WO2023201012A1 - Agents de dégradation d'ikzf2 et leurs utilisations - Google Patents

Agents de dégradation d'ikzf2 et leurs utilisations Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
carbocyclyl
compound
heterocyclyl
aryl
Prior art date
Application number
PCT/US2023/018583
Other languages
English (en)
Inventor
Xuqing Zhang
Shaomeng Wang
Paul Kirchhoff
Original Assignee
Regents Of The University Of Michigan
Oncopia Therapeutics, Inc. D/B/A/ Proteovant Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regents Of The University Of Michigan, Oncopia Therapeutics, Inc. D/B/A/ Proteovant Therapeutics, Inc. filed Critical Regents Of The University Of Michigan
Publication of WO2023201012A1 publication Critical patent/WO2023201012A1/fr

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formules I' et leurs sels, solvates ou stéréoisomères pharmaceutiquement acceptables, ainsi que leurs utilisations (par exemple comme agents de dégradation d'IKZF2).
PCT/US2023/018583 2022-04-15 2023-04-14 Agents de dégradation d'ikzf2 et leurs utilisations WO2023201012A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202263331558P 2022-04-15 2022-04-15
US63/331,558 2022-04-15
US202363446112P 2023-02-16 2023-02-16
US63/446,112 2023-02-16

Publications (1)

Publication Number Publication Date
WO2023201012A1 true WO2023201012A1 (fr) 2023-10-19

Family

ID=86386913

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/018583 WO2023201012A1 (fr) 2022-04-15 2023-04-14 Agents de dégradation d'ikzf2 et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2023201012A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019038717A1 (fr) * 2017-08-23 2019-02-28 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
WO2020165834A1 (fr) * 2019-02-15 2020-08-20 Novartis Ag Dérivés de 3-(1-oxoisoindoline-2-yl)pipéridine-2,6-dione substitués et leurs utilisations
WO2021087093A1 (fr) * 2019-10-30 2021-05-06 Dana-Farber Cancer Institute, Inc. Agents de dégradation à petites molécules d'hélios et procédés d'utilisation
WO2021260528A1 (fr) * 2020-06-23 2021-12-30 Novartis Ag Schéma posologique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2022029573A1 (fr) * 2020-08-03 2022-02-10 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione substitués par hétéroaryle et leurs utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019038717A1 (fr) * 2017-08-23 2019-02-28 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
WO2020165834A1 (fr) * 2019-02-15 2020-08-20 Novartis Ag Dérivés de 3-(1-oxoisoindoline-2-yl)pipéridine-2,6-dione substitués et leurs utilisations
WO2021087093A1 (fr) * 2019-10-30 2021-05-06 Dana-Farber Cancer Institute, Inc. Agents de dégradation à petites molécules d'hélios et procédés d'utilisation
WO2021260528A1 (fr) * 2020-06-23 2021-12-30 Novartis Ag Schéma posologique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2022029573A1 (fr) * 2020-08-03 2022-02-10 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione substitués par hétéroaryle et leurs utilisations

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
"Organic Reactions", vol. 55, 1942, JOHN WILEY & SONS
"Remington: The Science and Practice of Pharmacy", 2005, MACK PUB. CO
"Tetrahedron", vol. 33, 1977, pages: 2725
BAINE I ET AL., J IMMUNOL, vol. 190, 2013, pages 1008 - 1016
CARRUTHERS: "Some Modern Methods of Organic Synthesis", 1987, CAMBRIDGE UNIVERSITY PRESS
E. L. ELIELS. H. WILENL. N. MANDER: "Organic Synthesis: Concepts, Methods, Starting Materials", 1994, WILEY-LNTERSCIENCE
ELIEL: "Stereochemistry of Carbon Compounds", 1962, MCGRAW-HILL
FINK, E. C. ET AL., BLOOD, vol. 132, 2018, pages 1535 - 1544
GEMECHU, Y. ET AL., P NATL ACAD SCI USA, vol. 115, no. 11802-11807, 2018
H. O. HOUSE: "Tables of Resolving Agents and Optical Resolutions", 1972, UNIV. OF NOTRE DAME PRESS, pages: 268
HOFFMAN, R.V: "Organic Chemistry, An Intermediate Text", 1996, OXFORD UNIVERSITY PRESS
JACQUES ET AL.: "Enantiomers, Racemates and Resolutions", 1981, WILEY INTERSCIENCE
NAKAGAWA, H ET AL., PROC NATIONAL ACAD SCI, vol. 113, 2016, pages 6248 - 6253
S. R. SANDLER ET AL.: "Organic Functional Group Preparations", 1983, JOHN WILEY & SONS, INC
SMITHMARCH: "Comprehensive Organic Transformations", vol. 73, 1989, VCH PUBLISHERS, INC
SOLOMONS, T. W. G: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2000, JOHN WILEY & SONS
STOWELL, J.C: "Intermediate Organic Chemistry", 1993, WILEY-INTERSCIENCE
T. L. GILCHRIST: "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 1992, WILEY-INTERSCIENCE
THOMAS SORRELL: "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia", vol. 8, 1999, UNIVERSITY SCIENCE BOOKS
YATES, K ET AL.: "115", PROC NATIONAL ACAD SCI, 2018, pages 201720447

Similar Documents

Publication Publication Date Title
WO2022061251A1 (fr) Composés et procédés pour la modulation de kras et leurs indications
US10414754B2 (en) Indolizine compounds, a process for their preparation and pharmaceutical compositions containing them
AU2018391675A1 (en) Sulphonyl urea derivatives as NLRP3 inflammasome modulators
KR20240026521A (ko) Shp2 억제제로서 유용한 신규한 헤테로환형 유도체
JP2017178968A (ja) 化合物、その医薬組成物、及び癌治療用のｉｄｈ１突然変異阻害薬としてのその使用
JP7219902B2 (ja) ブルトン型チロシンキナーゼ阻害剤
TW202039471A (zh) Apol1抑制劑及其使用方法
JP7396369B2 (ja) アミド系化合物の調製方法及びその医学分野での使用
JP2023539194A (ja) Ａｐｏｌ１の阻害剤およびこれを使用する方法
TW202122382A (zh) 乙內醯脲衍生物
JP2021532103A (ja) 置換トリアゾロキノキサリン誘導体
AU2021248641A1 (en) Modulators of alpha-1 antitrypsin
KR20230035437A (ko) 7-치환된 1-아릴-나프티리딘-3-카르복실산 아미드 및 그의 용도
EP2595483B1 (fr) Nouveaux agonistes du récepteur 3-adrénergique dérivés de la pyrrolidine
WO2023183540A1 (fr) Dégradeurs d'ikzf2 et leurs utilisations
WO2023183607A1 (fr) Ligands du céréblon et leurs utilisations
WO2023201012A1 (fr) Agents de dégradation d'ikzf2 et leurs utilisations
WO2024015346A1 (fr) Ligands de céréblon et leurs utilisations
WO2023183919A1 (fr) Composés bicycliques contenant un hétéroaryle en tant qu'agents de dégradation d'ikzf2
WO2024073475A1 (fr) Ligands de cereblon et utilisations associées
WO2024086644A1 (fr) Ligands de céréblon et leurs utilisations
WO2024064316A1 (fr) Composés et compositions utilisés en tant qu'inhibiteurs de smarca2/4 et leurs utilisations
WO2024103069A1 (fr) Composés et compositions en tant qu'inhibiteurs d'eif4e et leurs utilisations
CA3215491A1 (fr) Composes amino aza-heteroaryles a substitution halo utilises en tant qu'inhibiteurs de la kinase des progeniteurs hematopoietiques 1 (hpk1)
WO2024103067A1 (fr) Composés et compositions en tant qu'inhibiteurs de eif4e et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23724477

Country of ref document: EP

Kind code of ref document: A1