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WO2023201012A1 - Ikzf2 degraders and uses thereof - Google Patents

Ikzf2 degraders and uses thereof Download PDF

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Publication number
WO2023201012A1
WO2023201012A1 PCT/US2023/018583 US2023018583W WO2023201012A1 WO 2023201012 A1 WO2023201012 A1 WO 2023201012A1 US 2023018583 W US2023018583 W US 2023018583W WO 2023201012 A1 WO2023201012 A1 WO 2023201012A1
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Prior art keywords
alkyl
carbocyclyl
compound
heterocyclyl
aryl
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PCT/US2023/018583
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French (fr)
Inventor
Xuqing Zhang
Shaomeng Wang
Paul Kirchhoff
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Regents Of The University Of Michigan
Oncopia Therapeutics, Inc. D/B/A/ Proteovant Therapeutics, Inc.
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Publication of WO2023201012A1 publication Critical patent/WO2023201012A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • IKZF2 DEGRADERS AND USES THEREOF RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/446,112, filed February 16, 2023, and U.S. Provisional Application No. 63/331,558, filed April 15, 2022, the contents of each of which are incorporated herein by reference in their entireties.
  • IKAROS Family Zinc Finger 2 (IKZF2) (also known as Helios) is one of the five members of the Ikaros family of transcription factors found in mammals.
  • IKZF2 contains four zinc finger domains near the N-terminus, which are involved in DNA binding, and two zinc finger domains at the C-terminus, which are involved in protein dimerization. IKZF2 is about 50% identical with Ikaros family members, Ikaros (IKZF1), Aiolos (IKZF3), and Eos (IKZF4) with highest homology in the zinc finger regions (80%+ identity). These four Ikaros family transcription factors bind to the same DNA consensus site and can heterodimerize with each other when co-expressed in cells.
  • IKZF5 The fifth Ikaros family protein, Pegasus (IKZF5), is only 25% identical to IKZF2, binds a different DNA site than other Ikaros family members and does not readily heterodimerize with the other Ikaros family proteins.
  • IKZF2, IKZFl and IKZF3 are expressed mainly in hematopoietic cells while IKZF4 and IKZF5 are expressed in a wide variety of tissues.
  • IKZF2 is a critical regulator of T cell activity and function. Genetic deletion of Helios resulted in an enhanced anti-tumor immune response. Notably, Helios is highly expressed in regulatory T cells, a subpopulation of T cells that restricts the activity of effector T cells.
  • An IKZF2-specific degrader has the potential to focus the enhanced immune response to areas within or near tumors providing a potentially more tolerable and less toxic therapeutic agent for the treatment of cancer.
  • Helios expression has also been reported to be upregulated in ‘exhausted’ T cells, in the settings of both chronic viral infections, as well as in dysfunctional chimeric antigen receptor (CAR) T cells. Overexpression or aberrant expression of Helios and various splice isoforms have been reported in several hematological malignancies, including T cell leukemias and lymphomas. Moreover, knockdown of Helios in a model of mixed lineage leukemia (MLL)-driven myeloid leukemia potently suppressed proliferation and increased cell death.
  • MLL mixed lineage leukemia
  • the present disclosure provides compounds of Formula (I’): and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables in Formula I’ is described, embodied, and exemplified herein.
  • the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.
  • the present disclosure further provides methods of degrading an IKZF2 protein in a subject or biological sample comprising administering a compound disclosed herein to the subject or contacting the biological sample with a compound disclosed herein.
  • the present disclosure further provides uses of a compound disclose herein in the manufacture of a medicament for degrading an IKZF2 protein in a subject or biological sample.
  • the present disclosure provides compounds disclosed herein for use in degrading an IKZF2 protein in a subject or biological sample.
  • the present disclosure provides methods of treating a disease or disorder comprising administering to a subject in need thereof a compound disclosed herein.
  • the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder.
  • the present disclosure provides compounds disclosed herein for use in treating a disease or disorder.
  • the present disclosure provides methods of (a) increasing IL 2 production; (b) suppressing regulatory T cells; (c) enhancing effector T cells; (d) inhibiting tumor growth; and/or (e) enhancing tumor regression in a subject, comprising administering to the subject in need thereof a compound disclosed herein.
  • the present disclosure provides use of a compound disclosed herein [0015] in the manufacture of a medicament for (a) increasing IL-2 production; (b) suppressing regulatory T cells; (c) enhancing effector T cells; (d) inhibiting tumor growth; and/or (e) enhancing tumor regression in a subject.
  • DETAILED DESCRIPTION [0016] The present disclosure relates to compounds and methods of degrading a IKZF2 protein comprising contacting a IKZF2 protein with a therapeutically effective amount of a IKZF2 degrader.
  • the invention also relates to methods of treating a IKZF2 protein-mediated disease or condition in a patient by administering a therapeutically effective amount of a IKZF2 degrader to a patient in need thereof.
  • the invention further relates to methods of treating a IKZF2-mediated disease or condition in a patient, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a IKZF2 degrader to a patient in need thereof.
  • the compound is a compound of Formula I’-1-i, I’-1-ii, I’-1- iii, I’-1-iv, I’-1-v, I’-1-vi, I’-1-vii, I’-1-viii, I’-1-ix, I’-1-x, I’-1-xi, I’-1-xii, or I’-1-xiii:
  • the compound is a compound of Formula I’-2-i, I’-2-ii, I’-2- iii, I’-2-iv, I’-2-v, I’-2-vi, I’-2-vii, I’-2-viii, I’-2-ix, I’-2-x, I’-2-xi, I’-2-xii, or I’-2-xiii: , , , ,
  • X and Y are not both -C(R 3 )2; and/or when p is 1, then X, Y, and Z are not all -C(R 3 ) 2 .
  • X is -O- and Y is -C(R 3 ) 2 -.
  • X is - C(R 3 ) 2 - and Y is -O-.
  • X is -O- and Y is -CH 2 -.
  • X is -CH2- and Y is -O-.
  • Z is -C(R 3 ) 2 or -O-.
  • p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2 [0027] In certain embodiments, p is 0, X is -O- and Y is -C(R 3 )2-. In certain embodiments, p is 0, X is -C(R 3 )2- and Y is -O-.
  • each R 3 is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy
  • C1-6 alkoxy e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy
  • each R 3 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R 3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C 6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R 3 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R 3 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • two geminal R 3 together form an oxo.
  • two geminal R 3 together with the carbon atom to which they are attached, form C 3-6 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more R u .
  • C 3 cyclopropyl
  • C 3 cyclopropenyl
  • C 4 cyclobutyl
  • C4 cyclobutenyl
  • C4 cyclopen
  • each R 4 is independently hydrogen or C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ), i- propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)) optionally substituted with one or more R u .
  • C1-6 alkyl e.g., methyl (C1), ethyl (C2),
  • Ring A is C 3-12 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C3) cyclobutyl (C4) cyclobutenyl (C4) cyclopentyl (C5) cyclopentenyl (C5) cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclode
  • R 1 is -M-L-Q-R 2 .
  • R 1 is -[C(R L )2]r-R 2 .
  • R 1 is -[CH2]r-R 2 .
  • R 1 is -C(R L ) 2 -R 2 .
  • R 1 is -CH2-R 2 .
  • M is absent.
  • L is absent or [-C(R L ) 2 -] r .
  • each R L is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C
  • each R L is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R L is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R L is independently hydrogen, halogen, -CN, -NO2, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • two geminal R L together with the carbon atom to which they are attached, form C 3-6 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more R u .
  • C 3 cyclopropyl
  • C 3 cyclopropenyl
  • C 4 cyclobutyl
  • C4 cyclobutenyl
  • C4 cyclopen
  • R Q is hydrogen or C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C6)) optionally substituted with one or more R u .
  • C1-6 alkyl e.g., methyl (C1), ethyl (C2), n- propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C6)
  • R 2 is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononen
  • R 2 is optionally substituted with one R 2a . In certain embodiments, R 2 is optionally substituted with two R 2a . In certain embodiments, R 2 is optionally substituted with three R 2a .
  • each R 2a is independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1- 6 alkoxy (e.g., methoxy (C 1 ), ethoxy
  • each R 2a is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -(C 1-6 alkylene)-(C 3- 12 carbocyclyl), -(C1-6 alkylene)-(3- to 12-membered heterocyclyl), -(C1-6 alkylene)-(C6-10 aryl), or -(C1-6 alkylene)-(5- to 10-membered heteroaryl), wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally
  • each R 2a is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C 6 aryl, 5- to 6-membered heteroaryl, -(C 1-6 alkylene)-(C 3-6 carbocyclyl), -(C1-6 alkylene)-(3- to 6-membered heterocyclyl), -(C1-6 alkylene)-(C6 aryl), -(C1- 6 alkylene)-(5- to 6-membered heteroaryl), wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted
  • each R 2a is independently oxo, hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, or -(C1-6 alkylene)-(C6-10 aryl), wherein the alkyl, alkylene, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • two vincinal R 2a together with the atoms to which they are bonded, form C5-12 carbocyclyl (e.g., cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), cyclodecenyl (
  • each occurrence of R A and R C is oxo, independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C 4 ), i-butoxy (C 4 ), s-butoxy (C 4 ), t-
  • each occurrence of R A and R C is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each occurrence of R A and R C is independently oxo, hydrogen, halogen -CN -NO2 -OH -NH2 C16 alkyl C16 alkoxy C16 alkylamino C26 alkenyl C26 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each occurrence of R A and R C is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each occurrence of R A and R C is independently oxo, hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • q is an integer selected from 0 to 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.
  • s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4, as valency permits. In certain embodiments, s is 5, as valency permits. In certain embodiments, s is 6, as valency permits. In certain embodiments, s is 7, as valency permits. In certain embodiments, s is 8, as valency permits. In certain embodiments, s is 9, as valency permits. In certain embodiments, s is 10, as valency permits. In certain embodiments, s is 11, as valency permits. In certain embodiments, s is 12, as valency permits.
  • each R E is independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1- 6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C 4 ), s-butoxy (C 4 ), t-butoxy (C
  • each R E is independently oxo, hydrogen, halogen, -CN, -NO 2 , -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R E is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R E is independently oxo, hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • e is an integer selected from 0 to 6, as valency permits. In certain embodiments, e is 0. In certain embodiments, e is 1. In certain embodiments, e is 2.
  • X is -O- and Y is -C(R 3 ) 2 -. In certain embodiments, X is - C(R 3 )2- and Y is -O-. In certain embodiments, X is -NR 4 - and Y is -C(R 3 )2-. In certain embodiments, X is -C(R 3 )2- and Y is -NR 4 -. [0084] In certain embodiments, Z is -C(R 3 ) 2 -, -NR 4 -, or -O-.
  • Z is - C(R 3 )2 or -O- [0085] In certain embodiments, when p is 0, then X and Y are not both -C(R 3 )2; or when p is 1, then X, Y, and Z are not all -C(R 3 )2. [0086] In certain embodiments, p is 0. In certain embodiments, p is 1. [0087] In certain embodiments, the compound is a compound of Formula (I-1-i) to (I-1-xiii):
  • each R L is independently hydrogen, halogen, -CN, -NO2, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R L is independently hydrogen or C 1-6 alkyl.
  • L is -CH 2 -.
  • two R L together with the carbon atom(s) to which they are attached, form C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl.
  • Q is absent.
  • Q is -NR Q -.
  • Q is -O-.
  • R Q is hydrogen or C1-6 alkyl. In certain embodiments, R Q is C1- 6 alkyl. In certain embodiments, R Q is hydrogen.
  • R 2 is C 6-10 aryl, 5- to 10-membered heteroaryl, C 5-10 carbocyclyl, or 5- to 10-membered heterocyclyl.
  • R 2 is phenyl.
  • R 2 is 5- to 10-membered heteroaryl.
  • R 2 is C 5-10 carbocyclyl.
  • R 2 is 5- to 10-membered heterocyclyl.
  • the compound is a compound of Formula (I-2-i) or (I-2-ii) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein u is an integer selected from 0 to 10, as valency permits.
  • two R 2a together form oxo.
  • each R 3 is independently H or C1-6 alkyl. In certain embodiments, each R 3 is H. In certain embodiments, two geminal R 3 together form oxo.
  • each R 4 is independently hydrogen, C 1-6 alkyl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u . In certain embodiments, each R 4 is independently H or C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more R u .
  • each occurrence of R A and R C is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6- 10 aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8. In certain embodiments, s is 9. In certain embodiments, s is 10. In certain embodiments, s is 11. In certain embodiments, s is 12. [0110] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [0111] In certain embodiments, m and n are independently 0 or 1. In certain embodiments, each of m and n is 0.
  • each R a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.
  • each R a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R a is independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R b is independently hydrogen, C1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C 2 ), n-prop
  • each R b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.
  • each R b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R b is independently hydrogen, C 1-6 alkyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R c and each R d is independently hydrogen, C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t- butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C 6 ), C 2-6 alkynyl (e.g., ethynyl
  • each R c and each R d is independently hydrogen, C1-6 alkyl, C3- 6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more R u .
  • R c and R d together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more R z .
  • R a , R b , R c , and R d is independently and optionally substituted with one or more R z .
  • R z is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1- 6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl.
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C 2 ), propoxy (C 3 ), i-propoxy (C 3 ), n-butoxy (C 4 ), i-butoxy (C 4 ), s-butoxy (C 4 ), t-butoxy (C 4 ), pentoxy (C 5 ), or hexoxy (C 6 )), C 1-6 alkyl (e.g.,
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6- membered
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C16 alkyl C16 alkoxy C16 alkylamino C36 carbocyclyl or 3- to 6-membered heterocyclyl wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.
  • two R u together with the carbon atom(s) to which they are attached, form C 3-6 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).
  • C 3 cyclopropyl
  • C 3 cyclopropenyl
  • C 4 cyclobutyl
  • C 4 cyclobutenyl
  • C 4 cyclopentyl
  • C 5 cyclopentenyl
  • two geminal R u together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C 6 )) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).
  • C3-6 carbocyclyl e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl
  • variables X, Y, and Z are described herein, the disclosure may be interpreted as excluding structures for non-operable compounds caused by certain combinations of the options (e.g., when two adjacent members of X, Y, an Z are both nitrogen or both oxygen; or one of two adjacent members of X, Y, and Z is nitrogen while the other is oxygen).
  • the options e.g., when two adjacent members of X, Y, an Z are both nitrogen or both oxygen; or one of two adjacent members of X, Y, and Z is nitrogen while the other is oxygen.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the compounds in Table 1 Table 1.
  • the compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known IKZF2 degrader.
  • the compounds of the present disclosure may display more potent estrogen receptor activity, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and/or AUC), and/or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction).
  • beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein.
  • a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt.
  • a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate.
  • a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate.
  • the compounds disclosed herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • suitable acid or base such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, magnesium, aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [0151] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”.
  • Solvates are within the scope of the invention. [0152] It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present invention. [0153] In some embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods of treating diseases by administering such solvates. The present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [0154] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like.
  • a solvent such as water, ethanol, and the like.
  • Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention [0158]
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent.
  • Tautomers [0159] In some embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. [0160] Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • compositions [0161]
  • the compound described herein is administered as a pure chemical.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • an appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration.
  • Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for intravenous injection.
  • the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.
  • the pharmaceutical composition is formulated as a tablet.
  • the compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis
  • the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • the compounds of the present disclosure i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)
  • SCHEME 1 [0168] According to SCHEME 1, commercially available or synthetically accessible substituted pyridine of formula III is reacted with benzyl bromide IV or the like; in a suitable solvent such as acetonitrile, CCl4, toluene, and the like; at temperatures ranging from 60 °C to 120 °C; to provide pyridinium salt of formula V.
  • Pyridinium salt of formula V is reduced with a suitable reductant such as NaBH 4 , NaCNBH 3 , and the like; in an alcoholic solvent such as MeOH, EtOH, and the like; at temperatures ranging from -20 °C to 25 °C, preferably 0 °C; to provide a compound of formula (VI).
  • a suitable reductant such as NaBH 4 , NaCNBH 3 , and the like
  • an alcoholic solvent such as MeOH, EtOH, and the like
  • Bromo benzoic acid of formula VIII is reacted with methanol in the presence of an acid such as acetic acid, HCl and the like; in a suitable solvent such as MeOH, THF and the like; at temperatures ranging from 25 °C to about 80 °C, preferably 50 °C; to provide a compound of formula (IX).
  • an acid such as acetic acid, HCl and the like
  • a suitable solvent such as MeOH, THF and the like
  • a compound of formula (IX) is reacted with a compound of formula (VI) under Mitsunobu condition, in the presence of a coupling agent such DIAD, DEAD, and the like; with a coupling co-agent such as Ph 3 P, Bu 3 P and the like; in a solvent such as diethyl ether, THF and the like; at temperatures ranging from -20 °C to about 50 °C, preferably 0 °C; to afford an ether compound of formula (X); a compound of formula (X) is cyclized under radical cyclization condition with a radical initiator such as BPO, AIBN and the like; in the presence of a suitable reductant such as Bu3SnH, (TMS)3SiH and the like; in a solvent such as benzene, toluene and the like; at temperatures ranging from 80 °C to about 120 °C, preferably 100 °C; to afford a compound of formula
  • a compound of formula (XI) is de-benzylated with hydrogenation under 1 atm or up to 50 psi hydrogen gas, in the presence of a suitable catalyst such as Pd on C, PtO2 and the like; in a solvent such as MeOH, EtOAc and the like; at temperatures ranging from 25 °C to about 50 °C, preferably 25 °C; to afford an amino compound of formula (XII).
  • a suitable catalyst such as Pd on C, PtO2 and the like
  • a solvent such as MeOH, EtOAc and the like
  • a compound of formula (XIII) is brominated by radical bromination with a radical initiator such as BPO, AIBN and the like; in the presence of a suitable bromine source such as NBS, Br2 and the like; in a solvent such as CCl4, benzene and the like; at temperatures ranging from 60 °C to about 100 °C, preferably 80 °C; to afford a bromo compound of formula (XIV).
  • a radical initiator such as BPO, AIBN and the like
  • a suitable bromine source such as NBS, Br2 and the like
  • a solvent such as CCl4, benzene and the like
  • a bromo compound of formula (XIV) is reacted with a commercially available or synthetically accessible amine of formula XV, in the presence of a suitable base such as TEA, DIPEA and the like; in a suitable solvent such as acetonitrile, THF and the like; at temperatures ranging from 60 °C to about 100 °C, preferably 80 °C; to afford a cyclized compound of formula (XVI).
  • a suitable base such as TEA, DIPEA and the like
  • a suitable solvent such as acetonitrile, THF and the like
  • a cyclized compound of formula (XVI) is de-protected with a suitable base such as TFA, HCl and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 50 °C, preferably 25 °C; to afford an amino compound of formula (XVII).
  • a suitable base such as TFA, HCl and the like
  • a suitable solvent such as DCM, THF and the like
  • SCHEME 4 According to SCHEME 4, commercially available or synthetically accessible substituted iodo compound of formula XVIII is reacted with 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane or potassium vinyltrifluoroborate; in the presence of a catalyst such as Pd(Ph 3 P) 4 , Pd 2 (dba) 3 , and the like; with an inorganic base such as Na 2 CO 3 , K 3 PO 4 , and the like; in a suitable solvent such as THF, dioxane, and the like; in a co-solvent such as water; at temperatures ranging from 60 °C to 120 °C, preferably at 80 °C; to provide an olefin compound of formula XIX.
  • a catalyst such as Pd(Ph 3 P) 4 , Pd 2 (dba) 3 , and the like
  • an inorganic base such as Na 2 CO 3 , K 3 PO 4 , and the like
  • a boron reductant such as BH 3 etherate, 9-BBN, and the like
  • a suitable solvent such as THF, dioxane, and the like
  • an oxidant such as 30% H2O2
  • an olefin compound of formula XIX is dihydroxylated with a catalyst such as OsO 4 , K 2 OsO 4 .2H 2 O, and the like; in a suitable oxidant such as NMO, and the like; in a suitable solvent such as t-BuOH, dioxane, and the like; at temperatures ranging from -20 °C to 25 °C, preferably 0 °C; to provide an aldehyde compound of formula XXI.
  • a catalyst such as OsO 4 , K 2 OsO 4 .2H 2 O, and the like
  • a suitable oxidant such as NMO, and the like
  • a suitable solvent such as t-BuOH, dioxane, and the like
  • a reductant such as NaBH4, NaBCNH3, and the like
  • a suitable solvent such as MeOH, THF, and the like
  • an aryl bromide compound of formula XXI is coupled with commercially available or synthetically accessible substituted boronic ester compound of formula XXII under Suzuki coupling conditions employing a suitable catalyst such as Pd(Ph 3 P) 4 , Pd 2 (dba) 3 , Pd(ddpf)Cl 2 and the like; a suitable base such a K 3 PO 4 , Cs 2 CO 3 and the like; in a suitable solvent such as dioxane, DMF and the like; with a co-solvent such as water; at temperatures ranging from 60 °C to about 120 °C, preferably 80 °C; to afford a claimed compound of formula XXIII.
  • a suitable catalyst such as Pd(Ph 3 P) 4 , Pd 2 (dba) 3 , Pd(ddpf)Cl 2 and the like
  • a suitable base such as K 3 PO 4 , Cs 2 CO 3 and the like
  • a suitable solvent such as diox
  • a compound of formula XXIII is reacted with a suitable bromine source such as Br 2 , NBS and the like under cyclization conditions; in a suitable solvent such as acetonitrile, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford a claimed compound of formula XXIV.
  • a suitable bromine source such as Br 2 , NBS and the like under cyclization conditions
  • a suitable solvent such as acetonitrile, THF and the like
  • a bromo compound of formula XXIV is reduced with a suitable reductant such as Bu 3 SnH, (TMS) 3 SiH and the like; in the presence of a radical initiator such as BPO, AIBN and the like under cyclization conditions; in a suitable solvent such as benzene, toluene and the like; at temperatures ranging from 80 °C to about 120 °C, preferably 100 °C; to afford a claimed compound of formula XXV.
  • a suitable reductant such as Bu 3 SnH, (TMS) 3 SiH and the like
  • a lactone compound of formula XXV is reacted with a suitable base such as LiOH, NaOH, and the like; in a suitable solvent such as THF, MeOH, and the like; in a co-solvent such as water; at temperatures ranging from 25 °C to 80 °C, preferably at 50 °C; to provide an acid compound of formula XXVI.
  • An acid compound of formula XXVI is oxidized in the presence of an oxidant such as MnO2, Dess- Martin periodinane, and the like; in a suitable solvent such as DCM, acetonitrile, and the like; at temperatures ranging from 0 °C to 50 °C, preferably at 25 °C; to provide a compound of formula XXVII.
  • An aldehyde compound of formula XXVII is reacted with a commercially available or synthetically accessible amine of formula XIV, in the presence of a suitable reductant such as NaBH(OAc)3, NaCNBH3 and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford a compound of formula (XXVIII).
  • a suitable reductant such as NaBH(OAc)3, NaCNBH3 and the like
  • a suitable solvent such as DCM, THF and the like
  • a compound of formula (XXVIII) is cyclized with a coupling agent such as HTAU, EDCI and the like; in the presence of a suitable base such as TEA, DIPEA and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford an cyclized compound of formula (XXIX).
  • a coupling agent such as HTAU, EDCI and the like
  • a suitable base such as TEA, DIPEA and the like
  • a suitable solvent such as DCM, THF and the like
  • a cyclized compound of formula (XXIX) is de-protected with a suitable reductant such as 1 atm or up to 50 psi of hydrogen and the like; in the presence of a suitable catalyst such as Pd on C or PtO 2 and the like; in a suitable solvent such as MeOH, EtOAc and the like; at temperatures ranging from 25 °C to about 60 °C, preferably 25 °C; to afford an amino compound of formula (XVII).
  • a suitable reductant such as 1 atm or up to 50 psi of hydrogen and the like
  • a suitable catalyst such as Pd on C or PtO 2 and the like
  • a suitable solvent such as MeOH, EtOAc and the like
  • a compound of formula I may be prepared according to the procedures shown in SCHEME 6 SCHEME 6 [0175] According to SCHEME 6, an amino compound of formula (XVII) is reacted with an aldehyde or ketone of formula R 1 D (D is aldehyde or ketone) under reductive amination conditions employing a suitable reductant such as NaBH(OAc)3, NaBCNH3 and the like; a catalytic amount of acid such AcOH, TFA and the like; in a suitable solvent such as MeOH, DCM, DMF and the like; at temperatures ranging from 0 °C to about 50 °C, preferably 25 °C; to afford a claimed compound of formula (I).
  • a suitable reductant such as NaBH(OAc)3, NaBCNH3 and the like
  • a catalytic amount of acid such AcOH, TFA and the like
  • a suitable solvent such as MeOH, DCM, DMF and the like
  • an amino compound of formula (XVII) is reacted with alkylating agent of formula R 1 D (D is a leaving group such as halogen or mesylate) under displacement conditions employing a suitable base such as Cs 2 CO 3 , NaH and the like; in a suitable solvent such as DMSO, DMF and the like; at temperatures ranging from 25 °C to about 80 °C, preferably 50 °C; to afford a claimed compound of formula (I).
  • a stereocenter exists in the compounds of the present dislosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein).
  • the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • HTRF signals are measured by displacing Cy5-labeled thalidomide with the testing compounds to His tagged CRBN+DDB-DLS7+CXU4. Data is analyzed using XLfit using four parameters dose response curve to determine IC50s [0183]
  • the cellular degradation activity of IKZF2 is measued by FACS in Jurkat cells with the testing compound concentrations from 0.05 to 10 ⁇ M for 24 hrs. Cells are stained with IKZF2 primary antibody and secondary antibodies followed by imaged on iQue Flowcytometer and IKZF2 levels are quantified using iQue software.
  • the cellular degradation activity of IKZF2 is measured by HiBit IKZF2 assay with the HiBiT protein tagging system applying to modified HEK293T Flp-in-HiBiT cells.
  • Test and reference compounds are diluted from 1 mM at 3 folds for 11 doses.
  • the Nano- Glo® HiBiT lytic detection system is utilized for detecting bioluminescence of the HiBiT tag in treated cells to determine abundance of the tag is proportionate to the level of luminescence.
  • dose-response curves are plotted (GraphPad Prism) to determine the concentration points at which 50% of HiBiT-Helios degradation is achieved by each compound.
  • the cellular degradation activity of IKZF1 is measured by HiBit IKZF1 assay with the HiBiT protein tagging system applying to modified HEK293T Flp-in-HiBiT cells.
  • Test and reference compounds are diluted from 1 mM at 3 folds for 11 doses.
  • the Nano-Glo® HiBiT lytic detection system is utilized for detecting bioluminescence of the HiBiT tag in treated cells to determine abundance of the tag is proportionate to the level of luminescence.
  • dose-response curves are plotted (GraphPad Prism) to determine the concentration points at which 50% of HiBiT-Ikaros degradation is achieved by each compound.
  • the present disclosure provides methods of degrading a IKZF2 protein in a subject, comprising administering to the subject a compound disclosed herein.
  • the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a IKZF2 protein in a subject.
  • the present disclsoure provides compounds disclosed herein for use in degrading a IKZF2 protein in a subject.
  • the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).
  • the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (eg in a therapeutically effective amount) [0191] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0192] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof. [0193] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorderin a subject in need thereof.
  • the present disclosure provides compounds disclosed herein for use in treating a disease or disorderin a subject in need thereof.
  • the disease or disorder is an IKZF2-mediated disease or disorder.
  • the disease or disorder is a cancer.
  • the cancer includes, but is not limited to, one or more of the cancers of Table A. Table A.
  • the cancer is a solid tumor.
  • the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table B.
  • the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.
  • the disease or disorder is T cell leukemia, T cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST).
  • the subject is a mammal.
  • the subject is a human.
  • Definitions [0202] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions [0203] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein.
  • 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 (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”).
  • an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”).
  • an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”).
  • C1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like.
  • each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH 3 ).
  • the alkyl group is substituted C 1- 10 alkyl.
  • Alkylene refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical
  • alkylene refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical
  • alkelene may be substituted or unsubstituted with one or more substituents as described herein.
  • exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (- CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Exemplary substituted divalent alkylene groups include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.
  • Alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2- 9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 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 (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like.
  • alkenyl examples include heptenyl (C7), octenyl (C8), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C2-10 alkenyl.
  • the alkenyl group is substituted C2-10 alkenyl.
  • Alkenylene refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C 2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2- 8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”).
  • 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 C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C7), octynyl (C8), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; eg for instance from 1 to 5 substituents 1 to 3 substituents or 1 substituent.
  • the alkynyl group is unsubstituted C2-10 alkynyl.
  • the alkynyl group is substituted C2-10 alkynyl.
  • Alkynylene refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical.
  • alkynylene refers to the range or number of carbons in the linear carbon divalent chain.
  • An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.
  • heteroalkyl refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-10 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1- 8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7 alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC 1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2 alkyl”).
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl.
  • heteroalkenyl refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkenyl”).
  • a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC 2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl.
  • the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
  • heteroalkynyl refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • one or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-10 alkynyl”). In certain embodiments a heteroalkynyl group has 2 to 9 carbon atoms at least one triple bond and 1 2 3, or 4 heteroatoms (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkynyl”).
  • a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-5 alkynyl”).
  • a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC 2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”).
  • each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl.
  • the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
  • heteroalkylene refers to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively.
  • heteroalkylene refers to the range or number of carbons in the linear divalent chain.
  • Heteroalkylene, “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl).
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene fluorene hexacene hexaphene hexalene as-indacene s-indacene indane indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C 6-14 aryl.
  • the aryl group is substituted C 6- 14 aryl.
  • heteroaryl refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”).
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups.
  • Bicyclic 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, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl is a 5- to 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- to 10-membered heteroaryl”).
  • a heteroaryl is a 5- to 9-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- to 9-membered heteroaryl”).
  • a heteroaryl is a 5- to 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- to 8-membered heteroaryl”).
  • a heteroaryl group is a 5- to 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- to 6-membered heteroaryl”).
  • the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl.
  • the heteroaryl group is substituted 5- to 14-membered heteroaryl.
  • Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6- membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7- membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6- bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl cinnolinyl quinoxalinyl phthalazinyl and quinazolinyl
  • Heteroarylene refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group.
  • a “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C3- 10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”).
  • Exemplary C3-6 carbocyclyl include, without limitation, 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 C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). In certain embodiments a carbocyclyl group has 5 to 8 ring carbon atoms (“C58 carbocyclyl”) In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Examples of C5-6 carbocyclyl include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3-6 carbocyclyl examples include the aforementioned C 5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (C 8 ).
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C3-12 carbocyclyl.
  • the carbocyclyl group is substituted C 3-12 carbocyclyl.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-12 carbocyclyl.
  • “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system.
  • “Spiro carbocyclyl” or or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded.
  • “Bridged carbocyclyl” or or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such share more than one bonds) with one or more carbocyclyl groups as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded.
  • the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded.
  • Carbocyclylene refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical.
  • the divalent radical may be present on different atoms or the same atom of the carbocyclylene group.
  • a “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Heterocyclyl refers to a radical of a 3- to 12-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, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 10- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 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- to 8-membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 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- to 6-membered heterocyclyl”).
  • the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents
  • the heterocyclyl group is unsubstituted 3- to 12- membered heterocyclyl.
  • the heterocyclyl group is substituted 3- to 12- membered heterocyclyl.
  • “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings.
  • the number of ring members designates the total number of ring members in the fused ring system.
  • “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.
  • the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.
  • “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.
  • Heterocyclylene refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical.
  • the divalent radical may be present on different atoms or the same atom of the heterocyclylene group.
  • heterocyclylene refers to the number of ring members in the heterocyclylene group.
  • a “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Alkoxy refers to the group -OR, wherein R is alkyl as defined herein.
  • C1-6 alkoxy refers to the group -OR, wherein each R is C1-6 alkyl, as defined herein. Exemplary C 1-6 alkyl is set forth above.
  • Alkylamino refers to the group -NHR or -NR2, wherein each R is independently alkyl, as defined herein.
  • C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C 1-6 alkyl, as defined herein.
  • Exemplary C 1-6 alkyl is set forth above.
  • heteroaryl When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.
  • Halo or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
  • Protecting group refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction.
  • a functional group e.g., hydroxyl, amino, thio, and carboxylic acid
  • Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.
  • hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), ⁇ -Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri- iso-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)).
  • ethers e.g., methoxymethyl (MOM), ⁇ -Methoxyeth
  • amino-protecting groups include but not limited to carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), p- methoxybenzyl (PMB) p-methoxyphenyl (PMP) and triphenylmethyl (trityl)) and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2- nitro
  • Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).
  • Common types of carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulf
  • Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • 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.
  • a mixture containing equal proportions of the enantiomers is termed a “racemic mixture”.
  • “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons.
  • two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)-compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound.
  • the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound. [0259] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound.
  • the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure (S)- compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound.
  • the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier [0260] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
  • the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range.
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity such as “either” “one of ” “only one of ” or “exactly one of ” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
  • the phrase “at least one,” in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • Preparative reverse-phase high performance liquid chromatography was performed on either: [0276] METHOD A. Prep-HPLC with YMC-Actus Triart 18C (5 ⁇ m, 20 x 250 mm), and mobile phase of 5-99% ACN in water (0.1% HCOOH) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min; or [0277] METHOD B. Preparative supercritical fluid high performance liquid chromatography (SFC) was performed either on a Thar 80 Prep-SFC system, or Waters 80Q Prep-SFC system from Waters.
  • SFC supercritical fluid high performance liquid chromatography
  • the ABPR was set to 100bar to keep the CO 2 in SF conditions, and the flow rate may verify according to the compound characteristics, with a flow rate ranging from 50g/min to 70g/min.
  • the column temperature was ambient temperature [0278]
  • Nuclear magnetic resonance (NMR) spectra were recorded using Brucker AVANCE NEO 400 MHz at around 20 - 30°C unless otherwise specified. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal.
  • Step C 1-benzyl-4-(hydroxymethyl)pyridin-1-ium bromide
  • (pyridin-4-yl)methanol 8.9 g, 81.6 mmol, 1.0 eq
  • CH3CN 80 mL
  • (bromomethyl)benzene 11.705 mL, 97.9 mmol, 1.2 eq
  • the reaction mixture was refluxed stirred at 90 o C for 3 h.
  • Step D (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol
  • 1-benzyl-4-(hydroxymethyl)pyridin-1-ium bromide (16.3 g, 81.4 mmol, 1.0 eq) in CH3OH (150 mL) was added NaBH4 (9.3 g, 244.2 mmol, 3.0 eq) in portions at -20 o C.
  • the mixture was stirred at -20 o C for 1 h.
  • the reaction was quenched with brine (100 mL) and extracted with EtOAc (200 mL x 3).
  • Step E methyl 5-[(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy]-4-bromo-2- methylbenzoate
  • methyl 4-bromo-5-hydroxy-2-methylbenzoate 200 mg, 0.82 mmol, 1.0 eq
  • (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol 166 mg, 0.82 mmol, 1.0 eq
  • PPh3 321 mg, 1.22 mmol, 1.5 eq
  • Step F methyl 1'-(cyclohexylmethyl)-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate
  • Tributyl tin hydride 0.5 mL, 1.84 mmol, 4.0 equiv
  • methyl 5-[(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy]-4-bromo-2-methylbenzoate 200 mg, 0.46 mmol, 1.0 eq
  • AIBN 15 mg, 0.09 mmol, 0.2 eq
  • Step G methyl 5-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylate
  • Step H 1'-(tert-butyl) 6-methyl 5-methyl-2H-spiro[benzofuran-3,4'-piperidine]-1',6- dicarboxylate
  • methyl 5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate 970 mg, 3.7 mmol, 1.0 eq
  • TEA 1 mL, 7.4 mmol, 2.0 eq
  • Boc 2 O 0.8 mL, 3.7 mmol, 2.0 eq
  • Step I 1'-(tert-butyl) 6-methyl 5-(bromomethyl)-2H-spiro[benzofuran-3,4'-piperidine]-1',6- dicarboxylate
  • Step J tert-butyl 6-(2,6-dioxopiperidin-3-yl)-7-oxo-6,7-dihydro-2H,5H-spiro[furo[2,3- f]isoindole-3,4'-piperidine]-1'-carboxylate
  • DIPEA 0.12 mL, 0.681 mmol, 3.0 eq
  • 1'-tert-butyl 6-methyl 5- (bromomethyl)-2H-spiro[1-benzofuran-34'-piperidine]-1'6-dicarboxylate 100 mg 0227 mmol, 1.0 eq
  • 3-aminopiperidine-2,6-dione hydrochloride 56 mg, 0.341 mmol, 1.5 eq
  • Step K 3-(7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6- yl)piperidine-2,6-dione [0293] To a solution of tert-butyl 6-(2,6-dioxopiperidin-3-yl)-7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-1'-carboxylate (50 mg, 0.11 mmol, 1.0 eq) in DCM (1 mL) was added HCl-dioxane solution (4 M, 1 mL, 4 mmol, 36 eq) and the mixture was stirred for 30 min.
  • Step B 5-bromo-6-ethenyl-1,3-dihydro-2-benzofuran-1-one [0298] To a stirred solution of 5-bromo-6-iodo-1,3-dihydro-2-benzofuran-1-one (10 g, 29.51 mmol, 1.0 eq) and Potassium Vinyltrifluoroborate (5.93 g, 44.26 mmol, 1.5 eq) in dioxane (250 mL) and H2O (50 mL) was added Pd(dppf)Cl2 (2.16 g, 2.95 mmol, 0.1 eq) and K2CO3 (12.23 g, 88.51 mmol, 3.0 eq).
  • Step C 6-bromo-3-oxo-1,3-dihydro-2-benzofuran-5-carbaldehyde
  • 5-bromo-6-ethenyl-1,3-dihydro-2-benzofuran-1-one 2.1 g, 8.78 mmol, 1.0 eq
  • H 2 O 10 mL
  • K 2 OsO 4 . 2H 2 O 0.32 g, 0.88 mmol, 0.1 eq
  • NMO (2.06 g, 17.57 mmol, 2.0 eq).
  • the resulting mixture was stirred at room temperature for 1 h.
  • Step D 5-bromo-6-(hydroxymethyl)-1,3-dihydro-2-benzofuran-1-one [0300] To a stirred mixture of 6-bromo-3-oxo-1,3-dihydro-2-benzofuran-5-carbaldehyde (1 g, 4.15 mmol, 1.0 eq) in THF (15 mL) was added NaBH4 (0.47 g, 12.45 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice-water (50 mL) and extracted with EtOAc (80 mL x 3).
  • Step E benzyl 4-[6-(hydroxymethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-yl]-1,2,3,6- tetrahydropyridine-1-carboxylate [0301] To a stirred solution of 5-bromo-6-(hydroxymethyl)-1,3-dihydro-2-benzofuran-1-one (1.2 g, 4.94 mmol, 1.0 eq) and benzyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine-1-carboxylate (1.69 g, 4.94 mmol, 1.0 eq) in dioxane (20 mL) and H 2 O (2 mL) were added Pd(dppf)Cl 2 (0.36 g, 0.49 mmol, 0.1 eq) and K 2 CO 3 (2.05 g, 14.81 mmol, 3.0 eq).
  • reaction mixture was stirred under nitrogen atmosphere at 90 °C for 2 h. After cooled to room temperature, the reaction mixture was filtered and the cake was washed with EA (30 mL). The mixture was diluted with H 2 O (40 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated.
  • Step F benzyl 3'-bromo-5-oxo-5,7-dihydro-3H-spiro[benzo[1,2-c:4,5-c'] difuran-1,4'- piperidine]-1'-carboxylate
  • benzyl 4-[6-(hydroxymethyl)-1-oxo-1,3-dihydro-2-benzofuran- 5-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (1 g, 2.64 mmol, 1.0 eq) in MeCN (15 mL) was added NBS (0.7 g, 3.95 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 1 h.
  • Step G benzyl 5-oxo-5,7-dihydro-3H-spiro[benzo[1,2-c:4,5-c'] difuran-1,4'-piperidine]-1'- carboxylate [0303] To a stirred mixture of benzyl 3'-bromo-5-oxo-5,7-dihydro-3H-spiro[benzo[1,2-c:4,5- c'] difuran-1,4'-piperidine]-1'-carboxylate (945 mg, 2.06 mmol, 1.0 eq) in toluene (20 mL) were added AIBN (0.610 mL, 4.12 mmol, 2.0 eq) and n-Bu3SnH (3.0 g, 10.31 mmol, 5.0 eq).
  • Step H 1'-[(benzyloxy)carbonyl]-6-(hydroxymethyl)-3H-spiro[2-benzofuran-1,4'-piperidine]- 5-carboxylic acid
  • benzyl 5-oxo-5,7-dihydro-3H-spiro[benzo[1,2-c:4,5-c'] difuran- 1,4'-piperidine]-1'-carboxylate 650 mg, 1.71 mmol, 1.0 eq
  • MeOH MeOH
  • H2O 5 mL
  • Step I 1'-[(benzyloxy)carbonyl]-6-formyl-3H-spiro[2-benzofuran-1,4'-piperidine]-5- carboxylic acid [0305] To a stirred solution of 1'-[(benzyloxy)carbonyl]-6-(hydroxymethyl)-3H-spiro[2- benzofuran-1,4'-piperidine]-5-carboxylic acid (610 mg, 1.54 mmol, 1.0 eq) in DCM (15 mL) was add active MnO 2 (1334.36 mg, 15.35 mmol, 10 eq).
  • Step J 1'-[(benzyloxy)carbonyl]-6- ⁇ [(2,6-dioxopiperidin-3-yl) amino] methyl ⁇ -3H-spiro[2- benzofuran-1,4'-piperidine]-5-carboxylic acid
  • 1'-[(benzyloxy)carbonyl]-6-formyl-3H-spiro[2-benzofuran- 1,4'-piperidine]-5-carboxylic acid 600 mg, 1.52 mmol, 1.0 eq
  • 3-Amino-2,6- piperidinedione hydrochloride 374.63 mg, 2.28 mmol, 1.5 eq
  • MeOH 10 mL
  • NaOAc 186.64 mg, 2.28 mmol, 1.5 eq
  • Step K benzyl 6-(2,6-dioxopiperidin-3-yl)-5-oxo-3,5,6,7-tetrahydrospiro[furo[3,4-f] isoindole-1,4'-piperidine]-1'-carboxylate [0307] To a stirred solution of 1'-[(benzyloxy)carbonyl]-6- ⁇ [(2,6-dioxopiperidin-3-yl) amino] methyl ⁇ -3H-spiro[2-benzofuran-1,4'-piperidine]-5-carboxylic acid (550 mg, 1.08 mmol, 1.0 eq) in DMF (8 mL) were added HATU (494.15 mg, 1.30 mmol, 1.2 eq) and DIEA (0.72 mL, 4.34 mmol, 4.0 eq).
  • Step L 3- ⁇ 5-oxo-3,5,6,7-tetrahydrospiro[furo[3,4-f] isoindole-1,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione [0308] To a stirred solution of benzyl 6-(2,6-dioxopiperidin-3-yl)-5-oxo-3,5,6,7- tetrahydrospiro[furo[34-f] isoindole-14'-piperidine]-1'-carboxylate (200 mg 041 mmol 10 eq) in TFE (8 mL) was add 10% Pd/C (100 mg) and the reaction mixture was stirred under H2 (1 atm) at 40 °C overnight.
  • Step B 5-bromo-6-( 2-hydroxyethyl)-1,3-dihydro-2-benzofuran-1-one
  • 5-bromo-6-ethenyl-1,3-dihydro-2-benzofuran-1-one 5.0 g, 20.91 mmol,1.0 eq
  • 9-BBN 9-BBN (1 N in THF) (25.2 mL, 25.2 mmol, 1.2 eq
  • Step C benzyl 4-[6-(2-hydroxyethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-yl]-1,2,3,6- tetrahydropyridine-1-carboxylate [0311] To a solution of 5-bromo-6-(2-hydroxyethyl)-1,3-dihydro-2-benzofuran-1-one (2.6 g, 10.11 mmol, 1.0 eq) and benzyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine-1-carboxylate (5.21 g, 15.17 mmol, 1.5 eq) in dioxane (50 mL) and H2O (1 mL) were added Pd(dppf)Cl2 (1.48 g, 2.02 mmol, 0.2 eq) and K2CO3 (4.19 g, 30.34 mmol, 3.0
  • reaction mixture was stirred under nitrogen atmosphere at 90 °C for 2 h. After cooled to room temperature, the reaction mixture was filtered and the cake was washed with EA (30 mL). The filtrate was diluted with H2O (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step D benzyl 3'-bromo-1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4-g]isochromene-5,4'- piperidine]-1'-carboxylate
  • Step E benzyl 1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4-g]isochromene-5,4'-piperidine]-1'- carboxylate [0313] To a stirred mixture of benzyl 3'-bromo-1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4- g]isochromene-5,4'-piperidine]-1'-carboxylate (3.5 g, 7.41 mmol, 1.0 eq) in toluene (80 mL) were added AIBN (2.192 mL, 14.82 mmol, 2.0 eq) and n-Bu3SnH (9.98 mL, 37.05 mmol, 5.0 eq).
  • Step F 1'-((benzyloxy)carbonyl)-7-(hydroxymethyl)spiro[isochromane-1,4'-piperidine]-6- carboxylic acid
  • benzyl 1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4-g]isochromene-5,4'- piperidine]-1'-carboxylate 2.3 g, 5.85 mmol, 1.0 eq
  • MeOH 30 mL
  • H2O 15 mL
  • NaOH 1.17 g 29.23 mmol, 5.0 eq
  • Step G 1'-((benzyloxy)carbonyl)-7-formylspiro[isochromane-1,4'-piperidine]-6-carboxylic acid
  • 1'-((benzyloxy)carbonyl)-7- (hydroxymethyl)spiro[isochromane-1,4'-piperidine]-6-carboxylic acid 240 mg, 0.58 mmol, 1.0 eq
  • DCM 15 mL
  • active MnO 2 506.62 mg, 5.83 mmol, 10 eq
  • the reaction mixture was stirred at room temperature for 2 h.
  • the reaction mixture was filtered and the MnO2 cake was washed with DCM (30 mL x 3).
  • Step H 1'-[(benzyloxy)carbonyl]-7- ⁇ [(2,6-dioxopiperidin-3-yl)amino]methyl ⁇ -3,4- dihydrospiro[2-benzopyran-1,4'-piperidine]-6-carboxylic acid [0317] To a stirred solution of 1'-[(benzyloxy)carbonyl]-7-formyl-3,4-dihydrospiro[2- benzopyran-1,4'-piperidine]-6-carboxylic acid (30 mg, 0.073 mmol, 1.0 eq), 3- aminopiperidine-2,6-dione hydrochloride (18.71 mg, 0.146 mmol, 2.0 eq) in MeOH (10 mL) was added NaOAc (8.98 mg, 0.110 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 40 min.
  • Step I benzyl 2'-(2,6-dioxopiperidin-3-yl)-1'-oxo-2',3',7',8'-tetrahydro-1'H-spiro[piperidine- 4,5'-pyrano[3,4-f]isoindole]-1-carboxylate [0318] To a stirred solution of 1'-[(benzyloxy)carbonyl]-7- ⁇ [(2,6-dioxopiperidin-3- yl)amino]methyl ⁇ -3,4-dihydrospiro[2-benzopyran-1,4'-piperidine]-6-carboxylic acid (30 mg, 0.058 mmol, 1.0 eq) in DMF (3 mL) were added HATU (32.81 mg, 0.086 mmol, 1.0 eq) and DI
  • Step B 8-fluoro-1-naphthaldehyde [0321] To a solution of 1-bromo-8-fluoronaphthalene (900 mg, 4 mmol, 1.0 eq) and HCOONa (1.4 g, 12 mmol, 3.0 eq) in DMF (10 mL) was added Pd(PPh3)2Cl2 (280.7 mg, 0.4 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred under N2 at 80 o C overnight. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (30 mL x 3).
  • Step B 8-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one [0327] To a solution of 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.7 g, 11.84 mmol, 1.0 eq) in DMF (30 mL) was added K2CO3 (3.27 g, 23.68 mmol, 2.0 eq) and the mixture waas stirred at 25 °C for 30 mins.
  • Step C 8-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • 8-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 2.9 g, 11.98 mmol, 1.0 eq
  • THF 20 mL
  • Borane-methyl sulfide complex 2 N in THF
  • Step D 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carbaldehyde [0329] To a solution of 8-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (500 mg, 2.19 mmol, 1.0 eq) in DMF (5 mL) were added sodium formate (596.26 mg, 8.77 mmol, 4.0 eq) and Bis(triphenylphosphine)palladium(II) chloride (170.56 mg, 0.22 mmol, 0.1 eq). The mixture was stirred under CO atmosphere (1 atm) at 80 °C overnight.
  • Step B 5-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one [0331] To a solution of 5-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.4 g, 10.52 mmol, 1.0 eq) in DMF (25 mL) were added K2CO3 (2.91 g, 21.05 mmol, 2.0 eq) and the mixture is stirred at 25 °C for 30 mins. Iodomethane (1.96 mL, 31.57 mmol, 3.0 eq) was dropwise added to above mixture and the mixture was stirred at 25 °C for 16 h.
  • Step C 5-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • 5-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 2.6 g, 10.74 mmol, 1.0 eq
  • Borane-methyl sulfide complex (2 N in THF) 21.48 mL, 42.96 mmol, 4.0 eq
  • Step D 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde [0333] To a solution of 5-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (500 mg, 2.19 mmol, 1.0 eq) in DMF (5 mL) were added sodium formate (596.2 mg, 8.77 mmol, 4.0 eq) and Bis(triphenylphosphine)palladium(II) chloride (170.56 mg, 0.22 mmol, 0.1 eq). The mixture was stirred under CO atmosphere (1 atm) at 80 °C overnight.
  • Step B 8-bromo-2,2-dimethylchroman-4-ol
  • MeOH MeOH
  • NaBH4 198.74 mg, 5.880 mmol, 3.0 eq
  • the reaction mixture was diluted with EtOAc (100 mL), washed with saturated aqueous NH4Cl solution (30 mL) and brine(30 mL).
  • Step C 8-bromo-2,2-dimethylchromane
  • Step D 2,2-dimethylchromane-8-carbaldehyde
  • a solution of 8-bromo-2,2-dimethylchromane (320 mg, 1.327 mmol, 1.0 eq), sodium formate (361.02 mg, 5.308 mmol, 4.0 eq) and Pd(PPh 3 ) 2 Cl 2 (103.26 mg, 0.133 mmol, 0.1 eq) in DMF (10 mL) was stirred under CO atmosphere (1 atm) at 90 o C for 18 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl solution (30 mL) and brine (30 mL).
  • Step B 5-bromo-2,2-dimethylchroman-4-ol
  • Step C 5-bromo-2,2-dimethylchromane
  • DCM dimethylethyl-silane
  • Boron trifluoride diethyl etherate (0.149 mL, 1.173 mmol, 0.5 eq) at 0 o C and the mixture was stirred 0 o C for 1 h.
  • the mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 3).
  • Step D 2,2-dimethylchromane-5-carbaldehyde
  • N-bromo-2,2-dimethylchromane 500 mg, 2.074 mmol, 1.0 eq
  • sodium formate 282.05 mg, 4.147 mmol, 2.0 eq
  • Pd(PPh3)2Cl2 291.09 mg, 0.415 mmol, 0.2 eq
  • the mixture was stirred under CO atmosphere (1 atm) at 80 o C overnight.
  • the reaction mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl solution (30 mL) and brine (30 mL).
  • Step B 2-oxo-2,3-dihydro-1H-indole-4-carbaldehyde
  • Ozone was bubbled into a solution of 4-ethenyl-2,3-dihydro-1H-indol-2-one (100 mg, 0.628 mmol, 1.0 eq) in DCM (8 mL) at -78 o C for 1 h.
  • DCM dimethylsulfide
  • Step B 6-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
  • 6-bromo-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one 1.2 g, 4.686 mmol, 1.0 eq
  • Borane-methyl sulfide complex (2 N in THF) 9.371 mL, 18.743 mmol, 4.0 eq
  • reaction mixture was cooled to 0 °C, slowly quenched with methanol (8 mL), and the resulting mixture was stirred at 70 °C for 30 minutes. After evaporation, the mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated dunder reduced pressure.
  • Step C 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde
  • 6-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine 500 mg, 2.065 mmol, 1.0 eq
  • sodium formate 561.70 mg, 8.260 mmol, 4.0 eq
  • Bis(triphenylphosphine)palladium(II) chloride 144.95 mg, 0.207 mmol, 0.1 eq
  • Step B 4-(diethoxymethyl)-1-phenyl-1H-1,2,3-triazole [0349] To a solution of azidobenzene (638 mg, 5.355 mmol, 1.0 eq) in t-BuOH (10 mL) and water (10 mL)were added 3,3-diethoxyprop-1-yne (0.768 mL, 5.355 mmol, 1.0 eq) and Sodium ascorbate (424.39 mg, 2.142 mmol, 0.4 eq), and CuSO4 (170.96 mg, 1.071 mmol, 0.2 eq).
  • Step C 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde
  • 4-(diethoxymethyl)-1-phenyl-1H-1,2,3-triazole 200 mg, 0.809 mmol, 1.0 eq
  • dioxane 2.5 mL
  • concentrated HCl solution 2.5 mL
  • the mixture was stirred at room temperature for 1 h.
  • the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0 to 20%) to give 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (140 mg, yield 99%) as a white solid.
  • Step B 2-oxo-1,2-dihydroquinoline-8-carbaldehyde
  • Ozone was bubbled into a solution of 8-ethenyl-1,2-dihydroquinolin-2-one (200 mg, 1.168 mmol, 1.0 eq) in DCM (8 mL) at -78 o C for 1 h.
  • Excess O3 was purged from the reaction with nitrogen and dimethylsulfide (10 mL) was added. The reaction mixture was stirred for 30 min.
  • Step B 4-hydroxyquinoline-8-carbaldehyde [0355] Ozone was bubbled into a solution of 8-ethenylquinolin-4-ol (230 mg, 1.34 mmol, 1.0 eq) in DCM (8 mL) at -78 o C for 1 h. Excess O3 was purged from the reaction with nitrogen and dimethylsulfide (10 mL) was added. The reaction mixture was stirred for 30 min.
  • Step B (2-(pyrrolidin-1-yl)pyrimidin-4-yl)methanol
  • methyl 2-(pyrrolidin-1-yl)pyrimidine-4-carboxylate 480 mg, 2.32 mmol, 1.0 eq
  • DIBAL-H 1 M in THF
  • Step C 2-(pyrrolidin-1-yl)pyrimidine-4-carbaldehyde [0360] To a solution of (2-(pyrrolidin-1-yl)pyrimidin-4-yl)methanol (390 mg, 2.18 mmol, 1.0 eq) in DCM (10.0 mL) was added Dess-Martin periodinane (1.38 g, 3.26 mmol, 1.5 eq) at 0 o C. The mixture was stirred at room temp for 1 hour. The reaction mixture was quenched with saturated aqueous Na2S2O3 solution (15 mL) and extracted with DCM (15 mL x 3). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure.
  • Step B 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde
  • Ozone was bubbled to a solution of 5-vinyl-2H-benzo[b][1,4]oxazin-3(4H)-one (380 mg, 2.17 mmol, 1.0 eq) in DCM (10.0 mL) at -70 o C for 1 h.
  • the residual ozone was swepted away and dimethyl sulfide (8 mL) was dropwise added to above mixture.
  • Step B 3-((1,1,1-trifluoropropan-2-yl)oxy)benzaldehyde [0369] To a solution of 3-hydroxybenzaldehyde (200 mg, 1.64 mmol, 1.0 eq) in DMF (4.00 mL) was added Cs2CO3 (1.07 g, 3.28 mmol, 2.0 eq). The mixture was stirred at 20 °C for 1 h.
  • 1,1,1-trifluoropropan-2-yl trifluoromethanesulfonate (806 mg, 3.28 mmol, 2.0 eq) was added to above mixture and the reaction mixture was stirred at 20 °C for 16 h. The mixture was cooled to room temperature and filtered. The filtrate is diluted with water (20 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (20 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step B 3-methyl-1H-indazole-7-carbaldehyde
  • O3 was bubbled to a solution of 3-methyl-7-vinyl-1H-indazole (150 mg, 948 ⁇ mol, 1.0 eq) in DCM (20.0 mL) at -70 o C for 2 h. Then the residual O3 was swept away and methyl sulfide (0.2 mL) was added to above mixture. The reaction mixture was stirred for 30 min, diluted with water (10 mL), and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Example 2 3-(1'-methyl-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'- piperidin]-6-yl)piperidine-2,6-dione [0377] To a solution of 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'- piperidine]-6-yl ⁇ piperidine-2,6-dione (50 mg, 0.141 mmol, 1.0 eq) in DMF (1 mL) were added formaldehyde (0.008 mL, 0.0423 mmol, 3.0 eq) and sodium cyanoborohydride (14 mg, 0.211 mmol, 1.5 eq).
  • the reaction was stirred at room temperature for 3 h.
  • the reaction mixture was diluted with saturated aqueous NaHCO 3 solution (1 mL) and extracted with DCM (1 mL x 3).
  • the organic layer was collected and concentrated to 1 mL of volume.
  • the residue was diluted with EA (15 mL), stirred at room temperature for 2 h, and the solid precipitated.
  • Example 3 3-(1'-acetyl-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'- piperidin]-6-yl)piperidine-2,6-dione
  • Step A methyl 1'-acetyl-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6-carboxylate
  • Step F To a solution of methyl 1'-benzyl-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate (intermediate from Example 1, Step F, 1.3 g, 3.7 mmol, 1.0 eq) in MeOH (15 mL) was added acetic anhydride (0.9 mL, 9.25 mmol, 2.5 eq) and 10% Pd/C (100 mg).
  • Step B methyl 1'-acetyl-5-(bromomethyl)-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate
  • Step C 3- ⁇ 1'-acetyl-7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl ⁇ piperidine-2,6-dione
  • DIPEA 0.13 mL, 0.785 mmol, 3 eq
  • methyl 1'-acetyl-5- (bromomethyl)-2H-spiro[1-benzofuran-3,4'-piperidine]-6-carboxylate 100 mg, 0.262 mmol, 1.0 eq
  • 3-aminopiperidine-2,6-dione hydrochloride 65 mg, 0.392 mmol, 1.5 eq
  • Example 4 3-(1'-(naphthalen-1-ylmethyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0381]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-naphthaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 5 3-(1'-(naphthalen-2-ylmethyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0382]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-naphthaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 6 3-(1'-((5-fluoronaphthalen-1-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0383]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 5-fluoro-1-naphthaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 7 3-(1'-((8-fluoronaphthalen-1-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0384]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 8-fluoro-1-naphthaldehyde (Intermediate 4) and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 8 -(1'-(isoquinolin-5-ylmethyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0386]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between isoquinoline-5-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 9 3-(7-oxo-1'-(quinolin-8-ylmethyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0387]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between quinoline-8-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 10 3-(1'-(isoquinolin-8-ylmethyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0388]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between isoquinoline-8-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 11 3-(7-oxo-1'-(quinolin-5-ylmethyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0389]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between quinoline-5-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 12 3-(1'-(benzo[b]thiophen-4-ylmethyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0390]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between benzo[b]thiophene-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 13 3-(1'-(benzo[b]thiophen-7-ylmethyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0391]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between benzo[b]thiophene-7-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 14 3-(1'-(benzo[d]thiazol-4-ylmethyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0392]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1,3-benzothiazole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 15 3-(1'-(benzo[d]thiazol-7-ylmethyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0393]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1,3-benzothiazole-7-carbaldehyde (Intermediate 5) and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 16 3-(1'-((1H-indol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0395]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indole-7-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 17 3-(1'-((1-methyl-1H-indol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0396]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-methyl-1H-indole-7-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 18 3-(1'-((1H-indol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0397]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 19 3-(1'-((3-methyl-1H-indol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0398]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-methyl-1H-indole-4-carbaldehyde (Intermediate 25) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 20 3-(1'-((1H-indol-3-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0400]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indole-3-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 21 3-(1'-((1-methyl-1H-indol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0401]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-methyl-1H-indole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 22 3-(1'-((2-methyl-1H-indol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0402]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-methyl-1H-indole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate [0403] LC-MS (ESI): mass calcd.
  • Example 23 3-(1'-((1H-indol-2-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0404]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indole-2-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 24 3-(1'-((2,3-dimethyl-1H-indol-6-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0406]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,3-dimethyl-1H-indole-6-carbaldehyde (Intermediate 30) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 25 3-(1'-((1H-indazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0408]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indazole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 26 3-(1'-((1-methyl-1H-indazol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0409]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-methyl-1H-indazole-7-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 27 3-(1'-((1H-indazol-6-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0410]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indazole-7-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 29 3-(1'-((2-ethyl-2H-indazol-6-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0412]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-ethyl-2H-indazole-6-carbaldehyde (Intermediate 6b) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 30 3-(1'-((1H-indazol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0413]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indazole-7-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 31 3-(1'-((1-methyl-1H-indazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0414]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-methyl-1H-indazole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 32 3-(1'-((3-methyl-1H-indazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0415]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-methyl-1H-indazole-4-carbaldehyde (Intermediate 26) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 33 3-(1'-((3-methyl-1H-indazol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0417]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-methyl-1H-indazole-7-carbaldehyde (Intermediate 29) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 34 3-(1'-((1H-benzo[d]imidazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0419]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-benzo[d]imidazole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 35 3-(7-oxo-1'-((2-oxo-1,2-dihydroquinolin-8-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0421]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-oxo-1,2-dihydroquinoline-8-carbaldehyde (Intermediate 16) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 36 3-(7-oxo-1'-((4-oxo-1,4-dihydroquinolin-8-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0423]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-oxo-1,4-dihydroquinoline-8-carbaldehyde (Intermediate 17) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 37 3-(1'-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-7-oxo-5,7-dihydro- 2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0425]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,3-dihydro-1,4-benzodioxine-5-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 38 3-(1'-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-7-oxo-5,7-dihydro- 2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0426]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,2-difluoro-3a,7a-dihydro-2H-1,3-benzodioxole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6- dione (Intermediate 1).
  • Example 39 3-(1'-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)methyl)-7-oxo- 5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0427]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carbaldehyde (Intermediate 7) and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 40 3-(1'-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)-7-oxo- 5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0428]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde (Intermediate 8) and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 41 3-(1'-((2,2-dimethylchroman-8-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0429]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,2-dimethylchromane-8-carbaldehyde (Intermediate 9) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 42 3-(1'-((2,2-dimethylchroman-5-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0431]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,2-dimethylchromane-5-carbaldehyde and (Intermediate 11) 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 43 3-(1'-((4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-7-oxo-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0433]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (Intermediate 13) and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]- 6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 44 3-(7-oxo-1'-((2-oxoindolin-4-yl)methyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0435]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-oxoindoline-4-carbaldehyde (Intermediate 12) and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 45 3-(7-oxo-1'-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0437]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (Intermediate 10) and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 46 3-(7-oxo-1'-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0439]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde (Intermediate 21) and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 47 3-(1'-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl)-7-oxo-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0441]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 22-dimethyl-23-dihydrobenzofuran-7-carbaldehyde and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 49 3-(1'-(3-cyclopropoxybenzyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0445]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-cyclopropoxybenzaldehyde (Intermediate 24) and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 50 3-(7-oxo-1'-(3-((1,1,1-trifluoropropan-2-yl)oxy)benzyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0447]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-((1,1,1-trifluoropropan-2-yl)oxy)benzaldehyde (Intermediate 27) and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6- dione (Intermediate 1).
  • Example 51 3-(7-oxo-1'-(3-phenoxybenzyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0449]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-phenoxybenzaldehyde and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 52 3-(1'-(3-(1H-pyrazol-1-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0451]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1H-pyrazol-1-yl)benzaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 53 3-((6-(2,6-dioxopiperidin-3-yl)-7-oxo-6,7-dihydro-2H,5H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-1'-yl)methyl)-N,N-dimethylbenzenesulfonamide [0453]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-formyl-N,N-dimethylbenzenesulfonamide (Intermediate 15) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 54 3-(1'-(3-(morpholinosulfonyl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0455]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(morpholinosulfonyl)benzaldehyde (Intermediate 18) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 55 3-(7-oxo-1'-(3-(phenylsulfonyl)benzyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0457]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(phenylsulfonyl)benzaldehyde (Intermediate 23) and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 56 3-(1'-((6-(isopropylthio)pyridin-2-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0459]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 6-(isopropylthio)picolinaldehyde (Intermediate 28) and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 57 3-(7-oxo-1'-((2-(pyrrolidin-1-yl)pyrimidin-4-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0461]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-(pyrrolidin-1-yl)pyrimidine-4-carbaldehyde (Intermediate 20) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 58 3-(7-oxo-1'-((2-(pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0463]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-(pyrrolidin-1-yl)pyrimidine-5-carbaldehyde (Intermediate 19) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 59 3-(1'-((1-benzyl-1H-pyrazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0465]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-benzyl-1H-pyrazole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 60 3-(7-oxo-1'-((1-phenyl-1H-pyrazol-4-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0467]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-phenyl-1H-pyrazole-4-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 61 3-(7-oxo-1'-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0469]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (Intermediate 14) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 62 3-(7-oxo-1'-((4-phenylthiophen-2-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0471]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-phenylthiophene-2-carbaldehyde and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate [0472] LC-MS (ESI): mass calced for: C 30 H 29 N 3 O 4 S 527.19; m/z found, 528.4 [M+H] + .
  • Example 63 3-(7-oxo-1'-((3-phenylthiophen-2-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0473]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-phenylthiophene-2-carbaldehyde (Intermediate 22) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 64 3-(7-oxo-1'-((3-(trifluoromethyl)thiophen-2-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0475]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(trifluoromethyl)thiophene-2-carbaldehyde (Intermediate 31) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 65 3-(1'-benzyl-5-oxo-5,7-dihydrospiro[furo[3,4-f]isoindole-1,4'-piperidin]- 6(3H)-yl)piperidine-2,6-dione [0477]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between benzaldehyde and 3-(5-oxo-5,7-dihydrospiro[furo[3,4-f]isoindole-1,4'- piperidin]-6(3H)-yl)piperidine-2,6-dione (Intermediate 2).
  • Example 66 3-(1-benzyl-1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione [0479]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between benzaldehyde and 3-(1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione (Intermediate 3).
  • Example 67 3-(1-methyl-1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione [0481]
  • the title compound was prepared in a manner analogous to Example 2 by reductive amination between formaldehyde and 3-(1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione (Intermediate 3).
  • Example 68 3-(1-acetyl-1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione [0483]
  • the title compound was prepared in a manner analogous to Example 3 by acetylation between acetic anhydride and 3-(1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione (Intermediate 3).
  • Example 69 3-(1'-(3-(1-methyl-1H-pyrazol-3-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0485]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (Intermediate 32) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 70 3-(1'-(3-(1-methyl-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0487]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-methyl-1H-pyrazol-4-yl)benzaldehyde (Intermediate 33) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 71 3-(1'-(3-(1-ethyl-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0488]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-ethyl-1H-pyrazol-4-yl)benzaldehyde (Intermediate 34) and 3- ⁇ 7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 72 3-(1'-(3-(1H-pyrazol-3-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0489]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1H-pyrazol-3-yl)benzaldehyde (Intermediate 35) and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • Example 73 3-(1'-(3-(1-cyclopropyl-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0490]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-cyclopropyl-1H-pyrazol-4-yl)benzaldehyde (Intermediate 36) and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6- dione (Intermediate 1).
  • Example 74 3-(1'-(3-(1-isopropyl-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0491]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-isopropyl-1H-pyrazol-4-yl)benzaldehyde (Intermediate 37) and 3- ⁇ 7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1)
  • Example 75 3-(1'-(3-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0492]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)benzaldehyde (Intermediate 38) and 3- ⁇ 7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6- dione (Intermediate 1).
  • Example 76 3-(1'-(3-(1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione [0493]
  • the title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1H-pyrazol-4-yl)benzaldehyde (Intermediate 39) and 3- ⁇ 7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl ⁇ piperidine-2,6-dione (Intermediate 1).
  • the reaction was conducted in total volume of 20 ⁇ L with addition of 2 nM His tagged CRBN+DDB-DLS7+CXU4 (Wuxi, catalogue # RP210521GA) to compounds followed by addition of 60 nM Fluorescent probe Cy5-labeled Thalidomide (Tenova Pharma, catalogue # T52461), and 0.4 nM of MAb Anti-6HIS Tb cryptate Gold (Cisbio, catalogue # 61HI2TLA in the assay buffer (50 mM HEPES pH 7.5, 1 mM TCEP, 0.01% Brij-35, 50 mM NaCl, and 0.1% BSA).
  • IKZF2 FACS assay [0495] Jurkat cells (ATCC, Cat # HB-8065) were cultured in RPMI1640 + 10% FBS + 1% P/S. Cells were treated at desired compound concentrations (0.05 to 10 ⁇ M) and DMSO as vehicle control for 24 hrs.
  • IKZF2 HiBit assay IKZF2 HiBit assay
  • the HiBiT protein tagging system was applied to modified HEK293T Flp-in-HiBiT cells (polyclone) via a CRISPR/Cas9 - mediated insertion of the HiBiT peptide tag (PromegaTM) to the N-terminus of the IKZF2 gene locus (NeonTM transfection system).
  • Test and reference compounds are diluted from 1 mM at 3 folds for 11 doses. 25 nL of diluted compound is transfered to assay plates (Corning3570) using ECHO550, the final DMSO concentration @ 0.1%. The cells are seeded in 3000/25 ⁇ L/well to compound plates. The plate is then incubated for 6 hrs in TC incubator. The amount of Nano-Glo® HiBiT lytic reagent needed to perform the desired experiments is calculated. The Nano-Glo® HiBiT lytic reagent is brought to room temperature.
  • the LgBiT protein is diluted to 1:100 and the Nano-Glo® HiBiT lytic substrate is diluted to 1:50 into an appropriate volume of room temperature Nano-Glo® HiBiT lytic buffer. 15 ⁇ L of the detection reagent (or without LgBiT) is dispensed to corresponding well according to the layout. The plate is then shaken for 10 mins at room temperature. After briefly centrifuge, the plate is read on Envision. At the indicated timepoints, the Nano-Glo® HiBiT lytic detection system (PromegaTM) was utilized for detecting bioluminescence ofthe HiBiT tag in treated cells: abundance of the tag is proportionate to the level of luminescence.
  • the Nano-Glo® HiBiT lytic detection system PromegaTM
  • IKZF1 HiBit assay IKZF1 HiBit assay
  • modified Cells modified HEK293T Flp-in- HiBiT-IKZF1 stable cell line (polyclone) via a CRISPR/Cas9 - mediated insertion of the HiBiT peptide tag (PromegaTM) to the N-terminus of the IKZF2 gene locus (NeonTM transfection system).
  • Test compound from 10 mM and reference compound are diluted at 3 folds for 11 doses.25 nL of diluted compound is transferred to assay plates (Corning3571) using ECHO550, the final DMSO concentration @ 0.1%. The cells are seeded in 3000/25 ⁇ L/well to compound plates. The plates are incubated for 6 hrs in TC incubator. The amount of Nano-Glo® HiBiT lytic reagent needed to perform the desired experiments is calculated. The Nano-Glo® HiBiT lytic reagent is brought to room temperature.
  • the LgBiT protein is diluted to 1:100 and the Nano-Glo® HiBiT lytic substrate is brought to 1:50 into an appropriate volume of room temperature Nano-Glo® HiBiT lytic buffer.15 ⁇ L of the detection reagent (or without LgBiT) is dispensed to corresponding well according to the layout. The plate is shaken for 10 mins at room temperature. After briefly centrifuging, the plate is read on Envision. At the indicated timepoints, the Nano-Glo® HiBiT lytic detection system (PromegaTM) was utilized for detecting bioluminescence ofthe HiBiT tag in treated cells: abundance of the tag is proportionate to the level of luminescence.
  • IKZF2 and IKZF1 degradation by HiBit IKZF2 degradation and evaluation of IL-2 production are important for immunosuppressive activity of regulatory T cells (T reg cells), which is linked to interlukin-2 (IL-2) repression.
  • T reg cells regulatory T cells
  • IKZF2 binds to the IL-2 promoter in Treg cells and suppresses transcriptional activation.
  • IKZF2 knockdown suppresses FoxP3 binding to IL- 2 promoter and results in higher IL-2 expression upon stimulation.
  • IKZF2 knockout leads to an unstable CD4 Treg phenotype in mice marked by production of effector cytokines and IKZF2 knockout in Tregs suppresses tumor growth. (Baine I.
  • Jurkat cells (ATCC, Cat # HB-8065) are treated with vehicle control (DMSO) or the compound for 16 -24 hrs. After 16 - 24 hrs of treatment cells are stimulated with CD3/CD28 stimulation beads at a 3:1 ratio for 24 hrs.
  • DMSO vehicle control
  • IKZF2 degradation in primary human Treg cells [0502] To measure whether the compounds of this disclosure can induce degradation of IKZF2 in Treg cells, human peripheral bone marrow cells (PBMCs) obtained from healthy donors purchased from Milestone Biological Science and Technology Company are treated with vehicle control (DMSO) or the compound for various time points (3 – 24 hrs).
  • PBMCs peripheral bone marrow cells
  • the cells are collected and stained with anti-CD3-APC-Cy7 (Clone SP34-2, BD), anti-CD4-FITC (Clone L200, BD), anti-CD45-BV510 (Clone HI30, Biolegend), and anti- CD25-BV421 (Clone BC96, Biolegend) in cell staining buffer (Biolegend, Cat#420201), washed and fixed with FOXP3 fix/perm buffer (Life Technologies, cat.
  • IKZF2 mean fluorescence intensity (MFI) and IKZF1 MFI are measured in Tregs (CD4+CD25+ FOXP3+) cells.
  • the compounds of this disclosure are expected to degrade IKZF2 in Treg cells, thereby suppressing the action of T reg cells.
  • T reg cells and T eff cells from matched human donors are co-cultured in the presence of vehicle control (DMSO) or compound.
  • Treg cells are isolated from human peripheral bone marrow cells (PBMCs) obtained from healthy donors purchased from Milestone Biological Science and Technology Company.
  • PBMCs peripheral bone marrow cells
  • CD4 enrichment by negative selection followed by CD25 enrichment by positive selection are performed using the human CD4 T cell isolation kit (cat.#130-096-533) and human CD25 microbeads (cat.#130-092-983) from Miltenyi Biotec (Cambridge, MA) according to manufacturer’s instructions.
  • Isolated T regs are expanded for 8-14 days in the presence of compound or DMSO, using Treg expander beads (ThermoFisher, cat.#11129D) or T-cell activator beads (ThermoFisher, cat.#11161D) at a 4:1 or 3:1 ratio, respectively, in the presence of 500 U/mL rhIL-2.
  • Treg expander beads ThermoFisher, cat.#11129D
  • T-cell activator beads ThermoFisher, cat.#11161D
  • Expanded T reg cells are dispensed in co-culture with carboxyfluorescein succinimidyl ester (CFSE)-labelled CD3+ T- Cells from the matched donor at various Treg:CD3+ T cell ratios in the presence of T-cell activator beads or soluble anti-CD3 antibody (30 ng/mL, OKT3, Thermofisher cat.# 16-0037- 81). After 3-5 days of incubation, proliferation of CD8+ T eff cells is assessed by analyzing CFSE dye dilution in CD8+ T-Cells (anti-CD8-PerCP/Cyanine5.5, clone SK1, Biolegend) using flow cytometry.
  • CFSE carboxyfluorescein succinimidyl ester
  • T eff cells that proliferate during the co-culture are identified as having diluted CFSE and data are plotted as the proportion of CFSE low, proliferated cells in the final culture.
  • the compounds of this disclosure are expected to suppress Treg cells, thereby enhancing T eff cell proliferation.
  • Cynomolgus moneys [0504] To determine in vivo efficacy of the compounds of this disclosure, non na ⁇ ve cynomolgus monkeys are treated with a single oral dose of vehicle or the compound.
  • Whole blood from the treated monkeys is collected across time (e.g., various timepoints between 0 hr – 96 hrs) and stained with anti-CD3-APC-Cy7 (Clone SP34-2, BD), anti-CD4-FITC (Clone L200 BD) anti-CD45-BV786 (Clone D058-1283 Biolegend) and anti-CD25-APC (Clone BC96, Biolegend) in cell staining buffer (Biolegend, Cat#420201), washed and fixed with FOXP3 fix/perm buffer (Life Technologies, cat.
  • IKZF2 mean fluorescence intensity (MFI) is measured in Tregs (CD4+CD25+FOXP3+) cells.
  • the compounds of this disclosure are expected to suppress IKZF2 + T regs in cynomolgus monkeys.
  • CRBN I391V mice are treated with a single oral dose of vehicle or the compound.
  • CRBN I391V mice are used because a single amino acid difference within the CRBN–Immunomodulatory drug (IMiD) binding region renders mouse CRBN resistant to degradation by IMiDs.
  • IMD immunomodulatory drug
  • a change from Ile 391 to Val in mouse CRBN restores IMiD-induced degradation of IKZF3. Fink, E. C. et al. Blood 132, 1535–1544 (2016); Gemechu, Y. et al. P Natl Acad Sci Usa 115, 11802–11807 (2016). 1.
  • IKZF2 degradation in mice Various doses of the vehicle and compound are tested in the mice and analyzed across time (e.g., various timepoints between 0 hr – 12 hrs) and analyzed using western blot assay to measure the percentage of IKZF2 remaining in tissues (e.g., spleen and thymus). Tissue is lysed in RIPA buffer (Cell Signaling, cat#9806) containing Halt TM protease/phosphatase inhibitor cocktail (Thermo, Cat#78440).
  • Te Test tumor volume endpoint
  • T 0 Test tumor volume at start of dosing
  • C e Vehicle control tumor volume endpoint
  • C0 Vehicle control tumor volume at start of dosing

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Abstract

Described herein are compounds of Formulae I' and their pharmaceutically acceptable salts, solvates, or stereoisomers, as well as their uses (e.g., as IKZF2 degraders).

Description

IKZF2 DEGRADERS AND USES THEREOF RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/446,112, filed February 16, 2023, and U.S. Provisional Application No. 63/331,558, filed April 15, 2022, the contents of each of which are incorporated herein by reference in their entireties. BACKGROUND [0002] IKAROS Family Zinc Finger 2 (IKZF2) (also known as Helios) is one of the five members of the Ikaros family of transcription factors found in mammals. IKZF2 contains four zinc finger domains near the N-terminus, which are involved in DNA binding, and two zinc finger domains at the C-terminus, which are involved in protein dimerization. IKZF2 is about 50% identical with Ikaros family members, Ikaros (IKZF1), Aiolos (IKZF3), and Eos (IKZF4) with highest homology in the zinc finger regions (80%+ identity). These four Ikaros family transcription factors bind to the same DNA consensus site and can heterodimerize with each other when co-expressed in cells. The fifth Ikaros family protein, Pegasus (IKZF5), is only 25% identical to IKZF2, binds a different DNA site than other Ikaros family members and does not readily heterodimerize with the other Ikaros family proteins. IKZF2, IKZFl and IKZF3 are expressed mainly in hematopoietic cells while IKZF4 and IKZF5 are expressed in a wide variety of tissues. [0003] IKZF2 is a critical regulator of T cell activity and function. Genetic deletion of Helios resulted in an enhanced anti-tumor immune response. Notably, Helios is highly expressed in regulatory T cells, a subpopulation of T cells that restricts the activity of effector T cells. Selective deletion of Helios in regulatory T cells resulted in both loss of suppressive activity and acquisition of effector T cell functions. Therefore, Helios is a critical factor in restricting T cell effector function in Tregs. Currently, anti-CTLA4 antibodies are used in the clinic to target Tregs in tumors. However, targeting CTLA4 often causes systemic activation of T- effector cells, resulting in excessive toxicity and limiting therapeutic utility. Up to 3/4 of patients treated with a combination of anti-PD-l and anti-CTLA4 have reported grade 3 or higher adverse events. Thus, a strong need exists to provide compounds that target Tregs in tumors without causing systemic activation of Τ-effector cells. An IKZF2-specific degrader has the potential to focus the enhanced immune response to areas within or near tumors providing a potentially more tolerable and less toxic therapeutic agent for the treatment of cancer. [0004] Helios expression has also been reported to be upregulated in ‘exhausted’ T cells, in the settings of both chronic viral infections, as well as in dysfunctional chimeric antigen receptor (CAR) T cells. Overexpression or aberrant expression of Helios and various splice isoforms have been reported in several hematological malignancies, including T cell leukemias and lymphomas. Moreover, knockdown of Helios in a model of mixed lineage leukemia (MLL)-driven myeloid leukemia potently suppressed proliferation and increased cell death. In line with these results, genomic profiling and chromatin accessibility analysis demonstrated that IKZF2 loss led to increased myeloid differentiation. These data suggest that IKZF2 is differentially required in myeloid leukemia cells compared to normal cells. Therefore, depletion of IKZF2 has preferential effect in leukemic stem cells compared to normal hematopoietic stem cells, providing a new strategy for targeting leukemic stem cells. SUMMARY [0005] In certain aspects, the present disclosure provides compounds of Formula (I’):
Figure imgf000003_0001
and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables in Formula I’ is described, embodied, and exemplified herein. [0006] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient. [0007] In certain aspects, the present disclosure further provides methods of degrading an IKZF2 protein in a subject or biological sample comprising administering a compound disclosed herein to the subject or contacting the biological sample with a compound disclosed herein. [0008] In certain aspects, the present disclosure further provides uses of a compound disclose herein in the manufacture of a medicament for degrading an IKZF2 protein in a subject or biological sample. [0009] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading an IKZF2 protein in a subject or biological sample. [0010] In certain aspects, the present disclosure provides methods of treating a disease or disorder comprising administering to a subject in need thereof a compound disclosed herein. [0011] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder. [0012] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorder. [0013] In certain aspects, the present disclosure provides methods of (a) increasing IL 2 production; (b) suppressing regulatory T cells; (c) enhancing effector T cells; (d) inhibiting tumor growth; and/or (e) enhancing tumor regression in a subject, comprising administering to the subject in need thereof a compound disclosed herein. [0014] In certain aspects, the present disclosure provides use of a compound disclosed herein [0015] in the manufacture of a medicament for (a) increasing IL-2 production; (b) suppressing regulatory T cells; (c) enhancing effector T cells; (d) inhibiting tumor growth; and/or (e) enhancing tumor regression in a subject. DETAILED DESCRIPTION [0016] The present disclosure relates to compounds and methods of degrading a IKZF2 protein comprising contacting a IKZF2 protein with a therapeutically effective amount of a IKZF2 degrader. The invention also relates to methods of treating a IKZF2 protein-mediated disease or condition in a patient by administering a therapeutically effective amount of a IKZF2 degrader to a patient in need thereof. The invention further relates to methods of treating a IKZF2-mediated disease or condition in a patient, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a IKZF2 degrader to a patient in need thereof. Compounds of the Present Disclosure [0017] In certain aspects, the present disclosure provides compounds of Formula (I’)
Figure imgf000005_0001
and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: X is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; Y is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; each Z is independently -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; p is 0, 1, or 2; each R3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two geminal R3 together form an oxo; or two geminal R3, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; each R4 is independently hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Ring A is C3-12 carbocycle or 3- to 12-membered heterocycle; R1 is hydrogen, C1-6 alkyl, -C(=O)(C1-6 alkyl), or -M-L-Q-R2; M is absent, -(C=O)-, -S(=O)-, or -S(=O)2-; L is absent or -[C(RL)2]-r; r is an integer selected from 1 to 3; each RL is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two geminal RL, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; Q is absent, -NRQ-, -O-, -C(=O)-, -S(=O)-, or -S(=O)2-; RQ is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; R2 is C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2a; each R2a is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -(C1-6 alkylene)-(C3-12 carbocyclyl), -(C1-6 alkylene)-(3- to 12-membered heterocyclyl), -(C1-6 alkylene)-(C6-10 aryl), -(C1-6 alkylene)- (5- to 10-membered heteroaryl), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two vincinal R2a, together with the atoms to which they are bonded, form C5-12 carbocycle or 5- to 12-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; each occurrence of RA and RC is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; q is an integer selected from 0 to 2; s is an integer selected from 0 to 12, as valency permits; each RE is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C610 aryl or 5- to 10-membered heteroaryl wherein the alkyl alkoxy alkylamino alkenyl alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; e is an integer selected from 0 to 6, as valency permits; U is -CH2- or -C(=O)-; R5 is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; and t is an integer selected from 0 to 2; wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and Rc and Rd are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more Rz, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl. [0018] In certain embodiments, the compound is a compound of Formula I’-1-i, I’-1-ii, I’-1- iii, I’-1-iv, I’-1-v, I’-1-vi, I’-1-vii, I’-1-viii, I’-1-ix, I’-1-x, I’-1-xi, I’-1-xii, or I’-1-xiii:
Figure imgf000008_0001
Figure imgf000009_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0019] In certain embodiments, the compound is a compound of Formula I’-2-i, I’-2-ii, I’-2- iii, I’-2-iv, I’-2-v, I’-2-vi, I’-2-vii, I’-2-viii, I’-2-ix, I’-2-x, I’-2-xi, I’-2-xii, or I’-2-xiii:
Figure imgf000009_0002
, ,
Figure imgf000009_0003
, ,
Figure imgf000010_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0020] In certain embodiments, when p is 0, then X and Y are not both -C(R3)2; and/or when p is 1, then X, Y, and Z are not all -C(R3)2. [0021] In certain embodiments, X is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-. [0022] In certain embodiments, Y is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-. [0023] In certain embodiments, X is -O- and Y is -C(R3)2-. In certain embodiments, X is - C(R3)2- and Y is -O-. In certain embodiments, X is -O- and Y is -CH2-. In certain embodiments, X is -CH2- and Y is -O-. [0024] In certain embodiments, Z is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-. [0025] In certain embodiments, Z is -C(R3)2 or -O-. [0026] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2 [0027] In certain embodiments, p is 0, X is -O- and Y is -C(R3)2-. In certain embodiments, p is 0, X is -C(R3)2- and Y is -O-. In certain embodiments, p is 0, X is -O- and Y is -CH2-. In certain embodiments, p is 0, X is -CH2- and Y is -O-. [0028] In certain embodiments, each R3 is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd -C(=O)Ra -C(=O)ORb or -C(=O)NRcRd wherein the alkyl alkoxy alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0029] In certain embodiments, each R3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0030] In certain embodiments, each R3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0031] In certain embodiments, each R3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0032] In certain embodiments, each R3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0033] In certain embodiments, two geminal R3 together form an oxo. [0034] In certain embodiments, two geminal R3, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more Ru. [0035] In certain embodiments, each R4 is independently hydrogen or C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i- propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)) optionally substituted with one or more Ru. [0036] In certain embodiments, Ring A is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3) cyclobutyl (C4) cyclobutenyl (C4) cyclopentyl (C5) cyclopentenyl (C5) cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) or 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S). [0037] In certain embodiments, R1 is hydrogen, C1-6 alkyl, -C(=O)(C1-6 alkyl), or -M-L-Q-R2. [0038] In certain embodiments, R1 is C1-6 alkyl or -C(=O)(C1-6 alkyl). [0039] In certain embodiments, R1 is -M-L-Q-R2. [0040] In certain embodiments, R1 is -[C(RL)2]r-R2. [0041] In certain embodiments, R1 is -[CH2]r-R2. [0042] In certain embodiments, R1 is -C(RL)2-R2. [0043] In certain embodiments, R1 is -CH2-R2. [0044] In certain embodiments, M is absent, -(C=O)-, -S(=O)-, or -S(=O)2-. [0045] In certain embodiments, M is absent. [0046] In certain embodiments, L is absent or [-C(RL)2-]r. [0047] In certain embodiments, each RL is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5) or hexenyl (C6)) C26 alkynyl (eg ethynyl (C2) 1-propynyl (C3) 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0048] In certain embodiments, each RL is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0049] In certain embodiments, each RL is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0050] In certain embodiments, each RL is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0051] In certain embodiments, two geminal RL, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more Ru. [0052] In certain embodiments, r is an integer selected from 1 to 3. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. [0053] In certain embodiments Q is absent -NRQ- -O- -C(=O)- -S(=O)- or -S(=O)2- [0054] In certain embodiments, Q is absent. [0055] In certain embodiments, RQ is hydrogen or C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)) optionally substituted with one or more Ru. [0056] In certain embodiments, R2 is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2a. [0057] In certain embodiments, R2 is optionally substituted with one R2a. In certain embodiments, R2 is optionally substituted with two R2a. In certain embodiments, R2 is optionally substituted with three R2a. [0058] In certain embodiments, each R2a is independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1- 6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino t-butylhexylamino or pentylhexylamino) C26 alkenyl (eg ethenyl (C2) 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -(C1-6 alkylene)-(C3-12 carbocyclyl), -(C1-6 alkylene)-(3- to 12-membered heterocyclyl), -(C1-6 alkylene)-(C6-10 aryl), -(C1-6 alkylene)-(5- to 10-membered heteroaryl), - SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0059] In certain embodiments, each R2a is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -(C1-6 alkylene)-(C3- 12 carbocyclyl), -(C1-6 alkylene)-(3- to 12-membered heterocyclyl), -(C1-6 alkylene)-(C6-10 aryl), or -(C1-6 alkylene)-(5- to 10-membered heteroaryl), wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0060] In certain embodiments, each R2a is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -(C1-6 alkylene)-(C3-6 carbocyclyl), -(C1-6 alkylene)-(3- to 6-membered heterocyclyl), -(C1-6 alkylene)-(C6 aryl), -(C1- 6 alkylene)-(5- to 6-membered heteroaryl), wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru [0061] In certain embodiments, each R2a is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -(C1-6 alkylene)-(C6-10 aryl), or -(C1-6 alkylene)-(5- to 10- membered heteroaryl), wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0062] In certain embodiments, each R2a is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, or -(C1-6 alkylene)-(C6-10 aryl), wherein the alkyl, alkylene, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0063] In certain embodiments, each R2a is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -(C1-6 alkylene)-(C6-10 aryl), -SRb, -S(=O)2Ra, or -S(=O)2NRcRd, wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0064] In certain embodiments, each R2a is independently oxo, halogen, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -(C1-6 alkylene)-(C6- 10 aryl), -SRb, -S(=O)2Ra, or -S(=O)2NRcRd, wherein the alkyl, alkylene, alkoxy, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0065] In certain embodiments, two vincinal R2a, together with the atoms to which they are bonded, form C5-12 carbocyclyl (e.g., cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) or 5- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 5- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more Ru. [0066] In certain embodiments, each occurrence of RA and RC is oxo, independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (eg dimethylamino diethylamino di-n-propylamino di-i-propylamino di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0067] In certain embodiments, each occurrence of RA and RC is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0068] In certain embodiments, each occurrence of RA and RC is independently oxo, hydrogen, halogen -CN -NO2 -OH -NH2 C16 alkyl C16 alkoxy C16 alkylamino C26 alkenyl C26 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0069] In certain embodiments, each occurrence of RA and RC is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0070] In certain embodiments, each occurrence of RA and RC is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0071] In certain embodiments, q is an integer selected from 0 to 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [0072] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4, as valency permits. In certain embodiments, s is 5, as valency permits. In certain embodiments, s is 6, as valency permits. In certain embodiments, s is 7, as valency permits. In certain embodiments, s is 8, as valency permits. In certain embodiments, s is 9, as valency permits. In certain embodiments, s is 10, as valency permits. In certain embodiments, s is 11, as valency permits. In certain embodiments, s is 12, as valency permits. [0073] In certain embodiments, each RE is independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1- 6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino propylhexylamino n-butylpentylamino i-butylpentylamino s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0074] In certain embodiments, each RE is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0075] In certain embodiments, each RE is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0076] In certain embodiments, each RE is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0077] In certain embodiments, e is an integer selected from 0 to 6, as valency permits. In certain embodiments, e is 0. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5. In certain embodiments, e is 6. [0078] In certain embodiments U is -CH2- or -C(=O)- In certain embodiments U is -CH2- [0079] In certain embodiments, R5 is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl. [0080] In certain embodiments, R5 is hydrogen. [0081] In certain embodiments, t is an integer selected from 0 to 2. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. [0082] In certain embodiments, the compound is a compound of Formula (I):
Figure imgf000021_0001
or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1 is hydrogen, C1-6 alkyl, -C(=O)(C1-6 alkyl), or -M-L-Q-R2; M is absent, -(C=O)-, -S(=O)-, or -S(=O)2-; L is absent or [-C(RL)2-]r; each RL is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RL, together with the carbon atom(s) to which they are attached, form C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; r is an integer from 1 to 3; Q is absent, -NRQ-, -O-, -C(=O)-, -S(=O)-, or -S(=O)2-; RQ is hydrogen, C1-6 alkyl, wherein the alkyl is optionally substituted with one or more Ru; R2 is C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R2a; each R2a is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -(C1-6 alkyl)-(C6-10 aryl), -(C1-6 alkyl)-(5- to 10-membered heteroaryl), -(C1-6 alkyl)-(C3-12 carbocyclyl), -(C1-6 alkyl)-(3- to 12- membered heterocyclyl), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each occurrence of RA and RC is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; q is an integer from 0 to 2; s is an integer from 0 to 12, as valency permits; m and n are independently an integer from 0 to 2; X is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; Y is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; each Z is independently -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; p is 0 or 1; each R3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two geminal R3 together form oxo; or two R3, together with the carbon atom(s) to which they are attached, form C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each R4 is independently hydrogen or C1-6 alkyl, wherein the alkyl is optionally substituted with one or more Ru; U is -CH2- or -C(=O)-; R5 is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; and t is an integer from 0 to 2; wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl. [0083] In certain embodiments, X is -O- and Y is -C(R3)2-. In certain embodiments, X is - C(R3)2- and Y is -O-. In certain embodiments, X is -NR4- and Y is -C(R3)2-. In certain embodiments, X is -C(R3)2- and Y is -NR4-. [0084] In certain embodiments, Z is -C(R3)2-, -NR4-, or -O-. In certain embodiments, Z is - C(R3)2 or -O- [0085] In certain embodiments, when p is 0, then X and Y are not both -C(R3)2; or when p is 1, then X, Y, and Z are not all -C(R3)2. [0086] In certain embodiments, p is 0. In certain embodiments, p is 1. [0087] In certain embodiments, the compound is a compound of Formula (I-1-i) to (I-1-xiii):
Figure imgf000024_0001
Figure imgf000025_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0088] In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is C1-6 alkyl. In certain embodiments, R1 is -C(=O)(C1-6 alkyl). In certain embodiments, R1 is -M-L-Q-R2. [0089] In certain embodiments, M is absent. In certain embodiments, M is -(C=O)-, -S(=O)-, or -S(=O)2-. [0090] In certain embodiments, L is -C(RL)2-. In certain embodiments, L is absent. [0091] In certain embodiments, each RL is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0092] In certain embodiments, each RL is independently hydrogen or C1-6 alkyl. [0093] In certain embodiments, L is -CH2-. [0094] In certain embodiments, two RL, together with the carbon atom(s) to which they are attached, form C3-12 carbocyclyl or 3- to 12-membered heterocyclyl. [0095] In certain embodiments, Q is absent. In certain embodiments, Q is -NRQ-, -O-, -C(=O)- , -S(=O)-, or -S(=O)2-. In certain embodiments, Q is -NRQ-. In certain embodiments, Q is -O-. In certain embodiments, Q is -C(=O)-. In certain embodiments, Q is -S(=O)-. In certain embodiments, Q is -S(=O)2-. [0096] In certain embodiments, RQ is hydrogen or C1-6 alkyl. In certain embodiments, RQ is C1- 6 alkyl. In certain embodiments, RQ is hydrogen. [0097] In certain embodiments, R2 is C6-10 aryl, 5- to 10-membered heteroaryl, C5-10 carbocyclyl, or 5- to 10-membered heterocyclyl. [0098] In certain embodiments, R2 is phenyl. [0099] In certain embodiments, R2 is 5- to 10-membered heteroaryl. [0100] In certain embodiments, R2 is C5-10 carbocyclyl. [0101] In certain embodiments, R2 is 5- to 10-membered heterocyclyl. [0102] In certain embodiments, the compound is a compound of Formula (I-2-i) or (I-2-ii)
Figure imgf000026_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein u is an integer selected from 0 to 10, as valency permits. [0103] In certain embodiments, each R2a is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10- membered heteroaryl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -(C1-6 alkyl)-(C6-10 aryl), -SRb, -S(=O)2Ra, or -S(=O)2NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0104] In certain embodiments, each R2a is independently oxo, halogen, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -(C1-6 alkyl)-(C6-10 aryl), -SRb, -S(=O)2Ra, or -S(=O)2NRcRd, wherein the alkyl, alkoxy, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0105] In certain embodiments, two R2a together form oxo. [0106] In certain embodiments, each R3 is independently H or C1-6 alkyl. In certain embodiments, each R3 is H. In certain embodiments, two geminal R3 together form oxo. [0107] In certain embodiments, each R4 is independently hydrogen, C1-6 alkyl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. In certain embodiments, each R4 is independently H or C1-6 alkyl, wherein the alkyl is optionally substituted with one or more Ru. [0108] In certain embodiments, each occurrence of RA and RC is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6- 10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0109] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8. In certain embodiments, s is 9. In certain embodiments, s is 10. In certain embodiments, s is 11. In certain embodiments, s is 12. [0110] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [0111] In certain embodiments, m and n are independently 0 or 1. In certain embodiments, each of m and n is 0. In certain embodiments, each of m and n are is 1. In certain embodiments, m is 0 and n is 1. In certain embodiments, m is 1 and n is 0. [0112] In certain embodiments, U is -CH2-. In certain embodiments, U is -C(=O)-. [0113] In certain embodiments, R5 is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl. In certain embodiments, R5 is hydrogen. In certain embodiments, R5 is deuterium. In certain embodiments, R5 is C1-6 haloalkyl. In certain embodiments, R5 is C1-6 alkyl. [0114] In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. [0115] In certain embodiments, the compound is a compound of Formula (II):
Figure imgf000027_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1 is hydrogen or -L-R2; L is -CH2-; R2 is C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R2a; each R2a is independently oxo, halogen, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -(C1-6 alkyl)-(C6-10 aryl), -SRb, -S(=O)2Ra, or - S(=O)2NRcRd, wherein the alkyl, alkoxy, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; X is -O-; Y is -CH2-; and p is 0; wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-12 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino C36 carbocyclyl or 3- to 6-memberred heterocyclyl [0116] In certain embodiments, each Ra is independently C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0117] In certain embodiments, each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl. [0118] In certain embodiments, each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0119] In certain embodiments, each Ra is independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0120] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[221]heptanyl (C7) bicyclo[222]octanyl (C8) cyclononyl (C9) cyclononenyl (C9) cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0121] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl. [0122] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0123] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0124] In certain embodiments, each Rc and each Rd is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0125] In certain embodiments, each Rc and each Rd is independently hydrogen, C1-6 alkyl, C3- 6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more Ru. [0126] In certain embodiments, Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more Rz. [0127] In certain embodiments, Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz. [0128] In certain embodiments, Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1- 6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl. [0129] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl- i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[221]heptanyl (C7) bicyclo[222]octanyl (C8) cyclononyl (C9) cyclononenyl (C9) cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0130] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl. [0131] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl. [0132] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0133] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C16 alkyl C16 alkoxy C16 alkylamino C36 carbocyclyl or 3- to 6-membered heterocyclyl wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0134] In certain embodiments, two Ru, together with the carbon atom(s) to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S). [0135] In certain embodiments, two geminal Ru, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S). [0136] Embodiments of the variables in any of the Formulae described herein, e.g., Formulae I and I’, as applicable, are described below. Any of the variables can be any moiety as described in the embodiments below. In addition, the combination of any moieties described for any of the variables, as applicable, with any moieties described for any of the remaining variables, is also contemplated. [0137] Without wishing to be limited by this statement, while various options for variables are described herein, it is understood that the present disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options. For example, while various options for variables X, Y, and Z are described herein, the disclosure may be interpreted as excluding structures for non-operable compounds caused by certain combinations of the options (e.g., when two adjacent members of X, Y, an Z are both nitrogen or both oxygen; or one of two adjacent members of X, Y, and Z is nitrogen while the other is oxygen). [0138] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0139] In certain embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof. [0140] In certain embodiments the compound is selected from the compounds in Table 1 Table 1.
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
[0141] The compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known IKZF2 degrader. For example, the compounds of the present disclosure may display more potent estrogen receptor activity, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and/or AUC), and/or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction). These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein. [0142] Due to the existence of double bonds, the compounds of the present disclosure may be in cis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration. [0143] In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate. [0144] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Forms of Compounds Disclosed Herein Pharmaceutically acceptable salts [0145] In some embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [0146] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [0147] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate. [0148] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4- methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3- hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. [0149] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, magnesium, aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. [0150] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [0151] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates are within the scope of the invention. [0152] It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present invention. [0153] In some embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods of treating diseases by administering such solvates. The present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [0154] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Isomers/Stereoisomers [0155] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” [0156] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. [0157] In some embodiments, the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention [0158] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers [0159] In some embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. [0160] Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Pharmaceutical Compositions [0161] In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [0162] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. [0163] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [0164] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [0165] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet. Preparation and Characterization of the Compounds [0166] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis By way of example the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The compounds of the present disclosure (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and/or synthesis described herein (e.g., in the Examples). General Synthetic Scheme [0167] A compound of formula XVII (when X = OH) may be prepared according to the procedures shown in SCHEMEs 1-3.
Figure imgf000051_0001
SCHEME 1 [0168] According to SCHEME 1, commercially available or synthetically accessible substituted pyridine of formula III is reacted with benzyl bromide IV or the like; in a suitable solvent such as acetonitrile, CCl4, toluene, and the like; at temperatures ranging from 60 °C to 120 °C; to provide pyridinium salt of formula V. Pyridinium salt of formula V is reduced with a suitable reductant such as NaBH4, NaCNBH3, and the like; in an alcoholic solvent such as MeOH, EtOH, and the like; at temperatures ranging from -20 °C to 25 °C, preferably 0 °C; to provide a compound of formula (VI).
Figure imgf000051_0003
Figure imgf000051_0002
SCHEME 2 [0169] According to SCHEME 2, commercially available or synthetically accessible carboxylic acid of formula VII is brominated in the presence of a brominating agent such as Br2, NBS and the like; in the presence of an acid such as acetic acid, pTSA and the like; in an alcoholic solvent such as MeOH, EtOH and the like; at temperatures ranging from 0 °C to about 50 °C, preferably 25 °C; to afford a compound of formula (VIII). Bromo benzoic acid of formula VIII is reacted with methanol in the presence of an acid such as acetic acid, HCl and the like; in a suitable solvent such as MeOH, THF and the like; at temperatures ranging from 25 °C to about 80 °C, preferably 50 °C; to provide a compound of formula (IX).
Figure imgf000052_0001
SCHEME 3 [0170] According to SCHEME 3, a compound of formula (IX) is reacted with a compound of formula (VI) under Mitsunobu condition, in the presence of a coupling agent such DIAD, DEAD, and the like; with a coupling co-agent such as Ph3P, Bu3P and the like; in a solvent such as diethyl ether, THF and the like; at temperatures ranging from -20 °C to about 50 °C, preferably 0 °C; to afford an ether compound of formula (X); a compound of formula (X) is cyclized under radical cyclization condition with a radical initiator such as BPO, AIBN and the like; in the presence of a suitable reductant such as Bu3SnH, (TMS)3SiH and the like; in a solvent such as benzene, toluene and the like; at temperatures ranging from 80 °C to about 120 °C, preferably 100 °C; to afford a compound of formula (XI). A compound of formula (XI) is de-benzylated with hydrogenation under 1 atm or up to 50 psi hydrogen gas, in the presence of a suitable catalyst such as Pd on C, PtO2 and the like; in a solvent such as MeOH, EtOAc and the like; at temperatures ranging from 25 °C to about 50 °C, preferably 25 °C; to afford an amino compound of formula (XII). An amino compound of formula (XII) was re-protected with Boc2O in the presence of a suitable base such as TEA, DIPEA and the like; in a solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford a compound of formula (XIII). A compound of formula (XIII) is brominated by radical bromination with a radical initiator such as BPO, AIBN and the like; in the presence of a suitable bromine source such as NBS, Br2 and the like; in a solvent such as CCl4, benzene and the like; at temperatures ranging from 60 °C to about 100 °C, preferably 80 °C; to afford a bromo compound of formula (XIV). A bromo compound of formula (XIV) is reacted with a commercially available or synthetically accessible amine of formula XV, in the presence of a suitable base such as TEA, DIPEA and the like; in a suitable solvent such as acetonitrile, THF and the like; at temperatures ranging from 60 °C to about 100 °C, preferably 80 °C; to afford a cyclized compound of formula (XVI). A cyclized compound of formula (XVI) is de-protected with a suitable base such as TFA, HCl and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 50 °C, preferably 25 °C; to afford an amino compound of formula (XVII). [0171] A compound of formula XVII (when Z = O, p=1) may be prepared according to the procedures shown in SCHEMEs 4-5.
Figure imgf000053_0001
SCHEME 4 [0172] According to SCHEME 4, commercially available or synthetically accessible substituted iodo compound of formula XVIII is reacted with 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane or potassium vinyltrifluoroborate; in the presence of a catalyst such as Pd(Ph3P)4, Pd2(dba)3, and the like; with an inorganic base such as Na2CO3, K3PO4, and the like; in a suitable solvent such as THF, dioxane, and the like; in a co-solvent such as water; at temperatures ranging from 60 °C to 120 °C, preferably at 80 °C; to provide an olefin compound of formula XIX. An olefin compound of formula XIX is hydroborated with a boron reductant such as BH3 etherate, 9-BBN, and the like; in a suitable solvent such as THF, dioxane, and the like; at temperatures ranging from -20 °C to 25 °C, preferably 0 °C; followed by the treatment of an oxidant such as 30% H2O2; at temperatures ranging from -20 °C to 25 °C, preferably 0 °C; to provide a compound of formula XX (where X= CH2, Y is CH2). Alternatively, an olefin compound of formula XIX is dihydroxylated with a catalyst such as OsO4, K2OsO4.2H2O, and the like; in a suitable oxidant such as NMO, and the like; in a suitable solvent such as t-BuOH, dioxane, and the like; at temperatures ranging from -20 °C to 25 °C, preferably 0 °C; to provide an aldehyde compound of formula XXI. An aldehyde compound of formula XXI is reduced in the presence of a reductant such as NaBH4, NaBCNH3, and the like; in a suitable solvent such as MeOH, THF, and the like; at temperatures ranging from 0 °C to 50 °C, preferably at 25 °C; to provide a compound of formula XX (Where X = CH2, Y is not existed).
Figure imgf000054_0001
SCHEME 5 [0173] According to SCHEME 5, an aryl bromide compound of formula XXIis coupled with commercially available or synthetically accessible substituted boronic ester compound of formula XXII under Suzuki coupling conditions employing a suitable catalyst such as Pd(Ph3P)4, Pd2(dba)3, Pd(ddpf)Cl2 and the like; a suitable base such a K3PO4, Cs2CO3 and the like; in a suitable solvent such as dioxane, DMF and the like; with a co-solvent such as water; at temperatures ranging from 60 °C to about 120 °C, preferably 80 °C; to afford a claimed compound of formula XXIII. A compound of formula XXIII is reacted with a suitable bromine source such as Br2, NBS and the like under cyclization conditions; in a suitable solvent such as acetonitrile, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford a claimed compound of formula XXIV. A bromo compound of formula XXIV is reduced with a suitable reductant such as Bu3SnH, (TMS)3SiH and the like; in the presence of a radical initiator such as BPO, AIBN and the like under cyclization conditions; in a suitable solvent such as benzene, toluene and the like; at temperatures ranging from 80 °C to about 120 °C, preferably 100 °C; to afford a claimed compound of formula XXV. A lactone compound of formula XXV is reacted with a suitable base such as LiOH, NaOH, and the like; in a suitable solvent such as THF, MeOH, and the like; in a co-solvent such as water; at temperatures ranging from 25 °C to 80 °C, preferably at 50 °C; to provide an acid compound of formula XXVI. An acid compound of formula XXVI is oxidized in the presence of an oxidant such as MnO2, Dess- Martin periodinane, and the like; in a suitable solvent such as DCM, acetonitrile, and the like; at temperatures ranging from 0 °C to 50 °C, preferably at 25 °C; to provide a compound of formula XXVII. An aldehyde compound of formula XXVII is reacted with a commercially available or synthetically accessible amine of formula XIV, in the presence of a suitable reductant such as NaBH(OAc)3, NaCNBH3 and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford a compound of formula (XXVIII). A compound of formula (XXVIII) is cyclized with a coupling agent such as HTAU, EDCI and the like; in the presence of a suitable base such as TEA, DIPEA and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford an cyclized compound of formula (XXIX). A cyclized compound of formula (XXIX) is de-protected with a suitable reductant such as 1 atm or up to 50 psi of hydrogen and the like; in the presence of a suitable catalyst such as Pd on C or PtO2 and the like; in a suitable solvent such as MeOH, EtOAc and the like; at temperatures ranging from 25 °C to about 60 °C, preferably 25 °C; to afford an amino compound of formula (XVII). [0174] A compound of formula I may be prepared according to the procedures shown in SCHEME 6
Figure imgf000056_0001
SCHEME 6 [0175] According to SCHEME 6, an amino compound of formula (XVII) is reacted with an aldehyde or ketone of formula R1D (D is aldehyde or ketone) under reductive amination conditions employing a suitable reductant such as NaBH(OAc)3, NaBCNH3 and the like; a catalytic amount of acid such AcOH, TFA and the like; in a suitable solvent such as MeOH, DCM, DMF and the like; at temperatures ranging from 0 °C to about 50 °C, preferably 25 °C; to afford a claimed compound of formula (I). [0176] Alternatively, an amino compound of formula (XVII) is reacted with alkylating agent of formula R1D (D is a leaving group such as halogen or mesylate) under displacement conditions employing a suitable base such as Cs2CO3, NaH and the like; in a suitable solvent such as DMSO, DMF and the like; at temperatures ranging from 25 °C to about 80 °C, preferably 50 °C; to afford a claimed compound of formula (I). [0177] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present dislosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). [0178] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [0179] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022- 9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0- 471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645- X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. Analytical Methods, Materials, and Instrumentation [0180] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC/MS) were collected using a SHIMADZU LCMS- 2020EV or Agilent 1260-6125B LCMS. Purity and low resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C182.7 μm 4.6 X 100 mm; Flow rate 0.8 mL/min; Solvent A (100/0.1 water/formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C181.7 µm 2.1 X 50 mm; Flow rate 0.5 mL/min; Solvent A (0.1%formic acid water), Solvent B (acetonitrile); gradient: hold 5%B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min. Biological Assays [0181] The biological activities of the compounds of the present disclosure can be assessed with methods and assays known in the art. [0182] The binding potency of the compounds to CRBN/DDB1 is determined using HTRF assay technology. HTRF signals are measured by displacing Cy5-labeled thalidomide with the testing compounds to His tagged CRBN+DDB-DLS7+CXU4. Data is analyzed using XLfit using four parameters dose response curve to determine IC50s [0183] The cellular degradation activity of IKZF2 is measued by FACS in Jurkat cells with the testing compound concentrations from 0.05 to 10 μM for 24 hrs. Cells are stained with IKZF2 primary antibody and secondary antibodies followed by imaged on iQue Flowcytometer and IKZF2 levels are quantified using iQue software. [0184] Alternatively, the cellular degradation activity of IKZF2 is measured by HiBit IKZF2 assay with the HiBiT protein tagging system applying to modified HEK293T Flp-in-HiBiT cells. Test and reference compounds are diluted from 1 mM at 3 folds for 11 doses. The Nano- Glo® HiBiT lytic detection system is utilized for detecting bioluminescence of the HiBiT tag in treated cells to determine abundance of the tag is proportionate to the level of luminescence. Following normalization to DMSO, dose-response curves are plotted (GraphPad Prism) to determine the concentration points at which 50% of HiBiT-Helios degradation is achieved by each compound. [0185] Alternatively, the cellular degradation activity of IKZF1 is measured by HiBit IKZF1 assay with the HiBiT protein tagging system applying to modified HEK293T Flp-in-HiBiT cells. Test and reference compounds are diluted from 1 mM at 3 folds for 11 doses. The Nano-Glo® HiBiT lytic detection system is utilized for detecting bioluminescence of the HiBiT tag in treated cells to determine abundance of the tag is proportionate to the level of luminescence. Following normalization to DMSO, dose-response curves are plotted (GraphPad Prism) to determine the concentration points at which 50% of HiBiT-Ikaros degradation is achieved by each compound. Methods of Use [0186] In certain aspects, the present disclosure provides methods of degrading a IKZF2 protein in a subject, comprising administering to the subject a compound disclosed herein. [0187] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a IKZF2 protein in a subject. [0188] In certain aspects, the present disclsoure provides compounds disclosed herein for use in degrading a IKZF2 protein in a subject. [0189] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount). [0190] In certain aspects, the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (eg in a therapeutically effective amount) [0191] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0192] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof. [0193] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorderin a subject in need thereof. [0194] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorderin a subject in need thereof. [0195] In certain embodiments, the disease or disorder is an IKZF2-mediated disease or disorder. [0196] In certain embodiments, the disease or disorder is a cancer. [0197] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers of Table A. Table A.
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
[0198] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table B. In certain embodiments, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. Table B.
Figure imgf000063_0001
[0199] In certain embodiments, the disease or disorder is T cell leukemia, T cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST). [0200] In certain embodiments, the subject is a mammal. [0201] In certain embodiments, the subject is a human. Definitions [0202] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions [0203] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. [0204] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, 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 (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). [0205] The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0206] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0207] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention which may include compounds pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. [0208] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1- 10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), i-Pr (-CH(CH3)2), n- Pr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2). [0209] “Alkylene” as used herein, refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkelene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (- CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like. [0210] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2- 9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 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 C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl. [0211] “Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkenylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH- ) and propenylene (e.g., - CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., - C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)- CH=CH-,-C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like. [0212] “Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2- 8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 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 C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; eg for instance from 1 to 5 substituents 1 to 3 substituents or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl. [0213] “Alkynylene” as used herein, refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like. [0214] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1- 8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7 alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl. [0215] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl. [0216] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkynyl”). In certain embodiments a heteroalkynyl group has 2 to 9 carbon atoms at least one triple bond and 1 2 3, or 4 heteroatoms (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl. [0217] Analogous to “alkylene,” “alkenylene,” and “alkynylene” as defined above, “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” as used herein, refer to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. “Heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein. [0218] “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 π electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). [0219] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene fluorene hexacene hexaphene hexalene as-indacene s-indacene indane indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14 aryl. In certain embodiments, the aryl group is substituted C6- 14 aryl. [0220] “Arylene” as used herein, refers to an aryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “arylene” group, it is understood that the range or number refers to the range or number of carbons in the aryl group. An “arylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0221] “Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. [0222] “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic 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, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). [0223] In certain embodiments, a heteroaryl is a 5- to 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- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 9-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- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 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- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 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- to 6-membered heteroaryl”). In certain embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl. [0224] Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6- membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl cinnolinyl quinoxalinyl phthalazinyl and quinazolinyl [0225] “Heteroarylene” as used herein, refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group. A “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0226] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3- 10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. [0227] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments a carbocyclyl group has 5 to 8 ring carbon atoms (“C58 carbocyclyl”) In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Examples of C5-6 carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 carbocyclyl include the aforementioned C5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). 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. In certain embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-12 carbocyclyl. [0228] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-12 carbocyclyl. [0229] “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings. [0230] “Spiro carbocyclyl” or or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embedded. [0231] “Bridged carbocyclyl” or or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such share more than one bonds) with one or more carbocyclyl groups as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embedded. [0232] “Carbocyclylene” as used herein, refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the carbocyclylene group. When a range or number of carbons is provided for a particular “carbocyclyl” group, it is understood that the range or number refers to the range or number of carbons in the carbocyclyl group. A “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein. [0233] “Heterocyclyl” refers to a radical of a 3- to 12-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, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 56-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. [0234] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 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- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 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- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [0235] As the foregoing examples illustrate, in certain embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents In certain embodiments the heterocyclyl group is unsubstituted 3- to 12- membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12- membered heterocyclyl. [0236] “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of ring members designates the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings. [0237] “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. [0238] “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. [0239] “Heterocyclylene” as used herein, refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocyclylene group. When a range or number of ring members is provided for a particular “heterocyclylene” group, it is understood that the range or number refers to the number of ring members in the heterocyclylene group. A “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0240] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl as defined herein. C1-6 alkoxy refers to the group -OR, wherein each R is C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above. [0241] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R is independently alkyl, as defined herein. C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above. [0242] “Oxo” refers to =O. When a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical. [0243] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. [0244] “Protecting group” as used herein is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively. [0245] Common types of hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), β-Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri- iso-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)). [0246] Common types of amino-protecting groups include but not limited to carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), p- methoxybenzyl (PMB) p-methoxyphenyl (PMP) and triphenylmethyl (trityl)) and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2- nitrophenylsulfenyl (Nps)). [0247] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)). [0248] Common types of carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline. [0249] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions [0250] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. [0251] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine diethanolamine triethanolamine N-methylglucamine and the like. Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. [0252] “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, 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 the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates. [0253] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that only differ in the arrangement of their atoms in space are termed “stereoisomers.” [0254] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. 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. A mixture containing equal proportions of the enantiomers is termed a “racemic mixture”. [0255] “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. [0256] The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [0257] As used herein and unless otherwise indicated, the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)-compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound. [0258] As used herein and unless otherwise indicated, the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound. [0259] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)- compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments the active ingredient can be formulated with little or no excipient or carrier [0260] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. [0261] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range. [0262] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0263] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements). [0264] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity such as “either” “one of ” “only one of ” or “exactly one of ” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0265] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. [0266] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. [0267] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure. [0268] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed. EXAMPLES [0269] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. I. Synthetic Routes and Procedures [0270] In the following examples, the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification. [0271] In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated. [0272] Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such as Na2SO4 or MgSO4. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure. [0273] Compound purification was carried out as needed using a variety of traditional methods including, but not limited to, preparative chromatography under acidic, neutral, or basic conditions using either normal phase or reverse phase HPLC or flash columns or Prep-TLC plates. [0274] Flash chromatography was performed on a Biotage Isolera One via column with silica gel particles of 200-300 mesh. Analytical and preparative thin-layer chromatography was performed using silica gel 60 GF254 plates. Normal-phase silica gel chromatography (FCC) was also performed on silica gel (SiO2) using prepacked cartridges. [0275] Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed on either: [0276] METHOD A. Prep-HPLC with YMC-Actus Triart 18C (5 µm, 20 x 250 mm), and mobile phase of 5-99% ACN in water (0.1% HCOOH) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min; or [0277] METHOD B. Preparative supercritical fluid high performance liquid chromatography (SFC) was performed either on a Thar 80 Prep-SFC system, or Waters 80Q Prep-SFC system from Waters. The ABPR was set to 100bar to keep the CO2 in SF conditions, and the flow rate may verify according to the compound characteristics, with a flow rate ranging from 50g/min to 70g/min. The column temperature was ambient temperature [0278] Nuclear magnetic resonance (NMR) spectra were recorded using Brucker AVANCE NEO 400 MHz at around 20 - 30°C unless otherwise specified. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution. [0279] Mass spectra (MS) were obtained on a SHIMADZU LCMS-2020 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass. [0280] Chemical names were generated using ChemDraw Ultra 12.0, ChemDraw Ultra 14.0 (CambridgeSoft Corp., Cambridge, MA) or ACD/Name Version 10.01 (Advanced Chemistry). [0281] Compounds designated as R* or S* are enantiopure compounds where the absolute configuration was not determined. Intermediate 1: 2.3-(7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]- 6-yl)piperidine-2,6-dione
Figure imgf000086_0001
Step A: 4-bromo-5-hydroxy-2-methylbenzoic acid. [0282] To a solution of 5-hydroxy-2-methylbenzoic acid (5.0 g, 32.9 mmol, 1.0 eq) in a mixture of ethanol (20 mL) and acetic acid (10 mL) was added dropwise bromine (3.4 mL, 65.7 mmol, 2.0 equiv). The reaction mixture was stirred for 10 h at room temperature, quenched with aqueous sodium thiosulfate solution (50 mL), and concentrated. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to get crude 4-bromo-5-hydroxy-2- methylbenzoic acid (7.6 g, yield 100%) as a white solid. The crude product was directly used in next step without further purification. LC-MS (ESI): mass calcd. for C8H7BrO3, 229.96; m/z found, 231.2 [M+H]+. Step B: methyl 4-bromo-5-hydroxy-2-methylbenzoate [0283] Con. H2SO4 (12 mL) was added to a suspension of 4-bromo-5-hydroxy-2- methylbenzoic acid (15 g, 65.72 mmol) in methanol (100 mL). The mixture was refluxed for 16 h. After evaporation, the residue was diluted with water (100 mL) and extracted with EA (100 mL x 3). The organic layer was washed with H2O (100 mL x 2), saturated aqueous NaHCO3 solution (100 mL x 2) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue purified by flash column chromatography on silica gel (PE/EA = 4/1) to afford methyl 4-bromo-5- hydroxy-2-methylbenzoate (7.5 g, yield 47%) as a colorless solid. LC-MS (ESI): mass calcd. for C9H9BrO3, 243.97; m/z found, 245.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.36 (s, 1H), 5.52 (s, 1H), 3.88 (s, 3H), 2.50 (s, 3H). Step C: 1-benzyl-4-(hydroxymethyl)pyridin-1-ium bromide [0284] To a solution of (pyridin-4-yl)methanol (8.9 g, 81.6 mmol, 1.0 eq) in CH3CN (80 mL) was added a solution of (bromomethyl)benzene (11.705 mL, 97.9 mmol, 1.2 eq) in CH3CN (40 mL). The reaction mixture was refluxed stirred at 90 oC for 3 h. After evaporation, the residue was slurried with methyl tert-butyl ether, filtered, and dried to afford 1-benzyl-4- (hydroxymethyl)pyridin-1-ium bromide (16.33 g, yield 100%) as a yellow solid. LC-MS (ESI): mass calcd. for C13H14NO, 200.11; m/z found, 200.3 [M]+ Step D: (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol [0285] To a solution of 1-benzyl-4-(hydroxymethyl)pyridin-1-ium bromide (16.3 g, 81.4 mmol, 1.0 eq) in CH3OH (150 mL) was added NaBH4 (9.3 g, 244.2 mmol, 3.0 eq) in portions at -20 oC. The mixture was stirred at -20 oC for 1 h. The reaction was quenched with brine (100 mL) and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH3OH in DCM, from 0% to 10%) to afford (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (15 g, yield 91%) as a red oil. LC-MS (ESI): mass calcd. for C13H17NO, 203.13; m/z found, 204.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.24 - 7.18 (m, 4H), 7.16 - 7.12 (m, 1H), 5.43 (s, 1H), 4.61 (s, 1H), 3.71 (s, 2H), 3.42 (s, 2H), 2.76 (s, 2H), 2.39 (t, J = 5.6 Hz, 2H), 1.91 (s, 2H). Step E: methyl 5-[(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy]-4-bromo-2- methylbenzoate [0286] To a solution of methyl 4-bromo-5-hydroxy-2-methylbenzoate (200 mg, 0.82 mmol, 1.0 eq), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (166 mg, 0.82 mmol, 1.0 eq), and PPh3 (321 mg, 1.22 mmol, 1.5 eq) in dry THF (10 mL) was added dropwise DIAD (0.25 mL, 1.22 mmol. 1.5 eq) at 0 oC under the N2 atmosphere. The solution was stirred for 2 h. After evaporation, the residue was purified by flash column chromatography on silica gel (PE/EA = 2/1 to 1/1) to afford methyl 5-[(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy]-4-bromo-2- methylbenzoate (300 mg, yield 85%) as a white solid. LC-MS (ESI): mass calcd. for C22H24BrNO3, 429.09; m/z found, 431.30 [M+H]+. Step F: methyl 1'-(cyclohexylmethyl)-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate [0287] Tributyl tin hydride (0.5 mL, 1.84 mmol, 4.0 equiv) was added to a solution of methyl 5-[(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy]-4-bromo-2-methylbenzoate (200 mg, 0.46 mmol, 1.0 eq) and AIBN (15 mg, 0.09 mmol, 0.2 eq) in toluene (10 mL). The solution was refluxed in a sealed tube for 6 h. After cooled down to room temperature, The solution was quenched with saturated potassium fluoride solution (40 mL) and stirred at room temperature for 0.5 h. The mixture was extracted with EA (40 mL x 3). The organic layer was washed brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (EA/PE = 1/1) to afford methyl 1'-(cyclohexylmethyl)-5- methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6-carboxylate (20 mg, yield 43%) as a yellow solid. LC-MS (ESI): mass calcd. for C22H25NO3, 351.18; m/z found, 352.30 [M+H]+. [0288] 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.27 (m, 6H), 6.99 (s, 1H), 4.37 (s, 2H), 3.85 (s, 3H), 3.54 (s, 2H), 2.89 (d, J = 10.2 Hz, 2H), 2.52 (s, 3H), 2.10 - 1.95 (m, 4H), 1.70 (d, J = 11.4 Hz, 2H). Step G: methyl 5-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylate [0289] A mixture of methyl 1'-benzyl-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate (1.0 g, 2.845 mmol, 1.0 eq), acetic acid (1 mL, 5.7 mmol, 6.1 eq), and 10% Pd/C (200 mg) in MeOH (20 mL) was stirred at 50 oC under H2 (1 atm) for 3 h. After filtration, the filtrate was concentrated to get methyl 5-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6- carboxylate (970 mg, yield 100%) as a colorless oil, which was directly used in the next step without further purification. LC-MS (ESI): mass calcd. for C15H19NO3, 261.14; m/z found, 262.40 (M+H)+. Step H: 1'-(tert-butyl) 6-methyl 5-methyl-2H-spiro[benzofuran-3,4'-piperidine]-1',6- dicarboxylate [0290] To a stirred solution of methyl 5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate (970 mg, 3.7 mmol, 1.0 eq) and TEA (1 mL, 7.4 mmol, 2.0 eq) in DCM (10 mL) was added dropwise Boc2O (0.8 mL, 3.7 mmol, 2.0 eq) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (10 mL) and extracted with DCM (30 mL x 2). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1'-(tert-butyl) 6-methyl 5-methyl-2H-spiro[benzofuran-3,4'- piperidine]-1',6-dicarboxylate (1.28 g, yield 100%) as a white solid. LC-MS (ESI): mass calcd. for C20H27NO5, 361.19; m/z found, 306.4 [M+H-56]+. Step I: 1'-(tert-butyl) 6-methyl 5-(bromomethyl)-2H-spiro[benzofuran-3,4'-piperidine]-1',6- dicarboxylate [0291] A mixture of methyl 1'-benzyl-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate (220 mg, 0.609 mmol, 1 eq), NBS (130 mg, 0.73 mmol, 1.2 eq), and BPO (60 mg, 0.243 mmol, 0.4 eq) in CCl4 (10 mL) was refluxed for 4 h. After cooled to room temperature, the mixture was filtered, then the filtration was concentrated and to give 1'-tert-butyl 6-methyl 5-(bromomethyl)-2H-spiro[1-benzofuran-3,4'-piperidine]-1',6-dicarboxylate (100 mg, yield 37%) as a light-yellow solid. LC-MS (ESI): mass calcd. for C20H26BrNO5, 439.10; m/z found, 462.20, [M+Na]+. Step J: tert-butyl 6-(2,6-dioxopiperidin-3-yl)-7-oxo-6,7-dihydro-2H,5H-spiro[furo[2,3- f]isoindole-3,4'-piperidine]-1'-carboxylate [0292] DIPEA (0.12 mL, 0.681 mmol, 3.0 eq) was added to 1'-tert-butyl 6-methyl 5- (bromomethyl)-2H-spiro[1-benzofuran-34'-piperidine]-1'6-dicarboxylate (100 mg 0227 mmol, 1.0 eq) and 3-aminopiperidine-2,6-dione hydrochloride (56 mg, 0.341 mmol, 1.5 eq) in MeCN (5 mL) under nitrogen. The resulting suspension was stirred at 80 oC for 24 h. The reaction mixture was cooled to room temperature and filtered. The solid was washed with MeCN and purified by prep-TLC (100% EtOAc) to afford tert-butyl 6-(2,6-dioxopiperidin-3- yl)-7-oxo-6,7-dihydro-2H,5H-spiro[furo[2,3-f]isoindole-3,4'-piperidine]-1'-carboxylate (50 mg, yield 48%) as a white solid. LC-MS (ESI): mass calcd. for C24H29N3O6, 455.51; m/z found, 456.50, (M+H)+. Step K: 3-(7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6- yl)piperidine-2,6-dione [0293] To a solution of tert-butyl 6-(2,6-dioxopiperidin-3-yl)-7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-1'-carboxylate (50 mg, 0.11 mmol, 1.0 eq) in DCM (1 mL) was added HCl-dioxane solution (4 M, 1 mL, 4 mmol, 36 eq) and the mixture was stirred for 30 min. After evaporation, the residue was purified by prep-HPLC with YMC- TA C18 (5 um, 20 x 250 mm), and mobile phase of 5-95% MeCN in water over 10 min, and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min to get 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione hydrochloride (30 mg, yield 70%) as a white solid. LC-MS (ESI): mass calcd. for C19H21N3O4, 355.19; m/z found, 356.20 [M+H]+. [0294] 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.78 (s, 2H), 7.36 (s, 1H), 7.06 (s, 1H), 5.11 - 5.06 (m, 1H), 4.58 (s, 2H), 4.38 (d, J = 17.0 Hz, 1H), 4.25 (d, J = 17.0 Hz, 1H), 3.30 - 3.27 (m, 2H), 3.04 - 2.92 (m, 2H), 2.93 - 2.84 (m, 1H), 2.62 - 2.56 (m, 1H), 2.44 - 2.29 (m, 1H), 2.09 - 1.97 (m, 3H), 1.90 - 1.79 (m, 2H). Intermediate 2: 3-{5-oxo-3,5,6,7-tetrahydrospiro[furo[3,4-f] isoindole-1,4'-piperidine]-6- yl} piperidine-2,6-dione
Figure imgf000089_0001
Step A: 5-bromo-6-iodo-1,3-dihydro-2-benzofuran-1-one [0295] To a solution of 5-bromo-1,3-dihydro-2-benzofuran-1-one (25 g, 117.35 mmol, 1 eq) in TFA (250 mL) and TfOH (25 mL) was added NIS (30.45 g, 176 mmol, 1.5 eq) at 0 °C in portions. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice-water (500 mL) and yellow solid precipitated. The mixture was filtered and the filter cake was washed with aqueous Na2S2O3 (300 mL x 3). The filter cake was suspend in EA (250 mL) and stirred for 1 h. After filtration, the cake was dried to afford 5-bromo-6-iodo-1,3-dihydro-2-benzofuran-1-one (11 g, yield 28%) as a white solid. The filtrate was concentrated under reduced pressure to afford 5-bromo-4-iodo-1,3-dihydro-2- benzofuran-1-one (6 g, yield 15%) as a yellow solid. LC-MS (ESI): mass calcd. for C8H4BrIO2, 337.84; m/z found, 338.85 [M+H]+. [0296] 5-bromo-6-iodo-1,3-dihydro-2-benzofuran-1-one : 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.11 (s, 1H), 5.33 (s, 2H). [0297] 5-bromo-4-iodo-1,3-dihydro-2-benzofuran-1-one: 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H). Step B: 5-bromo-6-ethenyl-1,3-dihydro-2-benzofuran-1-one [0298] To a stirred solution of 5-bromo-6-iodo-1,3-dihydro-2-benzofuran-1-one (10 g, 29.51 mmol, 1.0 eq) and Potassium Vinyltrifluoroborate (5.93 g, 44.26 mmol, 1.5 eq) in dioxane (250 mL) and H2O (50 mL) was added Pd(dppf)Cl2 (2.16 g, 2.95 mmol, 0.1 eq) and K2CO3 (12.23 g, 88.51 mmol, 3.0 eq). The reaction mixture was stirred under N2 at 70 oC overnight. After cooled to room temperature, the mixture was filtered and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel（PE/EtOAc = 1/1) to give 5-bromo-6-ethenyl-1,3-dihydro-2- benzofuran-1-one (2.6 g, yield 37%) as a brown solid. LC-MS (ESI): mass calcd. for C10H7BrO2, 237.96; m/z found, 238.97 [M+H]+. Step C: 6-bromo-3-oxo-1,3-dihydro-2-benzofuran-5-carbaldehyde [0299] To a stirred mixture of 5-bromo-6-ethenyl-1,3-dihydro-2-benzofuran-1-one (2.1 g, 8.78 mmol, 1.0 eq) in acetone (20 mL) and H2O (10 mL) were added K2OsO4 .2H2O (0.32 g, 0.88 mmol, 0.1 eq) and NMO (2.06 g, 17.57 mmol, 2.0 eq). The resulting mixture was stirred at room temperature for 1 h. NaIO4 (4.51 g, 21.08 mmol, 2.5 eq) was added to above mixture and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give 6-bromo-3-oxo-1,3-dihydro-2-benzofuran-5-carbaldehyde (1.1 g, yield 52%) as a white solid. LC-MS (ESI): mass calcd. for C9H5BrO3, 239.94; m/z found, 240.95 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 5.49 (s, 2H). Step D: 5-bromo-6-(hydroxymethyl)-1,3-dihydro-2-benzofuran-1-one [0300] To a stirred mixture of 6-bromo-3-oxo-1,3-dihydro-2-benzofuran-5-carbaldehyde (1 g, 4.15 mmol, 1.0 eq) in THF (15 mL) was added NaBH4 (0.47 g, 12.45 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice-water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give 5- bromo-6-(hydroxymethyl)-1,3-dihydro-2-benzofuran-1-one (700 mg, yield 69%) as a white solid. LC-MS (ESI): mass calcd. for C9H7BrO3, 241.96; m/z found, 242.97 [M+H]+. Step E: benzyl 4-[6-(hydroxymethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-yl]-1,2,3,6- tetrahydropyridine-1-carboxylate [0301] To a stirred solution of 5-bromo-6-(hydroxymethyl)-1,3-dihydro-2-benzofuran-1-one (1.2 g, 4.94 mmol, 1.0 eq) and benzyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine-1-carboxylate (1.69 g, 4.94 mmol, 1.0 eq) in dioxane (20 mL) and H2O (2 mL) were added Pd(dppf)Cl2 (0.36 g, 0.49 mmol, 0.1 eq) and K2CO3 (2.05 g, 14.81 mmol, 3.0 eq). The reaction mixture was stirred under nitrogen atmosphere at 90 ℃ for 2 h. After cooled to room temperature, the reaction mixture was filtered and the cake was washed with EA (30 mL). The mixture was diluted with H2O (40 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel （PE/EtOAc = 1/1) to give benzyl 4-[6-(hydroxymethyl)-1-oxo-1,3-dihydro-2-benzofuran-5- yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (1 g, yield 53%) as a white solid. LC-MS (ESI): mass calcd. for C22H21NO5, 379.14; m/z found, 380.15 [M+H]+. Step F: benzyl 3'-bromo-5-oxo-5,7-dihydro-3H-spiro[benzo[1,2-c:4,5-c'] difuran-1,4'- piperidine]-1'-carboxylate [0302] To a stirred mixture of benzyl 4-[6-(hydroxymethyl)-1-oxo-1,3-dihydro-2-benzofuran- 5-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (1 g, 2.64 mmol, 1.0 eq) in MeCN (15 mL) was added NBS (0.7 g, 3.95 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 solution (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with H2O (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give benzyl 3'-bromo-5-oxo-5,7- dihydro-3H-spiro[benzo[1,2-c:4,5-c']difuran-1,4'-piperidine]-1'-carboxylate (945 mg, yield 78%) as a white solid. LC-MS (ESI): mass calcd. for C22H20BrNO5, 457.05; m/z found, 458.06 [M+H]+. Step G: benzyl 5-oxo-5,7-dihydro-3H-spiro[benzo[1,2-c:4,5-c'] difuran-1,4'-piperidine]-1'- carboxylate [0303] To a stirred mixture of benzyl 3'-bromo-5-oxo-5,7-dihydro-3H-spiro[benzo[1,2-c:4,5- c'] difuran-1,4'-piperidine]-1'-carboxylate (945 mg, 2.06 mmol, 1.0 eq) in toluene (20 mL) were added AIBN (0.610 mL, 4.12 mmol, 2.0 eq) and n-Bu3SnH (3.0 g, 10.31 mmol, 5.0 eq). The resulting mixture was stirred at 85 ℃overnight. After cooled to room temperature, the reaction mixture was quenched with aqueous KF solution (50 mL), stirred for 1 h, and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 2/1) to give benzyl 5-oxo-5,7-dihydro-3H- spiro[benzo[1,2-c:4,5-c']difuran-1,4'-piperidine]-1'-carboxylate (611 mg, yield 78%) as a white solid. LC-MS (ESI): mass calcd. for C22H21NO5, 379.14; m/z found, 380.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.60 (s, 1H), 7.40 - 7.32 (m, 5H), 5.40 (s, 2H), 5.12 (s, 2H), 5.09 (s, 2H), 4.07 - 4.04 (m, 2H), 3.17 (s, 2H), 1.95 - 1.87 (m, 2H), 1.72 - 1.68 (m, 2H). Step H: 1'-[(benzyloxy)carbonyl]-6-(hydroxymethyl)-3H-spiro[2-benzofuran-1,4'-piperidine]- 5-carboxylic acid [0304] To a stirred mixture of benzyl 5-oxo-5,7-dihydro-3H-spiro[benzo[1,2-c:4,5-c'] difuran- 1,4'-piperidine]-1'-carboxylate (650 mg, 1.71 mmol, 1.0 eq) in THF (5 mL), MeOH (5 mL) and H2O (5 mL) was added sodium hydroxide (342.64 mg, 8.57 mmol, 4.0 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was adjusted to pH4-5 with diluted aqueous HCl solution (1 N) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give 1'- [(benzyloxy)carbonyl]-6-(hydroxymethyl)-3H-spiro[2-benzofuran-1,4'-piperidine]-5- carboxylic acid (610 mg, yield 89%) as a white solid. LC-MS: 398 (M+H)+. Revised as the following: LC-MS (ESI): mass calcd. for C22H23NO6, 397.15; m/z found, 398.16 [M+H]+. Step I: 1'-[(benzyloxy)carbonyl]-6-formyl-3H-spiro[2-benzofuran-1,4'-piperidine]-5- carboxylic acid [0305] To a stirred solution of 1'-[(benzyloxy)carbonyl]-6-(hydroxymethyl)-3H-spiro[2- benzofuran-1,4'-piperidine]-5-carboxylic acid (610 mg, 1.54 mmol, 1.0 eq) in DCM (15 mL) was add active MnO2 (1334.36 mg, 15.35 mmol, 10 eq). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the MnO2 cake was washed with DCM (30 mL x3). The combined filtrates were concentrated to afford 1'- [(benzyloxy)carbonyl]-6-formyl-3H-spiro[2-benzofuran-1,4'-piperidine]-5-carboxylic acid (600 mg, yield 99%) as a white solid. LC-MS (ESI): mass calcd. for C22H21NO6, 395.14; m/z found, 396.14 [M+H]+. Step J: 1'-[(benzyloxy)carbonyl]-6-{[(2,6-dioxopiperidin-3-yl) amino] methyl}-3H-spiro[2- benzofuran-1,4'-piperidine]-5-carboxylic acid [0306] To a stirred solution of 1'-[(benzyloxy)carbonyl]-6-formyl-3H-spiro[2-benzofuran- 1,4'-piperidine]-5-carboxylic acid (600 mg, 1.52 mmol, 1.0 eq) and 3-Amino-2,6- piperidinedione hydrochloride (374.63 mg, 2.28 mmol, 1.5 eq) in MeOH (10 mL) was added NaOAc (186.64 mg, 2.28 mmol, 1.5 eq) and the reaction mixture was stirred at room temperature for 40 min. NaBH3CN (286.79 mg, 4.55 mmol, 3.0 eq) was added to above mixture and the resulting reaction mixture was stirred at room temperature for 2 h. After evaporation, the residue was purified by Prep-TLC (DCM/MeOH = 10/1) to obtain 1'- [(benzyloxy)carbonyl]-6-{[(2,6-dioxopiperidin-3-yl) amino]methyl}-3H-spiro[2-benzofuran- 1,4'-piperidine]-5-carboxylic acid (550 mg, yield 71%) as a white solid. LC-MS (ESI): mass calcd. for C27H29N3O7, 507.20; m/z found, 508.21 [M+H]+. Step K: benzyl 6-(2,6-dioxopiperidin-3-yl)-5-oxo-3,5,6,7-tetrahydrospiro[furo[3,4-f] isoindole-1,4'-piperidine]-1'-carboxylate [0307] To a stirred solution of 1'-[(benzyloxy)carbonyl]-6-{[(2,6-dioxopiperidin-3-yl) amino] methyl}-3H-spiro[2-benzofuran-1,4'-piperidine]-5-carboxylic acid (550 mg, 1.08 mmol, 1.0 eq) in DMF (8 mL) were added HATU (494.15 mg, 1.30 mmol, 1.2 eq) and DIEA (0.72 mL, 4.34 mmol, 4.0 eq). The reaction mixture was stirred at room temperature for 3 h. After evaporation, the residue was purified by flash column chromatography on silica gel (DCM/MeOH = 10/1) to obtain benzyl 6-(2,6-dioxopiperidin-3-yl)-5-oxo-3,5,6,7- tetrahydrospiro[furo[3,4-f]isoindole-1,4'-piperidine]-1'-carboxylate (250 mg, yield 47%) as a white solid. LC-MS (ESI): mass calcd. for C27H27N3O6, 489.19; m/z found, 490.20 [M+H]+. Step L: 3-{5-oxo-3,5,6,7-tetrahydrospiro[furo[3,4-f] isoindole-1,4'-piperidine]-6-yl} piperidine-2,6-dione [0308] To a stirred solution of benzyl 6-(2,6-dioxopiperidin-3-yl)-5-oxo-3,5,6,7- tetrahydrospiro[furo[34-f] isoindole-14'-piperidine]-1'-carboxylate (200 mg 041 mmol 10 eq) in TFE (8 mL) was add 10% Pd/C (100 mg) and the reaction mixture was stirred under H2 (1 atm) at 40 ℃ overnight. After evaporation, the filtrate was concentrated to afford 3-{5-oxo- 3,5,6,7-tetrahydrospiro[furo[3,4-f] isoindole-1,4'-piperidine]-6-yl} piperidine-2,6-dione (100 mg, yield 69%) as a white solid. LC-MS (ESI): mass calcd. for C19H21N3O4, 355.15; m/z found, 356.16 [M+H]+. Intermediate 3: 3-(1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'-pyrano[3,4- f]isoindol]-2'-yl)piperidine-2,6-dione
Figure imgf000094_0001
Step A: 5-bromo-6-ethenyl-1,3-dihydro-2-benzofuran-1-one [0309] To a solution of 5-bromo-6-iodo-1,3-dihydro-2-benzofuran-1-one (8.6 g, 25.37 mmol, 1.0 eq) and potassium vinyltrifluoroborate (5.10 g, 38.06 mmol, 1.5 eq) in dioxane (200 mL) and H2O (40 mL) were added Pd(dppf)Cl2 (1.86 g, 2.54 mmol, 0.1 eq) and K2CO3 (10.52 g, 76.12 mmol, 3.0 eq). The reaction mixture was stirred under N2 at 70 oC overnight. After cooled to room temperature, the mixture was filtered and the filtrate was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give 5-bromo-6-ethenyl-1,3- dihydro-2-benzofuran-1-one (5.0 g, yield 82% ) as a brown solid. LC-MS (ESI): mass calcd. for C10H7BrO2, 237.96; m/z found, 238.97 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 8.02 (s, 1H), 7.03 (dd, J = 17.4, 11.0 Hz, 1H), 6.05 (d, J = 17.4 Hz, 1H), 5.54 (d, J = 11.0 Hz, 1H), 5.40 (s, 2H). Step B: 5-bromo-6-( 2-hydroxyethyl)-1,3-dihydro-2-benzofuran-1-one [0310] To a solution of 5-bromo-6-ethenyl-1,3-dihydro-2-benzofuran-1-one (5.0 g, 20.91 mmol，1.0 eq ) in THF (50 mL) at 0 oC was added 9-BBN (1 N in THF) (25.2 mL, 25.2 mmol, 1.2 eq) and the reaction mixture was stirred at room temperature overnight. A solution of Sodium peroxyborate (3.42 g, 41.829 mmol, 2.0 eq) in water (100 mL) was added to above mixture and the reaction mixture was stirred at room temperature for 2 h. The reaction solution was quenched with diluted HCl solution (1 N, 100 mL), stirred for 1 h, and extracted with ethyl acetate (1500 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA = 1 / 2) to obtain 5-bromo-6- ( 2-hydroxyethyl)-1,3-dihydro-2-benzofuran-1-one (2.4 g, yield 44.6%) as a white solid. LC- MS (ESI): mass calcd. for C10H7BrO2, 257.08; m/z found, 239.05 [M-OH]+. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.80 (s, 1H), 5.37 (s, 2H), 4.81 (t, J = 5.2 Hz, 1H), 3.66 (dd, J = 12.0, 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H). Step C: benzyl 4-[6-(2-hydroxyethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-yl]-1,2,3,6- tetrahydropyridine-1-carboxylate [0311] To a solution of 5-bromo-6-(2-hydroxyethyl)-1,3-dihydro-2-benzofuran-1-one (2.6 g, 10.11 mmol, 1.0 eq) and benzyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine-1-carboxylate (5.21 g, 15.17 mmol, 1.5 eq) in dioxane (50 mL) and H2O (1 mL) were added Pd(dppf)Cl2 (1.48 g, 2.02 mmol, 0.2 eq) and K2CO3 (4.19 g, 30.34 mmol, 3.0 eq). The reaction mixture was stirred under nitrogen atmosphere at 90 ℃ for 2 h. After cooled to room temperature, the reaction mixture was filtered and the cake was washed with EA (30 mL). The filtrate was diluted with H2O (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel（PE/EtOAc = 1/1) to give benzyl 4-[6-(2-hydroxyethyl)-1-oxo- 1,3-dihydro-2-benzofuran-5-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (2.5 g, yield 62.8%) as a white solid. LC-MS (ESI): mass calcd. for C23H23NO5, 393.44; m/z found, 394.15 [M+H]+. Step D: benzyl 3'-bromo-1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4-g]isochromene-5,4'- piperidine]-1'-carboxylate [0312] To a mixture of benzyl 4-[6-(2-hydroxyethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-yl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (3.9 g, 9.91 mmol, 1.0 eq) in MeCN (30 mL) was added NBS (2.12 g, 11.89 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 solution (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with H2O (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give benzyl 3'-bromo-1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4- g]isochromene-5,4'-piperidine]-1'-carboxylate (3.5 g, 7.410 mmol, 74.75%) as a white solid. LC-MS (ESI): mass calcd. for C23H22BrNO5, 472.34; m/z found, 472.06 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.69 (s, 1H), 7.39 - 7.33 (m, 5H), 5.44 - 5.32 (m, 2H), 5.18 - 5.04 (m, 2H), 4.79 - 4.76 (m, 1H), 4.25 - 4.14 (m, 2H), 4.07 (d, J = 13.6 Hz, 1H), 3.85 (dt, J = 11.4, 5.8 Hz, 1H), 3.32 - 3.18 (m, 2H), 3.05 (t, J = 6.1 Hz, 2H), 2.78 - 2.65 (m, 1H), 1.61 (d, J = 14.0 Hz, 1H). Step E: benzyl 1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4-g]isochromene-5,4'-piperidine]-1'- carboxylate [0313] To a stirred mixture of benzyl 3'-bromo-1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4- g]isochromene-5,4'-piperidine]-1'-carboxylate (3.5 g, 7.41 mmol, 1.0 eq) in toluene (80 mL) were added AIBN (2.192 mL, 14.82 mmol, 2.0 eq) and n-Bu3SnH (9.98 mL, 37.05 mmol, 5.0 eq). The resulting mixture was stirred under N2 at 110 ℃ overnight. After cooled to room temperature, the reaction mixture was quenched with aqueous KF solution (100 mL), stirred for 2 h, and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 2/1) to give benzyl 1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4-g]isochromene-5,4'-piperidine]- 1'-carboxylate (2.3 g, yield 79%) as a white solid. LC-MS (ESI): mass calcd. for C23H23NO5, 393.44; m/z found, 394.15 [M+H]+. [0314] 1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.62 (s, 1H), 7.40 - 7.39 (m, 4H), 7.36 - 7.32 (m, 1H), 5.34 (s, 2H), 5.11 (s, 2H), 3.96 (d, J = 14.2 Hz, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.23 - 3.10 (m, 2H), 2.91 (t, J = 5.4 Hz, 2H), 1.96 - 1.79 (m, 4H). Step F: 1'-((benzyloxy)carbonyl)-7-(hydroxymethyl)spiro[isochromane-1,4'-piperidine]-6- carboxylic acid [0315] To a mixture of benzyl 1-oxo-1,3,7,8-tetrahydrospiro[furo[3,4-g]isochromene-5,4'- piperidine]-1'-carboxylate (2.3 g, 5.85 mmol, 1.0 eq) in THF (30 mL), MeOH (30 mL) and H2O (15 mL) was added NaOH (1.17 g 29.23 mmol, 5.0 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was adjusted to pH4-5 with diluted aqueous HCl solution (1 N) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give 1'-((benzyloxy)carbonyl)-7-(hydroxymethyl)spiro[isochromane-1,4'- piperidine]-6-carboxylic acid (2.2 g, yield 91.5%) as a white solid. LC-MS (ESI): mass calcd. for C23H25NO6, 411.45; m/z found, 412.16 [M+H]+. Step G: 1'-((benzyloxy)carbonyl)-7-formylspiro[isochromane-1,4'-piperidine]-6-carboxylic acid [0316] To a stirred solution of 1'-((benzyloxy)carbonyl)-7- (hydroxymethyl)spiro[isochromane-1,4'-piperidine]-6-carboxylic acid (240 mg, 0.58 mmol, 1.0 eq) in DCM (15 mL) was add active MnO2 (506.62 mg, 5.83 mmol, 10 eq). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the MnO2 cake was washed with DCM (30 mL x 3). The combined filtrates were concentrated to afford 1'-((benzyloxy)carbonyl)-7-formylspiro[isochromane-1,4'-piperidine]-6-carboxylic acid (160 mg, yield 67%) as a white solid. LC-MS (ESI): mass calcd. for C23H23NO6, 409.44; m/z found, 410.14 [M+H]+. Step H: 1'-[(benzyloxy)carbonyl]-7-{[(2,6-dioxopiperidin-3-yl)amino]methyl}-3,4- dihydrospiro[2-benzopyran-1,4'-piperidine]-6-carboxylic acid [0317] To a stirred solution of 1'-[(benzyloxy)carbonyl]-7-formyl-3,4-dihydrospiro[2- benzopyran-1,4'-piperidine]-6-carboxylic acid (30 mg, 0.073 mmol, 1.0 eq), 3- aminopiperidine-2,6-dione hydrochloride (18.71 mg, 0.146 mmol, 2.0 eq) in MeOH (10 mL) was added NaOAc (8.98 mg, 0.110 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 40 min. Sodium cyanoborohydride (4.59 mg, 0.073 mmol, 1.0 eq) was added to above mixture and the resulting reaction mixture was stirred at room temperature for 2 h. After evaporation, the residue was purified by Prep-TLC (DCM/MeOH = 10/1) to obtain 1'- [(benzyloxy)carbonyl]-7-{[(2,6-dioxopiperidin-3-yl)amino]methyl}-3,4-dihydrospiro[2- benzopyran-1,4'-piperidine]-6-carboxylic acid (18 mg, yield 47.10%) as a white solid. LC-MS (ESI): mass calcd. for C28H31N3O7, 511.20; m/z found, 512.21 [M+H]+. Step I: benzyl 2'-(2,6-dioxopiperidin-3-yl)-1'-oxo-2',3',7',8'-tetrahydro-1'H-spiro[piperidine- 4,5'-pyrano[3,4-f]isoindole]-1-carboxylate [0318] To a stirred solution of 1'-[(benzyloxy)carbonyl]-7-{[(2,6-dioxopiperidin-3- yl)amino]methyl}-3,4-dihydrospiro[2-benzopyran-1,4'-piperidine]-6-carboxylic acid (30 mg, 0.058 mmol, 1.0 eq) in DMF (3 mL) were added HATU (32.81 mg, 0.086 mmol, 1.0 eq) and DIPEA (0.019 mL, 0.115 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 3 h. After evaporation, the residue was purified by flash column chromatography on silica gel (DCM/MeOH = 10/1) to obtain benzyl 2'-(2,6-dioxopiperidin-3- yl)-1'-oxo-2',3',7',8'-tetrahydro-1'H-spiro[piperidine-4,5'-pyrano[3,4-f]isoindole]-1- carboxylate (8 mg, yield 27.62%) as a white solid. LC-MS (ESI): mass calcd. for C28H29N3O6, 503.19; m/z found, 504.20 [M+H]+.1H NMR(400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 7.40 - 7.39 (m, 4H), 7.36 - 7.32 (m, 1H), 5.14 - 5.06 (m, 3H), 4.38 (d, J = 16.8 Hz, 1H), 4.26 (d, J = 16.8 Hz, 1H), 3.96 (d, J = 13.6 Hz, 2H), 3.88 (t, J = 5.4 Hz, 2H), 316 (s 2H) 289 (s 3H) 260 - 256 (m 1H) 248 - 242 (m 1H) 200 - 184 (m 5H) Step J: 3-{1'-oxo-2',3',7',8'-tetrahydro-1'H-spiro[piperidine-4,5'-pyrano[3,4-f]isoindole]-2'- yl}piperidine-2,6-dione [0319] To a stirred solution of benzyl 2'-(2,6-dioxopiperidin-3-yl)-1'-oxo-2',3',7',8'-tetrahydro- 1'H-spiro[piperidine-4,5'-pyrano[3,4-f]isoindole]-1-carboxylate (300 mg, 0.596 mmol, 1.0 eq) in TFE (10 mL) was add 10% Pd/C (50 mg) and the reaction mixture was stirred under H2 (1 atm) at 40 oC overnight. After filtration, the filtrate was concentrated to get 3-{1'-oxo- 2',3',7',8'-tetrahydro-1'H-spiro[piperidine-4,5'-pyrano[3,4-f]isoindole]-2'-yl}piperidine-2,6- dione (130 mg, yield 59.0%) as a white solid. LC-MS (ESI): mass calcd. for C20H23N3O4, 369.15; m/z found, 370.16 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 5.10 - 5.06 (m, 1H), 4.45 (d, J = 16.8 Hz, 1H), 4.32 (d, J = 16.8 Hz, 1H), 3.88 (s, 2H), 3.07 - 2.88 (m, 6H), 2.60 - 2.56 (m, 1H), 2.48 - 2.36 (m, 2H), 2.03 - 1.87 (m, 5H). Intermediate 4: 8-fluoro-1-naphthaldehyde
Figure imgf000098_0001
Step A: 1-bromo-8-fluoronaphthalene [0320] To a solution of 1,8-dibromonaphthalene (2.0 g, 7.0 mmol, 1.0 eq) in dry THF (20 mL) was added dropwise n-butyl lithium (2.5 M in n-hexane) (2.9 mL, 7.25 mmol, 1.05 eq) under N2 at -78 oC and the reaction mixture was stirred for at least one hour at -78 oC. A solution of NFSI (2.2 g, 7.0 mmol, 1.0 eq) in THF (20 mL) was added slowly to above mixture and the resulting mixture was stirred at -78 °C for additional 1 h. Then the reaction mixture was allowed to warm to room temperature overnight, poured into NH4Cl solution (50 mL), and extracted with n-hexane (50 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (100% PE) to afford 1-bromo-8-fluoronaphthalene (1.4 g, yield 71%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H6BrF, 223.96; m/z, found, 224.97 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.74 - 7.69 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.26 - 7.11 (m, 2H). Step B: 8-fluoro-1-naphthaldehyde [0321] To a solution of 1-bromo-8-fluoronaphthalene (900 mg, 4 mmol, 1.0 eq) and HCOONa (1.4 g, 12 mmol, 3.0 eq) in DMF (10 mL) was added Pd(PPh3)2Cl2 (280.7 mg, 0.4 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred under N2 at 80 oC overnight. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EA = 10/1) to give 8-fluoronaphthalene-1- carbaldehyde (100 mg, yield 14%) as a yellow solid. LC-MS (ESI): mass calcd. for C11H7FO, 174.05; m/z found, 175.05 [M+H]+.1HNMR (400 MHz, CDCl3) δ 10.96 - 10.91 (m, 1H), 8.18 (dd, J = 7.2, 1.2 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 7.33 - 7.27 (m, 1H). Intermediate 5: 1,3-benzothiazole-7-carbaldehyde
Figure imgf000099_0001
[0322] To a solution of 7-bromo-1,3-benzothiazole (300 mg, 1.40 mmol, 1.0 eq) in DMF (8 mL) were added Pd(PPh3)2Cl2 (98.36 mg, 0.14 mmol, 0.01 eq) and HCOONa (285.90 mg, 4.20 mmol, 3.0 eq). The reaction mixture was stirred under CO atmosphere (1 atm) at 80 oC overnight. After cooled to room temperature, the mixture was filtered and the filtrate is diluted with water (15 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give 1,3-benzothiazole-7-carbaldehyde (150 mg, yield 65.6%) as a white solid. LC- MS (ESI): mass calcd. for C9H6OS, 163.19; m/z found, 164.02 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J = 1.0 Hz, 1H), 9.59 (s, 1H), 8.47 (dd, J = 8.0, 1.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.89 - 7.82 (m, 1H). Intermediate 6a and 6b: 1-ethyl-1H-indazole-6-carbaldehyde (6a) and 2-ethyl-2H- indazole-6-carbaldehyde (6b)
Figure imgf000099_0002
[0323] To a solution of 1H-indazole-6-carbaldehyde (1.0 g, 6.842 mmol, 1.0 eq) in DMF (20 mL) was added K2CO3 (2.84 g, 20.527 mmol, 3.0 eq) and the mixture was stirred at 40 oC for 1 h. Iodoethane (0.821 mL, 10.26 mmol, 1.5 eq) was added to above mixture and the mixture was stirred at 40 oC overnight. After cooled to room temperature, the reaction mixture was diluted with EtOAc (200 mL) washed with H2O (30 mL) and brine (30 mL x 3) The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA in PE, from 0% to 50%) to give 1-ethyl-1H-indazole-6-carbaldehyde (650 mg, yield 54.53%) as a yellow solid and 2-ethyl-2H-indazole-6-carbaldehyde (445 mg, yield 37.33%) as a yellow solid. [0324] 1-ethyl-1H-indazole-6-carbaldehyde (6a): LC-MS (ESI): mass calcd. for C10H10N2O, 174.20; m/z found, 175.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). [0325] 2-ethyl-2H-indazole-6-carbaldehyde (6b): LC-MS (ESI): mass calcd. for C10H10N2O, 174.20; m/z found, 175.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 4.54 (q, J = 7.2 Hz, 2H), 1.54 (t, J = 7.2 Hz, 3H). Intermediate 7: 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carbaldehyde
Figure imgf000100_0001
Step A: 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one [0326] To a solution of 2-amino-6-bromophenol (3 g, 15.96 mmol, 1.0 eq) in acetonitrile (150 mL) was added K2CO3 (3.31 g, 23.93 mmol, 1.5 eq). Then 2-chloroacetyl chloride (1.4 mL, 17.55 mmol, 1.1 eq) was slowly added to above and the mixture was stirred at 80 ℃ for 16 h. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA in PE, 30%) to give 8-bromo-2H-benzo[b][1,4]oxazin- 3(4H)-one (3 g, yield 82%) as a yellow solid. LC-MS (ESI): mass calcd. for C8H6BrNO2, 226.9; m/z found, 227.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.24 (t, J = 4.8 Hz, 1H), 6.95 (d, J = 4.8 Hz, 2H), 4.75 (s, 2H). Step B: 8-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one [0327] To a solution of 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.7 g, 11.84 mmol, 1.0 eq) in DMF (30 mL) was added K2CO3 (3.27 g, 23.68 mmol, 2.0 eq) and the mixture waas stirred at 25 ℃ for 30 mins. Iodomethane (2.2 mL, 35.52 mmol, 3.0 eq) was added dropwise to above mixture and the resulting mixture was stirred at 25 ℃ for 16 h. After filtration, the filtrate was diluted with water (50 mL) and extracted with EA (30 mL x 3). The organic layer was washed with brine (30 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 8-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (2.9 g, yield 100%) as a yellow solid. LC-MS (ESI): mass calcd. for C9H8BrNO2, 240.97; m/z found, 241.97 [M+H]+. Step C: 8-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine [0328] To a solution of 8-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (2.9 g, 11.98 mmol, 1.0 eq) in THF (20 mL) was added Borane-methyl sulfide complex (2 N in THF) (23.96 mL, 47.92 mmol, 4.0 eq) at 0 oC. The mixture is stirred at 70 ℃ for 1.5 h. After cooled to 0 oC, the mixture was slowly quenched with methanol (15 mL) and stirred at 70 ℃ for 30 mins. After evpaoration, the residue was diluted with water (35 mL) and extracted with EA (35 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EA in PE, 9%) to give 8-bromo-4-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazine (2.6 g, yield 95%) as a yellow oily. LC-MS (ESI): mass calcd. for C9H10BrNO, 226.9; m/z found, 227.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 8.0, 1.0 Hz, 1H), 6.70 (t, J = 8.0 Hz, 1H), 6.59 (dd, J = 8.0, 1.0 Hz, 1H), 4.41 - 4.36 (m, 2H), 3.32 - 3.27 (m, 2H), 2.89 (s, 3H). Step D: 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carbaldehyde [0329] To a solution of 8-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (500 mg, 2.19 mmol, 1.0 eq) in DMF (5 mL) were added sodium formate (596.26 mg, 8.77 mmol, 4.0 eq) and Bis(triphenylphosphine)palladium(II) chloride (170.56 mg, 0.22 mmol, 0.1 eq). The mixture was stirred under CO atmosphere (1 atm) at 80 ℃ overnight. After cooled to room temperature, the mixture was filtered and the filtrate is diluted with water (15 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EA in PE, 13%) to give 4-methyl-3,4- dihydro-2H-benzo[b][1,4]oxazine-8-carbaldehyde (100 mg, yield 26%) as a yellow solid. LC- MS (ESI): mass calcd. for C10H11NO2, 177.08; m/z found, 178.08 [M+H]+.1HNMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 4.45 - 4.39 (m, 2H), 3.36 - 3.30 (m, 2H), 2.92 (s, 3H). Intermediate 8: 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde
Figure imgf000102_0001
Step A: 5-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one [0330] To a solution of 2-amino-3-bromophenol (2 g, 10.64 mmol, 1.0 eq) in acetonitrile (80 mL) was added K2CO3 (2.21 g, 15.96 mmol, 1.5 eq). Then 2-chloroacetyl chloride (0.93 mL, 11.70 mmol, 1.1 eq) was slowly added to above mxiture and the mixture was stirred at 80 ℃ for 16 h. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EA (30 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was collected and concentrated to give 5-bromo-2H- benzo[b][1,4]oxazin-3(4H)-one (2.4 g, yield 99%) as a yellow solid. LC-MS (ESI): mass calcd. for C8H6BrNO2, 226.9; m/z found, 227.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.87 (t, J = 8.0 Hz, 1H), 4.62 (s, 2H). Step B: 5-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one [0331] To a solution of 5-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.4 g, 10.52 mmol, 1.0 eq) in DMF (25 mL) were added K2CO3 (2.91 g, 21.05 mmol, 2.0 eq) and the mixture is stirred at 25 ℃ for 30 mins. Iodomethane (1.96 mL, 31.57 mmol, 3.0 eq) was dropwise added to above mixture and the mixture was stirred at 25 ℃ for 16 h. After filtration, the filtrate was diluted with water (50 mL) and extracted with EA (30 mL x 3). The organic layer was washed with brine (30 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 5-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (2.6 g, yield 100%) as a yellow solid. LC-MS (ESI): mass calcd. for C9H8BrNO2, 240.97; m/z found, 241.97 [M+H]+. Step C: 5-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine [0332] To a solution of 5-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (2.6 g, 10.74 mmol, 1.0 eq) in THF (20 mL) was added Borane-methyl sulfide complex (2 N in THF) (21.48 mL, 42.96 mmol, 4.0 eq) at 0 oC and the mixture is stirred at 70 ℃ for 1.5 h. After cooled to 0 oC, the mixture was slowly quenched with methanol (15 mL) and stirred at 70 ℃ for 30 mins. After evpaoration, the residue was diluted with water (35 mL) and extracted with EA (35 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EA in PE, 9%) to give 5-bromo-4-methyl-3,4-dihydro- 2H-benzo[b][1,4]oxazine (2.18 g, yield 89%) as a yellow oily. LC-MS (ESI): mass calcd. for C9H10BrNO, 226.9; m/z found, 227.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.13 (dd, J = 7.0, 2.0 Hz, 1H), 6.8706.78 (m, 2H), 4.2104.15 (m, 2H), 3.1703.10 (m, 2H), 2.88 (s, 3H). Step D: 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde [0333] To a solution of 5-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (500 mg, 2.19 mmol, 1.0 eq) in DMF (5 mL) were added sodium formate (596.2 mg, 8.77 mmol, 4.0 eq) and Bis(triphenylphosphine)palladium(II) chloride (170.56 mg, 0.22 mmol, 0.1 eq). The mixture was stirred under CO atmosphere (1 atm) at 80 ℃ overnight. After cooled to room temperature, the mixture was filtered and the filtrate is diluted with water (15 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EA in PE, 13%) to give 4-methyl-3,4- dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde (80 mg, yield 21%) as a yellow oil. LC-MS (ESI): mass calcd. for C10H11NO2, 177.08; m/z found, 178.08 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 4.23 - 4.17 (m, 2H), 3.33 - 3.27 (m, 2H), 2.99 (s, 3H). Intermediate 9: 2,2-dimethylchromane-8-carbaldehyde
Figure imgf000103_0001
Step A: 8-bromo-2,2-dimethylchroman-4-one [0334] To a mixture of 1-(3-bromo-2-hydroxyphenyl)ethan-1-one (3 g, 13.95 mmol, 1.0 eq) in MeOH (40 mL) and propan-2-one (6 mL) was added piperidine (2.07 mL, 20.92 mmol, 1.5 eq). The mixture was stirred in a sealed tube at 80 ℃ overnight. After cooled to room temperature, the reaction mixture was diluted with DCM (200 mL) and washed with H2O (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA in PE, from 1% to 16%) to provide 8-bromo-2,2-dimethylchroman-4-one (3.5 g, yield 98%) as a yellow oil. LC-MS (ESI): mass calcd. for C11H11BrO2, 255.11; m/z found, 255.11 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.74 (dd, J = 7.8, 1.6 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 2.88 (s, 2H), 1.43 (s, 6H). Step B: 8-bromo-2,2-dimethylchroman-4-ol [0335] To a solution of 8-bromo-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-one (500 mg, 1.96 mmol, 1.0 eq) in MeOH (20 mL) was added NaBH4 (198.74 mg, 5.880 mmol, 3.0 eq) in portions at 0 oC and the mixture was stirred at 0 oC for 1 h. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated aqueous NH4Cl solution (30 mL) and brine(30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA in PE, from 0% to 10%) to give 8-bromo-2,2-dimethylchroman-4-ol (390 mg, yield 77.4%) as a colorless oil. LC-MS (ESI): mass calcd. for C11H13BrO2, 257.13; m/z found, 239.11 [M- OH]+.1H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.31 (m, 2H), 6.81 (t, J = 7.8 Hz, 1H), 5.47 (d, J = 6.4 Hz, 1H), 4.72 - 4.66 (m, 1H), 2.10 (dd, J = 13.4, 6.0 Hz, 1H), 1.74 (dd, J = 13.4, 9.4 Hz, 1H), 1.40 (s, 3H), 1.26 (s, 3H). Step C: 8-bromo-2,2-dimethylchromane [0336] To a solution of 8-bromo-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-ol (390 mg, 1.517 mmol, 1.0 eq) in DCM (10 mL) and triethylsilane (10 mL) was slowly added boron trifluoride diethyl etherate (0.1 mL, 0.789 mmol, 0.5 eq) at 0 oC and the mixture was stirred at 0 oC for 1 h. The reaction mixture was diluted with DCM (100 mL), washed with saturated aqueous NaHCO3 solution (10 mL) and brine(30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (100% PE) to give 8-bromo-2,2-dimethyl-3,4- dihydro-2H-1-benzopyran (320 mg, yield 87.5%) as a colorless oil. LC-MS (ESI): mass calcd. for C11H13BrO, 241.13; m/z found, 241.11 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.37 - 7.32 (m, 1H), 7.09 (dd, J = 7.6, 1.4 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 2.76 (t, J = 6.8 Hz, 2H), 1.78 (t, J = 6.8 Hz, 2H), 1.30 (s, 6H). Step D: 2,2-dimethylchromane-8-carbaldehyde [0337] A solution of 8-bromo-2,2-dimethylchromane (320 mg, 1.327 mmol, 1.0 eq), sodium formate (361.02 mg, 5.308 mmol, 4.0 eq) and Pd(PPh3)2Cl2 (103.26 mg, 0.133 mmol, 0.1 eq) in DMF (10 mL) was stirred under CO atmosphere (1 atm) at 90 oC for 18 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by Prep-TLC (EtOAc/PE = 1/20) to give 2,2-dimethyl-3,4-dihydro-2H-1- benzopyran-8-carbaldehyde (55 mg, yield 21.8%) as a yellow solid. LC-MS (ESI): mass calcd. for C12H14O2, 190.24; m/z found, 191.11 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 6.80 (t, J = 7.6 Hz, 1H), 2.75 (t, J = 6.8 Hz, 2H), 1.81 (d, J = 6.8 Hz, 2H), 1.33 (s, 6H). Intermediate 10: 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde
Figure imgf000105_0001
[0338] To a solution of 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 2.193 mmol, 1.0 eq) in DMF (5 mL) were added sodium formate (596.39 mg, 8.770 mmol, 4.0 eq) and Bis(triphenylphosphine)palladium(II) chloride (153.90 mg, 0.219 mmol, 0.1 eq). The mixture was stirred under CO atmosphere (1 atm) at 80 ℃ overnight. After cooled to room temperature, the mixture was filtered and the filtrate is diluted with water (15 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EA in PE, 29%) to give 3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (60 mg, yield 16%) as a yellow solid. LC- MS (ESI): mass calcd. for C9H7NO3, 177.04; m/z found, 178.04 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.90 (s, 1H), 7.60 (dd, J = 8.2, 1.8 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.78 (s, 2H). Intermediate 11: 2,2-dimethylchromane-5-carbaldehyde
Figure imgf000105_0002
Step A: 5-bromo-2,2-dimethylchroman-4-one [0339] To a mixture of 1-(2-bromo-6-hydroxyphenyl)ethan-1-one (2 g, 9.30 mmol, 1 eq) in MeOH (20 mL) and propan-2-one (4 mL, 54.40 mmol, 6.0 eq) was added piperidine (1.4 mL, 13.95 mmol,1.5 eq). The mixture was stirred in a sealed tube at 80 ℃ overnight. After cooled to room temperature, the reaction mixture was diluted with DCM (200 mL) and washed with H2O (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 1% to 20 %) to afford 5- bromo-2,2-dimethylchroman-4-one (1.2 g, 4.704 mmol, 50.63%) as a yellow solid. LC-MS (ESI): mass calcd. for C11H11BrO2, 255.11; m/z found, 255.11 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.38 (t, J = 8.2 Hz, 1H), 7.26 (dd, J = 7.8, 1.2 Hz, 1H), 7.01 (dd, J = 8.2, 1.2 Hz, 1H), 2.84 (s, 2H), 1.38 (s, 6H). Step B: 5-bromo-2,2-dimethylchroman-4-ol [0340] To a solution of 5-bromo-2,2-dimethylchroman-4-one (1.2 g, 4.704 mmol, 1.0 eq) in THF (20 mL) and MeOH (5 mL) was added NaBH4 (0.48 g, 14.11 mmol, 3.0 eq) in portions at 0 oC and the mixture was stirred at 0 oC for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10 %) to afford 5-bromo-2,2-dimethylchroman-4-ol (1.1 g, yield 91%) as a white solid. LC-MS (ESI): mass calcd. for C11H13BrO2, 257.13; m/z found, 239 [M-OH]+.1H NMR (400MHz, DMSO-d6) δ 7.17 - 7.01 (m, 2H), 6.76 (dd, J = 7.8, 1.2 Hz, 1H), 5.18 (d, J = 4.8 Hz, 1H), 4.75 - 4.72 (m, 1H), 2.07 - 2.03 (m, 1H), 1.95 - 1.90 (m, 1H), 1.39 (s, 3H), 1.35 (s, 3H). Step C: 5-bromo-2,2-dimethylchromane [0341] To a solution of 5-bromo-2,2-dimethylchroman-4-ol (680 mg, 2.64 mmol, 1.0 eq) in DCM (10 mL) and Triethylsilane (10 mL) was added Boron trifluoride diethyl etherate (0.149 mL, 1.173 mmol, 0.5 eq) at 0 oC and the mixture was stirred 0 oC for 1 h. The mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10%) to afford 5- bromo-2,2-dimethylchromanen (530 mg, yield 83%) as a white solid. LC-MS (ESI): mass calcd. for C11H13BrO, 241.13; m/z found, 241,2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 2.66 (t, J = 6.8 Hz, 2H), 1.80 (t, J = 6.8 Hz, 2H), 1.27 (s, 6H). Step D: 2,2-dimethylchromane-5-carbaldehyde [0342] To a solution of 5-bromo-2,2-dimethylchromane (500 mg, 2.074 mmol, 1.0 eq) and sodium formate (282.05 mg, 4.147 mmol, 2.0 eq) in DMF (20 mL) was added Pd(PPh3)2Cl2 (291.09 mg, 0.415 mmol, 0.2 eq). The mixture was stirred under CO atmosphere (1 atm) at 80 oC overnight. After cooled to room temperature, the reaction mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10%) to afford 2,2-dimethylchromane-5-carbaldehyde (40 mg, yield 10.1%) as a white solid. LC-MS (ESI): mass calcd. for C12H14O2, 190.10; m/z found, 191 [M+H]+. Intermediate 12: 2-oxoindoline-4-carbaldehyde
Figure imgf000107_0001
Step A: 4-ethenyl-2,3-dihydro-1H-indol-2-one [0343] To a stirred solution of 4-bromo-2,3-dihydro-1H-indol-2-one (1.0 g, 4.72 mmol, 1.0 eq) and Pinacol vinylboronate (0.8 mL, 4.72 mmol, 1.0 eq) in dioxane (10 mL) and H2O (1 mL) were added Pd(PPh3)4 (0.27 g, 0.236 mmol, 0.05 eq) and Na2CO3 (1.00 g, 9.44 mmol, 2.0 eq). The reaction mixture was stirred under nitrogen atmosphere at 100 ℃ overnight. After cooled to room temperature, the reaction mixture was filtered and the cake was washed with EA (30 mL). The filtrate was diluted with H2O (20 mL) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel（PE/EtOAc = 1/1) to give 4-ethenyl-2,3-dihydro-1H- indol-2-one (500 mg, yield 66%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H9NO, 159.07; m/z found, 160.08 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.71 - 6.65 (m, 1H), 5.79 (d, J = 17.8 Hz, 1H), 5.36 (d, J = 11.2 Hz, 1H), 3.53 (s, 2H). Step B: 2-oxo-2,3-dihydro-1H-indole-4-carbaldehyde [0344] Ozone was bubbled into a solution of 4-ethenyl-2,3-dihydro-1H-indol-2-one (100 mg, 0.628 mmol, 1.0 eq) in DCM (8 mL) at -78 oC for 1 h. On completion, excess O3 was purged from the reaction mixture with nitrogen and dimethylsulfide (10 mL) was added. The reaction mixture was stirred for 1 h. After evaporation, the residue was purified by flash chromatography on silica gel (PE/EA = 1/1) to give 2-oxo-2,3-dihydro-1H-indole-4- carbaldehyde (50 mg, yield 49%) as a light yellow solid. LC-MS (ESI): mass calcd. for C9H7NO2, 161.05; m/z found, 162.06 [M+H]+. Intermediate 13: 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde
Figure imgf000108_0001
Step A: 6-bromo-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [0345] To a solution of 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (1 g, 4.385 mmol, 1.0 eq) in DMF (12 mL) was added K2CO3 (1.21 g, 8.770 mmol, 2.0 eq) and the mixture was stirred at 25 ℃ for 30 minutes. Then iodoethane (1.052 mL, 13.156 mmol, 3.0 eq) was added dropwise to above mixture and the resulting mixture was stirred at 25 ℃ for 16 hours. After filtration, the filtrate was diluted with water (30 mL) and extracted with EA (30 mL x 3). The organic layer was washed with brine (30 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 6-bromo-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)- one (1.1 g, yield 98%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H10BrNO2, 254.99; m/z found, 255.99 [M+H]+. Step B: 6-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine [0346] To a solution of 6-bromo-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (1.2 g, 4.686 mmol, 1.0 eq) in THF (10 mL) was added Borane-methyl sulfide complex (2 N in THF) (9.371 mL, 18.743 mmol, 4.0 eq) at 0 oC and the mixture is stirred at 70 ℃ overnight. The reaction mixture was cooled to 0 ℃, slowly quenched with methanol (8 mL), and the resulting mixture was stirred at 70 ℃ for 30 minutes. After evaporation, the mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated dunder reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 2%) to give 6-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (890 mg, yield 78%) as a red oil. LC-MS (ESI): mass calcd. for C10H12BrNO, 241.01; m/z found, 242.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 6.80 (s, 1H), 6.65 - 6.56 (m, 2H), 4.19 - 4.10 (m, 2H), 3.33 - 3.25 (m, 4H), 1.05 (t, J = 7.0 Hz, 3H). Step C: 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde [0347] To a solution of 6-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (500 mg, 2.065 mmol, 1.0 eq) in DMF (5 mL) were added sodium formate (561.70 mg, 8.260 mmol, 4.0 eq) and Bis(triphenylphosphine)palladium(II) chloride (144.95 mg, 0.207 mmol, 0.1 eq) and the mixture was stirred under CO atmosphere (1 atm) at 80 ℃ overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (15 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20%) to give 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (290 mg, yield 73%) as a yellow oil. LC-MS (ESI): mass calcd. for C11H13NO2, 191.01; m/z found, 192.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.0, 1.8 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 4.32 - 4.26 (m, 2H), 3.40 (q, J = 7.0 Hz, 2H), 3.32 (d, J = 4.4 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H). Intermediate 14: 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde
Figure imgf000109_0001
Step A: azidobenzene [0348] To a solution of aniline (0.490 mL, 5.369 mmol, 1.0 eq) in acetonitrile (11 mL) were dropwise added tert-Butyl nitrite (0.966 mL, 8.053 mmol, 1.5 eq) and TMSN3 (927.82 mg, 8.053 mmol, 1.5 eq) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give azidobenzene (638 mg, yield 99%) as a yellow oil. LC-MS (ESI): mass calcd. for C6H5N3, 119.13; m/z found, 120.13 [M+H]+. Step B: 4-(diethoxymethyl)-1-phenyl-1H-1,2,3-triazole [0349] To a solution of azidobenzene (638 mg, 5.355 mmol, 1.0 eq) in t-BuOH (10 mL) and water (10 mL)were added 3,3-diethoxyprop-1-yne (0.768 mL, 5.355 mmol, 1.0 eq) and Sodium ascorbate (424.39 mg, 2.142 mmol, 0.4 eq), and CuSO4 (170.96 mg, 1.071 mmol, 0.2 eq). The mixture was stirred at room temperature for 16 h. The reaction solution was diluted with water (10 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0 to 17%) to gave 4-(diethoxymethyl)-1-phenyl-1H-1,2,3- triazole (960 mg, yield 73%) as a yellow oil. LC-MS (ESI): mass calcd. for C13H17N3O2, 247.3; m/z found, 248.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.98 - 7.91 (m, 2H), 7.61 - 7.55 (m, 2H), 7.50 - 7.48 (m, 1H), 5.75 (s, 1H), 3.68 - 3.54 (m, 4H), 1.17 (t, J = 7.2 Hz, 6H). Step C: 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde [0350] To a solution of 4-(diethoxymethyl)-1-phenyl-1H-1,2,3-triazole (200 mg, 0.809 mmol, 1.0 eq) in dioxane (2.5 mL) was added concentrated HCl solution (2.5 mL). The mixture was stirred at room temperature for 1 h. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0 to 20%) to give 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (140 mg, yield 99%) as a white solid. LC-MS (ESI): mass calcd. for C9H7N3O, 173.18; m/z found, 174.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.58 (s, 1H), 7.99 (d, J = 7.8 Hz, 2H), 7.65 (t, J = 7.6 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H). Intermediate 15: 3-formyl-N,N-dimethylbenzenesulfonamide
Figure imgf000110_0001
[0351] To a solution of 3-bromo-N,N-dimethylbenzene-1-sulfonamide (300 mg, 1.136 mmol， 1.0 eq) and sodium formate (282.05 mg, 4.147 mmol, 2.0 eq) in DMF (25 mL) was added Pd(PPh3)2Cl2 (159.44 mg, 0.227 mmol, 0.2 eq). The mixture was stirred under CO (1 atm) at 90 oC overnight. After cooled to room temperature, the mixture was filtered and the filtrate was diluted with water (10.0 mL), and extracted with ethyl acetate (15.0 mL x 3). The combined organic layers were washed with brine (15.0 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10%) to afford 3- formyl-N,N-dimethylbenzene-1-sulfonamide (140 mg, yield 58%) as a white solid. LC-MS (ESI): mass calcd. for C9H11NO3S, 213.05; m/z found, 214.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6 ) δ 10.01 (s, 1H), 8.18 (t, J = 1.6 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.97 - 7.92 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 2.67 (s, 6H). Intermediate 16: 2-oxo-1,2-dihydroquinoline-8-carbaldehyde
Figure imgf000110_0002
Step A: 8-ethenyl-1,2-dihydroquinolin-2-one [0352] To a stirred mixture of 8-bromo-1,2-dihydroquinolin-2-one (600 mg, 2.678 mmol, 1.0 eq) in dioxane (10 mL) and H2O (1 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (0.454 mL, 2.678 mmol, 1.0 eq), Pd(PPh3)4 (154.78 mg, 0.134 mmol, 0.05 eq), and Na2CO3 (851.48 mg, 8.034 mmol, 3.0 eq). The reaction mixture was stirred under nitrogen atmosphere at 100 ℃ overnight. After cooled to room temperature, the reaction mixture was filtered and the cake was washed with EA (30 mL). The filtrate was diluted with H2O (20 mL) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give 8-ethenyl-1,2-dihydroquinolin-2-one (400 mg, yield 87%) as a light yellow solid. LC-MS (ESI): mass calcd. for C11H9NO, 171.07; m/z found, 172.2 [M+H] +. Step B: 2-oxo-1,2-dihydroquinoline-8-carbaldehyde [0353] Ozone was bubbled into a solution of 8-ethenyl-1,2-dihydroquinolin-2-one (200 mg, 1.168 mmol, 1.0 eq) in DCM (8 mL) at -78 oC for 1 h. Excess O3 was purged from the reaction with nitrogen and dimethylsulfide (10 mL) was added. The reaction mixture was stirred for 30 min. After evaporation, the residue was purified by flash column chromatography on silica gel (PE/EA = 1/1) to give 2-oxo-1,2-dihydroquinoline-8-carbaldehyde (130 mg, yield 64%) as a white solid. LC-MS (ESI): mass calcd. for C10H7NO2, 173.05; m/z found, 174.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.17 (s, 1H), 8.18 (dd, J = 7.6, 1.2 Hz, 1H), 8.12 - 8.01 (m, 2H), 7.46 (dd, J = 9.4, 5.8 Hz, 1H), 6.67 (dd, J = 9.4, 2.0 Hz, 1H). Intermediate 17: 4-hydroxyquinoline-8-carbaldehyde Step A: 8-vinylquinolin-4-ol [0354] To a stirred mixture of 8-bromoquinolin-4-ol (500 mg, 2.232 mmol, 1.0 eq) in dioxane (10 mL) and H2O (1 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.379 mL, 2.232 mmol, 1.0 eq), Pd(PPh3)4 (128.93 mg, 0.112 mmol, 0.05 eq), and Na2CO3 (709.56 mg, 6.695 mmol, 3.0 eq). The reaction mixture was stirred under nitrogen atmosphere at 100 ℃ overnight. After cooled to room temperature, the reaction mixture was filtered and the cake was washed with EA (30 mL). The filtrate was diluted with H2O (20 mL) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give 8-ethenylquinolin-4- ol (250 mg, yield 65%)as a light yellow solid. LC-MS (ESI): mass calcd. for C11H9NO, 171.07; m/z found, 172.2 [M+H]+. Step B: 4-hydroxyquinoline-8-carbaldehyde [0355] Ozone was bubbled into a solution of 8-ethenylquinolin-4-ol (230 mg, 1.34 mmol, 1.0 eq) in DCM (8 mL) at -78oC for 1 h. Excess O3 was purged from the reaction with nitrogen and dimethylsulfide (10 mL) was added. The reaction mixture was stirred for 30 min. After evaporation, the residue was purified by flash column chromatography on silica gel (MeOH/DCM = 1/10) to give 4-hydroxyquinoline-8-carbaldehyde (200 mg, yield 86%) as a light yellow solid. LC-MS (ESI): mass calcd. for C10H7NO2, 173.05; m/z found, 174.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.20 (s, 1H), 8.47 (dd, J = 8.0, 1.6 Hz, 1H), 8.38 (dd, J = 7.2, 1.6 Hz, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.62 (dd, J = 8.0, 7.4 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H). Intermediate 18: 3-(morpholinosulfonyl)benzaldehyde
Figure imgf000112_0001
[0356] A mixture of 4-((3-bromophenyl)sulfonyl)morpholine (300 mg, 980 µmol， 1.0 eq), Bis-(triphenylphosphino)-palladous chloride (68.8 mg, 98.0 µmol, 0.1 eq), and Sodium formate (267 mg, 149 µL, 3.92 mmol, 4.0 eq) in DMF (6.00 mL) was stirred under CO atmosphere (1 atm) at 90 oC overnight. The mixture was cooled to room temperature and filtered. The fitrate was diluted with EtOAc (50 mL), washed with saturated aqueous NH4Cl solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Prep-TLC (EtOAc/PE = 1/3) to give 3-(morpholinosulfonyl)benzaldehyde (80.0 mg, yield 32%) as a yellow solid. LC-MS (ESI): mass calced for: C11H13NO4S 255.06; m/z found, 256.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.26 - 8.22 (m, 2H), 8.07 - 8.04 (m, 1H), 7.90 (t, J = 7.8 Hz, 1H), 3.68 - 3.61 (m, 4H), 2.95 - 2.88 (m, 4H). Intermediate 19: 2-(pyrrolidin-1-yl)pyrimidine-5-carbaldehyde
Figure imgf000112_0002
[0357] To a mixture of 2-chloropyrimidine-5-carbaldehyde (200 mg, 1.40 mmol, 1.0 eq) and pyrrolidine (120 mg, 0.14 mL, 1.68 mmol, 1.2 eq) in MeCN (4.00 mL) was added Diisopropylethylamine (544 mg, 723 µL, 4.21 mmol, 3.0 eq) at 20 oC and the mixture was stirred at room temperature for 1 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with H2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 1% to 25%) to provide 2- (pyrrolidin-1-yl)pyrimidine-5-carbaldehyde (208 mg, yield 79%) as a yellow solid. LC-MS (ESI): mass calced for: C9H11N3O 177.09; m/z found, 178.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.78 (s, 2H), 3.61 - 3.57 (m, 4H), 2.00 - 1.91 (m, 4H). Intermediate 20: 2-(pyrrolidin-1-yl)pyrimidine-4-carbaldehyde
Figure imgf000113_0001
Step A: methyl 2-(pyrrolidin-1-yl)pyrimidine-4-carboxylate [0358] To a solution of methyl 2-chloropyrimidine-4-carboxylate (500 mg, 2.90 mmol, 1.0 eq) in DMF (8.00 mL) was added pyrrolidine (412 mg, 5.79 mmol, 2.0 eq), and then triethylamine (880 mg, 8.69 mmol, 3.0 eq) was slowly added to above mixture. The mixture was stirred at 60 ℃ for 16 h. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was diluted with water (25 mL) and extracted with EA (25 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 17%) to give methyl 2-(pyrrolidin-1-yl)pyrimidine-4-carboxylate (480 mg, yield 80%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H13N3O2, 207.23; m/z found, 208.23 [M+H]+. Step B: (2-(pyrrolidin-1-yl)pyrimidin-4-yl)methanol [0359] To a solution of methyl 2-(pyrrolidin-1-yl)pyrimidine-4-carboxylate (480 mg, 2.32 mmol, 1.0 eq) in THF (5.00 mL) was added DIBAL-H (1 M in THF) (4.63 mL, 4.63 mmol, 2.0 eq) at -78 oC. The reaction mixture was stirred under N2 atmosphere at 0 oC for 1 h. The mixture was diluted with THF (20 mL), slowly quenched with Na2SO4.10H2O at 0 ℃, and filtered. The filtrate is concentrated and purified by flash column chromatography on silica gel (MeOH in DCM, 7%) to give (2-(pyrrolidin-1-yl)pyrimidin-4-yl)methanol (390 mg, yield 94%) as a colorless oil. LC-MS (ESI): mass calcd. for C9H13N3O, 179.22; m/z found, 180.2 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 8.30 (d, J = 5.0 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 5.38 (t, J = 5.8 Hz, 1H), 4.35 (d, J = 5.8 Hz, 2H), 3.44 (t, J = 6.6 Hz, 4H), 1.94 - 1.86 (m, 4H). Step C: 2-(pyrrolidin-1-yl)pyrimidine-4-carbaldehyde [0360] To a solution of (2-(pyrrolidin-1-yl)pyrimidin-4-yl)methanol (390 mg, 2.18 mmol, 1.0 eq) in DCM (10.0 mL) was added Dess-Martin periodinane (1.38 g, 3.26 mmol, 1.5 eq) at 0 oC. The mixture was stirred at room temp for 1 hour. The reaction mixture was quenched with saturated aqueous Na2S2O3 solution (15 mL) and extracted with DCM (15 mL x 3). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 14%) to give 2-(pyrrolidin-1-yl)pyrimidine-4-carbaldehyde (65.0 mg, yield 17%) as a white solid. LC-MS (ESI): mass calcd. for C9H11N3O, 177.21; m/z found, 178.21 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.62 (d, J = 4.6 Hz, 1H), 6.95 (d, J = 4.6Hz, 1H), 3.54 (s, 4H), 1.99 - 1.94 (m, 4H). Intermediate 21: 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde
Figure imgf000114_0001
Step A: 5-vinyl-2H-benzo[b][1,4]oxazin-3(4H)-one [0361] To a solution of 5-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (500 mg, 2.19 mmol, 1.0 eq) in dioxane (7.50 mL) and water (0.75 mL) were added potassium trifluoro(vinyl)borate (352 mg, 2.63 mmol, 1.2 eq), sodium carbonate (697 mg, 6.58 mmol, 3.0 eq), and Tetrakis(triphenylphosphine)palladium (253 mg, 219 µmol, 0.1 eq). The mixture was stirred under N2 at 100 ℃ for 16 h. After cooled to room temperature, the reaction solution was diluted with water (10 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20%) to give 5-vinyl-2H-benzo[b][1,4]oxazin-3(4H)-one (380 mg, yield 98%) as a white solid. LC-MS (ESI): mass calcd. for C10H9NO2, 175.19; m/z found, 176.19 [M+H]+. Step B: 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde [0362] Ozone was bubbled to a solution of 5-vinyl-2H-benzo[b][1,4]oxazin-3(4H)-one (380 mg, 2.17 mmol, 1.0 eq) in DCM (10.0 mL) at -70 oC for 1 h. The residual ozone was swepted away and dimethyl sulfide (8 mL) was dropwise added to above mixture. The resulting mixture was stirred at -70 ℃ for 30 minutes. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 22%) to give 3-oxo- 34-dihydro-2H-benzo[b][14]oxazine-5-carbaldehyde (100 mg yield 26%) as a white solid LC-MS (ESI): mass calcd. for C9H7NO3, 177.16; m/z found, 178.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 10.54 (s, 1H), 10.09 (s, 1H), 7.55 (dd, J = 7.6, 1.2 Hz, 1H), 7.33 (dd, J = 8.0, 1.2 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 4.73 (s, 2H). Intermediate 22: 3-phenylthiophene-2-carbaldehyde
Figure imgf000115_0001
[0363] To a solution of 3-bromothiophene-2-carbaldehyde (800 mg, 4.19 mmol, 1.0 eq) and phenylboronic acid (766 mg, 6.28 mmol, 1.5 eq) in dioxane (10 mL) and water (2 mL) were added 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (306 mg, 419 µmol, 0.1 eq) and K2CO3 (1.74 g, 12.6 mmol, 3.0 eq). The mixture was stirred under N2 at 100 oC for 2 h. The mixture was cooled to room temperarure and filtered. The fitrate was concentrated and the residue was poured into water (6 mL) and extracted with EtOAc (6 mL x 3). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to obtain 3-phenylthiophene-2-carbaldehyde (680 mg, yield 86%) as a yellow oil. LC- MS (ESI): mass calced for: C11H8OS 188.03; m/z found, 189.1 [M+H]+. Intermediate 23: 3-(phenylsulfonyl)benzaldehyde
Figure imgf000115_0002
[0364] To a solution of sodium benzenesulfinate (424 mg, 2.59 mmol, 1.2 eq) in DMF (15 mL) were added CuI (410 mg, 2.15 mmol, 1.0 eq) and 3-iodobenzaldehyde (500 mg, 2.15 mmol, 1.0 eq). The mixture was stirred under N2 at 130 ℃ for 16 h. After coole to room temperature, the mixture was diluted with water (50 mL) and extracted with EA (60 mL x 3). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resudue was purified by flahs column chromatography on silica gel (PE/EtOAc = 9 / 1) to afford 3-(phenylsulfonyl)benzaldehyde (360 mg, yield 68%) as a white solid. LC-MS (ESI): mass calced for: C13H10O3S 246.04; m/z found, 247.1 [M+H]+. Intermediate 24: 3-cyclopropoxybenzaldehyde
Figure imgf000116_0001
[0365] To a solution of 3-hydroxybenzaldehyde (500 mg, 4.09 mmol, 1.0 eq) in DMF (10.0 mL) were added Cs2CO3 (2.67 g, 8.19 mmol, 2.0 eq), KI (68.0 mg, 409 µmol, 0.1 eq), and bromocyclopropane (3.96 g, 32.8 mmol, 8.0 eq). The reaction mixture was stirred at 140 ℃ for 6 h. The mixture was cooled to room temperature and filtered. The filtrate is quenched with water (20 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (15 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5%) to give 3-cyclopropoxybenzaldehyde (230 mg, yield 35%) as a yellow oil. LC-MS (ESI): mass calcd. for C10H10O2, 162.19; m/z found, 163.2 [M+H]+. Intermediate 25: 3-methyl-1H-indole-4-carbaldehyde
Figure imgf000116_0002
[0366] To a solution of 4-bromo-3-methyl-1H-indole (200 mg, 952 µmol, 1.0 eq) in DMF (4.00 mL) were added sodium formate (259 mg, 3.81 mmol, 4.0 eq) and Bis- (triphenylphosphino)-palladous chloride (66.8 mg, 95.2 µmol, 0.1 eq). The mixture was stirred under CO atmosphere (1 atm) at 80 ℃overnight. The mixture was cooled to room temperature and filtered. The filtrate is diluted with water (10 mL) and extracted with EA (8 mL x 3). The organic layer was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE/EA = 3/1) to give 3-methyl-1H-indole-4-carbaldehyde (65.0 mg, yield 43%) as a yellow solid. LC- MS (ESI): mass calcd. for C10H9NO, 159.19; m/z found, 160.3 [M+H]+. Intermediate 26: 3-methyl-1H-indazole-4-carbaldehyde
Figure imgf000116_0003
[0367] A mixture of 4-bromo-3-methyl-1H-indazole (300 mg, 1.42 mmol, 1.0 eq), Bis- (triphenylphosphino)-palladous chloride (99.8 mg, 142 µmol, 0.1 eq), and sodium formate (387 mg, 5.69 mmol, 4.0 eq) in DMF (5.0 mL) was stirred under CO atmosphere (1 atm) at 90 oC overnight. The mixture was cooled to room temperature and filtered. The fitrate was diluted with EtOAc (50 mL), washed with saturated aqueous NH4Cl solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE = 1/2) to give 3-methyl-1H-indazole-4- carbaldehyde (35.0 mg, yield 11.5%) as a white solid. LC-MS (ESI): mass calced for: C9H8N2O 160.06; m/z found, 161.2 [M+H]+. Intermediate 27: 3-((1,1,1-trifluoropropan-2-yl)oxy)benzaldehyde
Figure imgf000117_0001
Step A: 1,1,1-trifluoropropan-2-yl trifluoromethanesulfonate [0368] To a solution of 1,1,1-trifluoropropan-2-ol (400 mg, 3.51 mmol, 1.0 eq) in DCM (6.00 mL) was added pyridine (305 mg, 3.86 mmol, 1.1 eq). Tf2O (989 mg, 3.51 mmol, 1.0 eq) was add dropwise to above mixture at 0 ° C and the reaction mixture was stirred at room temp for 1 h. The reaction liquid is filtered and directly used in next step whithout further purification. LC-MS (ESI): mass calcd. for C4H4F6O3S, 246.12; m/z found, 247.1 [M+H]+. Step B: 3-((1,1,1-trifluoropropan-2-yl)oxy)benzaldehyde [0369] To a solution of 3-hydroxybenzaldehyde (200 mg, 1.64 mmol, 1.0 eq) in DMF (4.00 mL) was added Cs2CO3 (1.07 g, 3.28 mmol, 2.0 eq). The mixture was stirred at 20 ℃ for 1 h. 1,1,1-trifluoropropan-2-yl trifluoromethanesulfonate (806 mg, 3.28 mmol, 2.0 eq) was added to above mixture and the reaction mixture was stirred at 20 ℃ for 16 h. The mixture was cooled to room temperature and filtered. The filtrate is diluted with water (20 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (20 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 22%) to give 3-((1,1,1- trifluoropropan-2-yl)oxy)benzaldehyde (100 mg, yield 28%) as a yellow oil. LC-MS (ESI): mass calcd. for C10H9F3O2, 218.18; m/z found, 219.18 [M+H]+.1H NMR (400 MHz, DMSO- d6) 9.99 (s, 1H), 7.64 - 7.55 (m, 3H), 7.46 - 7.40 (m, 1H), 5.44 - 5.34 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H). Intermediate 28: 6-(isopropylthio)picolinaldehyde
Figure imgf000118_0001
[0370] To a stirred mixture of 6-bromopicolinaldehyde (200 mg, 1.08 mmol, 1.0 eq) in 1,4- Dioxane (10.0 mL) were added Xantphos (62.2 mg, 108 µmol, 0.1 eq), Pd2(dba)3 (49.2 mg, 53.8 µmol, 0.05 eq), DIEA (278 mg, 375 µL, 2.15 mmol, 2.0 eq), and propane-2-thiol (81.9 mg, 1.08 mmol, 1.0 eq). The reaction mixture was stirred under nitrogen atmosphere at 100 ℃ overnight. After cooled to room temperature, the reaction mixture was filtered and the cake was washed with EA (30 mL). The filtrate was diluted with H2O (20 mL) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 3/1) to give 6- (isopropylthio)picolinaldehyde (130 mg, yield 66%) as a yellow oil. LC-MS (ESI): mass calcd. for C9H11NOS, 181.06; m/z found, 182.3 [M+H]. Intermediate 29: 3-methyl-1H-indazole-7-carbaldehyde
Figure imgf000118_0002
Step A: 3-methyl-7-vinyl-1H-indazole [0371] To a mixture of 7-bromo-3-methyl-1H-indazole (100 mg, 0.474 mmol, 1.0 eq), 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (146 mg, 0.95 mmol, 2.0 eq), and K2CO3 (196 mg, 1.42 mmol, 3.0 eq) in 1.4-dioxane (10.0 mL) and water (1.0 mL) was added Pd(PPh3)4 (54.8 mg, 0.0474 mmol, 0.1 eq). The mixture was stirred under N2 at 100 oC for 16 h. After cooled to room temperature, the reaction mixture was filtered and the filtrate was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 60%) to to afford 3-methyl-7-vinyl-1H-indazole (40 mg, yield 53%) as a yellow solid. LC-MS (ESI): mass calced for: C10H10N2,158.2; m/z found, 159.2 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.16 - 7.01 (m, 2H), 6.01 (d, J = 17.8 Hz, 1H), 5.44 (d, J = 11.6 Hz, 1H), 2.50 (s, 3H). Step B: 3-methyl-1H-indazole-7-carbaldehyde [0372] O3 was bubbled to a solution of 3-methyl-7-vinyl-1H-indazole (150 mg, 948 µmol, 1.0 eq) in DCM (20.0 mL) at -70 oC for 2 h. Then the residual O3 was swept away and methyl sulfide (0.2 mL) was added to above mixture. The reaction mixture was stirred for 30 min, diluted with water (10 mL), and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methanol in dichloromethane, from 0% to 25%) to afford 3- methyl-1H-indazole-7-carbaldehyde (70.0 mg, yield 46%) as a yellow solid. LC-MS (ESI): mass calcd. for C9H8N2O,160.18; m/z found,161 [M+H] + Intermediate 30: 2,3-dimethyl-1H-indole-6-carbaldehyde
Figure imgf000119_0001
Step A: 6-bromo-2,3-dimethyl-1H-indole [0373] To a solution of (3-bromophenyl)hydrazine (800 mg, 4.28 mmol, 1.0 eq) in AcOH (20 mL) was added butan-2-one (1.91 mL, 21.4 mmol, 4.0 eq) at 70 oC. The mixture was stirred under N2 at 110 oC overnight. After evaporation, the mixture was diluted with water (5 mL), adjusted to pH 8~9 with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 8%) to afford 6-bromo-2,3-dimethyl-1H-indole (250 mg, yield 26%) as a white solid. LC-MS (ESI): mass calcd. for C10H10BrN, 223.00; m/z found, 224.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.04 (dd, J = 8.3, 1.8 Hz, 1H), 2.29 (s, 3H), 2.13 (s, 3H) Step B: 2,3-dimethyl-1H-indole-6-carbaldehyde [0374] A mixture of 6-bromo-2,3-dimethyl-1H-indole (500 mg, 2.23 mmol, 1.0 eq), Bis- (triphenylphosphino)-palladous chloride (291.09 mg, 0.415 mmol, 0.2 eq), and sodium formate (607 mg, 8.92 mmol, 4.0 eq) in DMF (20 mL) was stirred under CO atmosphere (1 atm) at 90 oC overnight. After cooled to room temperature, the mixture was diluted with water (20 mL) and extracted withethyl acetate (30 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 25%) to afford 2,3-dimethyl-1H-indole-6-carbaldehyde (80 mg, yield 21%) as a white solid. LC-MS (ESI): mass calcd. for C11H11NO, 173.22; m/z found, 174.2 [M+H].1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.94 (s, 1H), 7.80 (s, 1H), 7.55 - 7.46 (m, 2H), 2.38 (s, 3H), 2.19 (s, 3H). Intermediate 31: 3-(trifluoromethyl)thiophene-2-carbaldehyde
Figure imgf000120_0001
[0375] To a solution of 3-bromothiophene-2-carbaldehyde (1.00 g, 5.23 mmol, 1.0 eq) in DMF (20.0 mL) were added CuI (498 mg, 2.62 mmol, 0.5eq) and the mixture was heated at 100 °C for 10 min under N2. Then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.51 g, 7.85 mmol, 1.5 eq) was added to above mixture and the mixture reaction was stirred under N2 at 100 °C for 6 h. After cooled to room temperature, the mixture was diluted with water (30 mL) and extracted with EA (30 mL x 3). The organic layer was washed with brine (30 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0 to 10%) to obtain 3-(trifluoromethyl)thiophene-2-carbaldehyde (570 mg, yield 60%) as a light yellow solid. LC-MS (ESI): mass calcd. for C6H3F3OS, 180.14; m/z found, 181.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.32 (d, J = 5.0 Hz, 1H), 7.64 (d, J = 5.0 Hz, 1H). Example 1. 3-(1'-benzyl-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'- piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000120_0002
[0376] To a solution of 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'- piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1, 40 mg, 0.124 mmol, 1.0 eq) in DMF (2 mL) were added benzaldehyde (0.013 mL, 0.124 mmol, 1.1 eq) and NaBH(OAc)3 (36 mg, 0.169 mmol, 1.5 eq). The reaction was stirred at room temperature for 3 h. The reaction was diluted with saturated sodium bicarbonate aqueous solution (1 mL) and extracted with DCM (1 mL x 3). The organic layer was collected and concentrated to 1 mL of volume. The residue was purified with Prep-TLC (EA) to get 3-{1'-benzyl-7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (12 mg, yield 24%) as a white solid. LC-MS (ESI): mass calcd. for C26H27N3O4, 445.20; m/z found, 446.20 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.47 (s, 1H), 7.34 - 7.25 (m, 5H), 7.00 (s, 1H), 5.09 - 5.04 (m, 1H), 4.47 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.50 (s, 2H), 2.96 - 2.74 (m, 3H), 2.53 - 2.38 (m, 1H), 2.07 - 1.88 (m, 6H), 1.69 - 1.66 (m, 2H). Example 2: 3-(1'-methyl-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'- piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000121_0001
[0377] To a solution of 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'- piperidine]-6-yl}piperidine-2,6-dione (50 mg, 0.141 mmol, 1.0 eq) in DMF (1 mL) were added formaldehyde (0.008 mL, 0.0423 mmol, 3.0 eq) and sodium cyanoborohydride (14 mg, 0.211 mmol, 1.5 eq). The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (1 mL) and extracted with DCM (1 mL x 3). The organic layer was collected and concentrated to 1 mL of volume. The residue was diluted with EA (15 mL), stirred at room temperature for 2 h, and the solid precipitated. The solid was filtered and purified by prep-HPLC with YMC-TA C18 (5 um, 20 x 250 mm), and mobile phase of 5-95% MeCN (0.1% HCOOH) in water over 10 min, and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min to give 3-{1'-methyl-7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione formate (10 mg, yield 19%) as a white solid. LC-MS (ESI): mass calcd. for C20H23N3O4, 369.17; m/z found, 370.20, (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.14 (s, 1H), 7.43 (s, 1H), 7.01 (s, 1H), 5.09 - 5.05 (m, 1H), 4.47 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 2.92 - 2.87 (m, 3H), 2.64 - 2.55 (m, 1H), 2.42 - 2.37 (m, 1H), 2.29 (s, 3H), 2.15 - 2.11 (m, 1H), 2.03 - 1.92 (m, 4H), 1.74 - 1.70 (m, 2H). Example 3: 3-(1'-acetyl-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'- piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000122_0001
Step A: methyl 1'-acetyl-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6-carboxylate [0378] To a solution of methyl 1'-benzyl-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate (intermediate from Example 1, Step F, 1.3 g, 3.7 mmol, 1.0 eq) in MeOH (15 mL) was added acetic anhydride (0.9 mL, 9.25 mmol, 2.5 eq) and 10% Pd/C (100 mg). The mixture was stirred under H2 (1 atm) for 3 h. After filtration, the filtrate was concentrated to provide methyl 1'-acetyl-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6-carboxylate (270 mg, yield 74%) as a white solid. LC-MS (ESI): mass calcd. for C17H21NO4, 303.15; m/z found, 304.2[M+H]+. Step B: methyl 1'-acetyl-5-(bromomethyl)-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate [0379] A mixture of methyl 1'-benzyl-5-methyl-2H-spiro[1-benzofuran-3,4'-piperidine]-6- carboxylate (50 mg, 0.142 mmol, 1.0 eq), NBS (28 mg, 0.156 mmol, 1.1 eq), and BPO (7 mg, 0.03 mmol, 0.3 eq) in CCl4 (2 mL) was refluxed for 4 h. After evaporation, the mixture was concentrated and purified by prep-TLC (EA/PE = 1/4) to obtain methyl 1'-acetyl-5- (bromomethyl)-2H-spiro[1-benzofuran-3,4'-piperidine]-6-carboxylate (20 mg, yield 28%) as a yellow oil. LC-MS (ESI): mass calcd. for C17H20BrNO4, 381.06; m/z found, 382.3 [M+H]+. Step C: 3-{1'-acetyl-7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl}piperidine-2,6-dione [0380] DIPEA (0.13 mL, 0.785 mmol, 3 eq) was added to a mixture of methyl 1'-acetyl-5- (bromomethyl)-2H-spiro[1-benzofuran-3,4'-piperidine]-6-carboxylate (100 mg, 0.262 mmol, 1.0 eq) and 3-aminopiperidine-2,6-dione hydrochloride (65 mg, 0.392 mmol, 1.5 eq) in MeCN (5 mL) under nitrogen. The resulting suspension was stirred at 80 oC for 24 h. The reaction mixture was cooled to room temperature and filtered. The cake was washed with MeCN and the product was purified by Prep-TLC (MeCN/DCM = 1/1) to afford 3-{1'-acetyl-7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (40 mg, yield 38%) as a white solid. LC-MS (ESI): mass calcd. for C21H23N3O5, 397.16; m/z found, 398.4 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.27 (s, 1H), 7.14 (s, 1H), 5.24 - 5.15 (m, 1H), 4.63 (d, J = 13.2 Hz, 1H), 4.59 - 4.48 (m, 2H), 4.42 - 4.38 (m, 1H), 4.27 (d, J = 15.6 Hz, 1H), 3.95 - 3.82 (m, 1H), 3.27 - 3.14 (m, 1H), 2.97 - 2.64 (m, 3H), 2.43- 2.27 (m, 1H), 2.24 - 2.11 (m, 4H), 1.89 - 1.82 (m, 4H). Example 4: 3-(1'-(naphthalen-1-ylmethyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000123_0001
[0381] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-naphthaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C30H29N3O4, 495.22; m/z found, 496 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.13 (s, 1H), 8.00 - 7.85 (m, 2H), 7.68 - 7.47 (m, 4H), 7.41 (s, 1H), 7.01 (s, 1H), 5.09 - 5.04 (m, 1H), 4.53 (s, 2H), 4.32 (d, J = 16.8 Hz, 1H), 4.20 (d, J = 16.8 Hz, 1H), 3.87 (s, 2H), 3.07 - 2.82 (m, 3H), 2.60 - 2.58 (m, 1H), 2.44 - 2.36 (m, 1H), 2.35 - 2.09 (m, 2H), 1.99 - 1.94 (m, 3H), 1.74 - 1.72 (m, 2H). Example 5: 3-(1'-(naphthalen-2-ylmethyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000123_0002
[0382] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-naphthaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C30H29N3O4, 495.22; m/z found, 496 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.91 (s, 3H), 7.84 (s, 1H), 7.51 (s, 4H), 7.01 (s, 1H), 5.09 - 5.05 (m, 1H), 4.50 (s, 2H), 4.33 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.71 (s, 2H), 2.93 - 2.90 (m, 3H), 2.67 - 2.63 (m, 1H), 2.42 - 2.39 (m, 1H), 2.17 - 2.14 (m, 2H), 1.99 - 1.92 (m, 3H), 1.74 -.1.71 (m, 2H). Example 6: 3-(1'-((5-fluoronaphthalen-1-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000124_0001
[0383] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 5-fluoro-1-naphthaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C30H28FN3O4, 513.57 m/z found, 514.4 [M+H]+.1H NMR(400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.16 (d,J = 7.0 Hz, 1H), 8.15 (s, 1H), 8.01 (dd, J = 6.6, 3.0 Hz, 1H), 7.62 - 7.53 (m, 3H), 7.46 (s, 1H), 7.36 (dd, J = 10.8, 7.6 Hz, 1H), 7.00 (s, 1H), 5.09 - 5.04 (m, 1H), 4.58 - 4.43 (m, 2H), 4.32 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 3.94 (s, 2H), 2.96 - 2.81 (m, 3H), 2.60 - 2.58 (m, 1H), 2.44 - 2.36 (m, 1H), 2.17 (t, J = 12.4 Hz, 2H), 1.99 - 1.97 (m, 1H), 1.87 (t, J = 12.8 Hz, 2H), 1.77 - 1.60 (m, 2H). Example 7: 3-(1'-((8-fluoronaphthalen-1-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000124_0002
[0384] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 8-fluoro-1-naphthaldehyde (Intermediate 4) and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0385] LC-MS (ESI): mass calcd. for C30H28FN3O4, 513.21; m/z found, 514.21 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.35 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 6.8 Hz, 1H), 7.56 - 7.45 (m, 3H), 7.32 (dd, J = 14.0, 6.8 Hz, 1H), 7.00 (s, 1H), 5.09 - 5.04 (m, 1H), 4.51 (s, 2H), 4.32 (d, J = 16.8 Hz, 1H), 4.20 (d, J = 16.8 Hz, 1H), 4.00 (d, J = 2.6 Hz, 2H), 2.91 - 2.86 (m, 3H), 2.63 - 2.59 (m, 1H), 2.39 - 2.35 (m, 1H), 2.19 (t, J = 12.2 Hz, 2H), 1.96 - 1.86 (m, 3H), 1.70 - 1.66 (m, 2H). Example 8: -(1'-(isoquinolin-5-ylmethyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000125_0001
[0386] The title compound was prepared in a manner analogous to Example 1 by reductive amination between isoquinoline-5-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd for C29H28N4O4, 496.21; m/z found, 497[M+H] +.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.32 (s, 1H), 8.56 (d, J = 5.8 Hz, 1H), 8.16 (d, J = 5.8 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.00 (s, 1H), 5.09 - 5.04 (m, 1H), 4.56 - 4.46 (m, 2H), 4.32 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 3.93 (s, 2H), 2.89 - 2.86 (m, 3H), 2.60 - 2.56 (m, 1H), 2.39 - 2.31 (m, 1H), 2.17 (s, 2H), 2.00 - 1.94 (m, 1H), 1.89 - 1.86 (m, 2H), 1.70 - 1.68 (m, 2H). Example 9: 3-(7-oxo-1'-(quinolin-8-ylmethyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000125_0002
[0387] The title compound was prepared in a manner analogous to Example 1 by reductive amination between quinoline-8-carbaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H28N4O4, 496.57, m/z found, 497.4 [M+H]+.1H NMR(400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.98 (d, J = 3.0 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 7.95 (dd, J = 16.0, 7.2 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.60 (dd, J = 8.2, 4.0 Hz, 1H), 7.47 (d, J = 10.2 Hz, 1H), 7.03 (d, J = 4.8 Hz, 1H), 5.10 - 5.06 (m, 1H), 4.61 - 4.52 (m, 2H), 4.38 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.23 (d, J = 16.89 Hz, 1H), 3.09 (s, 2H), 2.96 - 2.85 (m, 1H), 2.60 - 2.57 (m, 3H), 2.44 - 2.34 (m, 1H), 2.14 - 1.92 (m, 3H), 1.81 - 1.72 (m, 2H). Example 10: 3-(1'-(isoquinolin-8-ylmethyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000126_0001
[0388] The title compound was prepared in a manner analogous to Example 1 by reductive amination between isoquinoline-8-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H28N4O4, 496.57 ; m/z found, 497.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.74 (s, 1H), 8.53 (d, J = 5.8 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 5.8 Hz, 1H), 7.7487.68 (m, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.46 (s, 1H), 7.00 (s, 1H), 5.08 - 5.04 (m, 1H), 4.55 - 4.47 (m, 2H), 4.31 (d, J = 16.8 Hz, 1H), 4.18 (d, J = 16.8 Hz, 1H), 4.03 (s, 2H), 2.95 - 2.83 (m, 3H), 2.60 - 2.58 (m, 1H), 2.39 - 2.35 (m, 1H), 2.17 (t, J = 12.0 Hz, 2H), 2.00 - 1.96 (m, 1H), 1.85 - 1.82 (m, 2H), 1.70 - 1.66 (m, 2H). Example 11: 3-(7-oxo-1'-(quinolin-5-ylmethyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000126_0002
[0389] The title compound was prepared in a manner analogous to Example 1 by reductive amination between quinoline-5-carbaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H28N4O4, 496.21; m/z found, 497 [M+H].+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.93 (d, J = 2.8 Hz, 1H), 8.77 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.60 (dd, J = 8.4, 4.2 Hz, 2H), 7.42 (s, 1H), 7.01 (s, 1H), 5.09 - 5.04 (m, 1H), 4.52 (s, 2H), 4.32 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 4.04 (s, 2H), 3.01 - 2.82 (m, 3H), 2.60 - 2.56 (m, 1H), 2.42 - 2.12 (m, 3H), 2.02 - 1.95 (m, 1H), 1.89 - 1.85 (m, 2H), 1.72 - 1.70 (m, 2H). Example 12: 3-(1'-(benzo[b]thiophen-4-ylmethyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000127_0001
[0390] The title compound was prepared in a manner analogous to Example 1 by reductive amination between benzo[b]thiophene-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C28H27N3O4S, 501.6 ; m/z found, 502.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.79 (d, J = 19.2 Hz, 2H), 7.40 (d, J = 25.7 Hz, 3H), 7.01 (s, 1H), 5.09 - 5.05 (m, 1H), 4.51 (s, 2H), 4.33 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.88 (s, 2H), 2.94 - 2.85 (m, 3H), 2.60 - 2.56 (m, 1H), 2.42 - 2.34 (m, 1H), 2.17 (s, 2H), 2.00 - 1.83 (m, 3H), 1.80 - 1.63 (m, 2H). Example 13: 3-(1'-(benzo[b]thiophen-7-ylmethyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000127_0002
[0391] The title compound was prepared in a manner analogous to Example 1 by reductive amination between benzo[b]thiophene-7-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C28H27N3O4S, 501.17; m/z found, 502 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.75 (t, J = 4.6 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.40 - 7.28 (m, 2H), 7.02 (s, 1H), 5.10 - 5.05 (m, 1H), 4.51 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.23 (d, J = 16.8 Hz, 1H), 3.80 (s, 2H), 2.94 - 2.74 (m, 3H), 2.60 - 2.56 (m, 1H), 2.41 - 2.31 (m, 1H), 2.17 (s, 2H), 2.03 - 1.90 (m, 3H), 1.72 - 1.69 (m, 2H). Example 14: 3-(1'-(benzo[d]thiazol-4-ylmethyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000128_0001
[0392] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1,3-benzothiazole-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C27H26N4O4S, 502.17; m/z found, 503.18 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.39 (s, 1H), 8.09 - 8.06 (m, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.00 (s, 1H), 5.10 - 5.05 (m, 1H), 4.51 - 4.45 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 4.09 (s, 2H), 2.96 - 2.84 (m, 3H), 2.60 - 2.56 (m, 1H), 2.41 - 2.31 (m, 1H), 2.20 - 2.14 (m, 2H), 2.00 - 1.90 (m, 3H), 1.70 - 1.68 (m, 2H). Example 15: 3-(1'-(benzo[d]thiazol-7-ylmethyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000128_0002
[0393] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1,3-benzothiazole-7-carbaldehyde (Intermediate 5) and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C27H26N4O4S, 502.17; m/z found, 503.18 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.52 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 5.10 - 5.05 (m, 1H), 4.66 (d, J = 4.8 Hz, 2H), 4.62 (s, 2H), 4.37 (d, J = 17.0 Hz, 1H), 4.24 (d, J = 17.0 Hz, 1H), 3.29 (s, 2H), 2.95 - 2.85 (m, 1H), 2.59 (d, J = 16.4 Hz, 1H), 2.37 - 2.33 (m, 4H), 2.03 - 1.86 (m, 4H). [0394] Example 16: 3-(1'-((1H-indol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000129_0001
[0395] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indole-7-carbaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C28H28N4O4, 484.21; m/z found,485 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.84 (s, 1H), 7.45 - 7.32 (m, 3H), 7.12 - 6.84 (m, 3H), 6.46 (s, 1H), 5.10 - 5.05 (m,1H), 4.50 (s, 2H), 4.35 (d, J =16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.79 (s, 2H), 3.08 - 2.77 (m, 3H), 2.60 - 2.56 (m, 1H), 2.41 - 2.32 (m, 1H), 2.07 (s, 2H), 1.98 - 1.82 (m, 3H), 1.72 - 1.68 (m, 2H). Example 17: 3-(1'-((1-methyl-1H-indol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000129_0002
[0396] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-methyl-1H-indole-7-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H30N4O4, 498.23; m/z found, 499 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.26 (s, 1H), 7.01 (s, 1H), 6.91 (d, J = 3.6 Hz, 2H), 6.41 (s, 1H), 5.09 - 5.04 (m, 1H), 4.52 (s, 2H), 4.32 (d, J = 16.8 Hz, 1H), 4.24 - 4.09 (m, 4H), 3.80 (s, 2H), 2.95 - 2.74 (m, 3H), 2.59 - 2.56 (m, 1H), 2.43 - 2.32 (m, 1H), 2.10 - 2.07 (m, 2H), 2.03 - 1.92 (m, 1H), 1.86 – 1.82 (m, 2H), 1.76 - 1.72 (s, 2H). Example 18: 3-(1'-((1H-indol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000130_0001
[0397] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indole-4-carbaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C28H28N4O4, 484.56; m/z found, 485.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.97 (s, 1H), 8.13 (s, 1H), 7.40 (s, 3H), 7.10 (d, J = 6.2 Hz, 2H), 7.03 (s, 1H), 6.70 (s, 1H), 5.10 - 5.05 (m, 1H), 4.54 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.14 (d, J = 16.8 Hz, 1H), 4.04 (s, 2H), 3.09 (s, 2H), 2.93 - 2.86 (m, 1H), 2.60 - 2.56 (m, 3H), 2.43 - 2.33 (m, 1H), 2.03 –- 1.93 (m, 3H), 1.79 (s, 2H). Example 19: 3-(1'-((3-methyl-1H-indol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000130_0002
[0398] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-methyl-1H-indole-4-carbaldehyde (Intermediate 25) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0399] LC-MS (ESI): mass calcd. for C29H30N4O4, 498.58; m/z found, 499.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 10.96 (s, 1H), 10.71 (s, 1H), 7.46 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.65 (d, J = 1.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.46 (dd, J = 8.0, 1.6 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.49 - 4.42 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.78 - 3.76 (m, 2H), 2.95 - 2.85 (m, 3H), 2.59 (d, J = 16.6 Hz, 1H), 2.51 (s, 3H), 2.38 - 2.31 (m, 1H), 2.11 (t, J = 8.6 Hz, 2H), 1.89 (dd, J = 16.8, 8.4 Hz, 1H), 1.68 (s, 2H), 1.07 (t, J = 7.0 Hz, 2H). Example 20: 3-(1'-((1H-indol-3-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000131_0001
[0400] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indole-3-carbaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C28H28N4O4, 484.56 ; m/z found, 485.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.96 (s, 1H), 8.14 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.33 (s, 1H), 7.10 (t, J = 7.4 Hz, 1H), 7.07 - 6.98 (m, 2H), 5.09 - 5.05 (m, 1H), 4.49 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.84 (s, 2H), 3.03 – 2.89 (m, 3H), 2.60 - 2.56 (m, 1H), 2.46 - 2.34 (m, 3H), 2.03 - 1.91 (m, 3H), 1.74 (s, 2H). Example 21: 3-(1'-((1-methyl-1H-indol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000131_0002
[0401] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-methyl-1H-indole-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H30N4O4, 498.58; m/z found, 499.5 [M+H]+.1H NMR(400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 7.32 (dd, J = 11.8, 5.6 Hz, 2H), 7.14 - 7.09 (m, 1H), 7.05 - 6.98 (m, 2H), 6.62 (d, J = 3.2 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.48 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 2H), 2.93 - 2.81 (m, 3H), 2.60 - 2.58 (m, 1H), 2.40 - 2.36 (m, 1H), 2.10 (t, J = 12.2 Hz, 2H), 2.01 - 1.83 (m, 3H), 1.69 - 1.65 (m, 2H). Example 22: 3-(1'-((2-methyl-1H-indol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000132_0001
[0402] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-methyl-1H-indole-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate [0403] LC-MS (ESI): mass calcd. for C29H30N4O4,498.58; m/z found, 499.3 [M+H]+.1H NMR (400 MHz, DMSO-d6 ) δ 10.96 (s, 1H), 10.88 (s, 1H), 8.16 (s, 1H), 7.45 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.96 - 6.89 (m, 2H), 6.28 (s, 1H), 5.09 - 5.04 (m, 1H), 4.51 - 4.44 (m, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.20 (d, J = 17.0 Hz, 1H), 3.69 (s, 2H), 2.94 - 2.82 (m, 3H), 2.60 - 2.56 (m, 1H), 2.41 - 2.27 (m, 4H), 2.08 (t, J = 12.1 Hz, 2H), 2.00 - 1.84 (m, 3H), 1.68 - 1.66 (m, 2H). Example 23: 3-(1'-((1H-indol-2-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000132_0002
[0404] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indole-2-carbaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0405] LC-MS (ESI): mass calcd. for C28H28N4O4, 484.56; m/z found, 485.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.97 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.06 - 6.99 (m, 2H), 6.94 (t, J = 7.2 Hz, 1H), 6.30 (s, 1H), 5.10 - 5.05 (m, 1H), 4.52 - 4.43 (m, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.69 (s, 2H), 2.97 - 2.84 (m, 3H), 2.61 - 2.57 (m, 1H), 2.43 - 2.32 (m, 1H), 2.14 (t, J = 10.8 Hz, 2H), 2.01 - 1.90 (m, 3H), 1.73 - 1.69 (m, 2H). Example 24: 3-(1'-((2,3-dimethyl-1H-indol-6-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000133_0001
[0406] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,3-dimethyl-1H-indole-6-carbaldehyde (Intermediate 30) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0407] LC-MS (ESI): mass calcd. for C30H32N4O4, 512.6; m/z found, 513.4 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.57 (s, 1H), 7.45 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.00 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.10 - 5.05 ( m, 1H), 4.47 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.61 (s, 2H), 2.95 - 2.83 (m, 3H), 2.61 - 2.56 (m, 1H), 2.39 - 2.34 (m, 1H), 2.29 (s, 3H), 2.13 (s, 3H), 2.10 - 2.07 (m, 2H), 2.00 - 1.87 (m, 3H), 1.70 - 1.68 (m, 2H). Example 25: 3-(1'-((1H-indazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000133_0002
[0408] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indazole-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C27H27N5O4, 485.54; m/z found, 486.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 10.96 (s, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 6.8 Hz, 1H), 7.00 (s, 1H), 5.10 - 5.05 (m, 1H), 4.55 - 4.43 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.84 (s, 2H), 2.97 - 2.81 (m, 3H), 2.60 -2.56 (m, 1H), 2.39 - 2.35 (m, 1H), 2.13 (t, J = 11.6 Hz, 2H), 2.03 - 1.83 (m, 3H), 1.70 - 1.67 (m, 2H). Example 26: 3-(1'-((1-methyl-1H-indazol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000134_0001
[0409] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-methyl-1H-indazole-7-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C28H29N5O4, 499.22; m/z found, 500 [M+H]+.1HNMR(400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.01 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.17 (d, J = 6.8 Hz, 1H), 7.03 (dd, J = 14.2, 6.8 Hz, 2H), 5.09 - 5.06 (m, 1H), 4.51 (s, 2H), 4.41 (s, 3H), 4.32 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 3.84 (s, 2H), 2.95 - 2.80 (m, 3H), 2.59 - 2.56 (m, 1H), 2.39 - 2.34 (m, 1H), 2.13 (t, J = 11.6 Hz, 2H), 2.00 - 1.92 (m, 1H), 1.86 - 1.79 (m, 2H), 1.71 - 1.69 (m, 2H). Example 27: 3-(1'-((1H-indazol-6-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000134_0002
[0410] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indazole-7-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C27H27N5O4,485.21; m/z found, 486 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 10.97 (s, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 15.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 5.010 - 5.05 (m, 1H), 4.50 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.75 (s, 2H), 2.93 - 2.85 (m, 3H), 2.60 - 2.56 (m, 1H), 2.40 - 2.34 (m, 1H), 2.15 (s, 2H), 1.99 - 1.84 (m, 3H), 1.75 - 1.73 (m, 2H) Example 28: 3-(1'-((1-ethyl-1H-indazol-6-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000135_0001
[0411] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-ethyl-1H-indazole-6-carbaldehyde (Intermediate 6a) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H31N5O4, 513.60; m/z found, 514.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.01 (s, 1H), 5.10 - 5.06 (m, 1H), 4.50 - 4.46 (m, 2H), 4.43 (q, J = 7.2 Hz, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.70 (s, 2H), 2.95 - 2.87 (m, 3H), 2.60 - 2.56 (m, 1H), 2.46 - 2.34 (m, 1H), 2.15 (s, 2H), 1.98 - 1.91 (m, 3H), 1.71 (d, J = 14.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). Example 29: 3-(1'-((2-ethyl-2H-indazol-6-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000135_0002
[0412] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-ethyl-2H-indazole-6-carbaldehyde (Intermediate 6b) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H31N5O4,513.24; m/z found, 514 [M+H] +. 1H NMR(400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 16.6 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 5.09 - 5.05 (m, 1H), 4.47 (d, J = 11.6 Hz, 2H), 4.43 (q, J = 7.2 Hz, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.66 (s, 2H), 2.89 - 2.84 (m, 3H), 2.60 - 2.54 (m, 1H), 2.39 - 2.34 (m, 1H), 2.16 (s, 2H), 1.96 (d, J = 11.8 Hz, 3H), 1.73 (s, 2H), 1.50 (t, J = 7.2 Hz, 3H). Example 30: 3-(1'-((1H-indazol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000136_0001
[0413] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-indazole-7-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C27H27N5O4,485.21; m/z found, 486 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 10.97 (s, 1H), 8.10 (s, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 7.09 (t, J = 7.0 Hz, 1H), 7.01 (s, 1H), 5.09 - 5.05 (m, 1H), 4.49 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.83 (s, 2H), 2.90 - 2.86 (m, 3H), 2.60 - 2.56 (m, 1H), 2.42 - 2.36 (m, 1H), 2.17 - 1.91 (m, 5H), 1.69 (s,2H). Example 31: 3-(1'-((1-methyl-1H-indazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000136_0002
[0414] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-methyl-1H-indazole-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C28H29N5O4, 499.57 ; m/z found, 500.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.27 (d, J = 1.0 Hz, 1H), 8.18 (s, 1H), 7.55 - 7.47 (m, 2H), 7.34 (dd, J = 8.4, 7.0 Hz, 1H), 7.07 (d, J = 7.0 Hz, 1H), 7.00 (s, 1H), 5.09 - 5.04 (m, 1H), 4.50 - 4.43 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 4.04 (s, 3H), 3.82 (s, 2H), 2.94 - 2.79 (m, 3H), 2.60 - 2.57 (m, 1H), 2.44 - 2.35 (m, 1H), 2.10 - 2.07 (m, 2H), 2.01 - 1.86 (m, 3H), 1.69 - 1.66 (m, 2H). Example 32: 3-(1'-((3-methyl-1H-indazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000137_0001
[0415] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-methyl-1H-indazole-4-carbaldehyde (Intermediate 26) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0416] LC-MS (ESI): mass calced for: C28H29N5O 499.22; m/z found, 500.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.96 (s, 1H), 7.45 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.00 (s, 1H), 6.91 (d, J = 6.8 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.51 (s, 2H), 4.32 (d, J = 17.0 Hz, 1H), 4.19 (d, J = 17.0 Hz, 1H), 3.77 (s, 2H), 2.95 - 2.79 (m, 3H), 2.72 (s, 3H), 2.60 - 2.56 (m, 1H), 2.43 - 2.34 (m, 1H), 2.14 - 2.11 (m, 2H), 2.07 - 1.94 (m, 1H), 1.90 - 1.79 (m, 2H), 1.70 - 1.68 (m, 2H). Example 33: 3-(1'-((3-methyl-1H-indazol-7-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000137_0002
[0417] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-methyl-1H-indazole-7-carbaldehyde (Intermediate 29) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0418] LC-MS (ESI): mass calcd. for C28H29N5O4,499.57; m/z found, 500.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.97 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.24 (d, J = 6.8 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 7.01 (s, 1H), 5.10 - 5.05 (m, 1H), 4.52 - 4.43 (m, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.82 (s, 2H), 2.99 - 2.82 (m, 3H), 2.60 - 2.56 (m, 1H), 2.50 (s, 3H), 2.40 - 2.30 (m, 1H), 2.12 - 2.07 (m, 2H), 2.03 - 1.92 (m, 3H), 1.70 - 1.68 (m, 2H). Example 34: 3-(1'-((1H-benzo[d]imidazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000138_0001
[0419] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1H-benzo[d]imidazole-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0420] LC-MS (ESI): mass calcd. for C27H27N5O4,485.21; m/z found,486 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.29 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 7.26 (s, 2H), 7.04 (s, 1H), 5.10 - 5.06 (m, 1H), 4.54 (s, 2H), 4.36 (d, J = 16.89 Hz,1H), 4.23 (d, J = 16.8 Hz, 1H), 4.02 (s, 2H), 3.07 - 2.76 (m, 3H), 2.60 - 2.56 (m, 2H), 2.41 - 2.38 (m, 2H), 2.17 - 1.96 (m, 3H), 1.83 - 1.77 (m, 2H). Example 35: 3-(7-oxo-1'-((2-oxo-1,2-dihydroquinolin-8-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000138_0002
[0421] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-oxo-1,2-dihydroquinoline-8-carbaldehyde (Intermediate 16) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0422] LC-MS (ESI): mass calcd. for C29H28N4O5, 512.21; m/z found, 513.4 [M+H] +.1HNMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 10.88 (s, 1H), 9.09 (s, 1H), 7.92 (d, J = 9.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.24 - 7.22 (m, 2H), 6.99 (s, 1H), 6.53 (d, J = 9.4 Hz, 1H), 5.01 - 4.96 (m, 1H), 4.54 (s, 2H), 4.27 (d, J = 17.0 Hz, 1H), 4.15 (d, J = 17.0 Hz, 1H), 3.37 - 3.34 (m, 3H), 3.26 - 3.16 (m, 3H), 2.88 - 2.72 (m, 1H), 2.49 (d, J = 17.4 Hz, 1H), 2.27 - 2.24 (m, 1H), 1.99 - 1.89 (m, 5H). Example 36: 3-(7-oxo-1'-((4-oxo-1,4-dihydroquinolin-8-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000139_0001
[0423] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-oxo-1,4-dihydroquinoline-8-carbaldehyde (Intermediate 17) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0424] LC-MS (ESI): mass calcd. for C29H28N4O5, 512.21; m/z found, 513.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 10.96 (s, 1H), 8.13 (s, 1H), 8.05 (dd, J = 8.0, 1.4 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.55 (d, J = 6.0 Hz, 1H), 7.48 (s, 1H), 7.30 - 7.24 (m, 1H), 7.01 (s, 1H), 6.09 (d, J = 7.4 Hz, 1H), 5.09 - 5.05 (m, 1H), 4.52 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.23 (d, J = 16.8 Hz, 1H), 3.87 (s, 2H), 2.96 - 2.82 (m, 3H), 2.59 (d, J = 17.2 Hz, 1H), 2.49 - 2.36 (m, 1H), 2.16 - 2.12 (m, 2H), 1.99 - 1.96 (m, 3H), 1.72 - 1.69 (m, 2H). Example 37: 3-(1'-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-7-oxo-5,7-dihydro- 2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000139_0002
[0425] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,3-dihydro-1,4-benzodioxine-5-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C28H29N3O6, 503.21; m/z found, 504.21 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.10 (s, 1H), 7.47 (s, 1H), 7.01 (s, 1H), 6.91 (s, 1H), 6.80 (s, 2H), 5.10 - 5.05 (m, 1H), 4.47 (s, 2H), 4.35 - 4.21 (m, 6H), 3.49 (d, J = 13.4 Hz, 2H), 3.29 (s, 2H), 2.97 - 2.78 (m, 3H), 2.58 - 2.55 (s, 1H), 2.42 - 2.37 (m, 1H), 2.12 - 1.96 (m, 3H), 1.75 - 1.70 (m, 2H). Example 38: 3-(1'-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-7-oxo-5,7-dihydro- 2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000140_0001
[0426] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,2-difluoro-3a,7a-dihydro-2H-1,3-benzodioxole-4-carbaldehyde and 3- {7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6- dione (Intermediate 1). LC-MS (ESI): mass calcd. for C27H27F2N3O6, 525.51; m/z found, 526.4 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.46 (s, 1H), 7.32 (s, 1H), 7.23 (s, 2H), 7.01 (s, 1H), 5.10 - 5.05 (m , 1H), 4.47 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.62 (s, 2H), 2.98 - 2.70 (m, 3H), 2.60 - 2.56 (m, 1H), 2.44 - 2.34 (m, 1H), 2.12 - 2.07 (m, 2H), 2.02 - 1.87 (m, 3H), 1.71 (s, 2H). Example 39: 3-(1'-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)methyl)-7-oxo- 5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000140_0002
[0427] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carbaldehyde (Intermediate 7) and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H32N4O5, 516.24; m/z found, 517.24 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.27 (s, 1H), 7.06 (s, 1H), 6.85 - 6.79 (m, 3H), 5.11 - 5.06 (m, 1H), 4.55 (d, J = 34.8 Hz, 2H), 4.36 (dd, J = 16.8, 7.1 Hz, 3H), 4.25 (d, J = 17.2 Hz, 3H), 3.40 (s, 2H), 3.30 - 3.24 (m, 2H), 3.13 (d, J = 10.2 Hz, 2H), 2.92 (dd, J = 17.8, 4.8 Hz, 1H), 2.86 (s, 3H), 2.59 (d, J = 16.8 Hz, 1H), 2.38 - 2.21 (m, 3H), 1.99 - 1.92 (m, 3H). Example 40: 3-(1'-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)-7-oxo- 5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000141_0001
[0428] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde (Intermediate 8) and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H32N4O5, 516.24; m/z found, 517.24 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.47 - 7.24 (m, 1H), 7.23 - 7.00 (m, 3H), 6.90 - 6.66 (m, 1H), 5.09 - 5.05 (m, 1H), 4.60 - 4.20 (m, 8H), 3.51 (s, 2H), 3.19 - 2.84 (m, 5H), 2.73 (d, J = 27.8 Hz, 3H), 2.59 (d, J = 16.6 Hz, 1H), 2.33 (s, 1H), 2.08 (d, J = 5.8 Hz, 1H), 1.99 - 1.90 (m, 3H), 1.71 - 1.69 (m, 1H). Example 41: 3-(1'-((2,2-dimethylchroman-8-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000141_0002
[0429] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,2-dimethylchromane-8-carbaldehyde (Intermediate 9) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0430] LC-MS (ESI): mass calcd. for C31H35N3O5, 529.64; m/z found, 530.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.14 (s, 1H), 7.46 (s, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.50 - 4.40 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.48 (s, 2H), 2.96 - 2.84 (m, 3H), 2.74 (t, J = 6.8 Hz, 2H), 2.59 - 2.57 (m, 1H), 2.39 - 2.34 (m, 1H), 2.11 (t, J = 12.6 Hz, 2H), 2.02 - 1.86 (m, 3H), 1.76 (t, J = 6.8 Hz, 2H), 1.68 (d, J = 11.4 Hz, 2H), 1.28 (s, 6H). Example 42: 3-(1'-((2,2-dimethylchroman-5-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000142_0001
[0431] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,2-dimethylchromane-5-carbaldehyde and (Intermediate 11) 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0432] LC-MS (ESI): mass calcd. for C29H29N5O4, 529.26; m/z found, 530.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.29 (s, 1H), 7.47 (s, 1H), 7.06 - 6.94 (m, 2H), 6.80 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.09 - 5.05 (m, 1H),4.49 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.43 (s, 2H), 2.94 - 2.76 (m, 5H), 2.59 - 2.56 (m, 1H), 2.39 - 2.32 (m, 1H), 1.99 - 1.80 (m, 5H), 1.78 (t, J = 6.8 Hz, 2H), 1.69 (s, 2H), 1.27 (s, 6H). Example 43: 3-(1'-((4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-7-oxo-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000142_0002
[0433] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (Intermediate 13) and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]- 6-yl}piperidine-2,6-dione (Intermediate 1). [0434] LC-MS (ESI): mass calcd. for C30H34N4O5, 530.25; m/z found, 531.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.46 (s, 1H), 7.00 (s, 1H), 6.65 (d, J = 1.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.46 (dd, J = 8.0, 1.6 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.49 - 4.42 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 4.17 - 4.12 (m, 2H), 3.35 (d, J = 11.2 Hz, 4H), 3.28 - 3.22 (m, 2H), 2.95 - 2.85 (m, 1H), 2.81 (d, J = 9.8 Hz, 2H), 2.59 (d, J = 16.6 Hz, 1H), 2.39 - 2.36 (m, 1H), 2.04 - 1.94 (m, 3H), 1.91 - 1.88 (m, 2H), 1.68 - 1.66 (m, 2H), 1.07 (t, J = 7.0 Hz, 3H). Example 44: 3-(7-oxo-1'-((2-oxoindolin-4-yl)methyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000143_0001
[0435] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-oxoindoline-4-carbaldehyde (Intermediate 12) and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0436] LC-MS (ESI): mass calcd. for C10H9NO, 159.07; m/z found, 160.08 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.71 - 6.65 (m, 1H), 5.79 (d, J = 17.8 Hz, 1H), 5.36 (d, J = 11.2 Hz, 1H), 3.53 (s, 2H). Example 45: 3-(7-oxo-1'-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000143_0002
[0437] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (Intermediate 10) and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl}piperidine-2,6-dione (Intermediate 1). [0438] LC-MS (ESI): mass calcd. for C28H28N4O6, 516.2; m/z found, 517.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.66 (s, 1H), 7.44 (s, 1H), 7.01 (s, 1H), 6.92 - 6.83 (m, 3H), 5.09 - 5.06 (m, 1H), 4.55 (s, 2H), 4.50 - 4.43 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.40 (s, 2H), 2.96 - 2.85 (m, 1H), 2.79 (d, J = 10.8 Hz, 2H), 2.59 (d, J = 17.4 Hz, 1H), 2.41 - 2.32 (m, 1H), 2.00 - 1.91 (m, 3H), 1.88 - 1.85 (m, 2H), 1.69 - 1.66 (m, 2H). Example 46: 3-(7-oxo-1'-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000144_0001
[0439] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carbaldehyde (Intermediate 21) and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6- yl}piperidine-2,6-dione (Intermediate 1). [0440] LC-MS (ESI): mass calcd. for C28H28N4O6, 516.55; m/z found, 517.55 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 10.96 (s, 1H), 10.29 (s, 1H), 7.46 (s, 1H), 7.01 (s, 1H), 6.93 - 6.86 (m, 3H), 5.09 - 5.04 (m, 1H), 4.60 (s, 2H), 4.50 (s, 2H), 4.35 (d, J = 17.0 Hz, 1H), 4.22 (d, J = 17.0 Hz, 1H), 3.66 (s, 2H), 2.95 - 2.81 (m, 3H), 2.59 (d, J = 16.0 Hz, 1H), 2.41 - 2.32 (m, 1H), 2.10 (t, J = 11.6 Hz, 2H), 2.01 - 1.84 (m, 3H), 1.75 - 1.72 (m, 2H). Example 47: 3-(1'-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl)-7-oxo-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000144_0002
[0441] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 22-dimethyl-23-dihydrobenzofuran-7-carbaldehyde and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0442] LC-MS (ESI): mass calcd. for C30H33N3O5, 515.24; m/z found, 516.25 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.46 (s, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 7.00 (s, 1H), 6.78 (t, J = 7.4 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.45 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.43 (s, 2H), 2.99 (s, 2H), 2.95 - 2.79 (m, 3H), 2.60 - 2.56 (m, 1H), 2.41 - 2.31 (m, 1H), 2.10 - 2.02 (m, 2H), 1.97 (d, J = 5.6 Hz, 1H), 1.90 (t, J = 12.4 Hz, 2H), 1.68 - 1.65 (m, 2H), 1.40 (s, 6H) Example 48: 3-(1'-((2,2-dimethyl-2,3-dihydrobenzofuran-4-yl)methyl)-7-oxo-5,7- dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000145_0001
[0443] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2,2-dimethyl-2,3-dihydrobenzofuran-4-carbaldehyde and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0444] LC-MS (ESI): mass calcd. for C30H33N3O5, 515.24; m/z found, 516.25 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.47 (s, 1H), 7.03 (dd, J = 14.2, 6.4 Hz, 2H), 6.77 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 5.08 - 5.06 (m, 1H), 4.49 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.41 (s, 2H), 3.03 (s, 2H), 2.96 - 2.84 (m, 1H), 2.79 (d, J = 8.4 Hz, 2H), 2.58 (d, J = 17.6 Hz, 1H), 2.43 - 2.32 (m, 1H), 2.07 - 1.96 (m, 3H), 1.93 - 1.83 (m, 2H), 1.69 - 1.67 (m, 2H), 1.41 (s, 6H). Example 49: 3-(1'-(3-cyclopropoxybenzyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000145_0002
[0445] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-cyclopropoxybenzaldehyde (Intermediate 24) and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0446] LC-MS (ESI): mass calcd. for C29H31N3O5, 501.58; m/z found, 502.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 10.96 (s, 1H), 8.15 (s, 1H), 7.48 (s, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.00 (s, 2H), 6.94 (dd, J = 13.0, 5.0 Hz, 2H), 5.10 - 5.05 (m, 1H), 4.51 - 4.42 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.83 - 3.80 (m, 1H), 3.48 (s, 2H), 2.96 - 2.85 (m, 1H), 2.81 (d, J = 10.8 Hz, 2H), 2.59 (d, J = 16.2 Hz, 1H), 2.42 - 2.36 (m, 1H), 2.10 - 1.85 (m, 5H), 1.68 (d, J = 10.8 Hz, 2H), 0.79 - 0.76 (m, 2H), 0.68 - 0.61 (m, 2H). Example 50: 3-(7-oxo-1'-(3-((1,1,1-trifluoropropan-2-yl)oxy)benzyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000146_0001
[0447] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-((1,1,1-trifluoropropan-2-yl)oxy)benzaldehyde (Intermediate 27) and 3- {7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6- dione (Intermediate 1). [0448] LC-MS (ESI): mass calcd. for C29H30F3N3O5, 557.57; m/z found, 558.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 10.96 (s, 1H), 7.48 (s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.04 - 6.95 (m, 4H), 5.24 - 5.20 (m, 1H), 5.10 - 5.05 (m, 1H), 4.50 - 4.43 (m, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.49 (s, 2H), 2.90 - 2.85 (m, 1H), 2.80 (d, J = 10.6 Hz, 2H), 2.58 (d, J = 18.0 Hz, 1H), 2.41 - 2.31 (m, 1H), 2.08 - 1.87 (m, 5H), 1.68 (d, J = 10.4 Hz, 2H), 1.41 (d, J = 6.2 Hz, 3H). Example 51: 3-(7-oxo-1'-(3-phenoxybenzyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000146_0002
[0449] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-phenoxybenzaldehyde and 3-{7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3- f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0450] LC-MS (ESI): mass calced for: C32H31N3O5 537.23; m/z found, 538.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.14 (s, 1H), 7.46 (s, 1H), 7.43 - 7.37 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 7.18 - 7.09 (m, 2H), 7.02 (t, J = 1.6 Hz, 1H), 7.00 (d, J = 1.6 Hz, 3H), 6.89 (dd, J = 7.8, 2.0 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.50 - 4.43 (m, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.51 (s, 2H), 2.96 - 2.84 (m, 1H), 2.80 (d, J = 11.4 Hz, 2H), 2.59 (d, J = 17.0 Hz, 1H), 2.46 - 2.33 (m, 1H), 2.08 - 2.02 (m, 2H), 2.00 - 1.84 (m, 3H), 1.69 - 1.66 (m, 2H). Example 52: 3-(1'-(3-(1H-pyrazol-1-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000147_0001
[0451] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1H-pyrazol-1-yl)benzaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0452] LC-MS (ESI): mass calcd. for C29H29N5O4,511.22; m/z found,512.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6 ) δ 10.96 (s, 1H), 8.51 (d, J = 2.2 Hz, 1H), 7.86 (s, 1H), 7.76 (s, 2H), 7.48 (s, 2H), 7.31 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.56 (s, 1H), 5.10 - 5.05 (m,1H), 4.50 (s, 2H), 4.35 (d, J = 17.0 Hz, 1H), 4.22 (d, J = 17.0 Hz, 1H), 3.62 (s, 2H), 3.07 - 2.76 (m, 3H), 2.61 - 2.56 (m, 1H), 2.43 - 2.34 (m, 1H), 2.13 (s, 2H), 2.03 - 1.91 (m,3H), 1.74 (s, 2H). Example 53: 3-((6-(2,6-dioxopiperidin-3-yl)-7-oxo-6,7-dihydro-2H,5H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-1'-yl)methyl)-N,N-dimethylbenzenesulfonamide
Figure imgf000148_0001
[0453] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-formyl-N,N-dimethylbenzenesulfonamide (Intermediate 15) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0454] LC-MS (ESI): mass calcd. for C28H35N4O6S, 522.20; m/z found,553.4 [M+H] +. 1H NMR (400 MHz, DMSO-d6 ) δ 10.97 (s, 1H), 8.14 (s, 1H), 7.73 (s, 1H), 7.69 (d, J = 6.6 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.51 (s, 1H), 7.01 (s, 1H), 5.10 - 5.05 (m, 1H), 4.48 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.67 (s, 2H), 2.92 - 2.81 (m, 3H), 2.61 - 2.52 (m, 7H), 2.41 - 2.33 (m, 1H), 2.17 - 2.12 (m, 2H), 2.02 - 1.88 (m, 3H), 1.72 - 1.70 (m, 2H). Example 54: 3-(1'-(3-(morpholinosulfonyl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000148_0002
[0455] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(morpholinosulfonyl)benzaldehyde (Intermediate 18) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0456] LC-MS (ESI): mass calced for: C30H34N4O7S 594.21; m/z found, 594.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.99 (s, 1H), 7.95 (s, 1H), 7.85 - 7.79 (m, 3H), 7.31 (s, 1H), 7.07 (s, 1H), 5.10 - 5.06 (m, 1H), 4.60 (s, 2H), 4.51 (s, 2H), 4.37 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.0 Hz, 1H), 3.67 - 3.61 (m, 4H), 3.19 (s, 2H), 2.96 - 2.85 (m, 5H), 2.59 (d, J = 16.4 Hz, 1H), 2.46 (s, 1H), 2.38 - 2.30 (m, 2H), 2.11 (t, J = 13.4 Hz, 2H), 1.99 - 1.97 (m, 3H). Example 55: 3-(7-oxo-1'-(3-(phenylsulfonyl)benzyl)-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000149_0001
[0457] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(phenylsulfonyl)benzaldehyde (Intermediate 23) and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0458] LC-MS (ESI): mass calced for: C32H31N3O6S 585.19; m/z found, 586.0 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.14 (s, 1H), 8.01 - 7.94 (m, 2H), 7.93 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.72 - 7.56 (m, 5H), 7.50 (s, 1H), 7.01 (s, 1H), 5.09 - 5.04 (m, 1H), 4.51 - 4.42 (m, 2H), 4.35 (d, J = 17.0 Hz, 1H), 4.22 (d, J = 17.0 Hz, 1H), 3.61 (s, 2H), 2.97 - 2.85 (m, 1H), 2.75 (d, J = 10.8 Hz, 2H), 2.59 (d, J = 16.8 Hz, 1H), 2.49 - 2.38 (m, 1H), 2.07 (t, J = 11.8 Hz, 2H), 2.02 - 1.86 (m, 3H), 1.69 - 1.66 (m, 2H). Example 56: 3-(1'-((6-(isopropylthio)pyridin-2-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000149_0002
[0459] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 6-(isopropylthio)picolinaldehyde (Intermediate 28) and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0460] LC-MS (ESI): mass calcd. for C28H32N4O4S, 520.21; m/z found, 521.22 [M+H].1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.25 - 7.10 (m, 2H), 7.01 (s, 1H), 5.09 - 5.05 (m, 1H), 4.48 (s, 2H), 4.35 (d, J = 17.0 Hz, 1H), 4.22 (d, J = 17.0 Hz, 1H), 3.93 (s, 1H), 3.61 (s, 2H), 3.02 - 2.77 (m, 3H), 2.59 (d, J = 16.6 Hz, 1H), 2.44 - 2.34 (m, 1H), 2.15 - 2.12 (m, 2H), 2.02 - 1.88 (m, 3H), 1.71 (s, 2H), 1.34 (d, J = 6.8 Hz, 6H). Example 57: 3-(7-oxo-1'-((2-(pyrrolidin-1-yl)pyrimidin-4-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000150_0001
[0461] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-(pyrrolidin-1-yl)pyrimidine-4-carbaldehyde (Intermediate 20) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0462] LC-MS (ESI): mass calcd. for C28H32N6O4, 516.60; m/z found, 517.60 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.28 (d, J = 5.0 Hz, 1H), 7.49 (s, 1H), 7.01 (s, 1H), 6.70 (d, J = 5.0 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.52 - 4.44 (m, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.50 - 3.40 (m, 6H), 2.93 - 2.82 (m, 3H), 2.59 (d, J = 16.2 Hz, 1H), 2.42 - 2.31 (m, 1H), 2.20 - 2.13 (m, 2H), 2.02 - 1.88 (m, 7H), 1.69 - 1.68 (m, 2H). Example 58: 3-(7-oxo-1'-((2-(pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000150_0002
[0463] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 2-(pyrrolidin-1-yl)pyrimidine-5-carbaldehyde (Intermediate 19) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0464] LC-MS (ESI): mass calced for: C28H32N6O4 516.25; m/z found, 517.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.27 (s, 2H), 7.44 (s, 1H), 7.01 (s, 1H), 5.10 - 5.05 (m, 1H), 4.47 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.47 (t, J = 6.4 Hz, 4H), 3.30 (s, 2H), 3.00 - 2.73 (m, 3H), 2.60 (d, J = 2.2 Hz, 1H), 2.39 - 2.34 (m, 1H), 2.15 - 1.98 (m, 2H), 1.95 - 1.90 (m, 7H), 1.72 - 1.70 (m, 2H). Example 59: 3-(1'-((1-benzyl-1H-pyrazol-4-yl)methyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000151_0001
[0465] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-benzyl-1H-pyrazole-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0466] LC-MS (ESI): mass calcd. for C30H31N5O4,525.24; m/z found, 526.3 [M+H]+ . 1H NMR (400 MHz, DMSO-d6 ) δ 10.96 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 7.36 - 7.31 (m, 2H), 7.31 - 7.25 (m, 1H), 7.22 - 7.18 (m, 2H), 7.00 (s, 1H), 5.29 (s, 2H), 5.09 - 5.04 (m, 1H), 4.42 (s, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.20 (d, J = 17.0 Hz, 1H), 3.39 (s, 2H), 2.91 - 2.80 (m, 3H), 2.61 - 2.56 (m, 1H), 2.41 - 2.32 (m, 1H), 1.98 (t, J = 11.2 Hz, 3H), 1.88 - 1.84 (m, 2H), 1.68 - 1.65 (m, 2H). Example 60: 3-(7-oxo-1'-((1-phenyl-1H-pyrazol-4-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000151_0002
[0467] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-phenyl-1H-pyrazole-4-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0468] LC-MS (ESI): mass calcd. for C29H29N5O4, 511.22; m/z found, 512 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.44 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.70 (s, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.43 (s, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H), 5.10 - 5.05 (m, 1H), 4.47 (s, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.55 (s, 2H), 3.08 - 2.76 (m, 3H), 2.60 - 2.57 (m, 1H), 2.41 - 2.35 (m, 1H), 2.07 (s, 2H), 2.00 - 1.91 (m, 3H), 1.74 (s, 2H). Example 61: 3-(7-oxo-1'-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000152_0001
[0469] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (Intermediate 14) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0470] LC-MS (ESI): mass calcd. for C28H28N6O4, 512.57; m/z found, 513.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.74 (s, 1H), 7.95 - 7.89 (m, 2H), 7.60 (dd, J = 10.6, 5.0 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.43 (s, 1H), 7.01 (s, 1H), 5.09 - 5.05 (m, 1H), 4.51 - 4.43 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.70 (s, 2H), 2.93 - 2.90 (m, 3H), 2.61 - 2.58 (m, 1H), 2.42 - 2.30 (m, 1H), 2.15 (t, J = 12.0 Hz, 2H), 2.01 - 1.86 (m, 3H), 1.74 - 1.65 (m, 2H). Example 62: 3-(7-oxo-1'-((4-phenylthiophen-2-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000152_0002
[0471] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 4-phenylthiophene-2-carbaldehyde and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate [0472] LC-MS (ESI): mass calced for: C30H29N3O4S 527.19; m/z found, 528.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.16 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.49 (s, 1H), 7.44 - 7.36 (m, 3H), 7.28 (t, J = 7.4 Hz, 1H), 7.01 (s, 1H), 5.10 - 5.05 (m, 1H), 4.52 - 4.42 (m, 2H), 4.35 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.76 (s, 2H), 2.93 - 2.86 (m, 3H), 2.61 - 2.56 (m, 1H),2.44 - 2.33 (m, 1H), 2.12 (t, J = 11.8 Hz, 2H), 1.99 - 1.89 (m, 3H), 1.72 - 1.70 (m, 2H). Example 63: 3-(7-oxo-1'-((3-phenylthiophen-2-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000153_0001
[0473] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-phenylthiophene-2-carbaldehyde (Intermediate 22) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0474] LC-MS (ESI): mass calced for: C30H29N3O4S 527.19; m/z found, 528.01 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.14 (s, 1H), 7.57 - 7.39 (m, 6H), 7.39 - 7.28 (m, 1H), 7.12 (d, J = 5.2 Hz, 1H), 7.00 (s, 1H), 5.10 - 5.05 (m, 1H), 4.50 - 4.39 (m, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.76 (s, 2H), 3.01 - 2.81 (m, 3H), 2.61 - 2.58 (m, 1H), 2.49 – 2.38 (m, 1H), 2.16 - 1.83 (m, 5H), 1.70 - 1.68 (m, 2H). Example 64: 3-(7-oxo-1'-((3-(trifluoromethyl)thiophen-2-yl)methyl)-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000153_0002
[0475] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(trifluoromethyl)thiophene-2-carbaldehyde (Intermediate 31) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0476] LC-MS (ESI): mass calcd. for C25H24F3N3O4S, 519.54 ; m/z found, 520.4[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.65 (d, J = 5.4 Hz, 1H), 7.51 (s, 1H), 7.24 (d, J = 5.4 Hz, 1H), 7.01 (s, 1H), 5.11 - 5.06 (m, 1H), 4.54 - 4.46 (m, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.85 (s, 2H), 2.96 - 2.85 (m, 3H), 2.61 - 2.56 (m, 1H), 2.46 - 2.33 (m, 1H), 2.21(t, J = 12.0 Hz, 2H), 2.03 - 1.85 (m, 3H), 1.73 - 1.70 (m, 2H). Example 65: 3-(1'-benzyl-5-oxo-5,7-dihydrospiro[furo[3,4-f]isoindole-1,4'-piperidin]- 6(3H)-yl)piperidine-2,6-dione
Figure imgf000154_0001
[0477] The title compound was prepared in a manner analogous to Example 1 by reductive amination between benzaldehyde and 3-(5-oxo-5,7-dihydrospiro[furo[3,4-f]isoindole-1,4'- piperidin]-6(3H)-yl)piperidine-2,6-dione (Intermediate 2). [0478] LC-MS (ESI): mass calcd. for C26H27N3O4, 445.20; m/z found, 446.21 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.40 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 7.34 - 7.25 (m, 5H), 5.11 - 5.08 (m, 1H), 5.02 (s, 2H), 4.44 (d, J = 17.6 Hz, 1H), 4.30 (d, J = 17.6 Hz, 1H), 3.54 (s, 2H), 2.90 - 2.87 (m, 1H), 2.74 (d, J = 9.8 Hz, 2H), 2.60 - 2.54 (m, 1H), 2.39 - 2.32 (m, 3H), 2.01 - 1.92 (m, 3H), 1.69 - 1.67 (m, 2H). Example 66: 3-(1-benzyl-1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione
Figure imgf000154_0002
[0479] The title compound was prepared in a manner analogous to Example 1 by reductive amination between benzaldehyde and 3-(1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione (Intermediate 3). [0480] LC-MS (ESI): mass calcd. for C27H29N3O4, 459.20; m/z found, 460.21 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.51 - 7.40 (m, 7H), 5.12 - 5.08 (m, 1H), 4.42 (d, J = 17.0 Hz, 1H), 4.29 (d, J = 17.0 Hz, 1H), 3.86 (s, 2H), 2.94 - 2.89 (m, 6H), 2.60 - 2.56 (m, 1H), 2.46 - 2.32 (m, 2H), 2.12 (s, 3H), 1.96 (s, 4H). Example 67: 3-(1-methyl-1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione
Figure imgf000155_0001
[0481] The title compound was prepared in a manner analogous to Example 2 by reductive amination between formaldehyde and 3-(1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione (Intermediate 3). [0482] LC-MS (ESI): mass calcd. for C21H25N3O4, 383.20; m/z found, 384.21 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 5.09 - 5.05 (m, 1H), 4.45 (d, J = 16.8 Hz, 1H), 4.32 (d, J = 16.8 Hz, 1H), 3.88 (s, 2H), 3.07 (t, J = 12.2 Hz, 3H), 2.95 (d, J = 6.8 Hz, 2H), 2.90 (s, 2H), 2.74 (s, 3H), 2.60 - 2.46 (m, 1H), 2.38 - 2.33 (m, 2H), 2.03 - 1.87 (m, 5H). Example 68: 3-(1-acetyl-1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione
Figure imgf000155_0002
[0483] The title compound was prepared in a manner analogous to Example 3 by acetylation between acetic anhydride and 3-(1'-oxo-1',3',7',8'-tetrahydro-2'H-spiro[piperidine-4,5'- pyrano[3,4-f]isoindol]-2'-yl)piperidine-2,6-dione (Intermediate 3). [0484] LC-MS (ESI): mass calcd. for C22H25N3O5, 411.46; m/z found, 412.21 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 5.11 - 5.07 (m, 1H), 4.37 – 4.26 (m, 3H), 3.89 (t, J = 5.0 Hz, 2H), 3.72 (d, J = 13.0 Hz, 1H), 3.34 (s, 1H), 2.91 - 2.83 (m, 4H), 2.59 - 2.56 (m, 1H), 2.48 - 2.42 (m, 1H), 2.05 (s, 3H), 1.99 (d, J = 11.2 Hz, 2H), 1.91 - 1.77 (m, 3H). Example 69: 3-(1'-(3-(1-methyl-1H-pyrazol-3-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000156_0001
[0485] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (Intermediate 32) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). [0486] LC-MS (ESI): mass calcd. for C30H31N5O4, 525.24; m/z found, 526.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.15 (s, 1H), 7.76 (s, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.68 (d, J = 2.2 Hz, 1H), 5.09 - 5.04 (md, 1H), 4.51 - 4.45 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 2H), 2.91 - 2.82 (m, 3H), 2.59 (d, J = 16.0 Hz, 1H), 2.40 - 2.31 (m, 1H), 2.09 (t, J = 12.0 Hz, 2H), 1.99 - 1.89 (m, 3H), 1.70 (d, J = 10.8 Hz, 2H). Example 70: 3-(1'-(3-(1-methyl-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000156_0002
[0487] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-methyl-1H-pyrazol-4-yl)benzaldehyde (Intermediate 33) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C30H31N5O4, 525.24; m/z found, 526.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.14 (s, 2H), 7.85 (s, 1H), 7.53 (s, 1H), 7.46 (s, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.01 (s, 1H), 5.10 - 5.05 (m, 1H), 4.49 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.87 (s, 3H), 3.60 (s, 2H), 2.93 - 2.86 (m, 3H), 2.61 - 2.56 (m, 1H), 2.40 - 2.33 (m, 1H), 2.16 (s, 2H), 2.00 - 1.94 (m, 3H), 1.73 (s, 2H). Example 71: 3-(1'-(3-(1-ethyl-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000157_0001
[0488] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-ethyl-1H-pyrazol-4-yl)benzaldehyde (Intermediate 34) and 3-{7-oxo- 2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C31H33N5O4,539.64; m/z found, 540.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 7.50 - 7.44 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.02 (s, 1H), 5.10 - 5.05 (m, 1H), 4.48 (s, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 2.91 - 2.80 (m, 3H), 2.60 - 2.56 (m, 1H), 2.49 - 2.32 (m, 1H), 2.05 - 1.89 (m, 5H), 1.71 - 1.68 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H). Example 72: 3-(1'-(3-(1H-pyrazol-3-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000157_0002
[0489] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1H-pyrazol-3-yl)benzaldehyde (Intermediate 35) and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calcd. for C29H29N5O4, 511.58; m/z found, 512.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.14 (s, 1H), 7.88 - 7.61 (m, 3H), 7.48 (d, J = 10.0 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.71 (d, J = 2.0 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.49 (s, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.57 (s, 2H), 2.90 - 2.86 (m, 3H), 2.67 - 2.56 (m, 1H), 2.40 - 2.36 (m, 1H), 2.18 - 2.12 (m, 2H), 2.00 - 1.91 (m, 3H), 1.72 - 1.69 (m, 2H). Example 73: 3-(1'-(3-(1-cyclopropyl-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000158_0001
[0490] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-cyclopropyl-1H-pyrazol-4-yl)benzaldehyde (Intermediate 36) and 3- {7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6- dione (Intermediate 1). LC-MS (ESI): mass calcd. for C32H33N5O4, 551.25; m/z found, 552.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.23 (s, 2H), 7.84 (s, 1H), 7.51 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 5.09 - 5.04 (m, 1H), 4.46 (s, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.76 - 3.71 (m, 1H), 3.51 (s, 2H), 2.94 - 2.82 (m, 3H), 2.58 (d, J = 17.23 Hz, 1H), 2.40 - 2.33 (m, 1H), 2.06 - 1.92 (m, 5H), 1.70 - 1.66 (m, 2H), 1.10 - 1.06 (m, 2H), 0.99 - 0.95 (m, 2H). Example 74: 3-(1'-(3-(1-isopropyl-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000158_0002
[0491] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-isopropyl-1H-pyrazol-4-yl)benzaldehyde (Intermediate 37) and 3-{7- oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1) LC-MS (ESI): mass calcd for C32H35N5O4 55366; m/z found 5543 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.52 (s, 1H), 7.47 (d, J = 4.8 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 5.10 - 5.05 (m, 1H), 4.51 - 4.48 (m, 3H), 4.35 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.52 (s, 2H), 2.93 - 2.82 (m, 3H), 2.61 - 2.57 (m, 1H), 2.42 - 2.31 (m, 1H), 2.20 - 2.13 (m, 2H), 2.02 - 1.88 (m, 3H), 1.70 - 1.68 (m, 2H), 1.46 (s, 3H), 1.45 (s, 3H). Example 75: 3-(1'-(3-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H- spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000159_0001
[0492] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)benzaldehyde (Intermediate 38) and 3- {7-oxo-2,5,6,7-tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6- dione (Intermediate 1). LC-MS (ESI): mass calced for: C32H33N5O5, 567.65; m/z found, 568.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.54 (s, 1H), 7.51 - 7.44 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 5.61 - 5.57 (m, 1H), 5.09 - 5.04 (m, 1H), 4.99 - 4.89 (m, 4H), 4.53 - 4.42 (m, 2H), 4.34 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.52 (s, 2H), 2.91 - 2.82 (m, 3H), 2.59 (d, J = 16.2 Hz, 1H), 2.43 - 2.33 (m, 1H), 2.06 - 1.88 (m, 5H), 1.69 (d, J = 10.8 Hz, 2H). Example 76: 3-(1'-(3-(1H-pyrazol-4-yl)benzyl)-7-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3- f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione
Figure imgf000159_0002
[0493] The title compound was prepared in a manner analogous to Example 1 by reductive amination between 3-(1H-pyrazol-4-yl)benzaldehyde (Intermediate 39) and 3-{7-oxo-2,5,6,7- tetrahydrospiro[furo[2,3-f]isoindole-3,4'-piperidine]-6-yl}piperidine-2,6-dione (Intermediate 1). LC-MS (ESI): mass calced for: C29H29N5O4511.58; m/z found, 512.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.19 (s, 1H), 8.05 (s, 2H), 7.54 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 5.09 - 5.04 (m, 1H), 4.48 (s, 2H), 4.34 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.52 (s, 2H), 2.91 - 2.89 (m, 1H), 2.87 - 2.82 (m, 2H), 2.60 - 2.57 (m, 1H), 2.39 - 2.32 (m, 1H), 2.06 (t, J = 10.8 Hz, 2H), 2.00 - 1.88 (m, 3H), 1.69 (d, J = 10.0 Hz, 2H). II. Biological Assay In vitro Assay: IC50 Measurements for binding to CRBN/DDB1 [0494] The binding to cereblon (CRBN) was determined using HTRF assay technology (Perkin Elmer). Compounds were serially diluted in DMSO and 0.2 µL volume was transferred to white 384-well plate. The reaction was conducted in total volume of 20 µL with addition of 2 nM His tagged CRBN+DDB-DLS7+CXU4 (Wuxi, catalogue # RP210521GA) to compounds followed by addition of 60 nM Fluorescent probe Cy5-labeled Thalidomide (Tenova Pharma, catalogue # T52461), and 0.4 nM of MAb Anti-6HIS Tb cryptate Gold (Cisbio, catalogue # 61HI2TLA in the assay buffer (50 mM HEPES pH 7.5, 1 mM TCEP, 0.01% Brij-35, 50 mM NaCl, and 0.1% BSA). After one hour incubation at room temperature, the HTRF signals were read on Envision reader (Perkin Elemer). Data was analyzed using XLfit using four parameters dose response curve to determine IC50s. Results for CRBN/DDB1 binding are summarized in Table E1. Table E1. CRBN binding IC50
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
A: IC50 < 0.1 µM; B: 0.1 µM < IC50 < 0.5 µM; C: 0.5 µM < IC50 < 1 µM; D: 1 µM < IC50 < 5 µM; E: 5 µM < IC50 < 10 µM. In vitro Assay: IKZF2 FACS assay [0495] Jurkat cells (ATCC, Cat # HB-8065) were cultured in RPMI1640 + 10% FBS + 1% P/S. Cells were treated at desired compound concentrations (0.05 to 10 μM) and DMSO as vehicle control for 24 hrs. After 24 hrs of drug treatment cells were washed, fixed (3.7% PFA, and permeabilized with perm buffer (0.3% Triton X-100 in 1% BSA Solution). Subsequently, cells were stained with IKZF2 (1:100, Cell signaling) primary antibody and Alexa 488-labelend anti- rabbit IgG (1:200, Cell Signaling) secondary antibodies in staining buffer (1% BSA in PBS). Cells were images on iQue Flowcytometer and IKZF2 levels were quantified using iQue software. Data was further analyzed using XLfit using four parameters dose response curve to determine DC50 and Dmax. The half maximal degradation concentration values (DC50) and maximal degradation percentage (Dmax, %) of IKZF2 are summarized in Table E2. Table E2. IKZF2 degradation by FACS
Figure imgf000163_0002
Figure imgf000164_0001
Figure imgf000165_0001
DC50: A: 1-10 nM; B: 10 -100 nM; C: 100-1000 nM; D: > 1000 nM. Dmax: A: >60%; B: 40-60%; C: 20-40%; D: < 20%. In vitro Assay: IKZF2 HiBit assay [0496] The HiBiT protein tagging system was applied to modified HEK293T Flp-in-HiBiT cells (polyclone) via a CRISPR/Cas9 - mediated insertion of the HiBiT peptide tag (Promega™) to the N-terminus of the IKZF2 gene locus (Neon™ transfection system). Test and reference compounds are diluted from 1 mM at 3 folds for 11 doses. 25 nL of diluted compound is transfered to assay plates (Corning3570) using ECHO550, the final DMSO concentration @ 0.1%. The cells are seeded in 3000/25 µL/well to compound plates. The plate is then incubated for 6 hrs in TC incubator. The amount of Nano-Glo® HiBiT lytic reagent needed to perform the desired experiments is calculated. The Nano-Glo® HiBiT lytic reagent is brought to room temperature. The LgBiT protein is diluted to 1:100 and the Nano-Glo® HiBiT lytic substrate is diluted to 1:50 into an appropriate volume of room temperature Nano-Glo® HiBiT lytic buffer. 15 µL of the detection reagent (or without LgBiT) is dispensed to corresponding well according to the layout. The plate is then shaken for 10 mins at room temperature. After briefly centrifuge, the plate is read on Envision. At the indicated timepoints, the Nano-Glo® HiBiT lytic detection system (Promega™) was utilized for detecting bioluminescence ofthe HiBiT tag in treated cells: abundance of the tag is proportionate to the level of luminescence. Following normalization to DMSO, dose-response curves were plotted (GraphPad Prism) to determine the concentration points at which 50% of HiBiT-Helios degradation was achieved by each compound. The extent of degradation (range of luminescence) from the highest to lowest concentration points was calculated to determine the Dmax. In vitro Assay: IKZF1 HiBit assay [0497] The HiBiT protein tagging system was applied to modified Cells: modified HEK293T Flp-in- HiBiT-IKZF1 stable cell line (polyclone) via a CRISPR/Cas9 - mediated insertion of the HiBiT peptide tag (Promega™) to the N-terminus of the IKZF2 gene locus (Neon™ transfection system). [0498] Test compound from 10 mM and reference compound (CC-92480 from 50 µM and I- 57 from 10 mM) are diluted at 3 folds for 11 doses.25 nL of diluted compound is transferred to assay plates (Corning3571) using ECHO550, the final DMSO concentration @ 0.1%. The cells are seeded in 3000/25 µL/well to compound plates. The plates are incubated for 6 hrs in TC incubator. The amount of Nano-Glo® HiBiT lytic reagent needed to perform the desired experiments is calculated. The Nano-Glo® HiBiT lytic reagent is brought to room temperature. The LgBiT protein is diluted to 1:100 and the Nano-Glo® HiBiT lytic substrate is brought to 1:50 into an appropriate volume of room temperature Nano-Glo® HiBiT lytic buffer.15 µL of the detection reagent (or without LgBiT) is dispensed to corresponding well according to the layout. The plate is shaken for 10 mins at room temperature. After briefly centrifuging, the plate is read on Envision. At the indicated timepoints, the Nano-Glo® HiBiT lytic detection system (Promega™) was utilized for detecting bioluminescence ofthe HiBiT tag in treated cells: abundance of the tag is proportionate to the level of luminescence. Following normalization to DMSO, dose-response curves were plotted (GraphPad Prism) to determine the concentration points at which 50% of HiBiT- Ikaros degradation was achieved by each compound. The extent of degradation (range of luminescence) from the highest to lowest concentration points was calculated to determine the Dmax. [0499] The half maximal degradation concentration values (DC50) and maximal degradation percentage (Dmax, %) of IKZF2 and IKZF1 are summarized in Table E3. Table E3. IKZF2 and IKZF1 degradation by HiBit
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
IKZF2 degradation and evaluation of IL-2 production [0500] IKZF2 is important for immunosuppressive activity of regulatory T cells (Treg cells), which is linked to interlukin-2 (IL-2) repression. IKZF2 binds to the IL-2 promoter in Treg cells and suppresses transcriptional activation. IKZF2 knockdown suppresses FoxP3 binding to IL- 2 promoter and results in higher IL-2 expression upon stimulation. Further, IKZF2 knockout leads to an unstable CD4 Treg phenotype in mice marked by production of effector cytokines and IKZF2 knockout in Tregs suppresses tumor growth. (Baine I. et al., J Immunol 190, 1008– 1016 (2013); Nakagawa, H. et al. Proc National Acad Sci 113, 6248–6253 (2016); Yates, K., et al. Proc National Acad Sci 115, 201720447 (2018). [0501] To measure whether IKZF2 degradation with the compounds of this disclosure impacts IL-2 production, Jurkat cells (ATCC, Cat # HB-8065) are treated with vehicle control (DMSO) or the compound for 16 -24 hrs. After 16 - 24 hrs of treatment cells are stimulated with CD3/CD28 stimulation beads at a 3:1 ratio for 24 hrs. After 24 hrs, supernatants are collected and the concentration of IL-2 is measured using MSD V-PLEX Human IL-2 Kit (Cat#K151QQD, Mesoscale). The compounds of this disclosure are expected to increase IL-2 production, and thereby increase anti-tumor immunity. IKZF2 degradation in primary human Treg cells [0502] To measure whether the compounds of this disclosure can induce degradation of IKZF2 in Treg cells, human peripheral bone marrow cells (PBMCs) obtained from healthy donors purchased from Milestone Biological Science and Technology Company are treated with vehicle control (DMSO) or the compound for various time points (3 – 24 hrs). After desired treatment time, the cells are collected and stained with anti-CD3-APC-Cy7 (Clone SP34-2, BD), anti-CD4-FITC (Clone L200, BD), anti-CD45-BV510 (Clone HI30, Biolegend), and anti- CD25-BV421 (Clone BC96, Biolegend) in cell staining buffer (Biolegend, Cat#420201), washed and fixed with FOXP3 fix/perm buffer (Life Technologies, cat. #00-5523-00) followed by intracellular staining with anti-IKZF2-APC (Clone 22F6, BioLegend), anti-Ikaros-PE-Cy7 (Clone 16B5C71, BioLegend), and anti-FOXP3-PE (clone 206D, Biolegend). Samples are acquired on a Thermo Attune NxT flow cytometer (Thermo Fisher Scientific). IKZF2 mean fluorescence intensity (MFI) and IKZF1 MFI are measured in Tregs (CD4+CD25+ FOXP3+) cells. The compounds of this disclosure are expected to degrade IKZF2 in Treg cells, thereby suppressing the action of Treg cells. IKZF2 degradation and Teff cell proliferation [0503] To measure whether the compounds of this disclosure can enhance effector T cell (Teff) proliferation via suppression of Treg cells, Treg cells and Teff cells from matched human donors are co-cultured in the presence of vehicle control (DMSO) or compound. Treg cells are isolated from human peripheral bone marrow cells (PBMCs) obtained from healthy donors purchased from Milestone Biological Science and Technology Company. CD4 enrichment by negative selection followed by CD25 enrichment by positive selection are performed using the human CD4 T cell isolation kit (cat.#130-096-533) and human CD25 microbeads (cat.#130-092-983) from Miltenyi Biotec (Cambridge, MA) according to manufacturer’s instructions. Isolated Tregs are expanded for 8-14 days in the presence of compound or DMSO, using Treg expander beads (ThermoFisher, cat.#11129D) or T-cell activator beads (ThermoFisher, cat.#11161D) at a 4:1 or 3:1 ratio, respectively, in the presence of 500 U/mL rhIL-2. Expanded Treg cells are dispensed in co-culture with carboxyfluorescein succinimidyl ester (CFSE)-labelled CD3+ T- Cells from the matched donor at various Treg:CD3+ T cell ratios in the presence of T-cell activator beads or soluble anti-CD3 antibody (30 ng/mL, OKT3, Thermofisher cat.# 16-0037- 81). After 3-5 days of incubation, proliferation of CD8+ Teff cells is assessed by analyzing CFSE dye dilution in CD8+ T-Cells (anti-CD8-PerCP/Cyanine5.5, clone SK1, Biolegend) using flow cytometry. Analysis is performed using a Thermo Attune NxT flow cytometer (Thermo Fisher Scientific). Teff cells that proliferate during the co-culture are identified as having diluted CFSE and data are plotted as the proportion of CFSE low, proliferated cells in the final culture. The compounds of this disclosure are expected to suppress Treg cells, thereby enhancing Teff cell proliferation. In vivo pharmacology and efficacy studies Cynomolgus moneys [0504] To determine in vivo efficacy of the compounds of this disclosure, non naïve cynomolgus monkeys are treated with a single oral dose of vehicle or the compound. Whole blood from the treated monkeys is collected across time (e.g., various timepoints between 0 hr – 96 hrs) and stained with anti-CD3-APC-Cy7 (Clone SP34-2, BD), anti-CD4-FITC (Clone L200 BD) anti-CD45-BV786 (Clone D058-1283 Biolegend) and anti-CD25-APC (Clone BC96, Biolegend) in cell staining buffer (Biolegend, Cat#420201), washed and fixed with FOXP3 fix/perm buffer (Life Technologies, cat. #00-5523-00) followed by intracellular staining with anti-IKZF2-PE (Clone 22F6, BioLegend) and anti-FOXP3-BV421 (clone 206D, Biolegend). Samples are acquired on a Thermo Attune NxT flow cytometer (Thermo Fisher Scientific). IKZF2 mean fluorescence intensity (MFI) is measured in Tregs (CD4+CD25+FOXP3+) cells. The compounds of this disclosure are expected to suppress IKZF2+ Tregs in cynomolgus monkeys. Mice [0505] To determine in vivo efficacy of the compounds of this disclosure, CRBNI391V mice are treated with a single oral dose of vehicle or the compound. CRBNI391V mice are used because a single amino acid difference within the CRBN–Immunomodulatory drug (IMiD) binding region renders mouse CRBN resistant to degradation by IMiDs. A change from Ile 391 to Val in mouse CRBN restores IMiD-induced degradation of IKZF3. Fink, E. C. et al. Blood 132, 1535–1544 (2018); Gemechu, Y. et al. P Natl Acad Sci Usa 115, 11802–11807 (2018). 1. IKZF2 degradation in mice: Various doses of the vehicle and compound are tested in the mice and analyzed across time (e.g., various timepoints between 0 hr – 12 hrs) and analyzed using western blot assay to measure the percentage of IKZF2 remaining in tissues (e.g., spleen and thymus). Tissue is lysed in RIPA buffer (Cell Signaling, cat#9806) containing HaltTM protease/phosphatase inhibitor cocktail (Thermo, Cat#78440). After assessing protein concentration by BCA assay (Pierce), equal amounts of protein for each sample are loaded into 4–12% Bis-Tris gels (Invitrogen), transferred to nitrocellulose membranes and immunoblotted with antibodies against Helios (Cell Signaling, Cat#4247) and b-Actin (Cell Signaling, Cat#3700). Membranes are developed on an Odyssey detection system (LI-COR Biosciences) after incubation with IRDye800-labeled goat anti-rabbit IgG and IRDye680-labeled goat anti-mouse IgG (LI-COR) secondary antibodies. The compounds of this disclosure are expected to degrade IKZF2 in CRBNI391V mice. 2. Tumor growth inhibition in mice: To develop cancer cell line xenografts, CRBNI391V mice are implanted with MC38 cells (ATCC) subcutaneously to induce tumor formation. MC38 cells (e.g., five million) in 50% Matrigel are injected subcutaneously into CRBNI391V mice to induce tumor formation. Mice are treated with vehicle control (e.g., 5% DMSO, 10% solutol, 85% Water) or the compound once tumors reach ~80- 400 mm3, and sacrificed when tumor volume reached 2000 mm3 or at the end of the study (whichever occurs first) Tumor sizes and animal weights are measured 2-3 times per week. Tumor volume (mm3) = (length×width2)/2. Tumor growth inhibition is calculated using TGI (%) = (1-((Te-T0)/(Ce-C0))) ´ 100, where Te = Test tumor volume endpoint, T0 = Test tumor volume at start of dosing, Ce = Vehicle control tumor volume endpoint, C0 = Vehicle control tumor volume at start of dosing The compounds of this disclosure are expected to inhibit MC38 tumor growth in CRBNI391V mice. INCORPORATION BY REFERENCE [0506] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS [0507] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. [0508] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I’):
Figure imgf000173_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; Y is -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; each Z is independently -C(R3)2-, -NR4-, -O-, -S-, -S(=O)-, or -S(=O)2-; p is 0, 1, or 2; each R3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two geminal R3 together form an oxo; or two geminal R3, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; each R4 is independently hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Ring A is C3-12 carbocycle or 3- to 12-membered heterocycle; R1 is hydrogen, C1-6 alkyl, -C(=O)(C1-6 alkyl), or -M-L-Q-R2; M is absent, -(C=O)-, -S(=O)-, or -S(=O)2-; L is absent or [-C(RL)2-]r; r is an integer selected from 1 to 3; each RL is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two geminal RL, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; Q is absent, -NRQ-, -O-, -C(=O)-, -S(=O)-, or -S(=O)2-; RQ is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; R2 is C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2a; each R2a is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -(C1-6 alkylene)-(C3-12 carbocyclyl), -(C1-6 alkylene)-(3- to 12-membered heterocyclyl), -(C1-6 alkylene)-(C6-10 aryl), -(C1-6 alkylene)- (5- to 10-membered heteroaryl), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two vincinal R2a, together with the atoms to which they are bonded, form C5-12 carbocycle or 5- to 12-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; each occurrence of RA and RC is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; q is an integer selected from 0 to 2; s is an integer selected from 0 to 12 as valency permits; each RE is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; e is an integer selected from 0 to 6, as valency permits; U is -CH2- or -C(=O)-; R5 is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; and t is an integer from 0 to 2; wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and Rc and Rd are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more Rz, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl.
2. The compound of claim 1, wherein when p is 0, then X and Y are not both -C(R3)2; and when p is 1, then X, Y, and Z are not all -C(R3)2.
3. The compound of claim 1 or 2, wherein X is -O- and Y is -C(R3)2- or X is -C(R3)2- and Y is -O-.
4. The compound of any one of claims 1-3, wherein Z is -C(R3)2 or -O-.
5. The compound of claim 1, wherein the compound is a compound of Formula I’-1-ii, I’- 1-iii, I’-1-iv, I’-1-v, I’-1-xi, I’-1-xii, or I’-1-xiii:
Figure imgf000176_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
6. The compound of any one of claims 1-5, wherein Ring A is 3- to 12-membered heterocycle.
7. The compound of any one of claims 1-5, wherein
Figure imgf000177_0001
Figure imgf000177_0002
, wherein m and n are independently an integer from 0 to 2.
8. The compound of claim 7, wherein the compound is a compound of Formula I’-2-ii, I’- 2-iii, I’-2-iv, I’-2-v, I’-2-xi, I’-2-xii, or I’-2-xiii:
Figure imgf000177_0003
Figure imgf000178_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
9. The compound of claim 7 or 8, wherein m and n are independently 0 or 1.
10. The compound of claim 7 or 8, wherein each of m and n is 1.
11. The compound of any one of claims 1-10, wherein each R3 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.
12. The compound of any one of claims 1-10, wherein each R3 is hydrogen.
13. The compound of any one of claims 1-12, wherein R1 is C1-6 alkyl or -C(=O)(C1-6 alkyl).
14. The compound of any one of claims 1-12, wherein R1 is -L-R2.
15. The compound of claim 14, wherein L is -C(RL)2-.
16. The compound of claim 15, wherein each RL is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.
17. The compound of claim 15, wherein each RL is hydrogen.
18. The compound of any one of claims 14-17, wherein R2 is phenyl optionally substituted with one or more R2a.
19. The compound of any one of claims 14-17, wherein R2 is 5- to 10-membered heteroaryl optionally substituted with one or more R2a.
20. The compound of any one of claims 14-19, wherein each R2a is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -(C1-6 alkylene)-(C6-10 aryl), -SRb, -S(=O)2Ra, or -S(=O)2NRcRd, wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.
21. The compound of any one of claims 14-19, wherein each R2a is independently oxo, halogen, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -(C1-6 alkylene)-(C6-10 aryl), -SRb, -S(=O)2Ra, or -S(=O)2NRcRd, wherein the alkyl, alkylene, alkoxy, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.
22. The compound of any one of claims 14-19, wherein two vincinal R2a, together with the atoms to which they are bonded, form 5- to 12-membered heterocycle optionally substituted with one or more Ru.
23. The compound of any one of claims 1-22, wherein each occurrence of RA and RC is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.
24. The compound of any one of claims 1-23, wherein s is 0.
25. The compound of any one of claims 1-24, wherein q is 0.
26. The compound of any one of claims 1-25, wherein each of RE is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.
27. The compound of any one of claims 1-26, wherein e is 0.
28. The compound of any one of claims 1-27, wherein U is -CH2-.
29. The compound of any one of claims 1-28, wherein R5 is hydrogen.
30. The compound of any one of claims 1-29, wherein t is 1.
31. The compound of claim 1, wherein the compound is selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising the compound of any one of claims 1-31, and a pharmaceutically acceptable excipient.
33. A method of degrading an IKZF2 protein in a subject or biological sample comprising administering the compound of any one of claims 1-31 to the subject or contacting the biological sample with the compound of any one of claims 1-31.
34. Use of the compound of any one of claims 1-31 in the manufacture of a medicament for degrading an IKZF2 protein in a subject or biological sample.
35. A compound of any one of claims 1-31 for use in degrading an IKZF2 protein in a subject or biological sample.
36. A method of treating or preventing a disease or disorder a subject in need thereof, comprising administering to the subject the compound of any one of claims 1-31.
37. Use of the compound of any one of claims 1-31 in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.
38. A compound of any one of claims 1-31 for use in treating or preventing a disease or disorder in a subject in need thereof.
39. The method, use, or compound for use of any one of claims 36-38, wherein the disease or disorder is an IKZF2-mediated disease or disorder.
40. The method, use, or compound for use of any one of claims 36-38, wherein the disease or disorder is T cell leukemia, T cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST).
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