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WO2024097948A1 - Agents de dégradation de mdm2 et leurs utilisations - Google Patents

Agents de dégradation de mdm2 et leurs utilisations Download PDF

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Publication number
WO2024097948A1
WO2024097948A1 PCT/US2023/078619 US2023078619W WO2024097948A1 WO 2024097948 A1 WO2024097948 A1 WO 2024097948A1 US 2023078619 W US2023078619 W US 2023078619W WO 2024097948 A1 WO2024097948 A1 WO 2024097948A1
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optionally substituted
certain embodiments
compound
pharmaceutically acceptable
acceptable salt
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Inventor
Keith P. Moore
Frances Paola RODRIGUEZ-RIVERA
Ravi Kurukulasuriya
Jason Eugene IMBRIGLIO
Anthony William PARTRIDGE
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Roivant Discovery Inc
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Roivant Discovery Inc
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the p53 protein is a key tumor suppressor, and p53 signaling acts as an important defense mechanism against cancer onset and progression.
  • the p53 protein is negatively regulated by binding to MDM2, and therefore, overexpression of MDM2 has been detected in many malignancies, including cancers, such as leukemia, lung cancer, and colon cancer. Overexpression of MDM2 is also associated with chemotherapeutic resistance in malignancies, such as cancer. Strategies that reduce the level of MDM2 proteins in a subject and/inhibit the MDM2-p53 protein-protein interaction in a subject represent attractive therapeutic approaches for the treatment of proliferative disease, such as cancer. [003] The role of MDM2 in cancer—in particular, the role of the MDM2-p53 interaction in cancer—has been widely studied.
  • degraders of MDM2 proteins including compounds of any of the formulae described herein, pharmaceutical compositions and kits comprising the same, and methods of using the same (e.g., for the treatment and/or prevention of diseases (e.g., cancer) in a subject). Also provided herein are methods of preparing the compounds and pharmaceutical compositions described herein, and synthetic intermediates useful thereto.
  • G 1 is N or R 1 ; one instance of R 1 , R 1a , R 1b , R 1c , R N1 , R 2 , R 2a , R 3 , R 3a , or R N2 is of the formula: , and the rest are as defined herein; D is a degradation moiety; and Z 1 , L 1 , and Z 2 are as defined herein.
  • a compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • the group D is a degradation moiety.
  • the degradation moiety is a ubiquitin ligase (i.e., E3 ubiquitin ligase) binding moiety.
  • the ubiquitin ligase binding moiety comprises a Cereblon ligand, an Inhibitor of Apoptosis (IAP) ligand, an MDM2 ligand, or a von Hippel-Lindau (VHL) ligand.
  • IAP Inhibitor of Apoptosis
  • MDM2 MDM2
  • VHL von Hippel-Lindau
  • Other non-limiting examples of degradation moieties are provided herein.
  • a compound of Formula (I) is selected from the compounds recited in Table 1 (infra), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof.
  • compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • the pharmaceutical compositions described herein are useful for treating and/or preventing diseases (e.g., proliferative diseases, such as cancer) in a subject.
  • the pharmaceutical compositions provided herein may further comprise one or more additional therapeutic agents (e.g., anti-cancer agents).
  • a proliferative disease e.g., cancer
  • a pharmaceutically acceptable salt, stereoisomer, tautomer isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • Treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • the cancer is an MDM2-associated cancer.
  • (c) Inhibiting tumor growth in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • the tumor is an MDM2-associated tumor.
  • Methods of inhibiting MDM2 activity in vivo or in vitro comprising contacting an MDM2 protein with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • kits comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof (e.g., in a therapeutically effective amount), wherein the subject has a disease (e.g., cancer or a tumor).
  • a disease e.g., cancer or a tumor
  • the subject is diagnosed with the disease (e.g., cancer or a tumor).
  • kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • the kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof.
  • the kits described herein are useful in any method or use provided herein, and optionally further comprise instructions for using the kit (e.g., instructions for using the compound or composition included in the kit).
  • 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 can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be 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 can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms (“isotopically labeled derivatives”).
  • 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. [021] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided.
  • 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 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.
  • 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, inclusive.
  • 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 (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 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 (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 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 (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (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 C 1–12 alkyl (such as substituted C 1–6 alkyl, e.g., –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 , –CH 2 CF 3 , 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 (“C 1–10 haloalkyl”).
  • the haloalkyl moiety has 1 to 9 carbon atoms (“C 1–9 haloalkyl”).
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C 1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C 1–7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C 1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C 1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C 1–4 haloalkyl”).
  • the haloalkyl moiety has 1 to 3 carbon atoms (“C 1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group.
  • haloalkyl groups include –CHF 2 , ⁇ CH 2 F, ⁇ CF 3 , ⁇ CH 2 CF 3 , ⁇ CF 2 CF 3 , ⁇ CF 2 CF 2 CF 3 , ⁇ CCl 3 , ⁇ CFCl 2 , ⁇ CF 2 Cl, 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, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • the heteroalkyl group is an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and 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 refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–20 heteroalkyl”).
  • a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–12 heteroalkyl”).
  • a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–11 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–9 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–8 heteroalkyl”).
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–7 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–6 heteroalkyl”). 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 (“C 1–5 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C 1–4 heteroalkyl”).
  • a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C 1–3 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C 1–2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C 1 heteroalkyl”). 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 (“C 2-6 heteroalkyl”).
  • each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 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 2 to 20 carbon atoms (“C 2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C 2–12 alkenyl”).
  • an alkenyl group has 2 to 11 carbon atoms (“C 2–11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C4), and the like.
  • Examples of C2–6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), 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.
  • 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, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • the heteroalkenyl group is an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and 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 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–20 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–12 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–11 heteroalkenyl”).
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–10 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–9 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–8 heteroalkenyl”).
  • a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–7 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–6 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C 2–5 heteroalkenyl”).
  • a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C 2–4 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C 2–3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C 2 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C 2–6 heteroalkenyl”).
  • each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”).
  • an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
  • 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, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • the heteroalkynyl group is an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and 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 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C 2–20 heteroalkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C 2–10 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C 2–9 heteroalkynyl”).
  • a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C 2–8 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C 2–7 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C 2–6 heteroalkynyl”).
  • a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C 2–5 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“C 2–4 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2–3 heteroalkynyl”).
  • a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C 2 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C 1–6 heteroalkynyl”). 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.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system.
  • a carbocyclyl group has 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C 3-13 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 (“C 3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 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 (“C 3-6 carbocyclyl”).
  • a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 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 (“C 5-10 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl groups include cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), 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 (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-10 carbocyclyl groups as well as cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), 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 can be saturated or can contain 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. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 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 ).
  • C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) 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.
  • 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, sulfur, silicon, boron, and phosphorous (“3–14 membered heterocyclyl”).
  • the heterocyclyl group is 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.
  • the point of attachment can be either to a ring carbon atom or a ring heteroatom of the heterocyclyl group, as valency permits.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be 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 can be saturated or can contain 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 is substituted or unsubstituted, 3- to 8-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, tetrahydrobenzo- thienyl, 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]
  • 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”).
  • aromatic ring system e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C14 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.
  • 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, sulfur, silicon, boron, and phosphorous (“5-14 membered heteroaryl”).
  • the heteroaryl group is 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.
  • the point of attachment can be either to a ring carbon atom or a ring heteroatom of the heteroaryl group, as valency permits.
  • the point of attachment can be 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.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be 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.
  • the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • a heteroaryl group is a 5-10 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 (“5-10 membered heteroaryl”).
  • 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.
  • the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. [039] 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 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • 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.
  • acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • halo or “halogen” refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • sil refers to the group –Si(R aa ) 3 , wherein R aa is as defined herein.
  • Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., 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, and heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • 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.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the embodiments described herein are not limited in any manner by the exemplary substituents described herein.
  • 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.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms.
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb ) 2 , –CN, or –NO 2 .
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C 1–6 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb ) 2 , –CN, –SCN, or –NO 2 , wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1–6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-
  • 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 is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitro
  • each nitrogen protecting group 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- trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carb
  • each nitrogen protecting group is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms),
  • Ts p-toluenesulfonamide
  • each nitrogen protecting group is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N- 2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3- dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-di
  • a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds
  • At least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 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 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-methoxy
  • an oxygen protecting group is silyl.
  • an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM),
  • each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a sulfur protecting group.
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
  • 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 may be 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 – ), NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HCO 3 ⁇ , HSO 4 – , 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–2– sulfonate, and the like), carboxylate ions (e.g.
  • Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, mal
  • salts 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 the present 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.
  • 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 + (C 1–4 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 the present 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 + (C 1-4 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.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • 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.
  • tautomerizations include keto-to- enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • 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 described herein may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, 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. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. [074] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate.
  • a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, wherein R is the compound, and x is a number greater than 0.
  • a given compound 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 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)).
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. [076] The term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three- dimensional order.
  • a crystalline form of a solid is a solid form that is substantially not amorphous.
  • the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks.
  • amorphous or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order.
  • an amorphous form of a solid is a solid form that is substantially not crystalline.
  • the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 2 ⁇ of, e.g., between 20 and 70°, inclusive, using CuK ⁇ radiation.
  • the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures.
  • the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2 ⁇ of between 20 and 70°, inclusive is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band.
  • the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures.
  • 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.
  • 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.
  • 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.
  • Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.
  • the term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N- alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives 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.
  • Aliphatic or aromatic (e.g., alkyl, alkenyl, alkynyl, aryl, or arylalkyl) esters of the compounds described herein may be preferred.
  • references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof as described herein.
  • 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)).
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non- human animal may be a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disease.
  • tissue 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 cells obtained by microdissection
  • samples of whole organisms such as samples of yeasts or bacteria
  • cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
  • 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.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be 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.
  • the term “prevent,” “preventing,” or “prevention” 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. In certain embodiments, 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.
  • the terms “condition,” “disease,” and “disorder” are used interchangeably.
  • An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • an effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • 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.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for treating a disease (e.g., a proliferative disease such as cancer or a tumor) in a subject.
  • a therapeutically effective amount is an amount sufficient for degrading an MDM2 protein in a subject.
  • a “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a prophylactically effective amount is an amount sufficient for preventing a disease (e.g., an MDM2- associated disease) in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading an MDM2 protein in a subject.
  • MDM2 refers to the mouse double minute 2 (MDM2) protein that is encoded by the MDM2 gene. MDM2 proteins are the primary negative regulatory factor of p53 proteins. Without wishing to be bound by any particular theory, MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes.
  • MDM2 amplification and MDM2 protein overexpression is associated with many cancers including leukemia, lung cancer, and colon cancer. MDM2 overexpression is also associated with chemotherapeutic resistance in cancer.
  • Human MDM2 may also be referred to as “HDM2.” The sequence of human, wild-type MDM2 is provided below (SEQ ID NO: 1): [093]
  • MDM2-associated disease refers to a diseases or condition that is associated with cells that express or overexpress MDM2, and/or that is associated with aberrant (e.g., increased) activity (e.g., signaling) of MDM2 in a subject.
  • MDM2-associated diseases can be identified by assessing a cell or a biopsy of a tissue sample for MDM2 expression and comparing it to MDM2 expression in a reference cell or tissue sample.
  • MDM2-associated cancer and MDM2-associated tumor refer to cancers and tumors that are associated with cancer cells that express or overexpress MDM2, and/or that are associated with aberrant (e.g., increased) activity (e.g., signaling) of MDM2 in a subject.
  • MDM2-associated cancers and tumors can be identified by assessing a cell or a biopsy of a tissue sample for MDM2 expression and comparing it to MDM2 expression in a reference cell or tissue sample (e.g., a normal reference cell or tissue sample).
  • degrading a protein e.g., MDM2
  • a downstream effect e.g., MDM2 activity or a downstream effect
  • degrading an MDM2 protein leads to increased p53 signaling.
  • degradation refers to a small molecule compound comprising a degradation moiety, wherein the compound interacts with a protein of interest (e.g., MDM2) in a way that results in partial or complete degradation of the protein of interest (e.g., MDM2).
  • MDM2 protein of interest
  • Degraders are also referred to as proteolysis-targeting chimera protein degraders (“PROTACs”).
  • degraders comprise two ligands: (i) a first ligand that binds a protein of interest (e.g., MDM2); and (ii) a second ligand that binds a protease or ubiquitin ligase (i.e., E3 ubiquitin ligase).
  • a “degradation moiety” as used herein refers to a ligand that binds a protease or ubiquitin ligase (i.e., E3 ubiquitin ligase), and whose binding to the protease or ubiquitin ligase results in partial or complete degradation of the protein of interest (e.g., MDM2).
  • the degrader binds the protein of interest (e.g., MDM2) via the first ligand and the protease or ubiquitin ligase via the degradation moiety, thereby recruiting the protease or ubiquitin ligase to the protein of interest (e.g., MDM2) for degradation.
  • the degradation moiety binds a ubiquitin ligase (i.e., E3 ubiquitin ligase).
  • level means the amount or concentration of a protein compared to a reference. The reference can be any useful reference, as defined herein.
  • “Decreased level” of a protein means a decrease in amount or concentration of a protein, as compared to a reference.
  • a decreased level is a decrease by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100%.
  • a decreased level is a decrease by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or 100%.
  • a level of a protein may be expressed in mass/vol (e.g., g/dL, mg/mL, ⁇ g/mL, ng/mL) or percentage relative to total protein in a sample or cell.
  • decreasing the level of a protein leads to decreased activity of the protein or a downstream effect (e.g., MDM2 activity or a downstream effect), e.g., relative to a baseline or control level of activity.
  • the decrease in activity is by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100%.
  • the decrease in activity is by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or 100%.
  • the term refers to a reduction in the level of protein activity to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline or reference level of protein activity.
  • the term refers to a reduction of the level of protein activity (e.g., MDM2 activity) to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of protein activity.
  • a “reference” or “control” is meant any useful reference used to compare protein levels.
  • the reference can be any sample, standard, standard curve, or level that is used for comparison purposes.
  • the reference can be a normal reference sample or a reference standard or level.
  • a “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound described herein; a sample from a subject that has been treated by a compound described herein; or a sample of a purified protein (e.g., any described herein) at a known normal concentration.
  • reference standard or level is meant a value or number derived from a reference sample.
  • a “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker.
  • a normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound described herein.
  • the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health.
  • a standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference.
  • determining the level of a protein is meant the detection of a protein by methods known in the art either directly or indirectly.
  • Directly determining means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value.
  • “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value).
  • Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of- flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other partners (e.g., proteins, nucleic acids).
  • ELISA
  • FIGs.1-2 MDM2 degraders degrade MDM2 in live cells. HCT116 cells were treated with compounds at two concentrations for 2 h. FIG. 1. Cells were then washed, lysed and whole lysates were evaluated by Western blot. FIG.2. Graphs indicate quantification of band intensities after normalization to GAPDH.
  • CERTAIN EMBODIMENTS Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof.
  • Compound provided herein are inhibitors and/or degraders of MDM2 proteins and can therefore be used, for example, in the treatment and/or prevention of diseases (e.g., proliferative diseases, such as cancer).
  • pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same.
  • one instance means exactly one instance.
  • one instance of R 1 , R 1a , R 1b , R 1c , or R N1 is of the formula: .
  • one instance of R 1 , R 1a , R 1b , or R 1c is of the formula: .
  • R 1 is of the formula: .
  • R 1a is of the formula: .
  • R 1b is of the formula: .
  • R 1c is of the formula: .
  • a compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-a'): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-e) or (I-d): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of one of the following formulae: , or a pharmaceutically acceptable salt, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (I) is of Formula (II): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, wherein: each instance of R A1 is independently halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; R A2 and R A3 are independently hydrogen or optionally substituted alkyl, or R A2 and
  • a compound of Formula (II) is of the formula: , or a pharmaceutically acceptable salt, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (II) is of Formula (II-a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, wherein r1 is 0 or an integer from 1-20, inclusive; and each instance of r3 is independently 1, 2, or 3.
  • a compound of Formula (II-a) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (II-a) is of Formula (II-b): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (II-b) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (II-a) is of Formula (II-c): or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound of Formula (II-c) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.
  • a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically labeled derivative thereof.
  • a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof.
  • a compound provided herein is a compound of Formula (I) or any subgenus or species thereof.
  • a compound of Formula (I) is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof.
  • a compound of Formula (I) is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopically labeled derivatives thereof.
  • a compound of Formula (I) is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts and stereoisomers thereof. In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1. Table 1
  • the recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
  • D is a degradation moiety as defined herein.
  • the degradation moiety is a ubiquitin ligase (i.e., E3 ubiquitin ligase) binding moiety.
  • the ubiquitin ligase binding moiety comprises a Cereblon (CRBN) ligand, an Inhibitor of Apoptosis (IAP) ligand, an MDM2 ligand, or a von Hippel-Lindau (VHL) ligand.
  • D comprises a Cereblon ligand. In certain embodiments, D comprises an Inhibitor of Apoptosis (IAP) ligand. In certain embodiments, D comprises a von Hippel-Lindau (VHL) ligand.
  • the degradation moiety binds an E3 ubiquitin ligase selected from CRBN, VHL, cIAP1, XIAP, aryl hydrocarbon receptor (AhR), MDM2, KEAP1, DCAF15, DCAF16, DCAF11, RNF4, RNF114, RNF43, FEM1B, and BIRC2.
  • the degradation moiety D binds an E3 ubiquitin ligase described in, e.g., Schneider et al., Nat Rev Drug Discov (2021) 20, 789–797; Kramer et al., Current Research in Chemical Biology (2022) 2, 100020; Nomura et al., “Ligandability of E3 Ligases for Targeted Protein Degradation Applications” Biochemistry 2021; Kannt et al., Cell Chemical Biology (2021) 28, 1014-1031, the entire contents of each of which is incorporated herein by reference.
  • the foregoing also include examples of degradation moieties capable of binding the E3 ubiquitin ligases.
  • degradation moieties and E3 ubiquitin ligases can be found in, e.g., Sun et al., Signal Transduction and Targeted Therapy, vol. 4, no.64 (2019); Paiva et al., Current Opinion in Chemical Biology, vol.50 (2019), pp.111-119; Troup, et al., Exploration of Targeted Anti-Tumor Therapy, 2020, 1, 273-312; Zhou et al. European Journal of Medicinal Chemistry, vol. 203 (2020), 112539; Scheepstra et al., Computational and Structural Biotechnology Journal, Vol.17 (2019), pp.160- 176, the entire contents of each of which is incorporated herein by reference.
  • D is an E3 ubiquitin ligase ligand described in International PCT Application Publication No. WO 2017/176957, published October 12, 2017; or WO 2021/188948, published September 23, 2021, the entire contents of each of which is incorporated herein by reference.
  • D is: . In certain embodiments, D is: .
  • D is of one of the following formulae: , wherein: R B1 and R B2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; R B3 is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R B4 is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R B7 and R B8 are each independently hydrogen, halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted
  • D is of the formula: . [140] In certain embodiments, D is of the formula: . [141] In certain embodiments, D is of the formula: . [142] In certain embodiments, D is of the formula: , wherein R B6 is hydrogen or methyl. [143] In certain embodiments, D is of the formula: , wherein R B6 is hydrogen or methyl. . [145] In certain embodiments, D is of the formula: . [146] In certain embodiments, D is of the formula: . .
  • Z 1 is a bond.
  • Z 1 is –O–.
  • Z 1 is –NR N –.
  • Z 1 is –NH–.
  • Z 1 is –S–.
  • Z 2 is a bond.
  • Z 2 is –O–.
  • Z 2 is –NR N –.
  • Z 2 is –NH–.
  • Z 2 is –S–.
  • L 1 is a linker selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted acylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, and combinations thereof.
  • L 1 comprises optionally substituted alkylene.
  • L 1 comprises optionally substituted alkenylene.
  • L 1 comprises optionally substituted alkynylene.
  • L 1 comprises: optionally substituted C 1-20 alkylene; optionally substituted C 1-20 heteroalkylene comprising 1-10 heteroatoms, inclusive, independently selected from O and N; optionally substituted C 2-20 alkenylene; optionally substituted C 2-20 alkynylene; optionally substituted C 3-8 carbocyclylene; optionally substituted 3-8 membered heterocyclylene comprising 1 or 2 heteroatoms independently selected from O and N; or any combination thereof.
  • L 1 comprises optionally substituted C 1-20 alkylene.
  • L 1 is of one of the following formulae: , ,
  • each instance of r1 is independently 0 or an integer from 1-20, inclusive. In certain embodiments, each instance of r1 is independently an integer from 1-20, inclusive. In certain embodiments, each instance of r1 is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of r1 is independently 0 or an integer from 1-5, inclusive. In certain embodiments, at least one instance of r1 is 0. In certain embodiments, at least one instance of r1 is 1. In certain embodiments, at least one instance of r1 is 2. In certain embodiments, at least one instance of r1 is 3.
  • At least one instance of r1 is 4. In certain embodiments, at least one instance of r1 is 5. In certain embodiments, at least one instance of r1 is 6. In certain embodiments, at least one instance of r1 is 7. In certain embodiments, at least one instance of r1 is 8. In certain embodiments, at least one instance of r1 is 9. In certain embodiments, at least one instance of r1 is 10. In certain embodiments, at least one instance of r1 is 11. In certain embodiments, at least one instance of r1 is 12. In certain embodiments, at least one instance of r1 is 13. In certain embodiments, at least one instance of r1 is 14. In certain embodiments, at least one instance of r1 is 15.
  • each instance of r2 is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of r2 is independently an integer from 1-10, inclusive. In certain embodiments, each instance of r2 is independently 0 or an integer from 1-5, inclusive. In certain embodiments, at least one instance of r2 is 0. In certain embodiments, at least one instance of r2 is 1.
  • At least one instance of r2 is 2. In certain embodiments, at least one instance of r2 is 3. In certain embodiments, at least one instance of r2 is 4. In certain embodiments, at least one instance of r2 is 5. In certain embodiments, at least one instance of r2 is 6. In certain embodiments, at least one instance of r2 is 7. In certain embodiments, at least one instance of r2 is 8. In certain embodiments, at least one instance of r2 is 9. In certain embodiments, at least one instance of r2 is 10. [159] As defined herein, each instance of r3 is independently 1, 2, or 3. In certain embodiments, at least one instance of r3 is 1. In certain embodiments, at least one instance of r3 is 2.
  • each instance of r4 is independently 0, 1, or 2. In certain embodiments, at least one instance of r4 is 0. In certain embodiments, at least one instance of r4 is 1. In certain embodiments, at least one instance of r4 is 2. [161] As defined herein, each instance of Y 2 is independently –O–, –N(R N )–, –S–, or –CH 2 –. In certain embodiments, each instance of Y 2 is independently –O– or –N(R N )–. In certain embodiments, at least one instance of Y 2 is –O–.
  • At least one instance of Y 2 is –N(R N )–. In certain embodiments, at least one instance of Y 2 is –NH–.
  • L 1 is of one of the following formulae: wherein z1 indicates the point of attachment to Z 1 and z2 indicates the point of attachment to Z 2 . [163] In certain embodiments, L 1 is of one of the following formulae:
  • z1 indicates the point of attachment to Z 1 and z2 indicates the point of attachment to Z 2 .
  • z1 indicates the point of attachment to Z 1 and z2 indicates the point of attachment to Z 2 .
  • z2 indicates the point of attachment to Z 2 .
  • ⁇ Z 1 -L 1 -Z 2 — is of one of the following formulae:
  • L 1 comprises one of the following:
  • L 1 comprises one of the following:
  • L 1 is a 6-membered aromatic ring having 0, 1, 2, or 3 heteroatoms (e.g., 0, 1, or 2 heteroatoms) selected from O and N (e.g., N);
  • W L2 is a 6-membered aromatic ring have 0, 1, 2, or 3 heteroatoms (e.g., 0, 1, or 2 heteroatoms) selected from O and N (e.g., N); and
  • m and o are as defined herein.
  • L 1 comprises one of the following:
  • L 1 comprises a formula selected from:
  • L 1 comprises one of the following:
  • each instance of m is independently 0 or an integer from 1-20, inclusive. In certain embodiments, each instance of m is independently an integer from 1-20, inclusive. In certain embodiments, each instance of m is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of m is independently 0 or an integer from 1-5, inclusive. In certain embodiments, each instance of m is independently 0, 1, 2, or 3. In certain embodiments, at least one instance of m is 0. In certain embodiments, at least one instance of m is 1. In certain embodiments, at least one instance of m is 2. In certain embodiments, at least one instance ofm is 3. In certain embodiments, at least one instance of m is 4.
  • At least one instance of m is 5. In certain embodiments, at least one instance of m is 6. In certain embodiments, at least one instance of m is 7. In certain embodiments, at least one instance of m is 8. In certain embodiments, at least one instance of m is 9. In certain embodiments, at least one instance of m is 10. In certain embodiments, at least one instance of m is 11. In certain embodiments, at least one instance of m is 12. In certain embodiments, at least one instance of m is 13. In certain embodiments, at least one instance of m is 14. In certain embodiments, at least one instance of m is 15. In certain embodiments, at least one instance of m is 16. In certain embodiments, at least one instance of m is 17.
  • each instance of s is independently 0 or an integer from 1-20, inclusive. In certain embodiments, each instance of s is independently an integer from 1-20, inclusive. In certain embodiments, each instance of s is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of s is independently 0 or an integer from 1-5, inclusive. In certain embodiments, each instance of s is independently 0, 1, 2, or 3. In certain embodiments, at least one instance of s is 0. In certain embodiments, at least one instance of s is 1.
  • At least one instance of s is 2. In certain embodiments, at least one instance ofm is 3. In certain embodiments, at least one instance of s is 4. In certain embodiments, at least one instance of s is 5. In certain embodiments, at least one instance of s is 6. In certain embodiments, at least one instance of s is 7. In certain embodiments, at least one instance of s is 8. In certain embodiments, at least one instance of s is 9. In certain embodiments, at least one instance of s is 10. In certain embodiments, at least one instance of s is 11. In certain embodiments, at least one instance of s is 12. In certain embodiments, at least one instance of s is 13. In certain embodiments, at least one instance of s is 14.
  • each instance of r is independently 0 or an integer from 1-20, inclusive. In certain embodiments, each instance of r is independently an integer from 1-20, inclusive. In certain embodiments, each instance of r is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of r is independently 0 or an integer from 1-5, inclusive.
  • each instance of r is independently 0, 1, 2, or 3. In certain embodiments, at least one instance of r is 0. In certain embodiments, at least one instance of r is 1. In certain embodiments, at least one instance of r is 2. In certain embodiments, at least one instance ofm is 3. In certain embodiments, at least one instance of r is 4. In certain embodiments, at least one instance of r is 5. In certain embodiments, at least one instance of r is 6. In certain embodiments, at least one instance of r is 7. In certain embodiments, at least one instance of r is 8. In certain embodiments, at least one instance of r is 9. In certain embodiments, at least one instance of r is 10. In certain embodiments, at least one instance of r is 11.
  • At least one instance of r is 12. In certain embodiments, at least one instance of r is 13. In certain embodiments, at least one instance of r is 14. In certain embodiments, at least one instance of r is 15. In certain embodiments, at least one instance of r is 16. In certain embodiments, at least one instance of r is 17. In certain embodiments, at least one instance of r is 18. In certain embodiments, at least one instance of r is 19. In certain embodiments, at least one instance of r is 20. [174] As defined herein, each instance of q is independently 0 or an integer from 1-20, inclusive. In certain embodiments, each instance of q is independently an integer from 1-20, inclusive.
  • each instance of q is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of q is independently 0 or an integer from 1-5, inclusive. In certain embodiments, each instance of q is independently 0, 1, 2, or 3. In certain embodiments, at least one instance of q is 0. In certain embodiments, at least one instance of q is 1. In certain embodiments, at least one instance of q is 2. In certain embodiments, at least one instance ofm is 3. In certain embodiments, at least one instance of q is 4. In certain embodiments, at least one instance of q is 5. In certain embodiments, at least one instance of q is 6. In certain embodiments, at least one instance of q is 7. In certain embodiments, at least one instance of q is 8.
  • At least one instance of q is 9. In certain embodiments, at least one instance of q is 10. In certain embodiments, at least one instance of q is 11. In certain embodiments, at least one instance of q is 12. In certain embodiments, at least one instance of q is 13. In certain embodiments, at least one instance of q is 14. In certain embodiments, at least one instance of q is 15. In certain embodiments, at least one instance of q is 16. In certain embodiments, at least one instance of q is 17. In certain embodiments, at least one instance of q is 18. In certain embodiments, at least one instance of q is 19. In certain embodiments, at least one instance of q is 20.
  • each instance of o is independently 0 or an integer from 1-20, inclusive. In certain embodiments, each instance of o is independently an integer from 1-20, inclusive. In certain embodiments, each instance of o is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of o is independently 0 or an integer from 1-5, inclusive. In certain embodiments, each instance of o is independently 0, 1, 2, or 3. In certain embodiments, at least one instance of o is 0. In certain embodiments, at least one instance of o is 1. In certain embodiments, at least one instance of o is 2. In certain embodiments, at least one instance ofm is 3. In certain embodiments, at least one instance of o is 4.
  • At least one instance of o is 5. In certain embodiments, at least one instance of o is 6. In certain embodiments, at least one instance of o is 7. In certain embodiments, at least one instance of o is 8. In certain embodiments, at least one instance of o is 9. In certain embodiments, at least one instance of o is 10. In certain embodiments, at least one instance of o is 11. In certain embodiments, at least one instance of o is 12. In certain embodiments, at least one instance of o is 13. In certain embodiments, at least one instance of o is 14. In certain embodiments, at least one instance of o is 15. In certain embodiments, at least one instance of o is 16. In certain embodiments, at least one instance of o is 17.
  • each instance of p is independently 0 or an integer from 1-20, inclusive. In certain embodiments, each instance of p is independently an integer from 1-20, inclusive. In certain embodiments, each instance of p is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of p is independently 0 or an integer from 1-5, inclusive. In certain embodiments, each instance of p is independently 0, 1, 2, or 3. In certain embodiments, at least one instance of p is 0. In certain embodiments, at least one instance of p is 1.
  • At least one instance of p is 2. In certain embodiments, at least one instance ofm is 3. In certain embodiments, at least one instance of p is 4. In certain embodiments, at least one instance of p is 5. In certain embodiments, at least one instance of p is 6. In certain embodiments, at least one instance of p is 7. In certain embodiments, at least one instance of p is 8. In certain embodiments, at least one instance of p is 9. In certain embodiments, at least one instance of p is 10. In certain embodiments, at least one instance of p is 11. In certain embodiments, at least one instance of p is 12. In certain embodiments, at least one instance of p is 13. In certain embodiments, at least one instance of p is 14.
  • each instance of n is independently 0 or an integer from 1-20, inclusive. In certain embodiments, each instance of n is independently an integer from 1-20, inclusive. In certain embodiments, each instance of n is independently 0 or an integer from 1-10, inclusive. In certain embodiments, each instance of n is independently 0 or an integer from 1-5, inclusive.
  • each instance of n is independently 0, 1, 2, or 3. In certain embodiments, at least one instance of n is 0. In certain embodiments, at least one instance of n is 1. In certain embodiments, at least one instance of n is 2. In certain embodiments, at least one instance of m is 3. In certain embodiments, at least one instance of n is 4. In certain embodiments, at least one instance of n is 5. In certain embodiments, at least one instance of n is 6. In certain embodiments, at least one instance of n is 7. In certain embodiments, at least one instance of n is 8. In certain embodiments, at least one instance of n is 9. In certain embodiments, at least one instance of n is 10. In certain embodiments, at least one instance of n is 11.
  • At least one instance of n is 12. In certain embodiments, at least one instance of n is 13. In certain embodiments, at least one instance of n is 14. In certain embodiments, at least one instance of n is 15. In certain embodiments, at least one instance of n is 16. In certain embodiments, at least one instance of n is 17. In certain embodiments, at least one instance of n is 18. In certain embodiments, at least one instance of n is 19. In certain embodiments, at least one instance of n is 20.
  • G 1 , R 1 , R 1a , R 1b , and R 1c [178] As defined herein, G 1 is N or CR 1 . In certain embodiments, G 1 is N. In certain embodiments, G 1 is CR 1 .
  • R 1 is hydrogen, halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl.
  • R 1 is hydrogen.
  • R 1 is halogen.
  • R 1 is –CN. In certain embodiments, R 1 is –N 3 . In certain embodiments, R 1 is –NO 2 . In certain embodiments, R 1 is –OR O . In certain embodiments, R 1 is –N(R N ) 2 . In certain embodiments, R 1 is –SR S . In certain embodiments, R 1 is optionally substituted alkyl. In certain embodiments, R 1 is optionally substituted heteroalkyl. In certain embodiments, R 1 is optionally substituted alkenyl. In certain embodiments, R 1 is optionally substituted alkynyl. In certain embodiments, R 1 is optionally substituted carbocyclyl. In certain embodiments, R 1 is optionally substituted heterocyclyl.
  • R 1 is optionally substituted aryl. In certain embodiments, R 1 is optionally substituted heteroaryl. In certain embodiments, R 1 is optionally substituted acyl. In certain embodiments, R 1 is optionally substituted sulfinyl. In certain embodiments, R 1 is optionally substituted sulfonyl.
  • R 1a is hydrogen, halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl.
  • R 1a is hydrogen.
  • R 1a is halogen.
  • R 1a is –CN. In certain embodiments, R 1a is –N 3 . In certain embodiments, R 1a is –NO 2 . In certain embodiments, R 1a is –OR O . In certain embodiments, R 1a is –N(R N ) 2 . In certain embodiments, R 1a is –SR S . In certain embodiments, R 1a is optionally substituted alkyl. In certain embodiments, R 1a is optionally substituted heteroalkyl. In certain embodiments, R 1a is optionally substituted alkenyl. In certain embodiments, R 1a is optionally substituted alkynyl. In certain embodiments, R 1a is optionally substituted carbocyclyl.
  • R 1a is optionally substituted heterocyclyl. In certain embodiments, R 1a is optionally substituted aryl. In certain embodiments, R 1a is optionally substituted heteroaryl. In certain embodiments, R 1a is optionally substituted acyl. In certain embodiments, R 1a is optionally substituted sulfinyl. In certain embodiments, R 1a is optionally substituted sulfonyl. [181] In certain embodiments, R 1a is –OR O . In certain embodiments, R 1a is optionally substituted –O-C 1-6 alkyl. In certain embodiments, R 1a is –O-C 1-6 alkyl.
  • R 1a is optionally substituted –O-C 1-3 alkyl. In certain embodiments, R 1a is aboutO-C 1-3 alkyl. In certain embodiments, R 1a is –OMe.
  • R 1b is hydrogen, halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl.
  • R 1b is hydrogen. In certain embodiments, R 1b is halogen. In certain embodiments, R 1b is –CN. In certain embodiments, R 1b is –N 3 . In certain embodiments, R 1b is –NO 2 . In certain embodiments, R 1b is –OR O . In certain embodiments, R 1b is –N(R N ) 2 . In certain embodiments, R 1b is –SR S . In certain embodiments, R 1b is optionally substituted alkyl. In certain embodiments, R 1b is optionally substituted heteroalkyl. In certain embodiments, R 1b is optionally substituted alkenyl. In certain embodiments, R 1b is optionally substituted alkynyl.
  • R 1b is optionally substituted carbocyclyl. In certain embodiments, R 1b is optionally substituted heterocyclyl. In certain embodiments, R 1b is optionally substituted aryl. In certain embodiments, R 1b is optionally substituted heteroaryl. In certain embodiments, R 1b is optionally substituted acyl. In certain embodiments, R 1b is optionally substituted sulfinyl. In certain embodiments, R 1b is optionally substituted sulfonyl. [183] In certain embodiments, R 1b is –OR O . In certain embodiments, R 1b is optionally substituted –O-C 1-6 alkyl. In certain embodiments, R 1b is–O-C 1-6 alkyl.
  • R 1b is optionally substituted –O-C 1-3 alkyl. In certain embodiments, R 1b is aboutO-C 1-3 alkyl. In certain embodiments, R 1b is –OMe.
  • R 1c is hydrogen, halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl.
  • R 1c is hydrogen. In certain embodiments, R 1c is halogen. In certain embodiments, R 1c is –CN. In certain embodiments, R 1c is –N 3 . In certain embodiments, R 1c is –NO 2 . In certain embodiments, R 1c is –OR O . In certain embodiments, R 1c is –N(R N ) 2 . In certain embodiments, R 1c is –SR S . In certain embodiments, R 1c is optionally substituted alkyl. In certain embodiments, R 1c is optionally substituted heteroalkyl. In certain embodiments, R 1c is optionally substituted alkenyl. In certain embodiments, R 1c is optionally substituted alkynyl.
  • R 1c is optionally substituted carbocyclyl. In certain embodiments, R 1c is optionally substituted heterocyclyl. In certain embodiments, R 1c is optionally substituted aryl. In certain embodiments, R 1c is optionally substituted heteroaryl. In certain embodiments, R 1c is optionally substituted acyl. In certain embodiments, R 1c is optionally substituted sulfinyl. In certain embodiments, R 1c is optionally substituted sulfonyl.
  • R 2 is hydrogen, halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl.
  • R 2 is hydrogen.
  • R 2 is halogen. In certain embodiments, R 2 is –CN. In certain embodiments, R 2 is –N 3 . In certain embodiments, R 2 is –NO 2 . In certain embodiments, R 2 is –OR O . In certain embodiments, R 2 is –N(R N ) 2 . In certain embodiments, R 2 is –SR S . In certain embodiments, R 2 is optionally substituted alkyl. In certain embodiments, R 2 is optionally substituted heteroalkyl. In certain embodiments, R 2 is optionally substituted alkenyl. In certain embodiments, R 2 is optionally substituted alkynyl. In certain embodiments, R 2 is optionally substituted carbocyclyl.
  • R 2 is optionally substituted heterocyclyl. In certain embodiments, R 2 is optionally substituted aryl. In certain embodiments, R 2 is optionally substituted heteroaryl. In certain embodiments, R 2 is optionally substituted acyl. In certain embodiments, R 2 is optionally substituted sulfinyl. In certain embodiments, R 2 is optionally substituted sulfonyl. [186] In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is –F. In certain embodiments, R 2 is –Br. In certain embodiments, R 2 is –I. In certain embodiments, R 2 is –Cl.
  • each instance of R 2a is independently halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl.
  • at least one instance of R 2a is halogen.
  • At least one instance of R 2a is –CN. In certain embodiments, at least one instance of R 2a is –N 3 . In certain embodiments, at least one instance of R 2a is –NO 2 . In certain embodiments, at least one instance of R 2a is –OR O . In certain embodiments, at least one instance of R 2a is –N(R N ) 2 . In certain embodiments, at least one instance of R 2a is –SR S . In certain embodiments, at least one instance of R 2a is optionally substituted alkyl. In certain embodiments, at least one instance of R 2a is optionally substituted heteroalkyl. In certain embodiments, at least one instance of R 2a is optionally substituted alkenyl.
  • At least one instance of R 2a is optionally substituted alkynyl. In certain embodiments, at least one instance of R 2a is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R 2a is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R 2a is optionally substituted aryl. In certain embodiments, at least one instance of R 2a is optionally substituted heteroaryl. In certain embodiments, at least one instance of R 2a is optionally substituted acyl. In certain embodiments, at least one instance of R 2a is optionally substituted sulfinyl. In certain embodiments, at least one instance of R 2a is optionally substituted sulfonyl.
  • R 3 is hydrogen, halogen, –CN, –N3, –NO2, –OR O , –N(R N )2, –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is –CN. In certain embodiments, R 3 is –N 3 . In certain embodiments, R 3 is –NO 2 . In certain embodiments, R 3 is –OR O . In certain embodiments, R 3 is –N(R N ) 2 . In certain embodiments, R 3 is –SR S . In certain embodiments, R 3 is optionally substituted alkyl. In certain embodiments, R 3 is optionally substituted heteroalkyl. In certain embodiments, R 3 is optionally substituted alkenyl. In certain embodiments, R 3 is optionally substituted alkynyl.
  • R 3 is optionally substituted carbocyclyl. In certain embodiments, R 3 is optionally substituted heterocyclyl. In certain embodiments, R 3 is optionally substituted aryl. In certain embodiments, R 3 is optionally substituted heteroaryl. In certain embodiments, R 3 is optionally substituted acyl. In certain embodiments, R 3 is optionally substituted sulfinyl. In certain embodiments, R 3 is optionally substituted sulfonyl. [190] In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is –F. In certain embodiments, R 3 is –Br. In certain embodiments, R 3 is –I. In certain embodiments, R 3 is –Cl.
  • each instance of R 3a is independently hydrogen, halogen, –CN, –N 3 , –NO 2 , –OR O , –N(R N ) 2 , –SR S , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl.
  • at least one instance of R 3a is hydrogen.
  • At least one instance of R 3a is halogen. In certain embodiments, at least one instance of R 3a is –CN. In certain embodiments, at least one instance of R 3a is –N 3 . In certain embodiments, at least one instance of R 3a is –NO 2 . In certain embodiments, at least one instance of R 3a is –OR O . In certain embodiments, at least one instance of R 3a is –N(R N ) 2 . In certain embodiments, at least one instance of R 3a is –SR S . In certain embodiments, at least one instance of R 3a is optionally substituted alkyl. In certain embodiments, at least one instance of R 3a is optionally substituted heteroalkyl.
  • At least one instance of R 3a is optionally substituted alkenyl. In certain embodiments, at least one instance of R 3a is optionally substituted alkynyl. In certain embodiments, at least one instance of R 3a is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R 3a is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R 3a is optionally substituted aryl. In certain embodiments, at least one instance of R 3a is optionally substituted heteroaryl. In certain embodiments, at least one instance of R 3a is optionally substituted acyl. In certain embodiments, at least one instance of R 3a is optionally substituted sulfinyl.
  • R 3a is optionally substituted sulfonyl.
  • each R 3a is hydrogen.
  • R N1 and R N2 [193] As defined herein, R N1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R N1 is hydrogen. In certain embodiments, R N1 is optionally substituted alkyl. In certain embodiments, R N1 is optionally substituted acyl. In certain embodiments, R N1 is a nitrogen protecting group. [194] In certain embodiments, R N1 is optionally substituted C 1-6 alkyl. In certain embodiments, R N1 is unsubstituted C 1-6 alkyl.
  • R N1 is optionally substituted C 1-3 alkyl. In certain embodiments, R N1 is unsubstituted C 1-3 alkyl. In certain embodiments, R N1 is methyl (Me), ethyl (Et), n- propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), isobutyl (i-Bu), sec-butyl (s-Bu), or tert-butyl (t-Bu). In certain embodiments, R N1 is isopropyl (i-Pr). [195] As defined herein, R N2 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group.
  • R N2 is hydrogen. In certain embodiments, R N2 is optionally substituted alkyl. In certain embodiments, R N2 is optionally substituted acyl. In certain embodiments, R N2 is a nitrogen protecting group. [196] In certain embodiments, R N2 is optionally substituted C 1-6 alkyl. In certain embodiments, R N2 is unsubstituted C 1-6 alkyl. In certain embodiments, R N2 is optionally substituted C 1-3 alkyl. In certain embodiments, R N2 is unsubstituted C 1-3 alkyl.
  • R N2 is methyl (Me), ethyl (Et), n- propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), isobutyl (i-Bu), sec-butyl (s-Bu), or tert-butyl (t-Bu). In certain embodiments, R N2 is methyl (Me).
  • each instance of R N is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group, or two R N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.
  • at least one instance of R N is hydrogen.
  • at least one instance R N is optionally substituted alkyl.
  • at least one instance of R N is optionally substituted acyl.
  • at least one instance of R N is a nitrogen protecting group.
  • each instance of R N is hydrogen.
  • each instance of R O is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.
  • at least one instance of R O is hydrogen.
  • at least one instance R O is optionally substituted alkyl.
  • at least one instance of R O is optionally substituted acyl.
  • At least one instance of R O is an oxygen protecting group. In certain embodiments, each instance of R O is hydrogen.
  • each instance of R S is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a sulfur protecting group. In certain embodiments, at least one instance of R S is hydrogen. In certain embodiments, at least one instance R S is optionally substituted alkyl. In certain embodiments, at least one instance of R S is optionally substituted acyl. In certain embodiments, at least one instance of R S is a sulfur protecting group. In certain embodiments, each instance of R S is hydrogen.
  • compositions comprising a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof).
  • the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers.
  • a compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • Such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross- linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross- linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulfin
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® , methylparaben, Germall ® 115, Germaben ® II, Neolone ® , Kathon ® , and Euxyl ® .
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • solubilizing agents such as Cremophor ®
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerator
  • a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • the dosage form may include a buffering agent.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi- liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • compositions can be 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.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low-boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may further comprise additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • a flavoring agent such as saccharin sodium
  • a volatile oil such as a liquid oil
  • a buffering agent such as a liquid oil
  • a surface active agent such as methylhydroxybenzoate
  • a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
  • compositions suitable for administration to humans in order to render the 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.
  • Compounds provided herein 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 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 compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, 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, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal nasal,
  • contemplated routes are 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.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • 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 compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • a compound or composition, as described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents).
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
  • activity e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof
  • improve bioavailability improve safety
  • reduce drug resistance, reduce and/or modify metabolism inhibit excretion, and/or modify distribution in a subject or cell.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • the additional pharmaceutical agent achieves a desired effect for the same disorder.
  • the additional pharmaceutical agent achieves different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • CFR Code of Federal Regulations
  • proteins proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • CFR Code of Federal Regulations
  • the additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti- cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents (NSAIDs), immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, and hormones.
  • NSAIDs steroidal or non-steroidal anti-inflammatory agents
  • immunosuppressants anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti–coagulants, inhibitors
  • the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent.
  • Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents.
  • biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon ⁇ , interferon ⁇ ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g.
  • biotherapeutic anti-cancer agents include PD-1 and PD-L1 inhibitors including, but not limited to, pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), and dostarlimab (Jemperli).
  • chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g.
  • tamoxifen raloxifene, and megestrol
  • LHRH agonists e.g. goscrclin and leuprolide
  • anti-androgens e.g. flutamide and bicalutamide
  • photodynamic therapies e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)
  • nitrogen mustards e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan
  • nitrosoureas e.g.
  • carmustine BCNU
  • lomustine CCNU
  • alkylsulphonates e.g. busulfan and treosulfan
  • triazenes e.g. dacarbazine, temozolomide
  • platinum containing compounds e.g. cisplatin, carboplatin, oxaliplatin
  • vinca alkaloids e.g. vincristine, vinblastine, vindesine, and vinorelbine
  • taxoids e.g.
  • paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g.
  • etoposide etoposide phosphate, teniposide, topotecan, 9- aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C
  • anti-metabolites DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g.
  • uracil analogs e.g.5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine
  • cytosine analogs e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine
  • purine analogs e.g. mercaptopurine and Thioguanine
  • Vitamin D3 analogs e.g. EB 1089, CB 1093, and KH 1060
  • isoprenylation inhibitors e.g.
  • lovastatin dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g.
  • thapsigargin Ca 2+ ATPase inhibitors
  • imatinib thalidomide, lenalidomide
  • tyrosine kinase inhibitors e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN TM , AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI- 272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT
  • axitinib
  • the compound is administered in combination with an additional pharmaceutical agent described in, e.g., Haronikova et al., Cellular & Molecular Biology Letters (2021) 26:53, pp.1-33; Konopleva et al., Leukemia (2020) 34, pp.2858-2874; International PCT Application Publication No. WO 2017/176957, published October 12, 2017; or WO 2021/188948, published September 23, 2021, the entire contents of each of which is incorporated herein by reference.
  • an additional pharmaceutical agent described in, e.g., Haronikova et al., Cellular & Molecular Biology Letters (2021) 26:53, pp.1-33; Konopleva et al., Leukemia (2020) 34, pp.2858-2874; International PCT Application Publication No. WO 2017/176957, published October 12, 2017; or WO 2021/188948, published September 23, 2021, the entire contents of each of which is incorporated herein by reference
  • the compound is administered in combination with a BCL-2 inhibitor, MEK inhibitor, BRAF inhibitor, CDK inhibitor, tyrokine kinase (TK) inhibitor, proteasome inhibitor, PKC inhibitor, FLT3 inhibitor, CDK4/6 inhibitor, JAK1/2 inhibitor, anti-CD20 antibody, anti-PD-L1 antibody, anti-PD-1 antibody, anti-LAG-3 antibody, anti-Tim3 antibody, or a combination thereof.
  • a BCL-2 inhibitor MEK inhibitor
  • BRAF inhibitor BRAF inhibitor
  • CDK inhibitor tyrokine kinase (TK) inhibitor
  • proteasome inhibitor proteasome inhibitor
  • PKC inhibitor FLT3 inhibitor
  • CDK4/6 inhibitor FLT3 inhibitor
  • JAK1/2 inhibitor JAK1/2 inhibitor
  • anti-CD20 antibody anti-PD-L1 antibody
  • anti-PD-1 antibody anti-PD-1 antibody
  • anti-LAG-3 antibody anti-Tim3 antibody
  • the compound is administered in combination with doxorubicin, cytarabine, idarubicin, daunorubicin, venetoclax, trametinib, dabrafenib, ribociclib, quizartinib, 5- azacitidine, pimasertib, cyclophosphamide, topotecan, fludarabine, ixazomib, dexamethasone, decitabine, ruxolitinib, carfilzomib, lenalidomide, carboplatin, trametinib, ribociclib, midostaurin, paclitaxel, docetaxel, decitabine, idarubicin, quizartinib, obinutuzumab, rituximab, atezolizumab, pembrolizumab, toripalimab, ezanbenlimab, spartalizumab,
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • kits e.g., pharmaceutical packs.
  • the kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.
  • kits including a first container comprising a compound or pharmaceutical composition described herein.
  • the kits are useful for treating a disease (e.g., cancer) in a subject in need thereof.
  • a kit described herein further includes instructions for using the kit.
  • a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
  • the information included in the kits is prescribing information.
  • the kits provide instructions for treating a disease (e.g., cancer) in a subject in need thereof.
  • kits provide instructions for preventing a disease in a subject in need thereof.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • Methods of Treatment and Uses [251] Compounds provided herein are MDM2 degraders and are therefore useful in, e.g., treating and/or preventing diseases (e.g., proliferative diseases, such as cancer) in a subject, inhibiting tumor growth in a subject, and degrading MDM2 proteins in vitro or in vivo.
  • diseases e.g., proliferative diseases, such as cancer
  • Compounds provided herein can also inhibit MDM2 activity and are therefore useful in, e.g., treating and/or preventing diseases (e.g., proliferative diseases, such as cancer) in a subject, inhibiting tumor growth in a subject, and inhibiting MDM2 activity in vitro or in vivo.
  • diseases e.g., proliferative diseases, such as cancer
  • methods of treating and/or preventing a disease in a subject in need thereof comprising administering to the subject a therapeutically and/or prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • the method is for treating a disease in a subject. In certain embodiments, the method is for preventing a disease in a subject. In certain embodiments, the disease is an MDM2-associated disease. In certain embodiments, the disease is a proliferative disease (e.g., cancer).
  • a proliferative disease e.g., cancer
  • Provided herein are methods of treating and/or preventing a proliferative disease in a subject in need thereof comprising administering to the subject a therapeutically and/or prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • the method is for treating a proliferative disease in a subject. In certain embodiments, the method is for preventing a proliferative disease in a subject. In certain embodiments, the disease is an MDM2-associated proliferative disease. In certain embodiments, the proliferative disease is cancer. [254] Provided herein are methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the cancer is an MDM2-associated cancer.
  • the cancer is an MDM2-associated solid cancer. In certain embodiments, the cancer is an MDM2-associated hematological cancer.
  • the cancer is colorectal cancer (CRC), lung cancer, breast cancer, prostate cancer, liver cancer, liposarcoma, osteosarcoma, Ewing sarcoma, melanoma, or Merkel cell carcinoma.
  • the cancer is leukemia (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL)).
  • AML acute myeloid leukemia
  • ALL acute lymphocytic leukemia
  • the cancer is a cancer disclosed in International PCT Application Publication No.
  • the cancer is selected from adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lympho
  • the cancer is selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT- midline carcinoma, multiple myeloma, small cell lung cancer (SCLC), neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • SCLC small cell lung cancer
  • neuroblastoma Burkitt's lymphoma
  • cervical cancer esophageal cancer
  • ovarian cancer colorectal cancer
  • colorectal cancer prostate cancer
  • breast cancer breast cancer
  • a tumor growth in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • the tumor is an MDM2-associated tumor.
  • a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (See, e.g., Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • angiogenesis refers to the physiological process through which new blood vessels form from pre-existing vessels.
  • Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development.
  • Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue.
  • angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer.
  • 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, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.”
  • An exemplary pre-malignant neoplasm is a teratoma.
  • a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue.
  • a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • cancer 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.
  • 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 is a solid tumor.
  • the cancer is a hematopoietic cancer (i.e., hematological cancer).
  • the cancer is a hematopoietic cancer (e.g., leukemia (e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B- cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma (e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL)), non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma)), folli
  • ALL acute lymphoc
  • the cancer is leukemia.
  • the cancer is acute lymphoblastic leukemia (ALL).
  • the cancer is early T-cell precursor (ETP)-acute lymphoblastic leukemia (ALL).
  • ETP early T-cell precursor
  • ALL acute lymphoblastic leukemia
  • the cancer is liver cancer (e.g., hepatocellular cancer (HCC) (e.g., hepatocellular carcinoma, hepatoblastoma, hepatocellular adenoma), malignant hepatoma, hemangiomas, biliary cancer (e.g., cholangiocarcinoma)).
  • HCC hepatocellular cancer
  • hepatocellular carcinoma hepatoblastoma
  • malignant hepatoma hemangiomas
  • biliary cancer e.g., cholangiocarcinoma
  • the cancer is musculoskeletal cancer (e.g., bone cancer (e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, Ewing’s sarcoma, chordoma, malignant giant cell tumor chordoma, chondrosarcoma osteochondroma, benign chondroma, chondroblastoma chondromyxofibroma, myelodysplastic syndrome (MDS)), muscle cancer (e.g., rhabdomyosarcoma, rhabdomyoma), connective tissue cancer, synovioma).
  • bone cancer e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, Ewing’s sarcoma, chordoma, malignant giant cell tumor chordoma, chondrosarcoma osteochondroma, benign chondroma, chondroblastoma chondromyxo
  • the cancer is a nervous system cancer (e.g., brain cancer (e.g., astrocytoma, medulloblastoma, glioma (e.g., astrocytoma, oligodendroglioma), glioblastomas, glioblastoma multiform, medulloblastoma, ependymoma, germinoma (i.e., pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, craniopharyngioma), spinal cord cancer, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroblastoma, primitive neuroectodermal tumors (PNT), meningeal cancer (e.g., meningioma, meningiosarcoma, gliomatosis),
  • brain cancer e.g
  • the disease to be treated is a brain tumor.
  • the disease is pleomorphic xenoanthrocytoma (PXA).
  • the disease is pediatric pleomorphic xenoanthrocytoma (PXA).
  • the cancer is selected from endocrine/exocrine cancers (e.g., thyroid cancer (e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma), pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors, ductal adenocarcinoma, insulinoma, glucagonoma, vipoma), adrenal gland cancer, neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), sebaceous gland carcinoma, sweat gland carcinoma).
  • thyroid cancer e.g., papillary thyroid carcinoma, follicular thyroid
  • the cancer is sweat gland cancer (e.g., sweat gland carcinoma).
  • the cancer is head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN), adenoid cystic carcinoma).
  • the cancer is oral cancer (e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer, pharynx cancer, hypopharynx cancer (e.g., hypopharyngeal carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), salivary gland cancer).
  • the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett’s adenocarcinoma, esophageal leiomyosarcoma).
  • esophageal cancer e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett’s adenocarcinoma, esophageal leiomyosarcoma.
  • the cancer is gastrointestinal cancer (e.g., anal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gall bladder cancer, gastric cancer (e.g., stomach cancer (e.g., stomach adenocarcinoma)), gastrointestinal stromal tumor (GIST), small bowel cancer (e.g., appendix cancer, small bowel carcinoma, e.g., small bowel adenocarcinoma), small intestine cancer, large bowel cancer, large intestine cancer).
  • gastrointestinal cancer e.g., anal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gall bladder cancer, gastric cancer (e.g., stomach cancer (e.g., stomach adenocarcinoma)), gastrointestinal stromal tumor (GIST), small bowel cancer (e.g., appendix cancer, small bowel carcinoma, e
  • the cancer is cardiovascular cancer (e.g., primary cardiac tumors, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), cardiac myxoma, cardiac rhabdomyoma).
  • angiosarcoma e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma
  • endotheliosarcoma e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma
  • cardiac myxoma e.g., cardiac rhabdomyoma
  • the cancer is lung cancer (e.g., bronchus cancer (e.g., bronchogenic carcinoma, bronchial adenoma), alveolar carcinoma, mesothelioma, small cell lung cancer (SCLC), non- small cell lung cancer (NSCLC), lung adenocarcinoma, chondromatous hamartoma, papillary adenocarcinoma).
  • lung cancer e.g., bronchus cancer (e.g., bronchogenic carcinoma, bronchial adenoma), alveolar carcinoma, mesothelioma, small cell lung cancer (SCLC), non- small cell lung cancer (NSCLC), lung adenocarcinoma, chondromatous hamartoma, papillary adenocarcinoma).
  • the cancer is a genitourinary cancer (e.g., bladder cancer (e.g., urothelial carcinoma), urethral cancer, kidney cancer (e.g
  • Wilms tumor, renal cell carcinoma), testicular cancer (e.g., seminoma, testicular embryonal carcinoma), germ cell cancer, prostate cancer (e.g., prostate adenocarcinoma), penile cancer (e.g., Paget’s disease of the penis and scrotum)).
  • testicular cancer e.g., seminoma, testicular embryonal carcinoma
  • germ cell cancer e.g., prostate cancer
  • prostate cancer e.g., prostate adenocarcinoma
  • penile cancer e.g., Paget’s disease of the penis and scrotum
  • the cancer is a gynecological cancer (e.g., breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer, HER-2 positive breast cancer, HER2-negative breast cancer), endometrial cancer (e.g., uterine cancer (e.g., uterine sarcoma, choriocarcinoma), endometrial carcinoma), cervical cancer (e.g., cervical adenocarcinoma), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), germ cell cancer, vulvar cancer (e.g., Paget’s disease of the vulva) vaginal cancer, fallopian tube cancer).
  • breast cancer e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, me
  • the cancer is skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), dermatofribroma).
  • the cancer is a soft tissue cancer (e.g., intraepithelial neoplasms, epithelial carcinomas, epithelial sarcomas, adenocarcinomas, adenomas, fibrosarcomas, fibromas, liposarcomas, lipomas, myxomas, teratomas).
  • treating cancer and/or inhibiting tumor growth can result in a reduction in size or volume of a tumor.
  • tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment.
  • Size of a tumor may be measured by any reproducible means of measurement.
  • the size of a tumor may be measured as a diameter of the tumor or by any reproducible means of measurement.
  • treating cancer and/or inhibiting tumor growth can result in a reduction in the rate of growth or metastasis of the cancer or tumor.
  • treating cancer and/or inhibiting tumor growth may further result in a decrease in the number of tumors.
  • tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).
  • treating cancer and/or inhibiting tumor growth can result in a decrease in the number of metastatic nodules in other tissues or organs distant from the primary tumor site.
  • the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to the number prior to treatment.
  • the number of metastatic nodules may be measured by any reproducible means of measurement.
  • treating cancer and/or inhibiting tumor growth can result in an increase in average survival time of a population of subjects treated according to the present disclosure in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the present disclosure.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with the compound of the present disclosure.
  • treating cancer and/or inhibiting tumor growth can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with the compound of the present disclosure.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with the compound of the present disclosure.
  • treating cancer and/or inhibiting tumor growth can also result in an increased average progression-free survival time of a population of treated subjects in comparison to an untreated population.
  • the average progression-free survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average progression-free survival time of a population may be measured by any reproducible means.
  • An increase in average progression-free survival time of a population may be measured, for example, by calculating for a population the average length of progression-free survival following initiation of treatment with the compound of the present disclosure.
  • An increase in average progression-free survival time of a population may also be measured, for example, by calculating for a population the average length of progression-free survival following completion of a first round of treatment with the compound of the present disclosure.
  • “Progression-free survival” as used herein refers to the length of time during and after medication or treatment during which the disease being treated (e.g., cancer) does not get worse.
  • the degrading occurs in vitro.
  • the degrading occurs in vivo.
  • Methods of degrading an MDM2 protein include a step of contacting the MDM2 protein with a compound or composition described herein.
  • the inhibiting occurs in vitro.
  • the inhibiting occurs in vivo.
  • Methods of inhibiting MDM2 activity can include a step of contacting an MDM2 protein with a compound or composition described herein.
  • In vivo methods provided herein comprise administering to a subject (e.g., a human or non-human mammal) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • a subject e.g., a human or non-human mammal
  • In vitro methods provided herein can be carried out, for example, in a cell line, assay, biological sample, or other in vitro setting.
  • methods for inhibiting and/or degrading an MDM2 protein comprise contacting the MDM2 protein with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • methods for inhibiting and/or degrading an MDM2 protein in a cell comprise contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • methods for inhibiting and/or degrading an MDM2 protein in a biological sample comprise contacting the biological sample with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co- crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co- crystal, or prodrug thereof, or a pharmaceutical composition thereof.
  • the biological sample is obtained from a subject having or suspected of having a disease (e.g., a proliferative disease, such as cancer)
  • a disease e.g., a proliferative disease, such as cancer
  • compounds of Formula (I) and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, or prodrugs thereof, and pharmaceutical compositions thereof, for use in any of the methods described herein (e.g., treating and/or preventing a disease in a subject, treating and/or preventing a proliferative disease in a subject, treating cancer in a subject, inhibiting tumor growth in a subject, degrading an MDM2 protein in vitro or in vivo, inhibiting an MDM2 protein in vitro or in vivo).
  • kits comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof; wherein the subject has a disease (e.g., a proliferative disease, cancer, a tumor).
  • a disease e.g., a proliferative disease, cancer, a tumor.
  • the subject has been diagnosed with the disease.
  • a therapeutically effective amount is administered to the subject.
  • CTG Assay HCT116 cells: Cells were resuspended in McCoy's 5A media (Gibco, 16600082) and 45 uL/well were dispensed to obtain 400 cells/well in 384 Black Opaque bottom TC treated plates (Perkin Elmer, 6007668). For a 10-point dose response curve (3.3x dilution, 10 uM highest concentration, 0.1% DMSO final concentration), 5 uL of compound stock solutions were manually added to each well containing seeded cells in 45 uL of media. Next, assay plate was incubated at 37 °C and 5% CO 2 for 72 hours.
  • CTG Assay Rs4;11 cells Compounds (30 nL) were stamped to the assay plate using Echo550 to achieve 10-point dose response curve (3.3x dilution, 10 uM highest concentration, DMSO 0.1%).
  • MDM2 degradation by Western Blot HCT116 cells in McCoy’s 5A media (Gibco, 16600082) were seeded at a density of 0.75*10 6 cells/well in 6 well-plates. Following day, cells were treated with 10 and 100 nM of compounds or 0.1% DMSO for 2 h at 37 °C and 5% CO 2 . After 2 hours, the medium was discarded, and the cells are washed once with PBS. Next, cells were treated with 200 ⁇ L of trypsin, transferred to 1.5 mL eppendorf tubes and washed twice with PBS.
  • WB Western Blot
  • Step 1 To a stirred solution of ethyl 2-isocyanoacetate, 1 (100.0 g, 884.0 mmol) in EtOH (1.5 L) at 0 °C was added 1,1-dimethoxy-N, N-dimethylmethanamine, 2 (0.118 L, 884.0 mmol) and stirred the resulting reaction mixture at rt for 16 h. The reaction was monitored by TLC after completion, the reaction mixture was diluted with MTBE (750 mL), filtered on silica gel bed (100-200 Mesh) and the resulting filtrate was concentrated under reduced pressure to afford the crude compound.
  • MTBE 750 mL
  • silica gel bed 100-200 Mesh
  • Step 2 To a solution of ethyl (Z)-3-(dimethylamino)-2-isocyanoacrylate, 3 (20.0 g, 119.0 mmol) in n-BuOH (25 mL) at 0 oC was added dropwise propan-2-amine, 4 (17.57 g, 297.0 mmol). The mixture was heated to 100 oC and stirred it for 16 h. The reaction was monitored by TLC and after completion, the reaction mixture was diluted with MTBE (1.0 L) and stirred for 30 minutes. The reaction mixture was filtered on celite bed, washed with MTBE (300 mL) and concentrated under reduced pressure to afford the crude compound.
  • Step 3 To a stirred solution of ethyl 1-isopropyl-1H-imidazole-4-carboxylate, 5 (17.0 g, 93.0 mmol) in THF (250 mL), was added potassium phosphate (39.6 g, 187.0 mmol) at 0 °C. N- bromosuccinimide (41.5 g, 233.0 mmol) was added portion wise at 0 °C and after complete addition the reaction mixture was warmed up to rt and stirred for 16 h. The reaction was monitored by TLC and after completion, the reaction mixture was diluted with EtOAC (1 L), filtered on celite bed, washed with EtOAC (2 X 500 mL), concentrated under reduced pressure.
  • Step 4 To a stirred solution of ethyl 2-bromo-1-isopropyl-1H-imidazole-4-carboxylate, 6 (10.0 g, 38.3 mmol) in THF (50 mL) at -78 oC was added LDA (38.3 mL, 77.0 mmol) dropwise and stirred the mixture at -78 oC for 1 h. Next, 4-chlorobenzaldehyde, 7 (10.77 g, 77.0 mmol) in THF (50 mL) was added to the reaction mixture at -78 oC and stirred for another 1 h at -78 °C.
  • Step 5 To a stirred solution of ethyl 2-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl- 1H-imidazole-4-carboxylate, 8 (6.6 g, 16.43 mmol) in CH 2 Cl 2 (60 mL) was added DIPEA (5.72 mL, 32.9 mmol) at room temperature and then the reaction mixture was cooled to 0 oC and SOCl 2 (1.799 mL, 24.65 mmol) was added dropwise and the reaction mixture was stirred at 0 oC to room temperature for 1 h. The reaction was monitored by TLC and after completion the reaction mixture was quenched with saturated aq.
  • Step 6 To a stirred solution of ethyl 2-bromo-5-(chloro(4-chlorophenyl)methyl)-1-isopropyl-1H- imidazole-4-carboxylate, 9 (4.5 g, 10.71 mmol) in acetonitrile (45 mL) was added 3-amino-5-chloro-1- methylpyridin-2(1H)-one, 10 (2.038 g, 12.85 mmol) and DIPEA (3.73 mL, 21.42 mmol) at room temperature and stirred for 5 minutes. After that the reaction vial was transferred to heating block to heat at 80 oC for 16 h.
  • reaction mixture was then cooled down to room temperature and placed it to at ice- bath to get the solid precipitation, which was filtered out, washed with EtOAc (30 mL), dried under vacuum, and afforded the desired product ethyl 2-bromo-5-(((5-chloro-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)amino) (4-chlorophenyl)methyl)-1-isopropyl-1H-imidazole-4-carboxylate, 11 (3.3 g, 5.82 mmol, 54.4% yield) as off white solid, which was then directly used for the next step without any purification.
  • Step 7 To a solution of ethyl 2-bromo-5-(((5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)amino)(4-chlorophenyl)methyl)-1-isopropyl-1H-imidazole-4-carboxylate, 11 (2.3 g, 4.24 mmol) in THF:MeOH:H 2 O (53 mL:53 mL:35.3 mL) (1.5:1.5:1), was added NaOH (0.848 g, 21.21 mmol) at 0 oC, the reaction mixture was then allowed to room temperature and stirred for 16 h.
  • Step 8 A solution of compound 2-bromo-5-(((5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)amino)(4-chlorophenyl)methyl)-1-isopropyl-1H-imidazole-4-carboxylic acid, 12 (1.6 g, 3.11 mmol) in THF (50 mL) was heated to 50 oC and then carbonyldiimidazole, CDI (0.757 g, 4.67 mmol) was added portion wise. After ⁇ 30 min the reaction mixture was heated to 70 oC and continue stirred for 16 h.
  • reaction was monitoring by TLC and upon full consumption of starting material, the reaction mixture was then cooled to 50 oC, was added KO t Bu (0.175 g, 1.556 mmol) portion wise and again stirred the mixture at 70 oC another 2 h. The mixture was then cooled to room temperature, concentrated and the residue was taken in water (20 mL) and stirred for a while. After that, it was extracted with EtOAC (2 x 50 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and evaporated under reduced pressure.
  • EtOAC 2 x 50 mL
  • reaction mixture was purged with N 2 gas for 5 minutes, and then was added PdCl 2 (dppf)-CH 2 Cl 2 adduct (1.991 g, 2.438 mmol) to the reaction mixture.
  • PdCl 2 (dppf)-CH 2 Cl 2 adduct 1.991 g, 2.438 mmol
  • the reaction was then heated at 90 oC for 4 h.
  • the reaction was monitoring by TLC and upon full consumption of starting material, the reaction mixture was filtered through a celite pad and concentrated to get crude compound.
  • Step 10 To a stirred solution of methyl 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinate, 15 (1.4 g, 4.78 mmol) and ammonium acetate (0.736 g, 9.55 mmol) in THF (70 mL) and H 2 O (45 mL) was added sodium periodate (2.04 g, 9.55 mmol) at room temperature and stirred for 16 h. The reaction was monitored by TLC which showed completion of starting material.
  • Step 12 150 mg of intermediate 17 was chirally resoluted using chiral SFC purification using Chirakpak IK-(250*30)mm, 5 ⁇ m; Mobile Phase : CO 2 : 0.2%FA in IPA:ACN [60:40]; Total Flow : 120 mL/min; Back pressure: 100 bar; Wavelength: 220 nm; Cycle time: 11.0 minutes to afford methyl (R)-5- (5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6- tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxynicotinate, (+)
  • Step 13 To a stirred solution of methyl (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6- methoxynicotinate, 19 (180 mg, 0.309 mmol) in DCE (5 mL) at room temperature was added trimethylstannanol (838 mg, 4.64 mmol). Then the reaction mixture was heated to 80 oC for 20 h. Progress of the reaction was monitored by TLC.
  • reaction mixture was directly filtered through short-plug silica gel column to afford (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6- methoxynicotinic acid, 20 (161 mg, 0.283 mmol, 92% yield).
  • LC-MS (ESI+): Calculated mass C27H23Cl2N5O5 567.108; observed m/z: 568.0 [M+H] + .
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-1 (30 mg, 0.051 mmol) and afforded the crude product, N-(10-aminodecyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (21 mg, 0.038 mmol, 73.8% yield, 93.9% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (15 mg, 0.026 mmol), and N-(10-aminodecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (13.8 mg, 0.026 mmol) and coupling reagent, HATU (15.05 mg, 0.040 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-2 (50 mg, 0.074 mmol) and afforded the crude product, (2S,4R)-1-((S)-2-(7- aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40 mg, 0.070 mmol, 94% yield, 79% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (20 mg, 0.035 mmol), and (2S,4R)-1-((S)-2-(7-aminoheptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (21.4 mg, 0.035 mmol) and coupling reagent, HATU (26.8 mg, 0.070 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-3 (30 mg, 0.054 mmol) and afforded the crude product, N-(8-aminooctyl)-2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (20 mg, 0.040 mmol, 74.9% yield, 99.5% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (15 mg, 0.026 mmol), and N-(8-aminooctyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (15.67 mg, 0.032 mmol) and coupling reagent, HATU (15.05 mg, 0.040 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-4 (30 mg, 0.051 mmol) and afforded the crude product, N-(10-aminodecyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (22 mg, 0.040 mmol, 78% yield, 94.9% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (15 mg, 0.026 mmol), and N-(10-aminodecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (13.80 mg, 0.026 mmol) and coupling reagent, HATU (15.05 mg, 0.040 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-5 (50 mg, 0.094 mmol) and afforded the crude product, N-(6-aminohexyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (38 mg, 0.081 mmol, 85% yield, 99% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (15 mg, 0.026 mmol), and N-(6-aminohexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (14.79 mg, 0.032 mmol) and coupling reagent, HATU (15.05 mg, 0.040 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-6 (50 mg, 0.071 mmol) and afforded the crude product, (2S,4R)-1-((S)-2-(9- aminononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40 mg, 0.067 mmol, 93% yield, 81.4% purity ) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (15 mg, 0.026 mmol) and (2S,4R)-1-((S)-2-(9-aminononanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (20.15 mg, 0.032 mmol) and coupling reagent, HATU (20.07 mg, 0.053 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-7 (50 mg, 0.078 mmol) and afforded the crude product, (2S,4R)-1-((S)-2-(5- aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40 mg, 0.073 mmol, 93% yield, 98.7% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (15 mg, 0.026 mmol), and (2S,4R)-1-((S)-2-(5-aminopentanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (18.37 mg, 0.032 mmol) and coupling reagent, HATU (20.07 mg, 0.053 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-8 (30 mg, 0.057 mmol) and afforded the crude product, N-(6-aminohexyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (24 mg, 0.057 mmol, 76% yield, 84.1% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (15 mg, 0.026 mmol), and N-(6-aminohexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (14.79 mg, 0.032 mmol) and HATU (15.05 mg, 0.040 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-9 (30 mg, 0.054 mmol) and afforded the crude product, N-(8-aminooctyl)-2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (22 mg, 0.043 mmol, 80% yield, 97% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (15 mg, 0.026 mmol), and N-(8-aminooctyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (13.06 mg, 0.026 mmol) and HATU (20.07 mg, 0.053 mmol).
  • Step 1 To a stirred solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1, 5.0 g, 22.2 mmol) in Tetrahydrofuran (50 mL) at 0 oC was added Sodium hydride (60 %, 2.64 g, 66.1 mmol), the solution was then gradually heated to 70 o C. After 45 min at 70 o C the above reaction mixture was again cooled to 0 o C, and then 3-bromopiperidine-2,6-dione (21.14 g, 110 mmol) was added in portions.
  • reaction mixture was again heated to 70 o C and stirred for an additional 6 h.
  • the progress of the reaction was monitored by TLC/LCMS, after completion, the reaction was carefully quenched with water (50 mL) and extracted with Ethyl acetate (3 x 30 mL).
  • Step 2 To a stirred solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione (3, 0.80 g, 2.36 mmol) in DMF (3.0 mL) was added tert-butyl pent-4-yn-1- ylcarbamate (7, 0.65 g, 3.55 mmol), Cs 2 CO 3 (2.3 g, 7.1 mmol), CuI (22.3 mg, 0.11 mmol) and the resulting solution was thoroughly degassed using Argon for 10 min.
  • Step 3 To a stirred solution tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (35 mg, 0.079 mmol) in Dichloromethane (3 mL) was added Trifluoroacetic acid (0.023 ml, 0.302 mmol) at 0 o C.
  • Step 1 To a stirred solution 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione (0.25 g, 0.739 mmol) in DMF (2.0 mL) was added tert-butyl 4-(prop-2-yn-1- yloxy)piperidine-1-carboxylate (0.265 g, 1.109 mmol) followed by Cs 2 CO 3 (0.723 g, 2.2 mmol), CuI (7.04 mg, 0.03 mmol) and degassed using argon for 10 min.
  • Step 2 To a stirred solution tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (50 mg, 0.101 mmol) in DCM (3 mL) was added Trifluoroacetic acid (0.023 mL, 0.302 mmol) at 0 o C and the solution was warmed to room temperature and stirred for 2 h.
  • Step 2 To a stirred solution of tert-butyl 7-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)-2,7-diazaspiro 3.5]nonane-2-carboxylate (2, 22 mg, 0.042 mmol) in DCM (0.44 mL) was added Trifluoroacetic acid (14 mg, 0.13 mmol) at 0 o C. Reaction mixture was slowly brought to room temperature and stirred for 2 h. The progress of reaction was monitored by TLC/LCMS.
  • Step 3 To a stirred solution of (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxynicotinic acid (20, 20 mg, 0.035 mmol) in DMF (0.4 mL) was added 3 -(3-methyl-2-oxo-4-(3-(2-(2,2,2-trifluoroacetyl)- 2,7-diazaspiro[3.5]nonan-7-yl)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione (I-12, 27 mg, 0.053 mmol) followed by
  • Step 1 To a stirred solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1) (250 mg, 1.10 mmol) in THF (2.5 mL) was added 60% Sodium hydride (66 mg, 2.75 mmol) at 0 o C. Reaction mixture was slowly brought to room temperature and heated at 70 o C for 45 min. The above reaction mixture was again cooled to 0 o C and was added to it 3-bromopiperidine-2,6-dione (1.057 g, 5.51 mmol) in portions. Reaction mixture was again brought to room temperature and stirred at 70 o C for overnight.
  • Step 2 To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione (2, 50 mg, 0.15 mmol) in Acetonitrile (1.0 mL) was added tert-butyl 4- ethynylpiperidine-1-carboxylate (3, 77 mg, 0.37 mmol) followed by Trimethylamine (299 mg, 2.96 mmol) and degassed using Argon for 10 min.
  • Step 3 To a stirred solution of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)ethynyl)piperidine-1-carboxylate (4, 25 mg, 0.054 mmol) in DCM (0.5 mL) was added Trifluoroacetic acid (18 mg, 0.161 mmol) at 0 ° C. Reaction mixture was slowly brought to room temperature and stirred for 2 h. The progress of reaction was monitored by TLC/LCMS.
  • reaction mixture was warmed to 60 oC and stirred for 1 h. Then the solution was again cooled to 0 oC and 3-bromopiperidine-2,6-dione (2, 12.26 g, 63.90 mmol) was added and heated to 60 oC. The reaction was monitored by TLC which showed an appearance of new spot.
  • Step 2 To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione, (3, 0.400 g, 1.183 mmol) in 1,4 dioxane (1.0 mL), was added tert-butyl 4- ((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate potassium salt (4, 0.543 g, 1.774 mmol) followed by potassium phosphate (0.502 g, 2.366 mmol) in (0.20 mL) water, this solution was thoroughly degassed with argon for 5 min.
  • Step 2 To a stirred solution of 8-bromo-3-iodoimidazo[1,2-a]pyridine (5, 0.827 g, 2.56 mmol) and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (3, 0.50 g, 2.134 mmol) in 1,4 dioxane(1.0 mL), was added cesium carbonate (1.391 g, 4.27 mmol), copper iodide (0.041 g, 0.213 mmol) and (R,R)- ( ⁇ )-N,N′-Dimethyl-1,2-cyclohexanediamine (0.030 g, 0.213 mmol) the reaction mixture was stirred at 80 0 C.
  • Step 3 To a stirred solution of 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (6, 0.20 g, 0.466 mmol) in 1,4-dioxane (2.00 mL) was added tert-butyl 4-ethynylpiperidine-1-carboxylate (7, 0.146 g, 0.699 mmol), cesium carbonate (0.304 g, 0.932 mmol) and copper(I) iodide (8.87 mg, 0.047 mmol) under positive flow of nitrogen, finally bis(triphenylphosphine)palladium chloride (0.016 g, 0.023 mmol) was added and stirred at 80 oC.
  • reaction mixture was then warmed to 70 oC and stirred. After 16 h, the reaction was showed an appearance of new spot.
  • the reaction was quenched by the addition of water and extracted with EtOAc and the organic layer was washed with cold water, brine, dried over anhydrous sodium sulphate, filtered, concentrated and purified by silica gel columnn chromatography (21% EtOAc in Hexane), to afford tert-butyl (2-bromo-6-nitrophenyl)(methyl)carbamate (2, 4.00 g, 11.96 mmol, 55.3% yield) as brown oil.
  • Step 2 To a stirred solution of tert-butyl (2, 2-bromo-6-nitrophenyl)(methyl)carbamate (18.0 g, 54.4 mmol) in ethanol (48.0 mL) and THF (48.0 mL), was added ammonium chloride (29.10 g, 544 mmol) and zinc (35.50 g, 544 mmol) and the reaction mixture was stirred at rt. After 2 h, the TLC showed complete consumption of starting material with appearance of new polar spot.
  • Step 2 In a sealed tube, to a stirred solution of tert-butyl (2-amino-6- bromophenyl)(methyl)carbamate (3, 3.0 g, 9.96 mmol), 2,6-bis(benzyloxy)-3-iodopyridine (7, 4.99 g, 11.95 mmol) in t-BuOH (36.0 mL) was added cesium carbonate (9.74 g, 29.9 mmol) and the contents degassed with nitrogen for 5 min and then RuPhos (0.465 g, 0.996 mmol), Pd 2 (dba) 3 (0.912 g, 0.996 mmol) was added, and degassing continued for 2 min, the reaction mixture was then sealed and stirred at 100 oC.
  • Step 3 To a stirred 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one (8, 2.00 g, 3.87 mmol) in 1,4-dioxane (37.00 mL), water (37.00 mL) was added potassium hydroxide (0.478 g, 8.52 mmol) and solution degassed with nitrogen then t-BuXPhos (0.658 g, 1.549 mmol) and Pd 2 (dba) 3 (0.355 g, 0.387 mmol) were added and stirred at 90 °C.
  • Step 4 To a stirred of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-hydroxy-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one (9, 0.250 g, 0.551 mmol), tert-butyl-2-(tosyloxy)-7-azaspiro[3.5]nonane-7- carboxylate (5, 0.327 g, 0.827 mmol), in DMF (2.50 mL) was added cesium carbonate (0.539 g, 1.654 mmol) and stirred at 90 oC and the reaction was monitored by TLC.
  • 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-hydroxy-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one 9, 0.250 g, 0.551 mmol
  • Step 5 A solution of tert-butyl 2-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (10, 25.0 mg, 0.037 mmol) in ethyl acetate (0.20 mL) was degassed with nitrogen for 5 min.
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-14 (50.0 mg, 0.099 mmol) and afforded the product, N-(4-aminobutyl)-2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (40.0 mg, 0.073 mmol, 73.3% yield) which was directly used for the next step.
  • Step 2 The title compound was synthesized using General Procedure B from 20 (20.0 mg, 0.035 mmol), and N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (23.16 mg, 0.053 mmol) and coupling reagent, HATU (26.8 mg, 0.070 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-15 (40.0 mg, 0.071 mmol) and afforded the product, N-(4-aminobutyl)-2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (30.0 mg, 0.060 mmol, 85% yield) which was directly used for the next step.
  • LC-MS (ESI+): Calculated mass C 21 H 26 N 4 O 8 462.2; observed m/z: 463.2 [M+1] + .
  • Step 2 The title compound was synthesized using General Procedure B from 20 (25.0 mg, 0.044 mmol), and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)oxy)acetamide hydrochloride (26.3 mg, 0.053 mmol) and coupling reagent, HATU (33.4 mg, 0.088 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-16 (40.0 mg, 0.061 mmol) and afforded the product, N-(14-amino-3,6,9,12- tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (31.0 mg, 0.053 mmol, 86% yield) which was directly used for the next step.
  • Step 2 The title compound was synthesized using General Procedure B from 20 (35.0 mg, 0.061 mmol), and N-(14-amino-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (36.10 mg, 0.061 mmol) and coupling reagent, HATU (46.8 mg, 0.123 mmol).
  • Step 2 The title compound was synthesized using General Procedure B from 20 (20.0 mg, 0.035 mmol), and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 5-yl)oxy)acetamide hydrochloride (26.3 mg, 0.053 mmol) and coupling reagent, HATU (26.8 mg, 0.070 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection protocol described in General Procedure A from I-18 (32.0 mg, 0.040 mmol) and afforded the product, (2S,4R)-1-((S)-1-amino-17-(tert- butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecan-18-oyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (29.4 mg, 0.040 mmol, quantitative) which was directly used for the next step.
  • Step 2 The title compound was synthesized using General Procedure B from 20 (15.0 mg, 0.026 mmol), and (2S,4R)-1-((S)-1-amino-17-(tert-butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecan-18-oyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (29.1 mg, 0.040 mmol) and coupling reagent, HATU (20.07 mg, 0.053 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-19 (15 mg, 0.024 mmol) and afforded the product, (2S,4R)-1-((S)-2-(3- aminopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (13.0 mg, 0.024 mmol, 97% yield) which was directly used for the next step.
  • Step 2 The title compound was synthesized using General Procedure B from 20 (20 mg, 0.035 mmol), and (2S,4R)-1-((S)-2-(3-aminopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (13.0 mg, 0.024 mmol) and coupling reagent, HATU (17.91 mg, 0.047 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-20 (35.0 mg, 0.050 mmol) and afforded the product, (2S,4R)-1-((S)-2-(3-(2- (2-aminoethoxy)ethoxy) propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (29.8 mg, 0.046 mmol, 94% yield) which was directly used for the next step.
  • Step 2 The title compound was synthesized using General Procedure B from 20 (22 mg, 0.039 mmol), and (2S,4R)-1-((S)-2-(3-(2-(2-aminoethoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (29.70 mg, 0.046 mmol) and coupling reagent, HATU (29.4 mg, 0.077 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-20 (40.0 mg, 0.061 mmol) and afforded the product, N-(14-amino-3,6,9,12- tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (29.0 mg, 0.049 mmol, 80% yield) which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from 20 (33.7 mg, 0.059 mmol), and N-(14-amino-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (29.0 mg, 0.049 mmol) and coupling reagent, HATU (37.6 mg, 0.099 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)methyl)piperazine-1-carboxylate (39.0 mg, 0.085 mmol) and afforded the product, 3-(3-methyl-2-oxo-5-((4-(2,2,2-trifluoroacetyl)piperazin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol- 1-yl)piperidine-2,6-dione (38.6 mg, 0.085 mmol, quantitative yield) was directly used for the next step.
  • Step 2 The title compound was synthesized using General Procedure B from 20 (25.0 mg, 0.044 mmol) and 3-(3-methyl-2-oxo-5-((4-(2,2,2-trifluoroacetyl)piperazin-1-yl)methyl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (38 mg, 0.084 mmol) and coupling reagent, HATU (25.09 mg, 0.066 mmol).
  • Step 1 To a stirred solution of tert-butyl-4-((3-(3-(4-methoxybenzyl)-2,4- dioxotetrahydropyrimidin-1(2H)-yl)imidazo[1,2-a]pyridin-8-yl)ethynyl)piperidine-1-carboxylate (0.15 g, 0.269 mmol), was added Triflic acid (0.040 g, 0.269 mmol) and TFA (0.031 g, 0.269 mmol) the reaction mixture was stirred at 60 oC for 3 h.
  • Step 2 The title compound was synthesized using General Procedure B from 20 (10.0 mg, 0.018 mmol), and 1-(8-(piperidin-4-ylethynyl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (12.0 mg, 0.035 mmol) and coupling reagent, HATU (10.03 mg, 0.026 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (50.0 mg, 0.100 mmol) and afforded the product, 3-(4-((7-azaspiro[3.5]nonan-2-yl)oxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione hydrochloride (30.0 mg, 0.068 mmol, 68.1% yield) which was directly used for the next step.
  • Step 2 The title compound was synthesized using General Procedure B from 20 (20 mg, 0.035 mmol), and 3-(4-((7-azaspiro[3.5]nonan-2-yl)oxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione hydrochloride (16.83 mg, 0.039 mmol) and coupling reagent, HATU (20.07 mg, 0.053 mmol).
  • reaction mixture was directly filtered through short-plug silica gel column to afford (R)-5-(5- (5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6- tetrahydropyrrolo [3,4-d]imidazol-2-yl)-6-methoxynicotinic acid, 21 (90 mg, 0.157 mmol, 90% yield).
  • LC-MS (ESI+): Calculated mass C 27 H 23 Cl 2 N 5 O 5 567.108; observed m/z: 568.2 [M+H] + .
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-4 (30 mg, 0.051 mmol) and afforded the crude product, N-(10-aminodecyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (26 mg, 0.049 mmol, 97% yield, 99% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from, 21 (21 mg, 0.037 mmol), and (N-(10-aminodecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (26 mg, 0.049 mmol) and coupling reagent, HATU (28.1 mg, 0.074 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from I-6 (51 mg, 0.063 mmol) and afforded the crude product, (2S,4R)-1-((S)-2-(9- aminononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (crude 39 mg, 0.061 mmol, 97% yield, 84% purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from, 21 (21 mg, 0.037 mmol), and (2S, 4R)-1-((S)-2-(9-aminononanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (crude 39 mg, 0.061 mmol) and coupling reagent, BOP (32.7 mg, 0.074 mmol).
  • Step 1 General Procedure A was followed for Boc deprotection of I-21 (40 mg, 0.094 mmol) to obtain 3-(4-(5-aminopent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (30 mg, 0.082 mmol, 87% yield) as orange solid and which was directly used for the next step.
  • LC-MS (ESI+): Calculated mass C 18 H 19 N 3 O 3 325.14 observed m/z: 326.2 [M+H] + .
  • Step 2 To a stirred solution of 20 (25 mg, 0.044 mmol) in DMF (0.30 mL) was added DIPEA (0.077 ml, 0.440 mmol) and BOP (38.9 mg, 0.088 mmol) followed by 3-(4-(5-aminopent-1-yn-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (23.87 mg, 0.066 mmol) and stirred at RT for 16 h. Progress of the reaction monitored by LCMS. Reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3 x 5 mL).
  • Step 1 General Procedure A was followed for Boc-deprotection of tert-butyl (5-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)carbamate I-22 (100 mg, 0.235 mmol) to obtain 3-(4- (5-aminopentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (2) (60 mg, 0.134 mmol, 57.1% yield) as an off-white solid, which was directly used for the next step.
  • Step 2 To a stirred solution of 20 (30 mg, 0.053 mmol) in DMF (0.40 mL) was added DIPEA (0.092 ml, 0.528 mmol), BOP (46.7 mg, 0.106 mmol) followed by 3-(4-(5-aminopentyl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione hydrochloride (25.1 mg, 0.069 mmol) and stirred at RT for 16 h. Progress of the reaction monitored by LCMS.
  • Step 1 General Procedure A was followed for Boc-deprotection of I-23 (synthesized as per WO 2021011913 A1; 50 mg, 0.117 mmol) to obtain 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione hydrochloride (35 mg, 0.080 mmol, 68.2% yield) as orange solid, which was directly used for the next step.
  • LC-MS (ESI+): Calculated mass C 17 H 20 N 4 O 3 328.83; observed m/z: 329.1 [M+H] + .
  • Step 2 Compound 20 (25 mg, 0.044 mmol) was dissolved in DMF (0.30 mL). To this reaction mixture were added DIPEA (0.0384 mL, 0.220 mmol), BOP (38.9 mg, 0.088 mmol) followed by 3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (17.43 mg, 0.048 mmol) at RT. Once the addition complete, resulting reaction mixture was stirred at RT for 16 h. Progress of the reaction monitored by LCMS, SM completion and product formation was observed.
  • Step 1 To a stirred solution of tert-butyl (5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)pent-4-yn-1-yl)carbamate (75 mg, 0.170 mmol) in Ethyl acetate (4 mL) and THF (4 mL) was added 10% Pd/C (50% in water, 24 mg, 0.023 mmol) and 10% Pd(OH) 2 /C (24 mg, 0.034 mmol) and the reaction mixture was stirred under hydrogen (15 psi atmosphere pressure) at 25 oC for 16 h.
  • Step 2 To a stirred solution of tert-butyl (5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)pentyl)carbamate (70 mg, 0.157 mmol) in DCM (1.0 mL) was added 4 M HCl in dioxane (1.0 mL, 4.00 mmol) at 0 oC and stirred at RT for 2 h. Reaction mixture was monitored by UPLC and TLC, after completion.
  • Step 3 To a stirred solution of (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxynicotinic acid (70 mg, 0.123 mmol) and 3-(4-(5-aminopentyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione hydrochloride (51.6 mg, 0.135 mmol) in DMF (5.0 mL) were added DIPEA (0.215 mL, 1.232 mmol) and HATU (70.2 mg, 0.185 mmol) at 25 oC and stirred for 16 h.
  • DIPEA 0.15
  • Step 1 To the stirred solution of tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (71 mg, 0.143 mmol) in THF (10 mL) added 10% Pd/C (15 mg, 0.141 mmol), 10% Pd(OH) 2 /C (20.02 mg, 0.143 mmol) in tiny auto-clave and stirred at 50 oC for 16 h under 5-atm hydrogen pressure. The reaction progress was monitered by LCMS.
  • Step 2 To a stirred solution of tert-butyl 4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)propoxy)piperidine-1-carboxylate (61 mg, 0.122 mmol) in DCM (3 mL), at 0 o C was added 4 M HCl in dioxane (3 mL, 3.00 mmol) and stirred for 10 min and further stirred at RT for 2 h. Reaction progress was monitored by TLC.
  • Step 3 To a stirred solution of 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yloxy)propyl)-2,3-dihydro- 1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (42.3 mg, 0.106 mmol) in DMF (1.5 mL) added DIPEA (27.3 mg, 0.211 mmol) HATU (40.1 mg, 0.106 mmol) and (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazol-2- yl)-6-methoxynicotinic acid (40 mg, 0.070 mmol) was added and the resulting reaction mixture was stirred at 25 oC for
  • Step 1 To the stirred solution of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)ethynyl)piperidine-1-carboxylate (60 mg, 0.129 mmol) in MeOH (3.0 mL) was added 10% Pd/C (25 mg, 0.235 mmol) and hydrogenation was carried out at 20 Psi pressure for 16 h. The reaction progress was monitored by UPLC.
  • Step 2 To a stirred solution of tert-butyl 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carboxylate (55 mg, 0.128 mmol) in DCM (3 mL), at 0 oC added 4 M HCl in Dioxane (0.128 mL, 0.128 mmol) and stirred for 10 min at 0 oC and allowed to stirred at RT for 2 h. Reaction progress was monitored by TLC.
  • Step 3 To a stirred solution of 3-(3-methyl-2-oxo-5-(2-(piperidin-4-yl)ethyl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (39.1 mg, 0.106 mmol) in DMF (2.0 mL) was added DIPEA (34.1 mg, 0.264 mmol) HATU (50.2 mg, 0.132 mmol) and (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazol-2- yl)-6-methoxynicotinic acid (D20) (50 mg, 0.088 mmol) was added and the resulting reaction mixture was stirred at
  • Step 1 General Procedure A was used for the boc-deprotection of the tert-butyl 4-((4-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate 1 (30 mg, 0.053 mmol) afforded the product, 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(piperidin-4- ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (20 mg, 0.041 mmol, 77% yield) as yellow solid , which was directly used for the next step.
  • Step 2 To a strirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(piperidin-4- ylmethyl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride (20 mg, 0.032 mmol) in DMF (1.0 mL) was added DIPEA (0.041 mL, 0.238 mmol) and BOP (42.0 mg, 0.095 mmol) followed by 20 (30 mg, 0.048 mmol) and stirred at RT for 16 h.
  • Step 2 [411] A stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one 3 (500 mg, 0.968 mmol) in 5:1 dioxane/H 2 O (6 mL), was degassed for 15 min prior to the sequential addition of Pd 2 (dba) 3 (89 mg, 0.097 mmol), t-BuXPhos (82 mg, 0.194 mmol) and finally KOH (163 mg, 2.90 mmol). The resulting reaction mixture was degassed again for 15 min heated at 90 oC overnight in a sealed tube.
  • Step 3 [412] To a stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-hydroxy-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one 4 (200 mg, 0.441 mmol) and tert-butyl 4-((tosyloxy)methyl)piperidine-1- carboxylate 2 (293 mg, 0.794 mmol) in DMF (8 mL) was added Cs 2 CO 3 (431 mg, 1.323 mmol) at 25 oC. The resulting reaction mixture was heated at 90 oC for 16 h. The progress was monitored by LCMS analysis. Upon completion, the reaction mixture was passed through a pad of Celite.
  • Step 4 [413] To a stirred solution of tert-butyl 4-(((1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)methyl)piperidine-1-carboxylate 5 (144 mg, 0.113 mmol) in MeOH (15 mL), was added Pd/C (10% on carbon) (220 mg, 0.207 mmol) at 25 oC. The resulting reaction mixture was stirred under H 2 atmosphere overnight. The reaction was monitored by LCMS analysis. The reaction mixture was filtered through a pad of celite. The bed was washed with excess EtOAc.
  • Step 5 [414] To a stirred solution of tert-butyl 4-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)oxy)methyl)piperidine-1-carboxylate 6 (40 mg, 0.085 mmol) in ACN (2.0 mL), was added 4M HCl in dioxane (0.106 mL, 0.423 mmol) at 0 oC. The resulting reaction mixture was stirred for 30 min. After 30 min, LCMS analysis showed 17% unreacted starting material was remaining.
  • Step 6 [415] To a stirred solution of 20 (30 mg, 0.053 mmol) and 7 (crude, 34 mg) in DMF (5 mL), was added DIPEA (0.184 mL, 1.056 mmol), followed by propylphosphonic anhydride solution (50% in EA) (0.079 mL, 0.132 mmol) at 25 oC. The resulting reaction mixture was stirred for 3 h under N 2 . The reaction was monitored by LCMS analysis. Upon completion, the reaction mass was concentrated under reduced pressure and purified directly.
  • Step 2 [417] To a stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-hydroxy-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one (500 mg, 1.103 mmol), tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (588 mg, 1.654 mmol) in DMF (5 mL) was added Cs 2 CO 3 (1078 mg, 3.31 mmol) at 25 oC. The reaction mixture was heated to 90 oC for 18 h. Reaction progress was monitored by TLC, after completion.
  • Step 3 [418] To a stirred solution of tert-butyl 4-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)piperidine-1-carboxylate (320 mg, 0.503 mmol) in ethyl acetate (5 mL); degassed with N 2 gas for 5 min and was added 10% Pd/C (535 mg, 0.503 mmol), stirred under H 2 -atmosphere (15 psi) at 25 oC for 30 h. Reaction progress was monitored by UPLC.
  • Step 5 [420] To a stirred solution of (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxynicotinic acid 20 (50 mg, 0.088 mmol) and 3-(3-methyl-2-oxo-4-(piperidin-4-yloxy)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (41.7 mg, 0.106 mmol) in DMF (1.0 mL) was added DIPEA (0.154 mL, 0.880 mmol) and BOP (58.4 mg, 0.132 mmol) at 25 oC and stirred at 25 oC for 16
  • Step 2 [422] To a stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-hydroxy-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one (500 mg, 1.103 mmol) and tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (541 mg, 1.654 mmol) in DMF (5 mL), was added Cs 2 CO 3 (1078 mg, 3.31 mmol) and heated at 90 oC for 18 h. Reaction progress was monitored by TLC, after completion. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 50 mL).
  • Reaction mixture was degassed with N 2 for 5 min, then added 10% Pd/C (612 mg, 0.575 mmol) and stirred at 25 oC under hydrogen atmosphere (15 psi) for 30 h. Reaction progress was monitored by UPLC, after completion filtered through celite bed and bed was washed with EtOAc (10 mL) and filtrate was concentrated under reduced pressure.
  • Step 4 [424] To a stirred solution of tert-butyl 3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)oxy)azetidine-1-carboxylate (50 mg, 0.116 mmol) in DCM (1.0 mL) was added 2,2,2-trifluoroacetic acid (0.4 mL, 0.116 mmol) at 0 oC and stirred at 25 oC for 2 h. Reaction progress was monitored by UPLC.
  • Step 5 [425] To a stirred solution of (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxy nicotinic acid (50 mg, 0.088 mmol) and 3-(3-methyl-2-oxo-4-((1-(2,2,2-trifluoroacetyl)-1l4-azetidin-3-yl)oxy)- 2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (45.1 mg, 0.106 mmol) in DMF (1.0 mL) was added DIPEA (0.154 mL, 0.880 mmol) and BOP (58.4 mg, 0.
  • Step 1 To a stirred solution of tert-butyl 7-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (100 mg, 0.192 mmol) in EtOAc (10 mL) and THF (10 mL) and reaction mixture was purged with nitrogen for 5 min and 10% Pd(OH) 2 /C (135 mg, 0.192 mmol) was added and hydrogenation was carried out at 15 psi for 4 h.
  • Step 2 To a stirred solution of tert-butyl 7-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl) propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (54 mg, 0.103 mmol) in DCM (5 mL), was added TFA (0.5 mL, 6.49 mmol) at 0 oC.
  • Step 3 To a stirred solution of (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxynicotinic acid (50 mg, 0.088 mmol) and 3-(3-methyl-2-oxo-4-(3-(2-(2,2,2-trifluoroacetyl)-2l5,7-diazaspiro[3.5]nonan- 7-yl)propyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6
  • Step 1 To a stirred solution of 1-(8-(piperidin-4-ylethynyl)imidazo[1,2-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (0.1 g, 0.296 mmol) in THF (4 mL) was added Di-tert-butyl dicarbonate (0.065 g, 0.296 mmol) and Triethyl amine (0.090 g, 0.889 mmol) at 0 o C, the reaction mixture was stirred at room temperature about 12 h. The progress of reaction was monitored by TLC/UPLC.
  • Step 2 To a stirred solution of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)imidazo[1,2-a]pyridin-8-yl)ethynyl)piperidine-1-carboxylate (0.1 g, 0.229 mmol) in EtOH (6.0 mL), MeOH (6.0 mL), was added 10% Pd/C (40 mg, 0.229 mmol) the reaction mixture was stirred under H 2 atmosphere at RT for 4 h. The reaction progress was monitored by UPLC. After completion of the reaction, the reaction mixture was filterd through the celite bed and filtrate was evaporated.
  • Step 3 To a stirred solution of the tert-butyl 4-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)imidazo[1,2-a]pyridin-8-yl)ethyl)piperidine-1-carboxylate (60 mg, 0.136 mmol) in DCM (2.0 mL) was added 4M HCl in dioxane (5 mL) at 0 oC and the reaction mixture was slowly brought to room temperature and stirred at same temperature for 2 hours. The progress of reaction was monitored by TLC/LCMS.
  • Step 4 To a stirred solution of 1-(8-(2-(piperidin-4-yl)ethyl)imidazo[1,2-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (14.42 mg, 0.042 mmol) in DMF (1.0 mL) was added DIPEA (0.059 mL, 0.337 mmol), BOP (18.31 mg, 0.035 mmol), and 3-chloro-5-(2-((4aR,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-(((1r,4R)-4-methylcyclohexyl) methyl)-6-(5-oxo-4,5- di
  • Step 1 To a stirred solution of ethyl 2-isocyanoacetate, 1 (100.0 g, 884.0 mmol) in EtOH (1.5 L) at 0 °C was added 1,1-dimethoxy-N, N-dimethylmethanamine, 2 (0.118 L, 884.0 mmol) and stirred the resulting reaction mixture at rt for 16 h. The reaction was monitored by TLC after completion, the reaction mixture was diluted with MTBE (750 mL), filtered on silica gel bed (100-200 Mesh) and the resulting filtrate was concentrated under reduced pressure to afford the crude compound.
  • MTBE 750 mL
  • silica gel bed 100-200 Mesh
  • Step 2 To a solution of ethyl (Z)-3-(dimethylamino)-2-isocyanoacrylate, 3 (45.0 g, 268.0 mmol) in n-BuOH (20 mL) was added dropwise 3-aminopropan-1-ol, 4 (22.5 mL, 294.0 mmol) at 25 °C. The mixture was heated to 100 °C and stirred it for 16 h. The reaction was monitored by TLC and after completion, it was concentrated under reduced pressure to get crude compound.
  • Step 3 To a stirred solution of ethyl 1-(3-hydroxypropyl)-1H-imidazole-4-carboxylate, 5 (25.0 g, 126.0 mmol) in CH 2 Cl 2 (300 mL), was added imidazole (21.5 g, 315.0 mmol), and TBDPS-Cl (36.1 mL, 139.0 mmol) dropwise at 0 °C. After addition the reaction mixture was stirred at room temperature for another 16 h. Reaction was monitored by TLC.
  • Step 4 To a stirred solution of ethyl 1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-1H-imidazole-4- carboxylate, 6 (20.0 g, 45.8 mmol) in THF (200 mL), was added tripotassium phosphate (20.4 g, 96.0 mmol) at 0 °C. Next, N-bromosuccinimide (21.2 g, 119.0 mmol) was added portion wise at 0 °C and after complete addition the reaction mixture was warmed up to rt and stirred for another 16 h.
  • reaction was monitored by TLC and after completion, the reaction mixture was diluted with ethyl acetate (500 mL), filtered on celite bed, washed with ethyl acetate (2 X 250 mL), concentrated under reduced pressure.
  • Step 5 To a stirred solution of ethyl 2-bromo-1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-1H- imidazole-4-carboxylate, 7 (15.0 g, 24.2 mmol) in THF (150 mL) at -78 °C was added LDA (18.1 mL, 36.2 mmol) dropwise and stirred the mixture at -78 °C for 1 h, followed by 4-chlorobenzaldehyde, 8 (6.1 g, 43.5 mmol) in THF (5 mL) was added to the reaction mixture at -78 °C and stirred for another 1 h at - 78 °C.
  • LDA 18.1 mL, 36.2 mmol
  • the crude compound was purified by normal phase column chromatography (Mobile phase: 40% ethyl acetate: hexanes) eluted at 0 to 35% ethyl acetate: hexanes to afford ethyl 2-bromo-1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-((4- chlorophenyl)(hydroxy)methyl)-1H-imidazole-4-carboxylate, 9 (9.0 g, 11.9 mmol, 49.4% yield) as a light yellow solid.
  • Step 6 To a stirred solution of ethyl 2-bromo-1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-((4- chlorophenyl)(hydroxy)methyl)-1H-imidazole-4-carboxylate, 9 (2.8 g, 4.3 mmol) in CH 2 Cl 2 (30 mL) was added N,N-Diisopropylethylamine (1.5 mL, 8.5 mmol) at room temperature and then the reaction mixture was cooled to 0 °C and thionyl chloride (0.5 mL, 6.4 mmol) was added dropwise and the reaction mixture was stirred at 0 °C to room temperature for 1 h.
  • reaction was monitored by TLC and after completion the reaction mixture was quenched with saturated aq. NaHCO 3 solution (10 mL) at 0 °C. Then, the reaction mixture was diluted with H 2 O (50 mL) and CH 2 Cl 2 (100 mL) and aqueous layer was extracted with CH 2 Cl 2 (50 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to get the crude product.
  • Step 7 To a stirred solution of ethyl 2-bromo-1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5- (chloro(4-chlorophenyl)methyl)-1H-imidazole-4-carboxylate, 10 (5.0 g, 7.4 mmol) in acetonitrile (50 mL) was added N,N-Diisopropylethylamine (2.6 mL, 14.8 mmol) and 3-amino-5-chloro-1- methylpyridin-2(1H)-one, 11 (1.8 g, 11.1 mmol) at room temperature respectively and stirred for 5 minutes.
  • reaction vial was transferred to heating block to heat at 80 ° C for 16 h.
  • the reaction mixture was then cooled down to room temperature and placed it to at ice-bath to get the solid precipitation, which was filtered out, washed with ethyl acetate (30 mL), dried under vacuum, and afforded the desired product ethyl 2-bromo-1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-(((5-chloro-1- methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1H-imidazole-4-carboxylate, 12 (3.1 g, 3.7 mmol, 49.3% yield) as off white solid, which was then directly used for the next step without any purification.
  • Step 8 To a stirred N 2 -purged solution of ethyl 2-bromo-1-(3-((tert- butyldiphenylsilyl)oxy)propyl)-5-(((5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)(4- chlorophenyl)methyl)-1H-imidazole-4-carboxylate, 12 (5.1 g, 6.4 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added (2,4-dimethoxypyrimidin-5-yl)boronic acid, 13 (2.4 g, 12.8 mmol), potassium fluoride (1.5 g, 25.6 mmol), and 1,1'-bis
  • Step 9 To a stirred solution of ethyl 1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-(((5-chloro-1- methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-2-(2,4-dimethoxypyrimidin-5-yl)- 1H-imidazole-4-carboxylate, 14 (1.3 g, 1.5 mmol) in THF (20 mL) was added 1(M) TBAF in THF (3.01 ml, 3.01 mmol) at 0 °C and then it was stirred at room temperature for 2 h.
  • Step 10 To a solution of ethyl 5-(((5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)(4- chlorophenyl)methyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-hydroxypropyl)-1H-imidazole-4- carboxylate, 15 (1.8 g, 2.9 mmol) in THF:MeOH [27 mL (2:1)] was added aqueous NaOH (233 mg, 5.8 mmol) in water (9 mL) dropwise at 0 °C, the reaction mixture was then allowed to room temperature and stirred for 16 h.
  • Step 11 To a solution of 5-(((5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)(4- chlorophenyl)methyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-hydroxypropyl)-1H-imidazole-4-carboxylic acid, 16 (327 mg, 0.56 mmol), in CH 2 Cl 2 (8 mL) was added N,N-Diisopropylethylamine (0.5 mL, 2.8 mmol) and p-Toluenesulfonyl chloride (159 mg, 0.8 mmol) at 0 °C and stirred it at rt for 36 h.
  • reaction mixture was quenched with water (5 ml) and extracted with CH2Cl2 (20 mL x 2), combined organic layer was washed brine solution (10 mL), the combined organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure, to get crude material which was purified by silica gel column to afford the 5-(5-chloro-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-hydroxypropyl)-5,6- dihydropyrrolo[3,4-d]imidazol-4(1H)-one, 17 (180 mg, 0.26 mmol, 46.6% yield) as dark brown gel.
  • Step 12 To a solution of 5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-hydroxypropyl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one, 17 (207 mg, 0.
  • Step 13 To a stirred solution of crude 3-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6- (4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-4-oxo-5,6-dihydropyrrolo[3,4-d]imidazol-1(4H)- yl)propyl methanesulfonate (313 mg, 0.362 mmol, 75% purity) in N, N-Dimethylformamide (8 mL) , was added sodium azide (118 mg, 1.810 mmol) at rt.
  • reaction mixture was heated at 60 °C for 2 h.
  • the reaction was monitored by UPLC.
  • the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure the crude material, which was purified by normal phase column chromatography (MeOH/CH 2 Cl 2 ) to afford 1-(3-azidopropyl)-5-(5- chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)- 5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one, 19 (107 mg, 0.152 mmol, 42.1% yield).
  • Step 14 A reaction vial was charged with 1-(3-azidopropyl)-5-(5-chloro-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one, 19 (20 mg, 0.026 mmol), tert-butyl prop-2-yn-1-ylcarbamate, 20 (4.01 mg, 0.026 mmol), copper(II) sulfate pentahydrate (1.289 mg, 5.16 ⁇ mol) and sodium ascorbate (1.023 mg, 5.16 ⁇ mol) at room temperature and then was added T
  • reaction mixture was degassed with N 2 and stirred it at room temperature for 16 h.
  • the reaction was monitored by UPLC and TLC. After full consumption of starting materials, the reaction mixture was diluted with ethyl acetate (2 mL) and the organic layer was dried over anhydrous Na 2 SO 4 and concentrated under vacuo.
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (S)-21 (20 mg, 0.027 mmol) and afforded the crude product, (S)-1-(3-(4- (aminomethyl)-1H-1,2,3-triazol-1-yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (19 mg, 0.025 mmol, 97% LCMS purity) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A2 (5.3 mg, 0.013 mmol), and (S)-1-(3-(4-(aminomethyl)-1H-1,2,3-triazol-1- yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (9.5 mg, 0.013 mmol) and coupling reagent, BOP (11.8 mg, 0.026 mmol
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (S)-21 (20 mg, 0.027 mmol) and afforded the crude product, (S)-1-(3-(4- (aminomethyl)-1H-1,2,3-triazol-1-yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (19 mg, 0.025 mmol, 97% LCMS purity) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A1 (5.6 mg, 0.013 mmol), and (S)-1-(3-(4-(aminomethyl)-1H-1,2,3-triazol-1- yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (9.5 mg, 0.013 mmol) and coupling reagent, BOP (11.2 mg, 0.026 mmol
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (S)-21 (30 mg, 0.04 mmol) and afforded the crude product, (S)-1-(3-(4- (aminomethyl)-1H-1,2,3-triazol-1-yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (28 mg, 0.036 mmol, 99.9% LCMS purity) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A3 (12.3 mg, 0.019 mmol), and (S)-1-(3-(4-(aminomethyl)-1H-1,2,3-triazol-1- yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (14 mg, 0.019 mmol) and coupling reagent, BOP (41.4 mg, 0.094 mmol
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (S)-21 (30 mg, 0.04 mmol) and afforded the crude product, (S)-1-(3-(4- (aminomethyl)-1H-1,2,3-triazol-1-yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (28 mg, 0.036 mmol, 99.9% LCMS
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A4 (11.3 mg, 0.019 mmol), and (S)-1-(3-(4-(aminomethyl)-1H-1,2,3-triazol-1- yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (14 mg, 0.019 mmol) and coupling reagent, BOP (41.4 mg, 0.094 mmol
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (S)-21 (15 mg, 0.020 mmol) and afforded the crude product, (S)-1-(3-(4- (aminomethyl)-1H-1,2,3-triazol-1-yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (14.9 mg, 0.019 mmol, 92% LCMS pure) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A5 (8.3 mg, 0.019 mmol), and (S)-1-(3-(4-(aminomethyl)-1H-1,2,3-triazol-1- yl)propyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (14.9 mg, 0.019 mmol) and coupling reagent, BOP (17.7 mg, 0.04 m
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (R)-21 (10 mg, 0.013 mmol) and afforded the crude product, (R)-5-(5-chloro- 1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4- (((2,2,2-trifluoroacetyl)-l4-azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one trifluoroacetic acid salt (9.8 mg, 0.013 mmol, 99.9% LCMS purity) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A5 (7.8 mg, 0.019 mmol), and (R)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4-(((2,2,2-trifluoroacetyl)-l4- azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (7 mg, 9.35 ⁇ mol) and coupling rea
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (R)-21 (20 mg, 0.027 mmol) and afforded the crude product, (R)-5-(5-chloro- 1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4- (((2,2,2-trifluoroacetyl)-l4-azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one trifluoroacetic acid salt (19.9 mg, 0.027 mmol, 99.9% LCMS purity) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A2 (5.6 mg, 0.013 mmol), and (R)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4-(((2,2,2-trifluoroacetyl)-l4- azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (9.5 mg, 0.013 mmol) and coupling rea
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (R)-21 (10 mg, 0.013 mmol) and afforded the crude product, (R)-5-(5-chloro- 1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4- (((2,2,2-trifluoroacetyl)-l4-azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one trifluoroacetic acid salt (9.8 mg, 0.013 mmol, 99.9% LCMS purity) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A1 (6.0 mg, 0.013 mmol), and (R)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4-(((2,2,2-trifluoroacetyl)-l4- azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (10.0 mg, 0.013 mmol) and coupling rea
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (R)-21 (22 mg, 0.029 mmol) and afforded the crude product, (R)-5-(5-chloro- 1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4- (((2,2,2-trifluoroacetyl)-l4-azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one trifluoroacetic acid salt (20 mg, 0.028 mmol, 96% LCMS purity) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A4 (8.1 mg, 0.013 mmol), and (R)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4-(((2,2,2-trifluoroacetyl)-l4- azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (10 mg, 0.013 mmol) and coupling reagent
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from (R)-21 (22 mg, 0.029 mmol) and afforded the crude product, (R)-5-(5-chloro- 1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4- (((2,2,2-trifluoroacetyl)-l4-azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one trifluoroacetic acid salt (20 mg, 0.028 mmol, 96% LCMS purity) as yellow gel and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A3 (8.8 mg, 0.013 mmol), and (R)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(3-(4-(((2,2,2-trifluoroacetyl)-l4- azaneyl)methyl)-1H-1,2,3-triazol-1-yl)propyl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one trifluoroacetic acid salt (10 mg, 0.013 mmol) and coupling
  • Step 2 To a stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-hydroxy-3-methyl-1,3- dihydro-2H-benzo[d]imidazol-2-one (100 mg, 0.221 mmol), tert-butyl 6-(tosyloxy)-2- azaspiro[3.3]heptane-2-carboxylate (122 mg, 0.331 mmol) ) in N, N-Dimethylformamide ( 2 ml) was added Cs2CO3 (216 mg, 0.662 mmol) at 27°C under reaction nitrogen atmosphere. The reaction was stirred at 27°C for 3 h. Progress of the reaction monitored by LCMS.
  • reaction mixture was quenched by the addition of water (20 mL) and extracted with Ethyl acetate (2 x 25 mL). The combined organic layer was washed with cold water (15 mL), followed by brine (15 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude tert-butyl 6-((1-(2,6- bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate (100 mg, 0.146 mmol, 66.4 % yield) as an yellow solid and which was directly used for the next step.
  • Step 3 To a stirred solution of tert-butyl 6-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (100 mg, 0.154 mmol) was dissolved in Ethyl acetate (10 ml) was added 10% Pd-C (164 mg, 0.154 mmol resulting reaction mixture was stirred at RT for 16 h Under hydrogen gas atmosphere 1(5psi).
  • Step 4 To a stirred solution of tert-butyl 6-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (120mg, 0.255 mmol) in Dichloromethane (5ml) was added TFA (2ml) at 0 °C under reaction nitrogen atmosphere. The reaction was stirred at RT for 2 h.
  • Step 5 20 (35 mg, 0.044 mmol) was dissolved in N, N-Dimethylformamide (1.0 mL). To this reaction mixture were added N,N-Diisopropylethylamine (35.8 mg, 0.277 mmol), BOP (49.0 mg, 0.111 mmol) followed by 3-(3-methyl-2-oxo-4-((2-(2,2,2-trifluoroacetyl)-2l4-azaspiro[3.3]heptan-6-yl)oxy)- 2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (35.58 mg, 0.096 mmol) at RT.
  • N,N-Diisopropylethylamine 35.8 mg, 0.277 mmol
  • BOP 49.0 mg, 0.111 mmol
  • Step-1 To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (1, 5g, 18.23 mmol) in N, N-Dimethylformamide ( 75 ml). N,N-Diisopropylethylamine (3.53 g, 27.3 mmol) was added and it was stirred for 5 min. To this reaction mixture tert-butyl 2-bromoacetate (2, 5.33 g, 27.3 mmol) in N, N-Dimethylformamide (25 ml) was added dropwise, and the final mixture was stirred for 4h at rt.
  • Step-2 To a clean and dry RBF tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)oxy)acetate (3, 1.1 g, 2.83 mmol) was dissolved in Dichloromethane (40 ml) at 0 °C, trifluoroacetic acid (1.909 ml, 24.78 mmol) was added dropwise under nitrogen condition and then stirred on rt for overnight.
  • Step-3 In a 25 mL dried round bottom flask (1 neck) under nitrogen atmosphere,2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetic acid (4, 0.5 g, 1.505 mmol) and tert-butyl 4- aminopiperidine-1-carboxylate (5, 0.452 g, 2.257 mmol) was dissolved in N, N-Dimethylformamide (5 ml) To this reaction mixture, N,N-Diisopropylethylamine (1.314 ml, 7.52 mmol) and HATU (0.858 g, 2.257 mmol) were added at 0 °C under nitrogen atmosphere.
  • Reaction mixture was stirred at 25 °C for 3h under nitrogen atmosphere. Reaction monitored by UPLC showed desired mass peak. Reaction mixture was diluted with water (10 mL) and extracted with 5%MeOH/ Dichloromethane (20 mL X 3) and combined organic extract was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude.
  • Step-4 In a 25 mL dried round bottom flask (1 neck) under nitrogen atmosphere, tert-butyl 4-(2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)piperidine-1-carboxylate (6, 350 mg, 0.680 mmol) in Dichloromethane (3 ml) To this reaction mixture HCl in Dioxane (2 ml, 0.680 mmol) was added at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 3h under nitrogen atmosphere. Reaction monitored by UPLC showed desired mas peak.
  • Step-5 In a 25 mL dried round bottom flask (1 neck) under nitrogen atmosphere, 2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(piperidin-4-yl)acetamide, HCl (7, 500 mg, 1.109 mmol) was dissolved in N, N-Dimethylformamide (5 ml)).
  • Step-6 To a stirred solution of tert-butyl (4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetamido)piperidin-1-yl)butyl)carbamate (9, 500 mg, 0.854 mmol) in Dichloromethane (5 ml) was cooled to 0 °C was added Dioxane HCl (2.5 ml, 0.854 mmol) and the reaction mixture was stirred at 25 °C for 2h. Reaction mixture was monitored by TLC and UPLC.
  • Step-7 To a stirred solution of N-(1-(4-aminobutyl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide, HCl (10, 25 mg, 0.048 mmol) and (S)-5-(5-(5-chloro-1- methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6- tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxynicotinic acid (20, 27.2 mg, 0.048 mmol) in N, N- Dimethylformamide (1 ml), To this reaction mixture N,N-Diisopropylethylamine(0.042 ml)
  • Step-1 To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (1, 5g, 18.23 mmol) in N, N-Dimethylformamide ( 75 ml). N,N-Diisopropylethylamine (3.53 g, 27.3 mmol) was added and it was stirred for 5 min. To this reaction mixture tert-butyl 2-bromoacetate (2, 5.33 g, 27.3 mmol) in N, N-Dimethylformamide (25 ml) was added dropwise, and the final mixture was stirred for 4h at rt.
  • Step-2 To a clean and dry RBF tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)oxy)acetate (3, 1.1 g, 2.83 mmol) was dissolved in Dichloromethane (40 ml) at 0 °C, trifluoroacetic acid (1.909 ml, 24.78 mmol) was added dropwise under nitrogen condition and then stirred on rt for overnight.
  • Step-3 In a 50 mL dried round bottom flask (1 neck) under nitrogen atmosphere,4-aminobutan-1- ol (8, 1 g, 11.22 mmol) was dissolved in Acetone (10 ml) . To this reaction mixture N- (Benzyloxycarbonyloxy)succinimide (2.80 g, 11.22 mmol), was added at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 6 h under nitrogen atmosphere. Reaction was monitored by TLC showed new non polar spot was observed and UPLC showed desired mass peak. Reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL X 3).
  • Step-4 In a 50 mL dried round bottom flask (1 neck) attached with under nitrogen atmosphere, benzyl (4-hydroxybutyl)carbamate (9, 1.5 g, 6.72 mmol) was dissolved in Dichloromethane (25 ml) and cooled to 0 °C. To this reaction mixture, imidazole (0.869 g, 12.76 mmol),triphenylphosphine (2.73 g, 10.41 mmol) and iodine (2.80 g, 11.02 mmol) were added 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 16h under nitrogen atmosphere. Reaction mixture was monitored by UPLC showed desired mass peak.
  • Step-5 In a 25 mL dried round bottom flask (1 neck) under nitrogen atmosphere, benzyl (4- hydroxybutyl)carbamate (10, 500 mg, 2.239 mmol) was dissolved in N, N-Dimethylformamide (5 ml). To this reaction mixture, N, N-Diisopropylethylamine (1.173 ml, 6.72 mmol) and tert-butyl piperidin-4- ylcarbamate (11, 673 mg, 3.36 mmol) were added at 0 °C under nitrogen atmosphere.
  • Reaction mixture was stirred at 25 °C for 16h under nitrogen atmosphere. Reaction mixture was monitored by TLC showed one new polar spot in uv active and UPLC showed desired mass was showed. Reaction mixture was diluted with water (10 mL) and extracted with Ethyl acetate (20 mL X3). combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude.
  • Step-6 In a 25 mL dried round bottom flask (1 neck) benzyl (4-(4-((tert- butoxycarbonyl)amino)piperidin-1-yl)butyl)carbamate (12, 300 mg, 0.740 mmol) was dissolved in EtOH (3 ml)and the reaction mixture was degassed with nitrogen for 2 min. To this reaction mixture Pd/C 10% (60 mg, 0.740 mmol) was added and the reaction mixture stirred in presence of H2 with 50 psi at 50 °C for 5h. Reaction mixture was monitored by TLC showed SM was intact after 16hrs and Reaction was stirred at 50 °C for 2hr at 50 psi.
  • reaction mixture was bubbled with nitrogen gas for x min and then reaction mixture was filtered through celite bed and bed was washed with Methanol 200 mL . Filtrate was concentrated under reduced pressure get crude. Crude co-distilled with toluene 10 mL and dried under high vacuum to afford tert-butyl (1-(4- aminobutyl)piperidin-4-yl)carbamate (5, 250 mg, 0.912 mmol, 123 % yield) as a yellow liquid.
  • Step-7 In a 25 mL dried round bottom flask (1 neck) attached with condenser and temperature sensor under nitrogen atmosphere 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetic acid (4, 50 mg, 0.150 mmol) and tert-butyl (1-(4-aminobutyl)piperidin-4-yl)carbamate (5, 53.1 mg, 0.196 mmol) was dissolved in N, N-Dimethylformamide (3 ml).
  • Step-8 In a 25 mL dried round bottom flask (1 neck) under nitrogen atmosphere, tert-butyl (1-(4- (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)butyl)piperidin-4-yl)carbamate (6, 50 mg, 0.085 mmol) was dissolved in Dichloromethane (1 ml). To this reaction mixture,HCl in Dioxane (0.5 ⁇ l, 2.000 ⁇ mol) was added at 0 o C under nitrogen atmosphere. Reaction mixture was stirred at 25°C for 1h under nitrogen atmosphere. Reaction mixture was monitored by UPLC.
  • Step-9 In a 25 mL dried round bottom flask (1 neck) attached with condenser and temperature sensor under nitrogen atmosphere N-(4-(4-aminopiperidin-1-yl)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (7, 10 mg, 0.019 mmol) and (S)-5-(5-(5-chloro-1- methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6- tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxynicotinic acid (20, 14.16 mg, 0.025 mmol) was dissolved in N, N-Dimethylformamide (3 ml).
  • Step 1 To a stirred solution of tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (303 mg, 1.259 mmol) and 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one (500mg, 0.968 mmol) in t-Butanol (15 mL), was added Cs 2 CO 3 (946 mg, 2.90 mmol) at 25 °C.
  • the reaction was degassed with N 2 for 5 min, and added Ruphos (45.2 mg, 0.097 mmol)) followed by Pd 2 (dba) 3 (89 mg, 0.097 mmol) and degassing continued for 2 min at 25 °C.
  • the reaction mixture was stirred at 100 °C for 16 h.
  • the reaction was monitored by TLC, after completion.
  • the reaction was quenched with water (50 mL) and extracted with Ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • Step 2 To a stirred solution of tert-butyl 2-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (370 mg, 0.372 mmol) in ethyacetate (30 mL) was added 10% Pd/C (396 mg, 0.372 mmol) at 25 °C. reaction mixture was stirred at 25 °C for 48 h under H 2 atmosphere (balloon pressure). Reaction progress was monitored by UPLC.
  • Step 3 A stirred solution of tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate(35 mg, 0.070 mmol) in Dichloromethane (2 mL) was added TFA (1.0 mL, 12.98 mmol) at 0 oC. The reaction mixture was stirred at room temp for 1 h. Reaction was monitored by TLC, after completion.
  • Step 4 To a stirred solution of (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxynicotinic acid (25 mg, 0.044 mmol) and 3-(3-methyl-2-oxo-4-((7-(2,2,2-trifluoroacetyl)-7l4-azaspiro[3.5]nonan-2- yl)amino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (28.3 mg, 0.057 mmol) in N, N- Dimethylformamide (1 mL).
  • reaction mixture was added N,N-Diisopropylethylamine (56.8 mg, 0.440 mmol) and 50% T 3 P in Ethyl acetate (56.0 mg, 0.088 mmol) at 25 °C.
  • the reaction mixture was stirred at 25°C for 16 h.
  • Step 1 To a stirred solution of 2-bromo-3-fluoro-6-nitroaniline (1 g, 4.26 mmol) in dry N, N- Dimethylformamide (15 ml), was added NaH (60% in mineral oil) (170 mg, 4.26 mmol) portion-wise at 0 °C, under N 2 and the resulting reaction mixture was allowed to stir for 15 min. To this, was added MeI (0.319 ml, 5.11 mmol) drop-wise at 0 °C and the reaction mixture was stirred for 1 h. The reaction was monitored by TLC. Upon completion, the reaction was quenched with ice-water (50 mL) and the aq.
  • Step 2 To a stirred solution of crude 2-bromo-3-fluoro-N-methyl-6-nitroaniline (980 mg, 3.34 mmol) in THF (10 ml), was added N, N-Diisopropylethylamine (2.92 ml, 16.72 mmol), DMAP (40.9 mg, 0.334 mmol) and Boc 2 O (1.165 ml, 5.02 mmol) at 25 °C. The reaction mixture was stirred at 50 °C for 3 h. Upon completion, the reaction was quenched with water (50 mL), and the aq. phase was extracted with Ethyl acetate (3 ⁇ 50 mL).
  • Step 3 To a stirred solution of crude tert-butyl (2-bromo-3-fluoro-6-nitrophenyl) (methyl)carbamate (1.3 g, 3.72 mmol) in 1:1 Methanol /H 2 O (20 ml), was added NH 4 Cl (1.992 g, 37.2 mmol), followed by Zn-dust (1.217 g, 18.62 mmol) at 25 °C. The resulting reaction was stirred at 50 °C for 6 h. Upon completion, the reaction mixture was passed through Celite, and the bed was washed with Ethyl acetate (300 mL) and the filtrate was evaporated to dryness.
  • Step 4 To a stirred solution of tert-butyl (6-amino-2-bromo-3-fluorophenyl)(methyl)carbamate (0.350 g, 1.097 mmol) and 2,6-bis(benzyloxy)-3-iodopyridine (0.549 g, 1.316 mmol) in t-BuOH (10 ml), was added Cs 2 CO 3 (1.072 g, 3.29 mmol) at 25 °C. The reaction was degassed by bubbling with N 2 for 10 min.
  • Step 5 A stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluoro-3-methyl-1,3- dihydro-2H-benzo[d]imidazol-2-one (150 mg, 0.281 mmol) in 5:1 dioxane/water (12 ml) was degasified for 15 min prior to the sequential addition of Pd 2 (dba) 3 (25.7 mg, 0.028 mmol), t BuXPhos (23.84 mg, 0.056 mmol) and finally KOH (23.62 mg, 0.421 mmol).
  • Step 6 To a stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-4-hydroxy-3-methyl- 1,3-dihydro-2H-benzo[d]imidazol-2-one (86 mg, 0.182 mmol) and tert-butyl 4-(tosyloxy)piperidine-1- carboxylate (84 mg, 0.237 mmol) in N, N-Dimethylformamide (4 ml), was added Cs 2 CO 3 (178 mg, 0.547 mmol) at 25 °C and the resulting reaction mixture was stirred at 90 °C for 12 h. The progress was monitored by LC-MS analysis.
  • reaction mass was passed through Celite and the bed was washed with Ethyl acetate.
  • the filtrate was concentrated and purified by flash column chromatography, using 40% Ethyl acetate in hexanes to afford tert-butyl 4-((1-(2,6- bis(benzyloxy)pyridin-3-yl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)oxy)piperidine-1-carboxylate (106 mg, 0.123 mmol, 67.5 % yield) as a colorless oil.
  • Step 7 To a stirred solution of tert-butyl 4-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)piperidine-1-carboxylate (106 mg, 0.162 mmol) in Methanol (10 ml), was added Pd-C (10% on carbon, w/w) (55 mg, 0.052 mmol) at 25 °C.
  • Step 8 To a stirred solution of tert-butyl 4-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)piperidine-1-carboxylate (30 mg, 0.046 mmol) in Acetonitrile (3 ml), was added HCl (4M in dioxane) (0.057 ml, 0.229 mmol) at 0 °C.
  • Step 9 To a stirred solution of 20 (15 mg, 0.026 mmol) and 3-(5-fluoro-3-methyl-2-oxo-4- (piperidin-4-yloxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperi-dine-2,6-dione hydro-chloride (25 mg, 0.028 mmol) in N, N-Dimethylformamide (3 ml), was added N, N-Diisopropylethylamine (4.61 ⁇ l, 0.026 mmol), followed by T 3 P (50% in Ethyl acetate) (0.026 mmol) at 25 °C.
  • Step 1 To a stirred solution of tert-butyl 6-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (100 mg, 0.213 mmol) in THF (2 ml), was added Cs 2 CO 3 (208 mg, 0.638 mmol) and MeI (0.066 ml, 1.063 mmol) at 25 °C, and the reaction mixture was stirred for 16 h. The reaction was monitored by TLC and LC-MS analysis.
  • Step 2 To a stirred solution of tert-butyl 6-((3-methyl-1-(1-methyl-2,6-dioxopiperidin-3-yl)-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)-2-azaspiro[3.3]heptane-2-carbo-xylate (100 mg, 0.206 mmol) in Acetonitrile (10 ml), was added 4M HCl in dioxane (0.516 ml, 2.064 mmol) drop-wise at 0 °C and the resulting reaction mixture was stirred for 40 min.
  • Step 3 To a stirred solution of 20 (100 mg, 0.176 mmol) and 3-(4-((2-azaspiro[3.3]heptan-6- yl)oxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-methylpiperi-dine-2,6-dione hydrochloride (89 mg, 0.211 mmol) in N, N-Dimethylformamide (3 ml), was added N, N- Diisopropylethylamine (0.615 ml, 3.52 mmol), followed by T 3 P (50% in EA) (0.262 ml, 0.440 mmol) at 25 °C and the resulting reaction mixture was stirred under N 2 overnight.
  • Step 1 To a stirred solution of tert-butyl 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carboxylate (100 mg, 0.213 mmol) in THF (3 ml), was added Cs 2 CO 3 (208 mg, 0.638 mmol), followed by MeI (0.066 ml, 1.063 mmol) slowly at 25 °C and the resulting reaction mix was stirred overnight. The progress of the reaction was monitored by LC-MS analysis.
  • reaction mixture was filtered through Celite and the pad was washed with Ethyl acetate (70 mL).
  • the filtrate was concentrated and purified by flash column chromatography, using 5% Methanol in Dichloromethane, to afford the desired product tert-butyl 4-(2-(3-methyl-1-(1-methyl- 2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carboxylate (104 mg, 0.204 mmol, 96 % yield) as a colorless oil.
  • Step 2 To a stirred solution of tert-butyl 4-(2-(3-methyl-1-(1-methyl-2,6-dioxopiperidin-3-yl)-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carboxylate (104 mg, 0.215 mmol) in Acetonitrile (3 ml), was added HCl (4M in dioxane) (0.268 ml, 1.073 mmol), slowly at 0 °C and the resulting reaction mixture was then stirred for 30 min.
  • Step 3 To a stirred solution of 20 (100 mg, 0.176 mmol) and 1-methyl-3-(3-methyl-2-oxo-5-(2- (piperidin-4-yl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (89 mg, 0.211 mmol) in N, N-Dimethylformamide (3 ml), was added N, N-Diisopropylethylamine (22.74 mg, 0.176 mmol), followed by T 3 P (50% in EA) (0.105 ml, 0.176 mmol) at 25 °C and the resulting reaction mixture was stirred for 4 h.
  • Step 2 To a stirred solution of tert-butyl (R)-4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (47 mg, 0.095 mmol) in Acetonitrile (3 ml), was added TFA (162 mg, 1.420 mmol) at 25 °C and the resulting reaction mixture was stirred at 25 °C for 4 h.
  • Step 3 To a stirred solution of 20 (25 mg, 0.044 mmol) and (R)-3-(3-methyl-2-oxo-4-(3-((1- (2,2,2-trifluoroacetyl)-1l4-piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione (26.0 mg, 0.053 mmol) in N, N-Dimethylformamide (3 ml), was added N, N- Diisopropylethylamine (0.038 ml, 0.220 mmol), followed by T3P (50% in EA) (0.065 ml, 0.110 mmol) at 25 °C and the resulting reaction mixture was stirred under N 2 for 4 h.
  • Step 4 To a stirred solution of tert-butyl (S)-4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (40 mg, 0.081 mmol) in Acetonitrile (3 ml), was added TFA (138 mg, 1.208 mmol) at 25 °C and the resulting reaction mix was stirred at 25 °C for 4 h. The progress of the reaction was monitored by LC-MS analysis.
  • Step 5 To a stirred solution of 20 (15 mg, 0.026 mmol) and (S)-3-(3-methyl-2-oxo-4-(3-((1-(2,2,2- trifluoroacetyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d] imidazol-1-yl)piperidine- 2,6-dione (19.49 mg, 0.040 mmol) in N, N-Dimethylformamide (2.5 ml), was added N, N- Diisopropylethylamine (68.2 mg, 0.528 mmol), followed by T 3 P (50% in EA) (42.0 mg, 0.066 mmol) at 25 °C and the resulting reaction mixture was stirred under N 2 for 4 h.
  • Step 1 In a 1000 mL dried two neck RB flask charged with ethyl 2-isocyanoacetate (97 ml, 884 mmol) and EtOH (600 ml) under N 2 at 0 °C. To this reaction mixture, was added 1,1-dimethoxy-N,N- dimethylmethanamine (153 ml, 1149 mmol) using dropping funnel at 0 °C. The resulting reaction mixture was stirred at rt for 24 h. The reaction was monitored by TLC.
  • Step 2 A 250 mL sealed tube was charged with ethyl (Z)-3-(dimethylamino)-2-isocyanoacrylate (25 g, 149 mmol), 4-aminobutan-1-ol (14.57 g, 163 mmol) and n-Butanol (7 ml), and the resulting reaction mixture was slowly refluxed at 130 °C for 24 h. The reaction was monitored by TLC.
  • Step 3 To a stirred solution of ethyl 1-(4-hydroxybutyl)-1H-imidazole-4-carboxylate (20 g, 94 mmol) in Dichloromethane (200 ml) was added imidazole (12.83 g, 188 mmol) and TBDPS-Cl (36.3 ml, 141 mmol) at 0 °C and stirred at rt for 4 h. The reaction was monitored by TLC. The reaction was quenched with water (500 mL) and the aq. phase was extracted with Dichloromethane (2 ⁇ 300 mL). Collective organic phase was dried over Na2SO4, filtered and concentrated.
  • Step 4 To a stirred solution of ethyl 1-(4-((tert-butyldiphenylsilyl)oxy)butyl)-1H-imidazole-4- carboxylate (10. g, 22.19 mmol) in THF (200 ml), was added K 3 PO 4 (11.78 g, 55.5 mmol), followed by NBS (7.90 g, 44.4 mmol) at 0 °C and the reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. Upon completion, the reaction was quenched with ice-cold water (100 mL) and the aq.
  • Step 5 To a stirred solution of ethyl 2-bromo-1-(4-((tert-butyldiphenylsilyl)oxy) butyl)-1H- imidazole-4-carboxylate (5.0 g, 9.44 mmol) in THF (50 ml), was added LDA (9.44 ml, 18.88 mmol) at - 78 °C dropwise and the stirring was continued for 1 h. To this, was added 4-chlorobenzaldehyde (1.991 g, 14.16 mmol) in THF (1 mL) drop-wise, and the resulting reaction mixture was stirred for 2 h at -78 °C.
  • reaction was monitored by TLC and LC-MS. Upon completion, the reaction was quenched with sat. NH 4 Cl at -78 °C and the aq. phase was extracted with Ethyl acetate (3 ⁇ 100 mL). The collective organic phase was dried over Na 2 SO 4 , filtered and concentrated.
  • Step 6 To a stirred solution of compound ethyl 2-bromo-1-(4-((tert-butyldiphenylsilyl)oxy)butyl)- 5-((4-chlorophenyl)(hydroxy)methyl)-1H-imidazole-4-carboxylate (10.5 g, 15.67 mmol) in Dichloromethane (80 ml), was added N, N-Diisopropylethylamine (13.68 ml, 78 mmol), followed by SOCl 2 (1.705 ml, 23.50 mmol) at 0 °C, and the reaction was stirred for 1 h. The reaction was monitored by TLC.
  • reaction was quenched with sat. aq. NaHCO 3 solution (25 mL) at 0 °C.
  • aqueous layer was extracted with Dichloromethane (3 ⁇ 50 mL).
  • the combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step 7 In a pressure vessel, ethyl 2-bromo-1-(4-((tert-butyldiphenylsilyl)oxy)butyl)-5-(chloro(4- chlorophenyl)methyl)-1H-imidazole-4-carboxylate (5.0 g, 7.46mmol) in Acetonitrile (50 ml) was treated with N, N-Diisopropylethylamine (2.009 ml, 11.19 mmol) and 3-amino-5-chloro-1-methylpyridin-2(1H)- one (1.420 g, 8.95 mmol) and the reaction mixture was stirred at 80 °C for 24 h. The reaction was monitored by TLC.
  • Step 8 To a stirred solution of ethyl 2-bromo-1-(4-((tert-butyldiphenyl-silyl)oxy)butyl)-5-(((5- chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)(4-chloro-phenyl)methyl)-1H-imidazole-4- carboxylate (3 g, 3.70 mmol) (3.0 g, 3.70 mmol) in 4:1 dioxane/H 2 O (35 ml), was added LiOH (0.443 g, 18.50 mmol) at rt and the resulting reaction mixture was stirred for 16 h at rt.
  • Step 9 To a stirred solution of 2-bromo-1-(4-((tert-butyldiphenylsilyl)oxy)butyl)-5-(((5-chloro-1- methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1H-imidazole-4-carboxylic acid (2 g, 2.56 mmol) in Dichloromethane (5 ml), was added N, N-Diisopropylethylamine (1.339 ml, 7.67 mmol), followed by TsCl (0.585 g, 3.07 mmol) in portions at 0 °C and the resulting reaction was stirred for 16 h at rt.
  • Step 11 To a stirred solution of 1-(4-((tert-butyldiphenylsilyl)oxy)butyl)-5-(5-chloro-1-methyl-2- oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5,6- dihydropyrrolo[3,4-d]imidazol-4(1H)-one (900 mg, 1.038 mmol) in THF (10 ml), was added TBAF (2M in THF) (2.59 ml, 5.19 mmol), followed by AcOH (62.3 mg, 1.038 mmol) at 0 °C and the resulting reaction mixture was stirred at rt for 16
  • Step-12 To a stirred solution of (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-(4-hydroxybutyl)-5,6-dihy-dropyrrolo[3,4-d]imidazol- 4(1H)-one (0.7 g, 1.196 mmol) in Acetonitrile (5 ml), was added NMO (1.401 g, 11.96 mmol), TPAP (0.042 g, 0.120 mmol) and the resulting reaction mixture was stirred at rt for 16 h.
  • Step 13 4-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-4-oxo-5,6-dihydropyrrolo[3,4-d]imidazol-1(4H)-yl)butanoic acid (123 mg, 0.205 mmol) was chirally resoluted by chiral SFC purification, using R,R-Whelk column; Instrument: PIC 22-027; Column: R,R-Whelk 30 mm (250 ⁇ 30) mm, 5 ⁇ m; Mobile Phase: CO 2 : 0.2% FA in IPA: Acetonitrile [50:50];
  • Step 2 To a stirred solution of A6 (15 mg, 0.025 mmol) and 3-(3-methyl-2-oxo-4-(piperidin-4- ylmethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochlo--ride (15.35 mg, 0.038 mmol) in N, N-Dimethylformamide (2 ml), was added N, N-Diisopropylethylamine (0.087 ml, 0.500 mmol), followed by T 3 P (50% in EA) (0.037 ml, 0.063 mmol) at 25 °C and the resulting reaction mixture was stirred under N 2 overnight.
  • A6 15 mg, 0.025 mmol
  • Step 1 To a stirred solution of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)piperidine-1-carboxylate (35 mg, 0.076 mmol) in Acetonitrile (3 ml), was added 4M HCl in dioxane (0.191 ml, 0.763 mmol) at 0 °C and the resulting reaction mixture was stirred for 30 min. The reaction was monitored by LC-MS analysis.
  • Step 2 To a stirred solution of A6 (15 mg, 0.025 mmol) and 3-(3-methyl-2-oxo-4-(piperidin-4- yloxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (14.82 mg, 0.038 mmol) in N, N-Dimethylformamide (3 ml), was added N, N-Diisopropylethylamine (0.087 ml, 0.500 mmol), followed by T 3 P (50% in EA) (39.8 mg, 0.063 mmol) at 25 °C and the resulting reaction mixture was stirred under N 2 atmosphere overnight.
  • A6 15 mg, 0.025 mmol
  • Step 1 To a stirred solution of tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (35 mg, 0.070 mmol) in Acetonitrile (3 ml), was added TFA (0.081 ml, 1.057 mmol) at 25 °C. The resulting reaction mix was then stirred at 25 °C for 4 h. The progress of the reaction was monitored by TLC and LC-MS analysis.
  • Step 2 To a stirred solution of A6 (15 mg, 0.025 mmol) and 3-(3-methyl-2-oxo-4-(3-((1-(2,2,2- trifluoroacetyl)-1l4-piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]-imidazol-1- yl)piperidine-2,6-dione (18.52 mg, 0.038 mmol) in N, N-Dimethylformamide (3 ml), was added N, N- Diisopropylethylamine (0.044 ml, 0.250 mmol), followed by T 3 P (50% in EA) (0.015 ml, 0.050 mmol) at 25 °C and the resulting reaction mixture was stirred for 4 h.
  • A6 15 mg, 0.025 mmol
  • Step 1 To a stirred solution of tert-butyl 7-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (40mg, 0.069 mmol) in Acetonitrile (5 ml), was added TFA (0.106 ml, 1.380 mmol) dropwise at 0 °C and the resulting reaction mixture was stirred under N 2 for 4 h. The reaction was monitored by LC-MS analysis.
  • Step 2 To a stirred solution of A6 (15 mg, 0.025 mmol) and 3-(3-methyl-2-oxo-4-(3-(2-(2,2,2- trifluoroacetyl)-2l4,7-diazaspiro[3.5]nonan-7-yl)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione (14.27 mg, 0.028 mmol) in N, N-Dimethylformamide (2 ml), was added N, N- Diisopropylethylamine (0.087 ml, 0.500 mmol), followed by T 3 P (50% in EA) (0.037 ml, 0.063 mmol) at 25 °C and the resulting reaction mixture was stirred under N 2 overnight.
  • A6 15 mg, 0.025 mmol
  • Step 1 To a stirred solution of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)ethynyl)piperidine-1-carboxylate (35 mg, 0.075 mmol) in Acetonitrile (3 ml), was added TFA (0.116 ml, 1.500 mmol) at 0 °C and the resulting reaction mixture was stirred for 3 h. The reaction was monitored by LC-MS analysis.
  • Step 2 To a stirred solution of A6 (15 mg, 0.025 mmol) and 3-(3-methyl-2-oxo-5-((1-(2,2,2- trifluoroacetyl)piperidin-4-yl)ethynyl)-2,3-dihydro-1H-benzo[d]-imidazol-1-yl)piperidine-2,6-dione (17.36 mg, 0.038 mmol) in N, N-Dimethylformamide (3 ml), was added N, N-Diisopropylethylamine (0.087 ml, 0.500 mmol), followed by T 3 P (50% in EA) (39.8 mg, 0.063 mmol) at 25 °C and the resulting reaction mixture was stirred under N 2 atmosphere overnight.
  • A6 15 mg, 0.025 mmol
  • Step-1 In a 25 mL dried round bottom flask (1 neck) under nitrogen atmosphere,tert-butyl 4-(((1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)methyl)piperidine- 1-carboxylate (30 mg, 0.063 mmol) was dissolved in Acetonitrile (4 ml). To this reaction mixture, 4N HCl in Dioxane (0.159 ml, 0.635 mmol) was added at 0 o C under nitrogen atmosphere. Reaction mixture was stirred at 25 °C for 2h under nitrogen atmosphere.
  • Step-2 To a stirred 3-(3-methyl-2-oxo-4-(piperidin-4-ylmethoxy)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride, 2 (16.37 mg, 0.040 mmol) and (S)-4-(5-(5- chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-4- oxo-5,6-dihydropyrrolo[3,4-d]imidazol-1(4H)-yl)butanoic acid (20 mg, 0.033 mmol) in N, N- Dimethylformamide (1 ml).
  • reaction mixture was was added N, N-Diisopropylethylamine (0.058 ml, 0.334 mmol) and T 3 P in Ethyl acetate (0.040 ml, 0.067 mmol) at 25 °C.
  • the reaction mixture was stirred at 25°C for 16h. After 16h reaction was monitored by UPLC.
  • Step-1 To a stirred solution of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)piperidine-1-carboxylate (0.03 g, 0.065 mmol) in Acetonitrile (4 ml).4M HCl in dioxane (0.164 ml, 0.654 mmol) was added dropwise at 0°C, and the reaction mixture was stirred for 4h at rt. Reaction was monitored by LCMS showed desired mass peak. The reaction mixture was concentrated under reduced pressure to get crude.
  • Step-2 To a clean and dry RBF 3-(3-methyl-2-oxo-4-((1-(2,2,2-trifluoroacetyl)piperidin-4- yl)oxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 2 (18.19 mg, 0.040 mmol) and (R)- 4-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin- 5-yl)-4-oxo-5,6-dihydropyrrolo[3,4-d]imidazol-1(4H)-yl)butanoic acid A7 (20 mg, 0.033 mmol) was dissolved in N, N-Dimethylformamide (2.5 ml) at 0 °C, N, N-Di
  • Step-1 To a stirred solution of tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (1) (30 mg, 0.060 mmol) in Acetonitrile (1 ml) was added TFA (0.070 ml, 0.906 mmol) at 0 °C. The reaction mixture was stirred at 25°C for 2 h, after 2h the reaction was monitored by LCMS showed desired mass peak.
  • Step-2 To a stirred solution of (S)-4-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-4-oxo-5,6-dihydropyrrolo[3,4-d]imidazol-1(4H)- yl)butanoic acid (A7), (20 mg, 0.042 mmol) and 3-(3-methyl-2-oxo-4-(3-((1-(2,2,2- trifluoroacetyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione(2) (20.54 mg, 0.042 mmol) in N, N-Dimethylformamide ( 0.5 ml).
  • N N- Diisopropylethylamine (0.073 ml, 0.417 mmol) and T 3 P in Ethyl acetate (0.05 ml, 0.083 mmol) were added and the reaction mixture stirred at 25°C for 16h. Reaction was monitored by LCMS was showed desired mass peak. The reaction mixture was evaporated under reduced pressure to get crude.
  • Step-1 In a 25 mL dried round bottom flask (1 neck) under nitrogen atmosphere, tert-butyl 7-(3- (1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl) prop-2-yn-1-yl)- 2,7-diazaspiro [3.5]nonane-2-carboxylate, 1 (30 mg, 0.058 mmol) was dissolved in Acetonitrile (2 ml). To this reaction mixture, TFA (0.066 ml, 0.863 mmol) was added at 0 °under nitrogen atmosphere.
  • TFA 0.066 ml, 0.863 mmol
  • Step-2 To a stirred 3-(3-methyl-2-oxo-4-(3-(2-(2,2,2-trifluoroacetyl)-2,7-diazaspiro [3.5] nonan- 7-yl)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, TFA, 2 (20.72 mg, 0.040 mmol) and (R)-4-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-4-oxo-5,6-dihydropyrrolo[
  • reaction mixture was added N, N- Diisopropylethylamine (43.1 mg, 0.334 mmol) and T3P in Ethyl acetate (42.5 mg, 0.067 mmol) at 0 °C.
  • the reaction mixture was stirred at 25°C for 16 h. After 16 h reaction was monitored by UPLC.
  • Step-1 To a stirred solution of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)ethynyl)piperidine-1-carboxylate, (0.030 g, 0.064 mmol) in Acetonitrile (2 ml). TFA (0.099 ml, 1.286 mmol) was added dropwise, and the final mixture was stirred for 4h at rt. Reaction was monitored by LCMS showed desired mass peak. The reaction mixture was concentrated under reduced pressure to get crude.
  • Step-2 To a clean and dry RBF 3-(3-methyl-2-oxo-5-((1-(2,2,2-trifluoroacetyl)piperidin-4- yl)ethynyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 2 (19.29 mg, 0.042 mmol) and (R)-4-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-4-oxo-5,6-dihydropyrrolo[3,4-d]imidazol-1(4H)-yl)butanoic acid A7 (25 mg, 0.042 mmol) was dissolved in N, N-Dimethylformamide (2 ml) at 0 °C, N
  • N N-Diisopropylethylamine (0.058 ml, 0.334 mmol mmol) and T3P in Ethyl acetate (0.040 ml, 0.067 mmol) were added and the reaction mixture stirred at 25°C for 16h . Reaction was monitored by LCMS, was showed desired mass peak. The reaction mixture was evaporated under reduced pressure to get crude.
  • Reaction mixture was stirred at 25 °C for 2h under nitrogen atmosphere. Reaction mixture was monitored by UPLC. Reaction mixture was diluted with D 2 O(5 mL) and extracted with 10% MeOD in Dichloromethane (3 x 10 mL).
  • Step-2 Methyl (R)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)- 1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl-6-d)-6-methoxynicotinate(100 mg, 0.176 mmol, 97 % yield) was purified by purified by SFC to afford using Lux column (Column : R,R- Whelk (250*20)mm, 5 ⁇ 5m; Mobile Phase: 0.2% FA in IPA Acetonitrile; flow rate 100 mL/min; Back pressure : 102.0 kgf/cm2r
  • Step-3 To a stirred solution of (S)-5-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl-6-d)-6-methoxynicotinic acid (10 mg, 0.018 mmol) and 3-(3-methyl-2-oxo-5-(2-(piperidin-4-yl)ethyl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (6.51 mg, 0.018 mmol) in N, N
  • Step 14 A reaction vial was charged with 1-(3-azidopropyl)-5-(5-chloro-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one (170 mg, 0.285 mmol), copper(II) sulfate pentahydrate (14.23 mg, 0.057 mmol) and Sodium ascorbate (11.29 mg, 0.057 mmol) at room temperature and then was added THF : water (1:2) (6 mL).
  • reaction mixture was degassed with N 2 and stirred it at room temperature for 16 h.
  • the crude reaction mixture solvent was evaporated under reduced pressure to afford crude product, which was purified in reverse phase at (25-30% formic acid in H 2 O and acetonitrile) afforded to get the product 1-(3-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-4-oxo-5,6-dihydropyrrolo[3,4-d]imidazol-1(4H)-yl)propyl)-1H-1,2,3-triazole- 4-carboxylic acid (35 mg, 0.051 mmol, 18.06% yield) as off-white solid.
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N1 (20 mg, 0.025 mmol) and afforded the crude product, (2S,4R)-1-((S)-3,3- dimethyl-2-(5-((2,2,2-trifluoroacetyl)-l4-azaneyl)pentanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4 methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (20 mg, 0.038 mmol, 98 % yield, 96.53% LCMS purity) as off-white solid and which was directly used for the next
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A8 (10 mg, 0.019 mmol), and (2S,4R)-1-((S)-3,3-dimethyl-2-(5-((2,2,2- trifluoroacetyl)-l4-azaneyl)pentanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (14.42 mg, 0.023 mmol) and coupling reagent, BOP (7.30 mg, 0.017 mmol).
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N2 (20 mg, 0.025 mmol) and afforded the crude product N-(4-aminobutyl)-2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide (18 mg, 0.049 mmol, 98 % yield, 97.71% LCMS Pure ) as colourless liquid, which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A8 (10 mg, 0.019 mmol), and N-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetamido)butyl)-2,2,2-trifluoroacetamide (10.76 mg, 0.021 mmol) and coupling reagent, BOP (6.86 mg, 0.016 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N3 (13 mg, 0.025 mmol) and afforded the crude product, N-(6-aminohexyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (11 mg, 0.023 mmol, 92% yield, 94% LCMS purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A8 (12.5 mg, 0.019 mmol), and N-(6-aminohexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (11 mg, 0.023 mmol) and coupling reagent, propylphosphonic anhydride solution (50% in ethyl acetate) (0.028 ml, 0.047 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N4 (13 mg, 0.023 mmol) and afforded the crude product, N-(2-(2-(2- aminoethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (11 mg, 0.022 mmol, 96% yield, 92% LCMS purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A8 (12.5 mg, 0.019 mmol), and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide hydrochloride (11 mg, 0.022 mmol) and coupling reagent, propylphosphonic anhydride solution (50% in ethyl acetate) (0.028 ml, 0.047 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N5 (13 mg, 0.026 mmol) and afforded the crude product, N-(4-aminobutyl)-2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (11 mg, 0.025 mmol, 96% yield, 100% LCMS purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A8 (12.5 mg, 0.019 mmol), and N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (11 mg, 0.025 mmol) and coupling reagent, propylphosphonic anhydride solution (50% in ethyl acetate) (0.028 ml, 0.047 mmol).
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N2 (20 mg, 0.025 mmol) and afforded the crude product, get N-(4- aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide (18 mg, 0.049 mmol, 98% yield, 97.71% LCMS Pure ) as colourless liquid, which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A9 (10 mg, 0.019 mmol), and N-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)acetamido)butyl)-2,2,2-trifluoroacetamide (10.76 mg, 0.021 mmol) and coupling reagent, BOP (7.30 mg, 0.017 mmol ).
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N1 (20 mg, 0.025 mmol) and afforded the crude product, (2S,4R)-1-((S)-3,3- dimethyl-2-(5-((2,2,2-trifluoroacetyl)-l4-azaneyl)pentanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (20 mg, 0.030 mmol, 95% yield, 93.58% LCMS purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A9 (10 mg, 0.019 mmol), and (2S,4R)-1-((S)-3,3-dimethyl-2-(5-((2,2,2- trifluoroacetyl)-l4-azaneyl)pentanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (14.42 mg, 0.023 mmol) and coupling reagent, propylphosphonic anhydride solution (50% in ethyl acetate) (0.018 mL, 0.030 mmol).
  • Step 1 The amine-TFA salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N4 (20 mg, 0.025 mmol) and afforded the crude product, get 2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(2-(2-(2-((2,2,2-trifluoroacetyl)-l4- azaneyl)ethoxy)ethoxy)ethyl)acetamide (25 mg, 0.052 mmol, 97% yield, 97% LCMS pure) as colourless liquid, which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A9 (10 mg, 0.019 mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)oxy)-N-(2-(2-(2-((2,2,2-trifluoroacetyl)-l4-azaneyl)ethoxy)ethoxy)ethyl)acetamide (12.59 mg, 0.023 mmol) and coupling reagent, BOP (7.30 mg, 0.017 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N3 (13 mg, 0.025 mmol) and afforded the crude product, N-(6-aminohexyl)- 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (11 mg, 0.024 mmol, 96% yield, 82% LCMS purity) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A9 (15.74 mg, 0.024 mmol), and N-(6-aminohexyl)-2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (11 mg, 0.024 mmol) and coupling reagent, Propylphosphonic anhydride solution (50% in EA) (0.018 mL, 0.059 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from N5 (12 mg, 0.024 mmol) and afforded the crude product, N-(4-aminobutyl)-2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (10 mg, 0.023 mmol, 95% yield) as off-white solid and which was directly used for the next step.
  • Step 2 The title compound was synthesized in analogy to the procedure described in General Procedure B from A9 (15.19 mg, 0.023 mmol), and N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)oxy)acetamide hydrochloride (10 mg, 0.023 mmol) and coupling reagent, propyl phosphonic anhydride solution (50% in EA) (0.017 mL, 0.057 mmol).
  • Step 1 The amine-HCl salt was synthesized using N-Boc deprotection procedure described in General Procedure A from tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)-7- azaspiro[3.5]nonane-7-carboxylate (200 mg, 0.414 mmol) and afforded the crude product, 3-(4-((7- azaspiro[3.5]nonan-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (174 mg, 0.406 mmol, 98% yield, 98% LCMS Purity) as off-white solid and which was directly used for the next step.

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Abstract

L'invention concerne des composés, comprenant des composés de formule (I) (par exemple, des composés de formule (I-a)), et des sels pharmaceutiquement acceptables, des stéréoisomères, des tautomères, des dérivés marqués de manière isotopique, des solvates, des hydrates, des polymorphes, des co-cristaux et des promédicaments de ceux-ci. Le composé selon l'invention est des agents de dégradation et/ou des inhibiteurs de protéines MDM2 et peut par conséquent être utilisé, par exemple, dans le traitement et/ou la prévention de maladies (par exemple, de maladies prolifératives, telles que le cancer). L'invention concerne également des compositions pharmaceutiques comprenant les composés selon l'invention, et des kits les comprenant. De plus, l'invention concerne des procédés de préparation des composés et des compositions pharmaceutiques décrits dans la description, et des intermédiaires utiles associés.
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CN118800363A (zh) * 2024-06-15 2024-10-18 南通大学附属医院 基于人工智能片段化技术的先导活性分子生成与筛选方法

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