WO2023183540A1 - Ikzf2 degraders and uses thereof - Google Patents

Ikzf2 degraders and uses thereof Download PDF

Info

Publication number
WO2023183540A1
WO2023183540A1 PCT/US2023/016177 US2023016177W WO2023183540A1 WO 2023183540 A1 WO2023183540 A1 WO 2023183540A1 US 2023016177 W US2023016177 W US 2023016177W WO 2023183540 A1 WO2023183540 A1 WO 2023183540A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbocyclyl
compound
alkyl
heterocyclyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2023/016177
Other languages
English (en)
French (fr)
Inventor
Zhixiang Chen
Rohan REJ
Xuqing Zhang
Longchuan Bai
Paul Kirchhoff
Shaomeng Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oncopia Therapeutics Inc D/b/a/ Proteovant Therapeutics Inc
University of Michigan System
University of Michigan Ann Arbor
Original Assignee
Oncopia Therapeutics Inc D/b/a/ Proteovant Therapeutics Inc
University of Michigan System
University of Michigan Ann Arbor
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 Oncopia Therapeutics Inc D/b/a/ Proteovant Therapeutics Inc, University of Michigan System, University of Michigan Ann Arbor filed Critical Oncopia Therapeutics Inc D/b/a/ Proteovant Therapeutics Inc
Priority to KR1020247035795A priority Critical patent/KR20250026153A/ko
Priority to US18/849,594 priority patent/US20250215012A1/en
Priority to JP2024556604A priority patent/JP2025512805A/ja
Priority to EP23719521.9A priority patent/EP4499649A1/en
Priority to CN202380041783.5A priority patent/CN119731179A/zh
Publication of WO2023183540A1 publication Critical patent/WO2023183540A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • IKAROS Family Zinc Finger 2 (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).
  • IKZF1 Ikaros
  • IKZF3 Aiolos
  • IKZF4 Eos
  • 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, IKZF1 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. Selective deletion of Helios in regulatory T cells resulted in both loss of suppressive activity and acquisition of effector T cell functions. Therefore, Helios is a critical factor in restricting T cell effector function in Tregs.
  • anti-CTLA4 antibodies are used in the clinic to target Tregs in tumors. However, targeting CTLA4 often causes systemic activation of T- effector cells, resulting in excessive toxicity and limiting therapeutic utility.
  • 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.
  • 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
  • IKZF2 loss led to increased myeloid differentiation.
  • IKZF2 is differentially required in myeloid leukemia cells compared to normal cells. Therefore, depletion of IKZF2 has preferential effect in leukemic stem cells compared to normal hematopoietic stem cells, providing a new strategy for targeting leukemic stem cells.
  • the present disclosure provides compounds of Formula (I'): wherein each of the variables in Formula I', is described, embodied, and exemplified herein. [0006] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.
  • 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. [0010] In certain aspects, the present disclosure provides methods of treating a disease or disorder comprising administering to a subject in need thereof a compound disclosed herein.
  • 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 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.
  • 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 present disclosure provides compounds of Formula (I'): and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein:
  • p is 0, 1, or 2;
  • each R 3 is independently deuterium, hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, Ci- 6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, Cg-
  • Ring A is C 3-12 carbocycle or 3- to 1 -membered heterocycle
  • R 1 is hydrogen or -M-L-Q-R 2 ;
  • each W is independently -C(R L ) 2 -, C3-4 carbocyclylene, or 3- to 4-membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is optionally substituted with one or more R u ; each R L is independently hydrogen, deuterium, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, Ci- 6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, Ce io 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
  • R Q is hydrogen or C 1-6 alkyl optionally substituted with one or more R u ;
  • R 2 is Cg-io aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R 2a ;
  • each R 2a is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -(C 1-6 alkyl)-(C 6-10 aryl), -(C 1-6 alkyl)-(5- to 10-membered hetero
  • R c and R d are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; or
  • R c and R d together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R z , wherein each occurrence of R a , R b , R c , and R d is independently and optionally substituted with one or more R z ; and each R z is independently oxo, halogen, -CN, -NO 2 , -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl.
  • the compound is a compound of Formula (I'-l-i), (I'-l-ii), (I’- 1-iii), (I'-l-iv), (I'-l-v), (I'-l-vi), (I'-l-vii), (I'-l-viii), (I'-l-ix), (I'-l-x), (I'-l-xi), (I'-l-xii), or (I'-l-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): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • Ring A is C3 12 carbocyclyl ⁇ e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6,) cyclohexadienyl (C6,) cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclocyclo
  • n are independently an integer from 0 to 2.
  • n is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.
  • each of m and n is 1.
  • R 1 is hydrogen or -M-L-Q-R 2 .
  • L is absent or [W] r .
  • each W is independently -C(R L )2-, C3-4 carbocyclylene e.g., cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), or cyclobutenylene (C4)), or 3- to 4-membered heterocyclylene ⁇ e.g., heterocyclylene comprising one 3- to 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the carbocyclylene or heterocyclylene is optionally substituted with one or more R u .
  • C3-4 carbocyclylene e.g., cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), or cyclobutenylene (C4)
  • 3- to 4-membered heterocyclylene ⁇ e.g., heterocyclylene comprising one 3- to 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the carbocycly
  • each R L is independently hydrogen, deuterium, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Cg)), C 1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5),
  • each R L is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C2-g alkenyl, Cz-g alkynyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, Cg 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, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 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, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 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 .
  • each R L is independently hydrogen, deuterium, or C 1-6 alkyl. [0033] In certain embodiments, L is -CH2-.
  • two geminal R L together with the carbon atom to which they are attached, form C3-6 carbocyclyl ⁇ e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 alkynyl e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl e.g., cyclopropyl (C3), cyclopropenyl (C3), cycl
  • R Q is hydrogen or C 1-6 alkyl ⁇ e.g., methyl (Ci), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)) optionally substituted with one or more R u .
  • R 2 is C3-12 carbocyclyl ⁇ e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6,) cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.
  • l]heptanyl C7, bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- lH-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl ⁇ e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), Cg-io aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, carbocycly
  • each R 2a is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (Ci), 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)), C 1-6 alkoxy (e.g.
  • C1 alkylamino e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-s-butylamino, methyl-methyl-butylamino, methyl-s-butylamino, methyl-
  • two R 2a together with the atoms to which they are bonded, form C3-8 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6,) cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8)) or 3- to 8-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-3 heterocyclyl (e.g., hetero
  • each occurrence of R A , R c , and R E is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C1), ethyl (C 2 ), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C 2 ), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), s-butoxy (C
  • each occurrence of R A , R c , and R E is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 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 occurrence of R A , R c , and R E is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 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 occurrence of R A , R c , and R E is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 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 .
  • q is an integer from 0 to 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.
  • s is an integer from 0 to 12, as valency permits. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5, 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.
  • e is an integer selected from 0 to 5. In certain embodiments, e is 0. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5.
  • 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-.
  • p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2.
  • each R 3 is independently deuterium, hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (Ci), 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)), C 1-6 alkoxy e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), 5-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexyl (C6)), C
  • each R 3 is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, Ce 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, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 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, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 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 .
  • each R 3 is independently hydrogen, deuterium, or C 1-6 alkyl.
  • two geminal R 3 together form oxo.
  • two geminal R 3 together with the carbon atom to which they are attached, form C3-6 carbocyclyl ⁇ e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 alkynyl ⁇ e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5)
  • each R 4 is independently hydrogen or C 1-6 alkyl ⁇ e.g., methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (Cg)) optionally substituted with one or more R u .
  • R 5 is hydrogen, deuterium, C 1-6 haloalkyl ⁇ e.g., C 1-6 alkyl substituted by 1 to 8 halogen atoms selected from -F, -Cl, -Br, or -I), or C 1-6 alkyl ⁇ e.g., methyl (Ci), 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)).
  • C 1-6 haloalkyl ⁇ e.g., C 1-6 alkyl substituted by 1 to 8 halogen atoms selected from -F, -Cl, -Br, or -I
  • C 1-6 alkyl ⁇ e.g., methyl (Ci), ethyl (
  • t is an integer from 0 to 2. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2.
  • the compound is a compound of Formula (I’): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
  • R 1 is hydrogen or -L-R 2 ;
  • each R L is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, Ci- 6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 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 ;
  • R 2 is Cg-io aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R 2a ; each R 2a is independently oxo, halogen, -CN
  • X is -O- or -NR 4 -; each R 4 is independently hydrogen or C 1-6 alkyl;
  • Y is -CH2- or -O-; and p is 0 or 1.
  • the present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein:
  • R 1 is hydrogen or -M-L-Q-R 2 ;
  • each R L is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u ; or two R L , together with the carbon atom(s) to which they are attached, form C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; r is an integer from 1 to 3;
  • R° is hydrogen, C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more R u ;
  • R 2 is C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R 2a ; each R 2a is independently halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 03-12 carbocyclyl, 3- to 12-membered heterocyclyl, -(C 1-6 alkyl)-(C 6-10 aryl), -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)-(C 3-12 carbocyclyl), -(C 1-6 alky
  • R c and R d together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of R a , R b , R c , and R d is independently and optionally substituted with one or more R z ; and each R z is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl.
  • X is -C(R 3 )2-.
  • X is -NR 4 -.
  • X is -O-.
  • X is -S-.
  • Y is -C(R 3 )2-.
  • Y is -NR 4 -.
  • Y is -O-.
  • Y is -S-.
  • X is -O- and Y is -C(R 3 )2-. In some embodiments, X is -O-, and Y is -CH2-. 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 -.
  • X is -O-
  • Y is -C(R 3 )2-
  • p is 0.
  • Z is -C(R 3 )2-, -NR 4 -, or -O-. In certain embodiments, Z is - C(R 3 ) 2 or -O-.
  • p is 0. In certain embodiments, p is 1.
  • the compound is a compound of Formula (I-l-i) to (I-l-xiii):
  • L is -C(R L )2-. In certain embodiments, L is absent.
  • each R L is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 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 or C 1-6 alkyl.
  • L is -CH2-.
  • two R L together with the carbon atom(s) to which they are attached, form C3-12 carbocyclyl or 3- to 12-membered heterocyclyl.
  • Q is absent.
  • Q is -NR Q -.
  • Q is -O-.
  • R Q is hydrogen or C 1-6 alkyl. In certain embodiments, R Q is Ci- 6 alkyl. In certain embodiments, R Q is hydrogen.
  • R 2 is C 6-10 aryl, 5- to 10-membered heteroaryl, C5-10 carbocyclyl, or 5- to 10-membered heterocyclyl.
  • R 2 is phenyl
  • R 2 is 5- to 10-membered heteroaryl.
  • R 2 is C5-10 carbocyclyl.
  • R 2 is 5- to 10-membered heterocyclyl.
  • each R 2a is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 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 2a together form oxo.
  • each R 3 is independently H or C 1-6 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, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, Cz e 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 .
  • 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.
  • q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.
  • m and n are independently 0 or 1. In certain embodiments, each of m and n is 0. In certain embodiments, each of m and n is 1. In certain embodiments, m is 0 and n is 1. In certain embodiments, m is 1 and n is 0.
  • R 5 is hydrogen, deuterium, C 1-6 haloalkyl, or C 1-6 alkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is deuterium. In certain embodiments, R 5 is C 1-6 haloalkyl. In certain embodiments, R 5 is C 1-6 alkyl.
  • t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2.
  • the compound is a compound of Formula (H ): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 1 is hydrogen or -L-R 2 ; L is -CH 2 -;
  • X is -O-
  • Y is -CH2-; and p is 0.
  • each R a is independently 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)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6,) C 2-6 alkynyl (e.g., ethynyl (C 2 ), 1-propynyl (C3)
  • C4 i-but
  • l]heptanyl C7, bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H -indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl,
  • each R a is independently C 1-6 alkyl, C 2 .6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C 6 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 C 1-6 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, C 1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), i-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6,) C 2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), n-butyl (
  • l]heptanyl C7, bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- lH-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl,
  • each R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, Ce aryl, or 5- to 6-membered heteroaryl.
  • each R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R b is independently hydrogen, C 1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C 2-6 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 (Ci), 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)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C 2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), i
  • l]heptanyl C7, bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl ⁇ e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-1 0 aryl ⁇ e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl ⁇ e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alky
  • each R c and each R d is independently hydrogen, C 1-6 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 .
  • heterocyclyl e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S
  • 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, -NH2, Ci- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl.
  • each R u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), 5-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 alkoxy ⁇ e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 alkylamino ⁇ e.g., dimethyl (Ci), ethy
  • each R u is independently oxo, 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, 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 substituents selected from oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocycl
  • each R u is independently oxo, 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, 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, and 3- to
  • each R u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.
  • each R u is independently oxo, halogen, -CN, -NOz, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 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 substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.
  • two R u together with the carbon atom(s) to which they are attached, form C3-6 carbocyclyl ⁇ e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Cg), cyclohexenyl (Cg), or cyclohexadienyl (Cg)) 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), cyclopenten
  • 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 (Cg), cyclohexenyl (Cg), or cyclohexadienyl (Cg)) 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
  • C 1-6 alkyl is intended to encompass, Ci, C2, C3, C4, C5, C6, Ci-6, Ci-5, C1-4, Ci-3, C1-2, C 2-6 , C2-5, C2-4, C2-3, C3-6, C3-5, C34, 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.
  • the compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known IKZF2 degraders.
  • the compounds of the present disclosure may display more potent estrogen receptor activity, more favorable pharmacokinetic properties (e.g., as measured by Cmax, T m ax, 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 may be measured according to methods commonly available in the art, such as methods exemplified herein.
  • the compounds of the present disclosure may be in cis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration.
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • a pharmaceutically acceptable salt e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • a solvate e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • 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.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate,
  • 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 add, 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 + (CI-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 quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
  • 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.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Isomers/Stereoisomers
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds.
  • the compounds disclosed herein include all cis, trans, syn, anti,
  • E
  • Z
  • All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the invention.
  • 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.
  • 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.
  • compounds described herein exist as tautomers.
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • 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.
  • 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)).
  • 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
  • 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.
  • 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 present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds disclosed herein.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 or Table 2.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1.
  • the compound is an isotopic derivative of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 2.
  • the isotopic derivative can be prepared using any of a variety of art-recognized techniques.
  • the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the isotopic derivative is a deuterium labeled compound.
  • the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1 or Table 2.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 2.
  • the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.
  • the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.
  • a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
  • 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)
  • Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modem Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • the binding to cereblon is determined using the Cereblon Binding Kit (Cisbio, #64BDCRBNPEG) following the manufacturer’s instruction. Briefly, serially diluted compounds are incubated with GST-tagged wild-type human CRBN protein, XL665-labelled Thalidomide and Europium Cryptate labelled GST antibody . Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) measurements are acquired with, e.g., MARS data analysis software (BMG Labtech. The readings are normalized to the control (0.5%) and the IC50 is calculated by nonlinear regression (four parameters sigmoid fitted with variable slope) analysis using, e.g., the GraphPad Prism 8 software.
  • TR-FRET Time Resolved Fluorescence Resonance Energy Transfer
  • Cells are lysed , resolved by SDS-PAGE , and transferred to a PVDF membrane (Millipore). Membranes are blocked, e.g., using Odyssey TBS Blocker Buffer (LI-COR). Secondary antibodies, e.g., IRDye 680RD and 800CW Dye-labeled are used. The washed membranes are scanned using e.g., an Odyssey CLx imager (LI-COR). The intensity of Western blot signaling is quantitated using the Odyssey software. Primary antibodies used include: Helios (D8W4X) XP® Rabbit mAh (Cell Signaling Technology, #42427) and GAPDH mouse monoclonal antibody (Santa Cruz Biotechnology, sc-47724).
  • IKZF2 HiBiT assay using the Jurkat- IKZF2-HiBiT (Promega) cell line. Briefly, cells are seeded in culture medium. Compounds are serially diluted in culture medium, and certain volume of the diluted compounds is added to the appropriate well of the plate. After the addition of compounds, the cells are incubated. At the end of treatment, Nano-Gio HiBiT Lytic Detection Reagent (Promega) is added to each well, and then the plates are incubated at room temperature for a certain time period. The luminescent signal is measured using a CALRIOstar plate reader (BMG Labtech). The readings are normalized to the DMSO-treated cells and the IC50 is calculated by nonlinear regression (four parameters sigmoid fitted with variable slope, least squares fit, and no constraint) analysis using the GraphPad Prism 8 software.
  • 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 (e.g., in a therapeutically effective amount).
  • 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.
  • 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.
  • 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.
  • 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 or T cell lymphoma, Hodgkin’s lymphoma or 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).
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • GIST gastrointestinal stromal tumor
  • the subject is a mammal.
  • the subject is a human.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure Equid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPFC high pressure Equid chromatography
  • the invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • C 1-6 alkyl is intended to encompass, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, C1-4, C1-3, C1-2, C 2-6 , C2-5, C2-4, C2-3, C3-6, C3-5, C3 , 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 (“C1-12 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 (“C1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“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 (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1.2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”).
  • Ci -6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6.)
  • Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like.
  • 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 C1-10 alkyl (e.g., -CH3).
  • the alkyl group is substituted Ci- 10 alkyl.
  • Alkylene refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical.
  • alkylene refers to the range or number of carbons in the linear carbon divalent chain.
  • An “alkelene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (- CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like.
  • Exemplary substituted divalent alkylene groups include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH 3 )CH2-,-CH 2 CH(CH3)-, -C(CH3) 2 CH2-,-CH 2 C(CH3)2-), substituted propylene (-CH(CH 3 )CH 2 CH2-, -CH 2 CH(CH 3 )CH2-, -CH2CH 2 CH(CH 3 )-, -C(CH 3 )2CH 2 CH 2 -, -CH 2 C(CH3)2CH 2 -, -CH2CH 2 C(CH 3 ) 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 (“C2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”).
  • 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 (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”).
  • the one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • C 2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Cg), and the like.
  • alkenyl examples include heptenyl (C7), octenyl (C8), octatrienyl (C8), 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 2-2 o alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2 -io 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 (“C 2 -7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2 -s alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2 -4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2.3 alkynyl”).
  • an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 -4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2 -4 alkynyl groups as well as pentynyl (C5), hexynyl (C6,) 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; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2 -io alkynyl.
  • the alkynyl group is substituted C 2 -io alkynyl.
  • Alkynylene refers to a alkynyl group wherein two hydrogens are removed to provide a divalent radical.
  • a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.
  • 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 (“heteroCi-io alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-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 (“heteroCi- 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 (“heteroCi-7 alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1-6 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroCi-s alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroCi-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroCi-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroCi-2 alkyl”).
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC 2-6 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 heteroCi-io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-io alkyl.
  • heteroalkenyl refers to an alkenyl group, as defined herein, which 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-io 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-s 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 (“heteroC2-s 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 (“heteroC2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-6 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-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.
  • heteroalkynyl refers to an alkynyl group, as defined herein, which 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.
  • 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 (“heteroC2-io alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2,
  • heteroC2-9 alkynyl a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-s 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”).
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 alkynyl”).
  • a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-s alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-6 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 heteroCi-io alkynyl.
  • the heteroalkynyl group is a substituted heteroCi-io 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 refers to the range or number of carbons in the linear divalent chain.
  • 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 it electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”).
  • an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci4 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 Ce-i4 aryl.
  • the aryl group is substituted Ce- 14 aryl.
  • An “arylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • 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 it 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”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • 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.
  • 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. In certain embodiments, 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. In certain embodiments, 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.
  • 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 (“C3-12 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 (“C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5 8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”).
  • Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6,) cyclohexenyl (C6,) cyclohexadienyl (C6), and the like.
  • Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H -indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”).
  • C5-6 carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5).
  • C3-6 carbocyclyl include the aforementioned C5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).
  • 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 C3-12 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 C3-12 carbocyclyl.
  • 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. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.
  • “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.
  • 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 Ce 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. In certain embodiments, 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. In certain embodiments, 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.
  • the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.
  • 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.
  • a range or number of ring members is provided for a particular “heterocyclylene” group, it is understood that the range or number refers to the number of ring members in the heterocyclylene group.
  • a “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Alkoxy refers to the group -OR, wherein R is alkyl as defined herein.
  • C 1-6 alkoxy refers to the group -OR, wherein each R is C 1-6 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.
  • C 1-6 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.
  • a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical.
  • 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, ammo-protecting groups, thiol-protectiug 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., methoxymethyl (MOM), ⁇ -Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g...
  • ethers e.g., methoxymethyl (MOM), ⁇ -Methoxyethoxymethyl (MEM), tetrahydropyranyl (TH
  • TDPS trimethylsilyl
  • TIPS triisopropylsilyl
  • TOM tri- iso-propylsilyloxymethyl
  • TDMS Z-butyldimethylsilyl
  • esters e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)
  • amino-protecting groups include but not limited to carbamates (e.g., Z-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), A-alkyl nitrobenzenesulfonamides (Nosyl), and 2- nitrophenyl
  • thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), Z-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).
  • sulfide e.g., p- methylbenzyl (Meb), Z-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)
  • carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-Z-butyl ester, silyl esters, and orthoesters) and oxazoline.
  • esters e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-Z-butyl ester, silyl esters, and orthoesters
  • oxazoline e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-Z-butyl ester, silyl esters, and orthoesters
  • “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, chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid
  • 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.
  • solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • an “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention.
  • the “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • a “therapeutically effective amount” refers to the effective amount for therapeutic treatment.
  • a “prophylatically effective amount” refers to the effective amount for prophylactic treatment.
  • Preventing refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or in a subject who is predisposed to the disease in advance of disease onset).
  • Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” relates to slowing the progression of the disease.
  • 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 (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.
  • 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.
  • 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.
  • Step 1-2
  • Step 7-8
  • Step 13 [0301] Compound WP08-12 was treated with TFA in DCM at room temperature to de-protect the N-Boc group to provide the cereblon ligand C-l.
  • Step 6 [0310] To a solution of compound WP08-4 (10 g, 1.0 eq.) in 100 mL of DMF, compound WP09-4 (16.2 g, 1.2 eq.) and K2CO3 (1.6 eq.) was added. The reaction mixture was heated to 70°C and stirred overnight. The reaction mixture was poured into ice- water and extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The solvent was evaporated at reduced pressure and the crude product was purified by silica gel column chromatography using 0-100% EtOAc/hexane. The desired product WP09-5 was obtained as a yellow foam (11 g, yield 60%).
  • Compound WP09-12 was treated with TFA in DCM at room temperature to de-protect the N-Boc group to provide the cereblon ligand C-2.
  • Step A tert-butyl 3-hydroxy-4-methylenepiperidine-l-carboxylate
  • Step B tert-butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-I-carboxylate
  • Step B (S)-tert-butyl 5-amino-4-(5-bromo-4-hydroxy-l-oxoisoindolin-2-yl)-5-oxopentanoate [0358] To the suspension of methyl 4-bromo-2-formyl-3-hydroxybenzoate (17.3 g, 72.4 mmol, 1.05 eq, HC1 salt) in MeOH (300 mL) was added DIPEA (9.37 g, 72.4 mmol, 12.6 mL, 1.05 eq), compound 2, (17.8 g, 69.0 mmol, 1.00 eq) and AcOH (6.22 g, 103 mmol, 5.92 mL, 1.50 eq) at 20 °C and stirred for 1.5 hrs, before NaBHiCN (8.67 g, 138 mmol, 2.00 eq) was added portion-wise at 20 °C, and the resulting mixture was stirred at 20 °C for 3 hrs.
  • Step C (S)-tert-butyl 4-(((2-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-5-bromo-l- oxoisoindolin-4-yl)oxy)methyl)-5,6-dihydropyridine-l(2H)-carboxylate
  • reaction mixture was stirred at 60 °C for 12 hrs, before being cooled to 20 °C again.
  • the resulting mixture was filtered, and filter cake was washed with DCM (2 x 500 mL).
  • Step E ( 3S )-3-( 6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4 '-piperidine] -7-yl)piperidine- 2,6-dione benzenesulfonate
  • the mixture was stirred at 100 °C for 12 hrs, before being cooled to 20 °C.
  • the mixture was filtered, and the filter cake was dried under reduce pressure.
  • the title compound (37.0 g) was obtained as a white solid, and the typical yield was 92.8%.
  • Step F ( 3S )-3-( 6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4 '-piperidine] -7-yl)piperidine- 2,6-dione hydrochloric acid
  • Step C tert-butyl 4-(bromomethyl-d2)-3,6-dihydropyridine-l(2H)-carboxylate
  • Step D tert-butyl 4-(((5-bromo-l-oxo-l,3-dihydroisobenzofuran-4-yl)oxy)methyl-d2)-3,6- dihydropyridine-l(2H)-carboxylate
  • Step E tert-butyl 6-oxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3,4'-piperidine]-l carboxylate-2,2-d2
  • Step F 1 '-(tert-butoxycarbonyl)-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6- carboxylic-2,2-d2 acid
  • Step G tert-butyl 8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3,4'- piperidine]-! '-carboxylate-2, 2-d2
  • Step H tert-butyl (S)-7-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-6-oxo-7,8-dihydro- 2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-I '-carboxylate-2, 2-d2
  • the reaction mixture was stirred at 40 °C for 2 h, then Sodium triacetoxyborohydride (4.08 g, 19.3 mmol, 20.0 eq). The mixture was stirred at 40 °C for 16 h. After cooled to room temperature, the mixture was dissolved in EA (40 mL), washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step I (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl-2,2- d2 )piperidine-2, 6-dione benzenesulfonate
  • Step B methyl 4-bromo-2-fluoro-5-hydroxybenzoate
  • Step D tert-butyl (S)-5-amino-4-(5-bromo-7-fluoro-4-hydroxy-l-oxoisoindolin-2-yl)-5- oxopentanoate
  • Step E benzyl (S)-4-(((2-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-5-bromo-6-fluoro-l- oxoisoindolin-4-yl)oxy)methyl)-3,6-dihydropyridine-l(2H)-carboxylate
  • Step F benzyl (S)-7-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-5-fluoro-6-oxo-7,8- dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-r-carboxylate
  • Step G tert-butyl (S)-5-amino-4-(5-fluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e ] isoindole-3, 4 '-piperidin ]-7-yl )-5-oxopentanoate
  • Step A tert-butyl (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3- e ] isoindole-3, 4 '-piperidine ]-l '-carboxylate
  • reaction mixture was quenched with water (10 mL) and exacted with EtOAc (15 mL x 3). The organic layer was washed with brine (20 mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step B tert-butyl (S)-5-chloro-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H- spiro]furo[2,3-e] isoindole-3, 4' -piperidine]-1'-carboxylate
  • Step C (S)-3-(5-chloro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]- 7-yl )piperidine-2, 6-dione
  • Step A (S)-tert-butyl 7-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-5-cyano-6-oxo-7,8- dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-l '-carboxylate
  • reaction mixture was quenched with water (20 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL x 4), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step B ( S )-7-(2, 6-dioxopiperidin-3-yl )-6-oxo-7, 8-dihydro-2H, 6H-spiro[furo[2,3-e]isoindole- 3, 4' -piperidine] -5 -carbonitrile
  • Step A tert-butyl (S)-7-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-5-bromo-6-oxo-7,8- dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-l'-carboxylate
  • Step B tert-butyl (S)-7-(l-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-methyl-6-oxo-7,8- dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1-carboxylate
  • reaction mixture was stirred under N2 at 80 °C for 2 h. After cooled to room temperature, the reaction mixture was filtered and the filtrate was diluted with water (10 mL), and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (10 mL), dried over NaiSO4, filtered and concentrated under reduced pressure.
  • Step C ( S )-3-(5-methyl-6-oxo-6, 8-dihydro-2H, 7H-spiro[furo[2, 3-e] isoindole-3, 4 '-piperidin ] - 7-yl )piperidine-2, 6-dione
  • Step A tert-butyl 4-methyl-l -oxa-6-azaspiro[2.5]octane-6-carboxylate
  • Step B tert-butyl 4-(hydroxymethyl)-3-methyl-3,6-dihydropyridine-l(2H)-carboxylate
  • Step C tert-butyl 4-(((5-bromo-l-oxo-l,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3-methyl- 3, 6-dihydropyridine- 1 ( 2H)-carboxylate
  • Step D tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3, d'piperidine] -1 '-carboxylate
  • Step E tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3, 'piperidine] -1 '-carboxylate
  • Step F 1 '-(tert-butoxycarbonyl)-7-formyl-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6- carboxylic acid
  • Step G tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-methyl-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2, 3-e] isoindole-3, 4' -piperidine ]-l '-carboxylate
  • Step H 3-(3'-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e] isoindole-3, 4'-piperidin] -7- yl )piperidine-2, 6-dione
  • Step A 1 '- tert-buloxycarbonyl)-3'-hydroxy-7-(hydroxymethyl)-2H-spiro[benzofuran-3, d'piperidine] -6-carboxy lie acid
  • Step B 1 '-(tert-butoxycarbonyl)-7-fonnyl-3 '-hydroxy-2H-spiro[benzofuran-3,4'-piperidine]-
  • Step C tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-hydroxy-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2, 3-e] isoindole-3, 4' -piperidine ]-l '-carboxylate
  • Step D 3 -(3 ' -hydroxy -6-oxo-6, 8-dihydro-2H, 7H-spiro[furo[2, 3-e] isoindole-3, 4 '-piperidin ] -
  • Step A tert-butyl 4-(((5-bromo-l-oxo-l ,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6- dihydropyridine-l(2H)-carboxylate
  • Step B tert-butyl 6-oxo-2', 3', 6, 8-tetrahydro-l 'H, 2H-spiro[benzo[2, 1 -b:3,4-c']difuran-3, d'pyridine]-! '-carboxylate
  • the mixture was stirred under N 2 at 70 °C for 16 h. After cooled to room temperature, the mixture was filtered and the cake was washed with EA (100 mL). The filtrate was washed with brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step C tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3,4'- piperidine]-! '-carboxylate
  • Step D tert-butyl 3', 6-dioxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3, d'piperidine] -1 '-carboxylate
  • the reaction was diluted with DCM (60 mL), washed with aqueous sodium thiosulfate solution (30 mL x 2) and washed with brine (40 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step E tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3,4'- piperidine]-!
  • reaction mixture was quenched with saturated aqueous NaHCCh solution (30 mL) and extracted with DCM (30 mLx 3). The separated organic phase was washed with brine (30 mL), dried over anhydrous NaiSCL, filtered, and concentrated under reduced pressure.
  • Step F 1 '-( tert-butoxycarbonyl)-3 ', 3 '-difluoro- 7-( hydroxymethyl)-2H-spiro[benzofuran-3, 4 '- piperidine] -6-carboxylic acid
  • Step G 1 '-( tert-butoxycarbonyl )-3',3 '-difluoro- 7-formyl-2H-spiro[benzofuran-3, 4 '- piperidine] -6-carboxylic acid
  • Step H tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H- spiro[furo[2, 3-e] isoindole-3, 4' -piperidine ]-l '-carboxylate
  • Step I afford 3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'- piperidin ]-7-yl)piperidine-2, 6-dione
  • Step B tert-butyl 6-oxo-2', 3', 6, 8-tetrahydro- H,2H-spiro[benzo[2,l-b:3,4-c']dlfuran-3, d'pyridine]-! '-carboxylate
  • the mixture was stirred under N 2 at 70 °C for 16 h. After cooled to room temperature, the mixture was filtered and the cake was washed with EA (300 mL). The filtrate was washed with brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step C tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,]-b:3,4-c']difuran-3, d'piperidine]-! '-carboxylate
  • Step D tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3,4'- piperidine]-l '-carboxylate
  • Step E tert-butyl 3', 6-dioxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4-c']difuran-3, d'piperidine]-! '-carboxylate
  • reaction mixture was quenched with saturated aqueous NaHCCh solution (60 mL) and extracted with DCM (100 mL x 3). The separated organic phase was washed with brine (100 mL x 3), dried over anhydrous Na 2 SO 4 filtered, and concentrated under reduced pressure.
  • Step F 1'-( tert-butoxycarbonyl)-3', 3 '-difluoro- 7-( hydroxymethyl)-2H-spiro[benzofuran-3, 4 '- piperidine] -6-carboxylic acid
  • Step G tert-butyl 2,2-difluoro-8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,l-b:3,4- c]difuran-3,4'-piperidine]-l'-carboxylate
  • Step H tert-butyl 7-((S)-l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-3',3'-difluoro-6-oxo- 7,8-dihydro-2H, 6H -spiro[furo[2, 3-e] isoindole-3, 4 '-piperidine ]-l '-carboxylate
  • Step A ethyl (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate
  • Step B ethyl l-(4-chlorophenyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate
  • Step C ( 1 -(4-chlorophenyl)-5-(trifluoromethyl)-lH-pyrazol-4-yl)methanol
  • Step D l-( 4-chlorophenyl)-5-( trifluoromethyl)-lH-pyrazole-4-carbaldehyde
  • Step A methyl 1 -methyl- lH-indazole-6-carboxy late and methyl 2-methyl-2H-indazole-6- carboxylate
  • Step C 6-(bromomethyl-d2)-l -methyl- 1H -indazole
  • Step A 4-bromo-l -( methyl-d3)-lH-pyrazole
  • Step B methyl 3-(l-(methyl-d3)-lH-pyrazol-4-yl)benzoate
  • Step C (3-(1-(methyl-d 3 )-lH-pyrazol-4-yl)phenyl)methan-d2-ol
  • Step D 4-(3-(bromomethyl-d2)phenyl)-l-(methyl-d3)-1H-pyrazole
  • Step A methyl 3-(l-(difluoromethyl)-lH-pyrazol-4-yl)benzoate
  • Step B (3-(! -(difluoromethyl)- 1H-pyrazol-4-yl) phenyl)methan-d2-ol
  • Step C 4-(3-(bromomethyl-d2) phenyl)-1-(difluoromethyl)-1H-pyrazole
  • 3-(l-(difluoromethyl)-lH-pyrazol-4-yl)phenyl)methan-d2-ol 145 mg, 641 ⁇ mol, 1.0 eq
  • Triphenylphosphine 252 mg, 961 ⁇ mol, 1.5 eq
  • carbon tetrabromide 319 mg, 961 ⁇ mol, 1.5 eq.
  • the reaction mixture was stirred at 50 °C for 1 h.
  • Step A methyl 3-(l-methyl-lH-pyrazol-4-yl)benzoate
  • Step B (3-(l-methyl-lH-pyrazol-4-yl)phenyl)methan-d2-ol
  • Step C 4-(3-(bromomethyl-d2)phenyl)-l-methyl-lH-pyrazole
  • Step A 4-bromo-l -(methyl-d3)-1H-pyrazole
  • Step B 3-(1 -(methyl-d3)-lH-pyrazol-4-yl)benzaldehyde
  • Step A 5-vinylindolin-2-one.
  • Step A 4-bromo-l -( oxetan-3-yl)-lH-pyrazole
  • Step B 3-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)benzaldehyde
  • the residue was purified by Prep-HPLC with YMC- Actus Triart Cl 8 (5 um, 20 x 250 mm), and mobile phase of 5-95% ACN in water (0.1% TFA) over 20 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min to to obtained 2-methyl-2H-indazole-7-carbaldehyde (60 mg, yield 11%) as a yellow solid and l-methyl-1H-indazole-7-carbaldehyde (110 mg, yield 20.1%) as a white solid.
  • Step B l-(( 1, 1 -dioxidotetrahydro-2H-thiopyran-4-yl)methyl)- lH-pyrazole-4-carbaldehyde
  • Step A benzyl 4-methylenepiperidine-l -carboxylate
  • Step B benzyl 2-hydroxy-4-methylenepiperidine-l -carboxylate
  • Step A 4-bromo-3-fluoro-5 -methoxybenzoic acid
  • Step B 4-bromo-3-fluoro-5 -hydroxybenzoic acid
  • Step D methyl 4-bromo-5-fluoro-2-formyl-3-hydroxybenzoate
  • Step E tert-butyl (S)-5-amino-4-(5-bromo-6-fluoro-4-hydroxy-l-oxoisoindolin-2-yl)-5- oxopentanoate
  • Step F Synthesis of benzyl (S)-4-(((2-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-5- bromo-6-fluoro-l-oxoisoindolin-4-yl)oxy)methyl)-3,6-dihydropyridine-l(2H)-carboxylate [0485] tert-Butyl (S)-5-amino-4-(5-bromo-6-fluoro-4-hydroxy- l-oxoisoindolin-2-yl)-5- oxopentanoate (202 mg, 0.47 mmol, 1 eq), benzyl 4-(chloromethyl)-3,6-dihydropyridine- l(2H)-carboxylate (Compound A, 280 mg, 0.49 mmol, 1.05 eq) and K2CO3 (194 mg, 1.41 mmol, 3 eq) were added
  • Step G benzyl (S)-7-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-4-fluoro-6-oxo-7,8- dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-r-carboxylate
  • Step H tert-butyl (S)-5-amino-4-(4-fluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e ] isoindole-3, 4 '-piperidin ]-7-yl )-5-oxopentanoate
  • Step B methyl 4-bromo-2-methyl-3-nitrobenzoate
  • Step C methyl 4-bromo-2-(bromomethyl)-3-nitrobenzoate
  • Step D tert-butyl 5-amino-4-(5-bromo-4-nitro-l-oxoisoindolin-2-yl)-5-oxopentanoate
  • tert-butyl (S)-4,5-diamino-5-oxopentanoate (2.94 g, 12.3 mmol)
  • DIEA 3.18 g, 24.7 mmol
  • Step E tert-butyl 5-amino-4-(4-amino-5-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate
  • Step F benzyl 4-(((2-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-5-bromo-l- oxoisoindolin-4-yl)amino)methyl)-3,6-dihydropyridine-l(2H)-carboxylate
  • Step G benzyl 7'-(l-amino-5-(tert-butoxy)-l,5-dioxopentan-2-yl)-6'-oxo-r,6',7',8'-tetrahydro- 2 'H- spiro [ piperidine-4, 3 '-pyrrolo[ 3,4-g] indole ]-l-carboxylate
  • Step H tert-butyl (S)-5-amino-5-oxo-4-(6'-oxo-r,2',6',8'-tetrahydro-7'H-spiro[piperidine- 4,3 '-pyrrolo[3, 4-g]indol ]- 7'-yl )pentanoate
  • the impure product was further purified by Prep-HPLC with YMC- Actus Triart Cl 8 (5 pm, 250 x 21 mm), and mobile phase of 5-95% ACN in water (0.1 % FA) over 10 min and then hold at 100% ACN for 3 min, at a flow rate of 20 mL/min to give (S)-3-(1'-((l-(4-chlorophenyl)-5- (trifhioromethyl)-1H-pyrazol-4-yl)methyl)-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3- e]isoindole-3,4'-piperidin]-7-yl)piperidine-2, 6-dione (6.50 mg, yield 8%) as a white solid, as a white solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/US2023/016177 2022-03-25 2023-03-24 Ikzf2 degraders and uses thereof Ceased WO2023183540A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
KR1020247035795A KR20250026153A (ko) 2022-03-25 2023-03-24 Ikzf2 분해제 및 이의 용도
US18/849,594 US20250215012A1 (en) 2022-03-25 2023-03-24 Ikzf2 degraders and uses thereof
JP2024556604A JP2025512805A (ja) 2022-03-25 2023-03-24 Ｉｋｚｆ２分解剤及びその使用
EP23719521.9A EP4499649A1 (en) 2022-03-25 2023-03-24 Ikzf2 degraders and uses thereof
CN202380041783.5A CN119731179A (zh) 2022-03-25 2023-03-24 Ikzf2降解剂及其用途

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202263323792P 2022-03-25 2022-03-25
US63/323,792 2022-03-25
US202363446105P 2023-02-16 2023-02-16
US63/446,105 2023-02-16

Publications (1)

Publication Number Publication Date
WO2023183540A1 true WO2023183540A1 (en) 2023-09-28

Family

ID=86185384

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/016177 Ceased WO2023183540A1 (en) 2022-03-25 2023-03-24 Ikzf2 degraders and uses thereof

Country Status (7)

Country Link
US (1) US20250215012A1 (https=)
EP (1) EP4499649A1 (https=)
JP (1) JP2025512805A (https=)
KR (1) KR20250026153A (https=)
CN (1) CN119731179A (https=)
TW (1) TW202341988A (https=)
WO (1) WO2023183540A1 (https=)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11976067B2 (en) 2022-01-18 2024-05-07 Maze Therapeutics, Inc. APOL1 inhibitors and methods of use
WO2025261456A1 (zh) * 2024-06-19 2025-12-26 甘李药业股份有限公司 一种雌激素受体蛋白降解靶向嵌合体化合物及其应用
US12565492B2 (en) 2024-08-09 2026-03-03 Triana Biomedicines, Inc. Anaplastic Lymphoma Kinase (ALK) degraders and uses thereof
EP4471033A4 (en) * 2022-01-29 2026-03-25 Gan & Lee Pharmaceuticals Co Ltd CEREBLON UBIQUITIN LIGASE E3 INHIBITOR

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019038717A1 (en) * 2017-08-23 2019-02-28 Novartis Ag 3- (1-OXOISOINDOLIN-2-YL) PIPERIDINE-2,6-DIONE DERIVATIVES AND USES THEREOF
WO2020165834A1 (en) * 2019-02-15 2020-08-20 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2021087093A1 (en) * 2019-10-30 2021-05-06 Dana-Farber Cancer Institute, Inc. Small molecule degraders of helios and methods of use
WO2021260528A1 (en) * 2020-06-23 2021-12-30 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2022029573A1 (en) * 2020-08-03 2022-02-10 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019038717A1 (en) * 2017-08-23 2019-02-28 Novartis Ag 3- (1-OXOISOINDOLIN-2-YL) PIPERIDINE-2,6-DIONE DERIVATIVES AND USES THEREOF
WO2020165834A1 (en) * 2019-02-15 2020-08-20 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2021087093A1 (en) * 2019-10-30 2021-05-06 Dana-Farber Cancer Institute, Inc. Small molecule degraders of helios and methods of use
WO2021260528A1 (en) * 2020-06-23 2021-12-30 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2022029573A1 (en) * 2020-08-03 2022-02-10 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
"Organic Reactions", 1942, JOHN WILEY & SONS
BAINE I. ET AL., J IMMUNOL, vol. 190, 2013, pages 1008 - 1016
BIOORG. MED. CHEM. LETT., vol. 26, 2016, pages 228 - 234
CARRUTHERS: "Some Modern Methods of Organic Synthesis", 1987, CAMBRIDGE UNIVERSITY PRESS
E. L. ELIES. 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, vol. 115, 2018, pages 11802 - 11807
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
JOURNAL OF PHARMACEUTICAL SCIENCE & TECHNOLOGY, vol. 2, no. 12, 2010, pages 380 - 390
LAROCK: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS, INC.
NAKAGAWA, H. ET AL., PROC NATIONAL ACAD SCI, vol. 113, 2016, pages 6248 - 6253
REMINGTON: "The Science and Practice of Pharmacy", 2005, MACK PUB. CO.
S. R. SANDLER ET AL.: "Organic Functional Group Preparations", 1983, JOHN WILEY & SONS, INC.
SMITHMARCH: "March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS, INC.
SOLOMONS, T. W. G.: "Modern Carbonyl Chemistry", 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", 1999, UNIVERSITY SCIENCE BOOKS
WILEN ET AL., TETRAHEDRON, vol. 33, 1977, pages 2725
YATES, K. ET AL., PROC NATIONAL ACAD SCI, vol. 115, 2018, pages 201720447

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11976067B2 (en) 2022-01-18 2024-05-07 Maze Therapeutics, Inc. APOL1 inhibitors and methods of use
US12344610B2 (en) 2022-01-18 2025-07-01 Maze Therapeutics, Inc. APOL1 inhibitors and methods of use
EP4471033A4 (en) * 2022-01-29 2026-03-25 Gan & Lee Pharmaceuticals Co Ltd CEREBLON UBIQUITIN LIGASE E3 INHIBITOR
WO2025261456A1 (zh) * 2024-06-19 2025-12-26 甘李药业股份有限公司 一种雌激素受体蛋白降解靶向嵌合体化合物及其应用
US12565492B2 (en) 2024-08-09 2026-03-03 Triana Biomedicines, Inc. Anaplastic Lymphoma Kinase (ALK) degraders and uses thereof

Also Published As

Publication number Publication date
US20250215012A1 (en) 2025-07-03
CN119731179A (zh) 2025-03-28
KR20250026153A (ko) 2025-02-25
JP2025512805A (ja) 2025-04-22
TW202341988A (zh) 2023-11-01
EP4499649A1 (en) 2025-02-05

Similar Documents

Publication Publication Date Title
TWI841200B (zh) 雜環類化合物、藥物組成物及其應用
CN112166110B (zh) Shp2磷酸酶抑制剂及其使用方法
EP3601239B1 (en) Novel heterocyclic derivatives useful as shp2 inhibitors
KR101862493B1 (ko) Fgfr4 억제제로서의 고리-융합된 비시클릭 피리딜 유도체
WO2023183540A1 (en) Ikzf2 degraders and uses thereof
JP2023553492A (ja) アザキナゾリン汎ＫＲａｓ阻害剤
WO2020103896A1 (en) Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and uses thereof
KR20220061958A (ko) Cd38의 억제제로서의 헤테로바이사이클릭 아미드
EP3303318A1 (en) Benzoxazinone derivatives and analogues thereof as modulators of tnf activity
BR112021002408A2 (pt) carboxamidas como inibidores da protease específica de ubiquitina
WO2023183607A1 (en) Cereblon ligands and uses thereof
JP2025510834A (ja) Ｉｋｚｆ２分解剤としての二環式ヘテロアリール含有化合物
EP4457230A1 (en) Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use
WO2024015412A1 (en) Tetrahydronaphthalene derivatives as estrogen receptor degraders
WO2024192064A1 (en) Compounds and compositions as smarca2/4 degraders and uses thereof
WO2024020419A1 (en) Aza-quinazoline compounds and methods of use
WO2024015408A1 (en) Indazole derivatives as estrogen receptor degraders
WO2023201012A1 (en) Ikzf2 degraders and uses thereof
WO2024064316A1 (en) Compounds and compositions as smarca2/4 inhibitors and uses thereof
HK40123004A (zh) 作为ikzf2降解剂的含二环杂芳基的化合物
HK40123006A (zh) Ikzf2降解剂及其用途
WO2025235363A1 (en) Cyclin-dependent kinase 4 degraders
EP4441034A1 (en) Fused pyrazole urea analogs as glucosylceramide synthase inhibitors
WO2025106472A1 (en) Compounds and compositions as smarca2/4 degraders and uses thereof
JP2025521173A (ja) Ｃｄ７３阻害剤化合物

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: 23719521

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2024556604

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2023719521

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2023719521

Country of ref document: EP

Effective date: 20241025

WWE Wipo information: entry into national phase

Ref document number: 202380041783.5

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 1020247035795

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 202380041783.5

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 18849594

Country of ref document: US