia or despair is known as clinical depression (or major depression), and may more generally be described as emotional dysregulation. Milder but prolonged depression can be diagnosed as dysthymia.
  • Bipolar disorder involves abnormally “high” or pressured mood states, known as mania or hypomania, alternating with normal or depressed mood. Patterns of belief, language use and perception can become disordered. Psychotic disorders centrally involving this domain include schizophrenia and delusional disorder. schizoaffective disorder is a category used for individuals showing aspects of both schizophrenia and affective disorders. Schizotypy is a category used for individuals showing some of the traits associated with schizophrenia but without meeting cut-off criteria. The fundamental characteristics of a person that influence his or her cognitions, motivations, and behaviors across situations and time - can be seen as disordered due to being abnormally rigid and maladaptive.
  • Categorical schemes list a number of different personality disorders, such as those classed as eccentric (e.g., paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder), those described as dramatic or emotional (antisocial personality disorder, Borderline personality disorder, histrionic personality disorder, narcissistic personality disorder) or those seen as fear-related (avoidant personality disorder, dependent personality disorder, obsessive-compulsive personality disorder).
  • eccentric e.g., paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder
  • those described as dramatic or emotional antisocial personality disorder, Borderline personality disorder, histrionic personality disorder, narcissistic personality disorder
  • fear-related avoidant personality disorder, dependent personality disorder, obsessive-compulsive personality disorder.
  • FIGs.1A to 1C Compounds #1, #4, #11, #12, #44, #128 and #133-135 degrade Bcl-xL in a dose-dependent manner in Jurkat and Hela cells, and some of these compounds also slightly reduce Bcl-2 protein levels in both Jurkat and Hela cells. However, none of these compounds degrades Bcl-w in Hela cells.
  • FIG.1A immunoblot analysis of Bcl-xL and Bcl-2 expression in Jurkat cells after treatment with increasing concentrations of the compound as indicated for 16 hours.
  • FIG.1B immunoblot analysis of Bcl-xL and Bcl-2 expression in Hela cells after treatment with increasing concentrations of the compound as indicated for 16 hours.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof: Formula (I); wherein: R1 is –O(substituted or unsubstituted alkyl) or –N(R a )2, wherein each instance of R a is independently substituted or unsubstituted alkyl or substituted or unsubstituted carbocyclyl, or two instances of R a are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; R2 is SO2CF3 or NO2; , wherein R b is halogen or substituted or unsubstituted alkyl; each instance of R 4 is independently F, Cl, –CN, –CFH 2 , –CF 2 H,
  • R 1 is –N(R a ) 2 , wherein each instance of R a is independently substituted or unsubstituted alkyl or substituted or unsubstituted carbocyclyl. In certain embodiments, R1 is –N(R a )2, wherein at least one instance of R a is unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is –N(R a ) 2 , wherein at least one instance of R a is substituted C 1-6 alkyl. In certain embodiments, R 1 is –N(R a ) 2 , wherein at least one instance of R a is C1-6 alkyl substituted at least with –OH.
  • R1 is – N(R a )2, wherein at least one instance of R a is substituted or unsubstituted carbocyclyl. In certain embodiments, R 1 is –N(R a ) 2 , wherein at least one instance of R a is unsubstituted monocyclic saturated carbocyclyl. In certain embodiments, R1 is –N(R a )2, wherein two instances of R a are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl.
  • R1 is –N(R a )2, wherein two instances of R a are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, monocyclic heterocyclyl.
  • R 1 is –N(R a ) 2 , wherein two instances of R a are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, monocyclic heterocyclyl comprising only carbon and nitrogen atoms in the heterocyclic ring system.
  • R1 is –N(R a )2, wherein two instances of R a are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, monocyclic heterocyclyl comprising only carbon, nitrogen, and oxygen atoms in the heterocyclic ring system.
  • R1 is –N(R a )2, wherein two instances of R a are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, fused bicyclic heterocyclyl.
  • the substituted or unsubstituted, fused bicyclic heterocyclyl is substituted or unsubstituted, monocyclic heterocyclyl fused with another substituted or unsubstituted, monocyclic heterocyclyl.
  • the substituted or unsubstituted, fused bicyclic heterocyclyl is substituted or unsubstituted, monocyclic heterocyclyl fused with substituted or unsubstituted, monocyclic carbocyclyl.
  • the fused bicyclic heterocyclyl is substituted at least with halogen (e.g., F), –OH, –O(substituted or unsubstituted alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted acyl.
  • R 1 is –N(R a ) 2 , wherein two instances of R a are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, bridged bicyclic heterocyclyl.
  • the substituted or unsubstituted, bridged bicyclic heterocyclyl comprises only carbon and oxygen atoms in the bicyclic heterocyclic ring system. In certain embodiments, the substituted or unsubstituted, bridged bicyclic heterocyclyl comprises only carbon, nitrogen, and oxygen atoms in the bicyclic heterocyclic ring system. In certain embodiments, the bridged bicyclic heterocyclyl is substituted at least with halogen (e.g., F), –OH, –O(substituted or unsubstituted alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted acyl.
  • halogen e.g., F
  • the substituted or unsubstituted, spiro bicyclic heterocyclyl is substituted or unsubstituted, monocyclic heterocyclyl spiroed with substituted or unsubstituted, monocyclic carbocyclyl.
  • the substituted or unsubstituted, spiro bicyclic heterocyclyl comprises only carbon and nitrogen atoms in the bicyclic heterocyclic ring system.
  • the substituted or unsubstituted, spiro bicyclic heterocyclyl comprises only carbon and oxygen atoms in the bicyclic heterocyclic ring system.
  • L 1 is substituted or unsubstituted, C 1-11 alkylene. In certain embodiments, L1 is unsubstituted C1-2 alkylene. In certain embodiments, L1 is –CH2–. In certain embodiments, L1 is unsubstituted, C3-5 alkylene. In certain embodiments, L1 is unsubstituted C6-8 alkylene. In certain embodiments, L 1 is unsubstituted, C 9-11 alkylene.
  • L1 is –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C 1-2 alkylene)–, – (substituted or unsubstituted, C 1-2 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-2 alkylene)–, or –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C 1-2 alkylene)–, optionally wherein one or two backbone carbon atoms in each instance of the substituted or unsubstituted, C1-2 alkylene are independently replaced with –O
  • L 1 is –(substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)2–, –(substituted or unsubstituted, C 1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene) 2 – (substituted or unsubstituted, C 1 alkylene)–, –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstitute
  • each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • Each p is independently 0, 1, 2, 3, or 4.
  • Each q is independently 1, 2, or 3.
  • Each r is independently 1 or 2.
  • Each s is independently 1, 2, 3, or 4.
  • Each t is independently 1, 2, 3, 4, or 5.
  • Each u is independently 0, 1, 2, 3, 4, or 5.
  • at least one instance of R 5 is hydrogen.
  • at least one instance of R5 is substituted or unsubstituted alkyl or substituted or unsubstituted carbocyclyl.
  • each instance of R 5 is hydrogen.
  • at least one instance of R 5 is not hydrogen.
  • no instance of R 5 is hydrogen.
  • At least one instance of R5 is substituted alkyl (e.g., alkyl substituted with one or more (e.g., two or three) instances of halogen (e.g., F)). In certain embodiments, at least one instance of R 5 is unsubstituted alkyl. In certain embodiments, at least one instance of R 5 is unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of R5 is Me. In certain embodiments, at least one instance of R5 is Et, Pr, or Bu. In certain embodiments, at least one instance of R 5 is substituted C 1-6 alkyl.
  • At least one instance of R 5 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R5 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted, C 2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R5 is substituted or unsubstituted alkynyl.
  • At least one instance of R5 is substituted or unsubstituted, C 2-6 alkynyl (e.g., substituted or unsubstituted ethynyl).
  • at least one instance of R5 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits).
  • At least one instance of R5 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl.
  • at least one instance of R 5 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl).
  • At least one instance of R5 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted aryl.
  • At least one instance of R 5 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R5 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R5 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl.
  • At least one instance of R5 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, L2 is substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C 2-12 alkenylene, or substituted or unsubstituted, C 2-12 alkynylene.
  • L2 is unsubstituted, C1-2 alkylene. In certain embodiments, L2 is unsubstituted, C3-4 alkylene. In certain embodiments, L2 is unsubstituted, C5-6 alkylene. In certain embodiments, L2 is unsubstituted, C 7-9 alkylene. In certain embodiments, L 2 is unsubstituted, C 10-12 alkylene. In certain embodiments, L2 is unsubstituted C2-12 alkenylene comprising only one unsaturated CC bond in the backbone. In certain embodiments, L2 is unsubstituted C2-12 alkynylene comprising only one unsaturated CC bond in the backbone.
  • L2 is –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)–, –(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C
  • L 2 is –(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)–, – (substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1
  • L 2 is substituted or unsubstituted heterocyclylene. In certain embodiments, L2 is substituted or unsubstituted, monocyclic heterocyclylene. In certain embodiments, L2 is substituted or unsubstituted, monocyclic, 3- to 8-membered heterocyclylene. In certain embodiments, L 2 is substituted or unsubstituted, bicyclic heterocyclylene. In certain embodiments, L2 is substituted or unsubstituted, bicyclic, 5- to 14-membered heterocyclylene. In certain embodiments, L2 is , , , , ,
  • R 6 is F, Cl, –CN, –CFH 2 , –CF 2 H, –CF 3 , or –OCH 3 .
  • R6 is H.
  • L 3 is a bond.
  • L 3 is substituted or unsubstituted, C 1-13 alkylene, substituted or unsubstituted, C 2-13 alkenylene, or substituted or unsubstituted, C2-13 alkynylene.
  • L3 is unsubstituted, C1-2 alkylene.
  • L3 is unsubstituted, C3-4 alkylene.
  • L3 is unsubstituted, C 5-6 alkylene. In certain embodiments, L 3 is unsubstituted, C 7-10 alkylene. In certain embodiments, L 3 is unsubstituted, C 10-13 alkylene. In certain embodiments, L 3 is unsubstituted C 2- 13 alkenylene comprising only one unsaturated CC bond in the backbone. In certain embodiments, L 3 is unsubstituted C 2-13 alkynylene comprising only one unsaturated CC bond in the backbone.
  • L3 is substituted or unsubstituted, monocyclic heterocyclylene or substituted or unsubstituted, bicyclic heterocyclylene.
  • L3 is –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C 1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, – (substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–, –(substituted or unsubstituted or unsubstituted
  • L 3 is –(substituted or unsubstituted, C 1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)– or –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–.
  • L 3 is –(substituted or unsubstituted, monocyclic heterocyclylene)2–, –(substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene) 2 –, –(substituted or unsubstituted, C 1 alkylene)– (substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–, or –(
  • L3 is attached to the 2 or 3 position. In certain embodiments, L3 is attached to the 1 or 4 position. In certain embodiments, the compound is of the formula: Compo Numb 1
  • the compound is of the formula:
  • a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof.
  • a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
  • a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a provided compound is a mixture (e.g., a racemic mixture) of stereoisomers.
  • a provided compound is any one of Compounds 1 to 20, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is any one of Compounds 1 to 20, or a pharmaceutically acceptable salt thereof.
  • Compounds provided herein can be obtained from natural sources or made or modified made by means known in the art of organic synthesis. Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. Reaction optimization and scale-up may advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g.
  • the compounds provided herein may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers are expressly included in the present disclosure.
  • the compounds herein may also be represented in multiple tautomeric forms, in such instances, the disclosure expressly includes all tautomeric forms of the compounds provided herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure. All crystal forms and polymorphs of the compounds provided herein are expressly included in the present disclosure.
  • Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more, more preferably the compound has an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more.
  • only one enantiomer or diastereomer of a chiral compound the present disclosure provides administered to cells or a subject.
  • the compounds of the formulae herein can be synthesized using methodology similarly to that described in Chen, Q. Y.; Liu, Y.; Cai, W.; Luesch, H. Improved Total Synthesis and Biological Evaluation of Potent Apratoxin S4 Based Anticancer Agents with Differential Stability and Further Enhanced Activity. J. Med.
  • the present disclosure provides compounds which are in a salt form.
  • the salt is a pharmaceutically acceptable salt.
  • Certain specific compounds provided herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • provided herein are compounds which are in a prodrug form.
  • Prodrugs of the compounds provided herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds provided herein. Additionally, prodrugs can be converted to the compounds provided herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds provided herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Certain compounds provided herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds provided herein may exist in multiple crystalline or amorphous forms.
  • the provided compounds bind to Bcl-2 with a dissociation constant (K d ) of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 ⁇ M, between 1 and 10 ⁇ M, between 10 and 30 ⁇ M, or between 30 and 100 ⁇ M.
  • K d dissociation constant
  • the provided compounds inhibit the activity of Bcl-2 with an IC 50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 ⁇ M, between 1 and 10 ⁇ M, between 10 and 30 ⁇ M, or between 30 and 100 ⁇ M.
  • the provided compounds inhibit the production of Bcl-2 with an IC50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 ⁇ M, between 1 and 10 ⁇ M, between 10 and 30 ⁇ M, or between 30 and 100 ⁇ M.
  • the provided compounds bind to Bcl-xL with a dissociation constant (Kd) of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 ⁇ M, between 1 and 10 ⁇ M, between 10 and 30 ⁇ M, or between 30 and 100 ⁇ M.
  • Kd dissociation constant
  • the provided compounds inhibit the activity of Bcl-xL with an IC50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 ⁇ M, between 1 and 10 ⁇ M, between 10 and 30 ⁇ M, or between 30 and 100 ⁇ M.
  • the provided compounds inhibit the production of Bcl-xL with an IC 50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 ⁇ M, between 1 and 10 ⁇ M, between 10 and 30 ⁇ M, or between 30 and 100 ⁇ M.
  • the provided compounds are able to bind to both Bcl-2 and Bcl- xL.
  • the provided compounds inhibit the activity of both Bcl-2 and Bcl- xL.
  • the provided compounds inhibit the production of both Bcl-2 and Bcl-xL.
  • the selectivity (e.g., as determined by K d or IC 50 ) of the provided compounds for Bcl-2 over a different Bcl-2 family protein (e.g., Bcl-xL) is between 2 and 3, between 3 and 5, between 5 and 10, between 10 and 30, between 30 and 100, between 100 and 300, or between 300 and 1000 folds, or greater than 1000 folds.
  • the ratio of human platelet toxicity (IC50) to anticancer activity (IC50) of the compound the present disclosure provides less than that of other Bcl-2 and/or Bcl-xL inhibitors (e.g., the another Bcl-2 inhibitor and the another Bcl-xL inhibitor described herein).
  • the provided compounds may be prepared by methods known in the art, e.g., the methods described in U.S. Patent Application Publication No.2022-0169628.
  • Pharmaceutical Compositions, Kits, and Administration provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises an effective amount of the provided compound.
  • the effective amount is a therapeutically effective amount.
  • Non-limiting examples of photodynamic therapeutic agents include aminolevulinic acid, methyl aminolevulinate, retinoids (alitretinon, tamibarotene, tretinoin), and temoporfin.
  • Other antineoplastic agents include anagrelide, arsenic trioxide, asparaginase, bexarotene, bropirimine, celecoxib, chemically linked Fab, efaproxiral, etoglucid, ferruginol, lonidamide, masoprocol, miltefosine, mitoguazone, talapanel, trabectedin, and vorinostat.
  • the additional pharmaceutical agent is another Bcl-2 inhibitor.
  • Such pharmaceutical compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. Provided compounds are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the provided compounds and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarticular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intraarticular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/
  • contemplated routes are intraarticular administration, oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the exact amount of a provided compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound of the disclosure, mode of administration, and the like.
  • the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • the pharmaceutical composition described herein is administered at a dose that is below the dose at which the agent causes non-specific effects. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose.
  • the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose. Dose ranges as described herein provide guidance for the administration of provided compounds or pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • the present disclosure provide a kit comprising a provided compound or pharmaceutical composition, and instructions for using the compound or pharmaceutical composition.
  • the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition.
  • the kit further comprises a second container.
  • the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition).
  • the second container includes an additional pharmaceutical agent.
  • the kit further comprises a third container.
  • the third container includes an additional pharmaceutical agent.
  • the provided compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form.
  • the provided compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form.
  • each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.
  • the instructions are for administering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein).
  • the instructions are for contacting a biological sample or cell with the provided compound or pharmaceutical composition.
  • the instructions comprise information required by a regulatory agency, such as the U.S.
  • kits and instructions comprise prescribing information.
  • the kits and instructions provide for treating a disease in a subject in need thereof.
  • the kits and instructions provide for preventing a disease in a subject in need thereof.
  • the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof.
  • the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of Bcl-xL and/or Bcl-2in a subject or cell.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate pharmaceutical composition.
  • the present disclosure provides a method of degrading a Bcl-2 protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition provided herein.
  • the present disclosure provides a method of degrading a Bcl-xL protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition provided herein.
  • the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.
  • the present disclosure provides a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.
  • the present disclosure provides a method of selectively killing one or more cancer cells in a tissue or biological sample, the method comprising contacting the tissue or biological sample with an effective amount of a compound or pharmaceutical composition of the present disclosure
  • the present disclosure provides a method of selectively killing one or more cancer cells in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the present disclosure.
  • a composition provided herein does not appreciably kill non-cancer cells at the same concentration.
  • a composition provided herein has reduced platelet toxicity and retained or improved toxicity in cancer cells when compared to other Bcl-2 and/or Bcl-xL inhibitors.
  • the median lethal dose or LD50 of the inhibitor in non-cancer cells may be about 5 to about 50 times higher than the LD 50 of the inhibitor in cancer cells.
  • the LD 50 is the concentration of inhibitor required to kill half the cells in the cell sample.
  • the LD50 of the inhibitor in non-cancer cells may be greater than about 5, about 6, about 7, about 8, about 9 or about 10 times higher than the LD 50 of the inhibitor in cancer cells.
  • the LD 50 of the inhibitor in non-cancer cells may be greater than about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 times higher than the LD50 of the inhibitor in cancer cells.
  • the LD 50 of the inhibitor in non-cancer cells may be greater than 50 times higher than the LD 50 of the inhibitor in cancer cells.
  • the LD 50 of the inhibitor in non-cancer cells is greater than 10 times higher than the LD500 of the inhibitor in cancer cells.
  • the LD50 of the inhibitor in non-cancer cells is greater than 20 times higher than the LD 50 of the inhibitor in cancer cells.
  • the cell, tissue, biological sample, or cancer cell is in vitro.
  • the cell, tissue, biological sample, or cancer cell is in vivo.
  • the cell, tissue, or biological sample is ex vivo.
  • the cell is a cancer cell.
  • the cell is a pre-cancer cell.
  • the cell, tissue, or biological sample is in a subject.
  • the disease is cancer.
  • the cancer is a Bcl-2-mediated cancer.
  • the cancer is a Bcl-xL-mediated cancer. In certain embodiments, the cancer is a hematological malignancy. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is acute myeloid leukemia, chronic lymphocytic leukemia, or acute lymphoblastic leukemia. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is T-cell lymphoma. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the anticancer activity is measured in MOLT-4 cells. In certain embodiments, the anticancer activity is measured in RS4 cells. In some embodiments, the anticancer activity is higher in MOLT-4 cells than in RS4 cells.
  • the anticancer activity is higher in RS4 cells than in MOLT-4 cells.
  • the ratio of the anticancer activity in MOLT-4 cells to the anticancer activity in RS4 cells is between 2:1 and 5:1, between 5:1 and 10:1, between 10:1 and 30:1, between 30:1 and 100:1, between 100:1 and 300:1, or between 300:1 and 1000:1, or greater than 1000:1.
  • the ratio of the anticancer activity in RS4 cells to the anticancer activity in MOLT-4 cells is between 2:1 and 5:1, between 5:1 and 10:1, between 10:1 and 30:1, between 30:1 and 100:1, between 100:1 and 300:1, or between 300:1 and 1000:1, or greater than 1000:1.
  • the disease is an age-related disease.
  • the disease is age-related cognitive dysfunction, age-related intervertebral disc disease, age-related muscle loss, Alzheimer’s disease, amyotrophic lateral sclerosis, ataxia, AV fistulae, bone marrow transplant complication, cardiac dysfunction, cataracts, chemotherapy complication, chronic obstructive, cirrhosis, COVID-19 complication, diabetes, frailty, glaucoma, hepatic steatosis, hyperoxic lung damage, idiopathic pulmonary fibrosis, macular degeneration, MGUS, myeloma, obesity, obesity-related neuropsychiatric dysfunction, organ transplantation complication, osteoarthritis, osteoporosis, Parkinson’s disease, pre-eclampsia, primary biliary cirrhosis, progerias, prostatic hypertrophy, psoriasis, pulmonary disease, radiation complication, renal dysfunction, urinary incontinence, vascular calc
  • the subject is an animal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human aged 18 years or older. In certain embodiments, the subject is a human aged 12-18 years, exclusive. In certain embodiments, the subject is a human aged 2-12 years. In certain embodiments, the subject is a human younger than 2 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. EXAMPLES The present disclosure will now be demonstrated using specific examples that are not to be construed as limiting. Preparation of Intermediate A
  • Step 1 Synthesis of tert-butyl (R)-(4-hydroxy-1-(phenylthio)butan-2-yl)carbamate (A-2).
  • A-1 2.7 g, 6.72 mmol
  • THF/MeOH 50 mL/5 mL
  • NaBH4 1.49 g, 40.35 mmol
  • the reaction mixture was added sat. aq. NH 4 Cl and extracted with DCM.
  • the combined organic layers were washed with sat. aq. NH4Cl, then dried over Na2SO4, filtered and concentrated.
  • Step 2 Synthesis of tert-butyl (R)-(4-oxo-1-(phenylthio)butan-2-yl)carbamate (A-3). DMP (2.08 g, 4.90 mmol) was added to a solution of A-2 (1.08 g, 3.63 mmol) in EtOAc (25 mL) and stirred at room temperature for 3 hours. The resulting mixture was filtered and the filtrate was concentrated.
  • Step 3 Synthesis of tert-butyl (R)-(4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2- yl)carbamate (A-4).
  • NaBH(OAc)3 (632 mg, 2.98 mmol) was added to a solution of 1,4- oxazepane hydrochloride (410 mg, 2.98 mmol), TEA (565 ⁇ L, 4.06 mmol) and A-3 (800 mg, 2.71 mmol) in DCM (15 mL), then stirred at room temperature overnight.
  • reaction mixture was washed with sat. aq. NH 4 Cl.
  • organic layers were dried over Na 2 SO 4 , filtered and concentrated.
  • the residue was purified by flash column chromatography (50% to 100% of EtOAc in hexanes, then 0% to 10% of MeOH in DCM) to afford A-4 (920 mg, 89% yield) as a white solid.
  • Step 4 Synthesis of (R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-amine hydrochloride (A-5).4 N HCl in dioxane (10 mL) was added to a stirring solution of A-4 (730 mg, 1.92 mmol) in DCM (10 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated to afford A-5 (850 mg, quantitative yield), which was directly used in the next step.
  • Step 5 Synthesis of (R)-4-((4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (intermediate A).
  • A-6 600 mg, 1.95 mmol was added to a stirring solution of A-5 (850 mg, HCl salt) and DIPEA (2.72 mL, 15.64 mmol) in DMSO (25 mL), then stirred at room temperature overnight.
  • the precipitate was collected via filtration and washed with water.
  • the filtered cake was dried under vacuum to afford B-3 (2.0 g, 92% yield) as a white solid.
  • Step 3 Synthesis of N-((4-(((R)-4-(1,4-Oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((R)-4'-chloro-4-formyl-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (intermediate B).
  • Step 2 Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(hydroxymethyl)benzoic acid (C-3).
  • B-2 2.2 g, 6.92 mmol
  • MeOH/THF 10 mL/10 mL
  • LiOH ⁇ H2O 553 mg, 13.84 mmol
  • water 5 mL
  • the reaction mixture was concentrated to remove the organic solvents, then extracted with EtOAc.
  • the precipitate was collected via filtration and washed with water.
  • Step 3 Synthesis of tert-butyl 4-(3-(hydroxymethyl)-4- (methoxycarbonyl)phenyl)piperazine-1-carboxylate (C-4).
  • (Trimethylsilyl)diazomethane (10% in hexanes, 22.4 g, 19.64 mmol) was added dropwise to a stirring solution of C-3 (2.2 g, 6.55 mmol) in MeOH/EtOAc (50 mL/50 mL) at room temperature. After completing the addition, the resulting mixture was stirred at room temperature for an extra 30 min.
  • Step 4 Synthesis of tert-butyl 4-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperazine- 1-carboxylate (C-5). Under argon atmosphere, to a solution of C-4 (2.2 g, 6.29 mmol) in THF (60 mL) were added triphenylphosphine (2.5 g, 9.43 mmol) and carbon tetrabromide (3.1 g, 9.43 mmol). The resulting mixture was stirred at room temperature for 1 hour, then washed with water and brine.
  • Step 1 Synthesis of 4-(4-((4'-chloro-4-((4-(2-chloroacetyl)piperazin-1-yl)methyl)-4-methyl- 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1- (phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (G- 1).
  • Step 2 Synthesis of tert-butyl 4-(2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino- 1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)- 2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)piperazine-1- carboxylate (G-2).
  • Step 2 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione (Intermediate K): HCl (2 mL, 4 N HCl in dioxane) was added to a stirring solution of K-1 (150 mg, 3.39 mmol) in DCM (4 mL), then stirred at room temperature for 2 hours. The resulting mixture was concentrated and dried under vacuum to afford Intermediate K (151 mg, quantitative yield), which was directly used in the next step.
  • Step 2 General procedure for the synthesis of tert-butyl 4-(3-formyl-4- (methoxycarbonyl)phenyl)-1,4-diazepane-1-carboxylate (L-2), tert-butyl 4-(3-formyl-4- (methoxycarbonyl)phenyl)-2,6-dimethylpiperazine-1-carboxylate (M-2), tert-butyl 5-(3- formyl-4-(methoxycarbonyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (N-2) and tert-butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (P-2).
  • Step 4 General procedure for the synthesis of 3-(5-(1,4-diazepan-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride (intermediate L), 3-(5-(3,5-dimethylpiperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (intermediate M), 3-(5-(2,5- diazabicyclo[2.2.1]heptan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (intermediate N) and 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine
  • Step 2 To a solution of the tert-butyl ester intermediate from Step 1 (1.0 equiv.) in DCM was added HCl (4 N HCl in dioxane), then stirred at room temperature overnight. The reaction mixture was concentrated to afford a carboxylic acid intermediate, which was directly used in the next step.
  • Step 3 To a solution of the carboxylic acid intermediate from step 2 (1.2 equiv.) and HATU (1.5 equiv.) in DCM was added a solution of Intermediate D (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound.
  • Step 2 HCl (4 N HCl in dioxane) or TFA was added to a stirring solution of the Boc-protected amine from step 1(1.0 equiv.) in DCM. Then the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to afford the corresponding amine, which was directly used in the next step.
  • Step 3 Intermediate B (1.0 equiv.) and NaBH(OAc)3 (1.2 equiv.) were added to a solution of the amine from step 2 (2.0 equiv.) and TEA (8.0 equiv.) in DCM, then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH 4 Cl.
  • Step 1 Aldehyde (1.2 equiv.) and NaBH(OAc)3 (1.5 equiv.) were added to a solution of amine (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature overnight, then washed with water and sat. aq. NH 4 Cl. The organic layers were dried over Na2SO4, filtered and concentrated.
  • Step 2 4 N HCl in dioxane or TFA was added to a stirring solution of the product from Step 1 (1.0 equiv.) in DCM and stirred at room temperature for 1 hour. The reaction mixture was concentrated to afford the corresponding de-Boc product, which was directly used in the next step.
  • Step 3 Intermediate B (1.0 equiv.) and NaBH(OAc) 3 (1.2 equiv.) were added to a solution of the product from Step 2 (2.0 equiv.) and TEA (8.0 equiv.) in DCM, then stirred at room temperature overnight.
  • Step 3 Intermediate B (1.0 equiv.) and NaBH(OAc)3 (1.2 equiv.) were added to a solution of the product from Step 2 (2.0 equiv.) and TEA (8.0 equiv.) in DCM, then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH 4 Cl and dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound.
  • Step 1 A reaction mixture of Intermediate H (1.0 equiv.), amine (1.5 equiv.) and DIPEA (3.0 equiv.) in DMSO were stirred at 80 °C overnight. The resulting mixture was cooled to room temperature and diluted with EtOAc, then washed with water and sat. aq. NHCl 4 . The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford a carboxylic acid intermediate.
  • Step 2 To a solution of the carboxylic acid intermediate from Step 1 (1.2 equiv.) and HATU (1.5 equiv.) in DCM was added a solution of Intermediate G (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound.
  • DCM/MeOH preparative TLC
  • Step 1 A reaction mixture of Intermediate H or I (1.0 equiv.), amine or bromide (1.2 equiv.) and DIPEA (3.0 equiv.) in NMP were irradiated at 110 °C for 3 hours. The resulting mixture was diluted with EtOAc and washed with water and sat. aq. NHCl 4 . The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford the corresponding product.
  • Step 2 To a solution of the product from Step 1 (1.0 equiv.) in DCM was added HCl (4 N HCl in dioxane), then stirred at room temperature overnight. The reaction mixture was concentrated to afford a carboxylic acid intermediate, which was directly used in the next step.
  • Step 3 To a solution of 19-3 or the carboxylic acid intermediate from Step 2 (1.2 equiv.) and HATU (1.5 equiv.) in DCM was added a solution of Intermediate G, 19-2, 20-2, or 21-2 (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq.
  • Step 2 Synthesis of 3-(1-oxo-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindolin-2- l) i idi 26 di (112) HCl (1 L 4 N HCl i di ) dd d t ti i l ti of 11-1 (70 mg, 0.13 mmol) in DCM (1 mL) at room temperature.
  • Step 2 Synthesis of tert-butyl 4-(5-((5-oxopentyl)oxy)pyridin-2-yl)piperazine-1-carboxylate (22-3).
  • Step 3 Synthesis of tert-butyl 4-(5-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin 1 yl)pentyl)oxy)pyridin 2 yl)piperazine 1 carboxylate (224) 223 (35 mg crude) and NaBH(OAc) 3 (50 mg, 0.24 mmol) were added to a solution of Intermediate K (30 mg, 0.079 mmol) and TEA (55 ⁇ L, 0.4 mmol) in DCM (2 mL), then stirred at room temperature overnight.
  • Step 4 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(5-((6-(piperazin-1-yl)pyridin-3- yl)oxy)pentyl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride (22-5).
  • HCl (1 mL, 4 N HCl in dioxane) was added to a stirring solution of 22-4 (20 mg, 0.029 mmol) in DCM (1 mL) and stirred at room temperature for 2 hours.
  • Step 1 Synthesis of tert-butyl 4-(5-(5-hydroxypent-1-yn-1-yl)pyridin-2-yl)piperazine-1- carboxylate (23-2).
  • Step 3 Synthesis of tert-butyl 4-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)pent-1-yn-1-yl)pyridin-2-yl)piperazine-1-carboxylate (23-4).23-3 (41 mg, crude) and NaBH(OAc)3 (75 mg, 0.24 mmol) were added to a solution of Intermediate K (30 mg, 0.079 mmol) and TEA (55 ⁇ L, 0.4 mmol) in DCM (2 mL), then stirred at room temperature overnight.
  • Step 4 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(5-(6-(piperazin-1-yl)pyridin-3-yl)pent-4- yn-1-yl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride (23-5).
  • HCl (1 mL, 4 N HCl in dioxane) was added to a stirring solution of 23-4 (20 mg, 0.03 mmol) in DCM (1 mL) at room temperature.
  • Step 5 Synthesis of 4-(4-((4'-chloro-4-((4-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)pyridin-2-yl)piperazin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4- morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (compound #23).
  • Compound #40 was prepared by following General Procedure B: tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)but-3-yn-1-yl)piperazine-1- carboxylate (40-1) (280 mg, 38% yield).
  • Step 2 Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidine-1-carboxylate (128-2).
  • a stirring mixture of 128-1 (203 mg, 0.48 mmol), and 10% palladium on carbon (40 mg) in EtOAc/MeOH (5 mL/5 mL) was hydrogenated overnight with a hydrogen balloon. The resulting mixture was filtered through celite and the filtration was concentrated.
  • Step 3 Synthesis of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione TFA salt (128-3).4 N HCl in dioxane (0.5 mL) was added to a stirring solution of 128-2 (15 mg, 0.037 mmol) in DCM (0.5 mL), then stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 128-3 (23 mg, quantitative yield) as TFA salt, which was directly used in the next step.
  • Step 4 Synthesis of N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-chloro-4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (compound #128).
  • Compound #130 was prepared by following General Procedure C: tert-butyl 4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)piperidine-1-carboxylate (130-1) (31 mg, 85% yield).
  • Compound #131 was prepared by following General Procedure C: tert-butyl 3-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)azetidine-1-carboxylate (131-1) (25 mg, 72% yield).
  • Compound #136 was prepared by following General Procedure C: tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4-diazepan-1-yl)methyl)- 4-methylpiperidine-1-carboxylate (136-1) (24 mg, 38% yield).
  • Step 2 Synthesis of methyl 2-fluoro-4-(piperazin-1-yl)benzoate hydrochloride (137-2).4 N HCl in dioxane (5 mL) was added to a stirring solution of 137-1 (200 mg, 0.59 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours, then concentrated to afford 137-2 (195 mg, quantitative yield), which was directly used in the next step.
  • tert-Butyl 4-formylpiperidine-1-carboxylate (189 mg, 0.89 mmol) and NaBH(OAc)3 (188 mg, 0.89 mmol) were added to a solution of 137-2 (195 mg, 0.71 mmol) and TEA (789 ⁇ L, 5.67 mmol) in DCM (10 mL), then stirred at room temperature overnight. The resulting mixture was washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10% to 40% of EtOAc in hexanes) to afford 137-3 (218 mg, 85% yield in two steps).
  • Step 1 Synthesis of tert-butyl (R)-4-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (138-1).
  • 137-4 15 mg, 0.036 mmol
  • HATU 17.6 mg, 0.046 mmol
  • DCM 0.5 mL
  • Step 4 Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1- yl)benzamide hydrochloride (139-4).
  • 139-3 (12 mg, 0.023 mmol) in DCM (0.5 mL) was added 4 N HCl in dioxane (0.5 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 139-4 (10 mg, quantitative yield), which was directly used in the next step.
  • Step 2 Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (140-2). To a solution of 137-1 (100 mg, 0.246 mmol) in DCM (4 mL) was added a solution of 4 N HCl in dioxane (4 mL) and stirred at room temperature for 2 hours. The resulting mixture was concentrated to afford 140-2 (112 mg, quantitative yield), which was directly used in the next step.
  • Step 3 Synthesis of N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-chloro-4-((4-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (compound #140).
  • Compound #141 was prepared by following General Procedure C: tert-butyl 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1- yl)methyl)piperidine-1-carboxylate (141-1) (115 mg, 70% yield).
  • Example 43 Cell viability assay of senescent cells To induce senescence in WI-38 and HUVEC, cells were subjected to x-ray irradiation at 20 Gray using X-RAD 320 biological irradiator. Following between 10 to 15 days after irradiation, senescence was induced in cells, and irradiation-induced senescent cells (IR-SC) were then used for cell viability and Western blotting tests.
  • IR-SC irradiation-induced senescent cells
  • WI-38 and HUVEC cells were incubated with increasing concentrations of degraders for 72 h.
  • Cell viability was measured using PrestoBlue HS cell viability reagent.
  • the IC50 values of individual compounds were calculated with GraphPad Prism and presented in Table 1.
  • Example 44 Protein degradation assays in Jurkat, Hela and WI-38 cells Jurkat and Hela cells were incubated with increasing concentrations of test compounds for 16 h. The cells were harvested and lysed in RIPA lysis buffer supplemented with protease and phosphatase inhibitor cocktails. An equal amount of protein (20 pg/lane) was resolved on a pre- cast 4-20% SDS-PAGE gel. Proteins were subsequently transferred to NOVEX PVDF membranes by electrophoresis.
  • the membranes were blocked in blocking buffer (5% non-fat dry milk in TBS-T), and incubated with primary antibodies (at optimized concentrations) overnight at 4 °C. After three washings in TBS-T, the membranes were incubated with an appropriate FIRP-conjugated secondary antibody for 1 h at room temperature. After extensive washing for three times, the proteins of interest were detected with ECL western blotting detection reagents and recorded with autoradiography (Pierce Biotech, Rockford, IL, USA).
  • the primary antibodies for Bcl-xL (Cat #2762), Bcl-2 (Cat #2872), Bcl-w (Cat #2724) and ⁇ -actin (Cat #4970) were purchased from Cell Signaling Technology.
  • Embodiments or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claims that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.
  • certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein.
  • any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the embodiments. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any embodiment, for any reason, whether or not related to the existence of prior art. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended embodiments. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Immunology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente divulgation concerne des composés de formule (I), qui peuvent être des inhibiteurs doubles de Bcl-xL et Bcl-2. Les composés peuvent cibler et dégrader Bcl-xL et Bcl-2. La présente divulgation concerne également des compositions pharmaceutiques, des kits et des méthodes d'utilisation des composés destinés à traiter une maladie (par exemple, le cancer).<i />
EP23875719.9A 2022-10-03 2023-10-03 Agents de dégradation doubles de bcl-xl/bcl-2 de recrutement de céréblon Pending EP4598905A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263412834P 2022-10-03 2022-10-03
PCT/US2023/075887 WO2024077023A2 (fr) 2022-10-03 2023-10-03 Agents de dégradation doubles de bcl-xl/bcl-2 de recrutement de céréblon

Publications (2)

Publication Number Publication Date
EP4598905A2 true EP4598905A2 (fr) 2025-08-13
EP4598905A4 EP4598905A4 (fr) 2026-04-15

Family

ID=90609052

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23875719.9A Pending EP4598905A4 (fr) 2022-10-03 2023-10-03 Agents de dégradation doubles de bcl-xl/bcl-2 de recrutement de céréblon

Country Status (6)

Country Link
EP (1) EP4598905A4 (fr)
JP (1) JP2025533820A (fr)
KR (1) KR20250099692A (fr)
CN (1) CN120659777A (fr)
AU (1) AU2023356963A1 (fr)
WO (1) WO2024077023A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202527930A (zh) 2023-11-07 2025-07-16 美商樹線生物科學公司 四氫異喹啉異雙功能ｂｃｌ－ｘｌ降解劑
TW202535872A (zh) 2023-11-07 2025-09-16 美商樹線生物科學公司 四氫異喹啉異雙功能ｂｃｌ－ｘｌ降解劑
WO2025101575A1 (fr) 2023-11-07 2025-05-15 Treeline Biosciences, Inc. Agents de dégradation de bcl-x l hétérobifonctionnels de tétrahydroisoquinoléine
WO2026015489A1 (fr) * 2024-07-08 2026-01-15 University Of Florida Research Foundation, Incorporated Agents de dégradation doubles de bcl-xl/bcl-2 et leurs utilisations
WO2026060321A1 (fr) * 2024-09-13 2026-03-19 Olema Pharmaceuticals, Inc. Composés de dégradation de kat6 et procédé associé

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3710443A1 (fr) * 2017-11-17 2020-09-23 Arvinas Operations, Inc. Composés et procédés pour la dégradation ciblée de polypeptides de kinase 4 associés au récepteur de l'interleukine 1
ES3041854T3 (en) * 2018-01-22 2025-11-17 Bioventures Llc Bcl-2 proteins degraders for cancer treatment
CN113660937A (zh) * 2019-02-08 2021-11-16 佛罗里达大学研究基金公司 治疗剂和治疗方法
WO2022187423A1 (fr) * 2021-03-03 2022-09-09 The Regents Of The University Of Michigan Ligands de céréblon

Also Published As

Publication number Publication date
AU2023356963A1 (en) 2025-04-03
KR20250099692A (ko) 2025-07-02
JP2025533820A (ja) 2025-10-09
WO2024077023A2 (fr) 2024-04-11
EP4598905A4 (fr) 2026-04-15
CN120659777A (zh) 2025-09-16
WO2024077023A3 (fr) 2024-05-23

Similar Documents

Publication Publication Date Title
JP7820423B2 (ja) 選択的なタンパク質分解を誘導するための低分子およびその使用法
US12528767B2 (en) HDAC6 inhibitors and uses thereof
EP3544970B1 (fr) Inhibiteurs de kinases associées au récepteur de l&#39;interleukine -1 et leurs utilisations
US12187701B2 (en) Taire family kinase inhibitors and uses thereof
EP4598905A2 (fr) Agents de dégradation doubles de bcl-xl/bcl-2 de recrutement de céréblon
AU2017252460A1 (en) EZH2 inhibitors and uses thereof
WO2016077581A1 (fr) Triazoles d&#39;isostéviol et leurs utilisations
WO2017027841A1 (fr) Dérivés de phénylsulfonamido-benzofurane et leurs utilisations dans le traitement de maladies prolifératives
WO2017127528A1 (fr) Agonistes peptoïdes de récepteurs de croissance des fibroblastes
US11130764B2 (en) Analogs of vincamine and uses thereof
US20230117680A1 (en) Cyclophilin d inhibitors and uses thereof
WO2025129024A1 (fr) Agents de dégradation de recrutement de céréblon de protéines bcl-2 anti-apoptotiques
WO2026015489A1 (fr) Agents de dégradation doubles de bcl-xl/bcl-2 et leurs utilisations
US20250177391A1 (en) Inhibitors of ddr1 and ddr2 for the treatment of arthritis
CA3001882A1 (fr) Sulfonamides de polyamine et leurs utilisations
HK40126954A (zh) 募集cereblon的bcl-xl/bcl-2双重降解剂
WO2022263927A2 (fr) Dérivés de plasmalogènes et leurs utilisations
US20200062776A1 (en) Hedgehog acyltransferase inhibitors and uses thereof
AU2020346814A1 (en) KDM inhibitors and uses thereof

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20250410

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20260316

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 211/70 20060101AFI20260310BHEP

Ipc: C07D 401/14 20060101ALI20260310BHEP

Ipc: C07D 401/04 20060101ALI20260310BHEP

Ipc: A61K 31/495 20060101ALI20260310BHEP

Ipc: A61K 31/365 20060101ALI20260310BHEP

Ipc: A61K 31/45 20060101ALI20260310BHEP

Ipc: A61P 35/00 20060101ALI20260310BHEP

Ipc: A61K 31/496 20060101ALI20260310BHEP

Ipc: A61K 31/553 20060101ALI20260310BHEP

Ipc: A61K 45/06 20060101ALI20260310BHEP

Ipc: A61P 17/06 20060101ALI20260310BHEP

Ipc: A61P 19/02 20060101ALI20260310BHEP

Ipc: A61P 35/02 20060101ALI20260310BHEP

Ipc: C07D 413/14 20060101ALI20260310BHEP

Ipc: C07D 487/04 20060101ALI20260310BHEP

Ipc: C07D 487/08 20060101ALI20260310BHEP

Ipc: C07D 487/10 20060101ALI20260310BHEP

Ipc: A61P 25/28 20060101ALI20260310BHEP

Ipc: A61P 19/10 20060101ALI20260310BHEP