WO2024015346A1 - Ligands de céréblon et leurs utilisations - Google Patents

Ligands de céréblon et leurs utilisations Download PDF

Info

Publication number
WO2024015346A1
WO2024015346A1 PCT/US2023/027353 US2023027353W WO2024015346A1 WO 2024015346 A1 WO2024015346 A1 WO 2024015346A1 US 2023027353 W US2023027353 W US 2023027353W WO 2024015346 A1 WO2024015346 A1 WO 2024015346A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbocyclyl
alkyl
certain embodiments
membered
heterocyclyl
Prior art date
Application number
PCT/US2023/027353
Other languages
English (en)
Inventor
Guozhang Xu
Zhenwu Li
Shaomeng Wang
Xuqing Zhang
Original Assignee
ONCOPIA THERAPEUTICS, INC. d.b.a PROTEOVANT THERAPEUTICS, INC.
Regents Of The University Of Michigan
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., Regents Of The University Of Michigan filed Critical ONCOPIA THERAPEUTICS, INC. d.b.a PROTEOVANT THERAPEUTICS, INC.
Publication of WO2024015346A1 publication Critical patent/WO2024015346A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • Cereblon a component of the DDBl-CUL4a-Rocl ubiquitin ligase complex, is a molecular target of immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide. Inhibition of CRBN ubiquitination by these agents may allow CRBN to accumulate, leading to the increased cullin-4 RING E3 ligase-mediated degradation of target proteins.
  • the discovery process of CRBN type E3 ligase ligand is related to the study of thalidomide's mechanism of action.
  • Cerebellar protein is part of the E3 ubiquitin ligase protein complex, which acts as a substrate receptor to select ubiquitinated proteins.
  • the study shows that thalidomide-cerebellar protein binding in vivo may be the cause of thalidomide teratogenicity.
  • the compound and related structures can be used as anti-inflammatory agents, anti- angiogenic agents and anti-cancer agents.
  • Lenalidomide and pomalidomide obtained by further modification of the structure of thalidomide have greatly improved their safety and significantly reduced their teratogenic effects.
  • Lenalidomide has been approved by the FDA in 2006 for marketing.
  • Two promising papers published in Science in 2014 pointed out that lenalidomide works by degrading two special B cell transcription factors, Ikaros family zinc finger structural proteins 1 and 3 (IKZF1 and IKZF3), which further reveals the structure of thalidomide may be combined with the E3 ubiquitin ligase protein complex of the cerebellar protein to further play a role in degrading the target protein (Science, 2014, 343, 301; Science, 2014, 343, 305).
  • IKZF1 and IKZF3 Ikaros family zinc finger structural proteins 1 and 3
  • E3 ubiquitin ligase protein complex of the cerebellar protein to further play a role in degrading the target protein
  • CRBN ligands are widely used in protein degradation, and a series of PROTACs molecules based on CRBN ligands have been developed.
  • the present disclosure provides compounds or conjugates of Formula II: and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables in Formula II is described, embodied, and exemplified herein.
  • the present disclosure provides compounds or conjugates of Formula I: and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables in Formula I is described, embodied, and exemplified herein.
  • the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.
  • methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.
  • methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.
  • provided herein are uses of a compound described herein in the manufacture of a medicament for binding cerebon E3 ubiquitin ligase protein complex in a subject or biological sample.
  • compounds described herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample are compounds described herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.
  • provided herein are methods of degrading a protein in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.
  • methods of degrading a protein in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.
  • uses of a compound described herein in the manufacture of a medicament for degrading a protein in a subject or biological sample are compounds described herein for use in degrading a protein in a subject or biological sample.
  • methods of reducing a protein in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.
  • provided herein are uses of a compound described herein in the manufacture of a medicament for reducing a protein in a subject or biological sample.
  • compounds described herein for use in reducing a protein in a subject or biological sample are compounds described herein for use in reducing a protein in a subject or biological sample.
  • methods of treating or preventing a disease or disorder a subject in need thereof comprising administering to the subject a compound described herein.
  • the present disclosure provides compounds of Formula II: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: B 1 is N or CR B1 ; B 2 is N or CR B2 ; B 3 is N or CR B3 ; B 4 is N or CR B4 ; B 5 is N or CR B5 ; wherein: i) B 5 is CR B5 , and either R B1 and R B5 or R B4 and R B5 , together with the carbon atoms to which they are bonded, form Ring A, wherein Ring A is optionally substituted C 5-16 fused or spiro carbocycle or 5- to 16-membered fused or spiro heterocycle; the remaining of R B1 , R B2 , R B3 , R B4 , and R B5 , when applicable, are independently hydrogen, halogen, -CN, -NO 2 , -OH,
  • B 1 is N or CR B1 . In certain embodiments, B 1 is N. In certain embodiments, B 1 is CR B1 .
  • B 2 is N or CR B2 . In certain embodiments, B 2 is N. In certain embodiments, B 2 is CR B2 .
  • B 3 is N or CR B3 . In certain embodiments, B 3 is N. In certain embodiments, B 3 is CR B3 .
  • B 4 is N or CR B4 . In certain embodiments, B 2 is N. In certain embodiments, B 4 is CR B4 .
  • B 5 is N or CR B5 .
  • B 2 is N.
  • B 5 is CR B5 .
  • B 5 is CR B5 , either R B1 and R B5 or R B4 and R B5 , together with the carbon atoms to which they are bonded, form Ring A, wherein Ring A is optionally substituted fused or spiro C 5-16 carbocycle or 5- to 16-membered fused or spiro heterocycle.
  • one of R B2 , R B3 , and R B4 or one of R B1 , R B2 , and R B3 is N.
  • R B2 , R B3 , and R B4 or two R B1 , R B2 , and R B3 are N.
  • the remaining of R B1 , R B2 , R B3 , R B4 , and R B5 when applicable, are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s- butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy
  • R B1 , R B2 , R B3 , R B4 , and R B5 when applicable, are independently hydrogen, 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 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R B1 , R B2 , R B3 , R B4 , and R B5 when applicable, are independently hydrogen, 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 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • R B1 , R B2 , R B3 , R B4 , and R B5 when applicable, are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each of the remaining of R B1 , R B2 , R B3 , R B4 , and R B5 when applicable, is hydrogen, halogen, or C 1-6 alkyl.
  • Ring A is optionally substituted with one or more R u , R A1 , R A1’ , R A2 , or R A2’ .
  • R u is R A1 .
  • R u is R A1’ .
  • R u is R A2 .
  • R u is R A2’ .
  • Ring A is optionally substituted with one or more R u , R A , R Ax , R A1 , or R A2 .
  • R u is R A1 . In certain embodiments, R u is R Ax .
  • R u is R A1 . In certain embodiments, R u is R A2 .
  • Ring A I is not carbocycle.
  • Ring A I is 5- to 8-membered heterocycle (e.g., heterocycle comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).
  • Ring A I is 5- to 8-membered heterocycle comprising one oxygen atom.
  • Ring A I is 5- to 8-membered heterocycle comprising one oxygen atom and one double bond.
  • Ring A I is 5- to 8-membered heterocycle comprising two oxygen atoms.
  • Ring A I is 5- to 8- membered heterocycle comprising one nitrogen atom.
  • Ring A I is 5- to 8-membered heterocycle comprising two nitrogen atoms. In certain embodiments, Ring A I is 5- to 8-membered heterocycle comprising one nitrogen atom and one oxygen atom.
  • Ring A II is C 3-8 carbocycle (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8
  • each A 1 is independently -C(R A1 ) 2 -, -NR A1’ -, or -O-.
  • each A 2 is independently -C(R A2 ) 2 -, -NR A2’ -, or -O-.
  • each occurrence of R A1 and R A2 is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (
  • each occurrence of R A1 and R A2 is independently hydrogen, 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 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each occurrence of R A1 and R A2 is independently hydrogen, 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 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each occurrence of R A1 and R A2 is independently hydrogen, 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 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each occurrence of R A1 and R A2 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each occurrence of R A1 and R A2 is hydrogen.
  • two geminal R A1 or two geminal R A2 together form oxo.
  • two geminal R A1 or two geminal R A2 together with the carbon atom to which they are attached, form C 3-6 carbocycle (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), or cyclohexadienyl (C 6 )) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more R u .
  • C 3 cyclopropyl
  • C 3 cyclopropenyl
  • C 4 cyclobutyl
  • C 4
  • each occurrence of R A1’ and R A2’ is independently hydrogen, C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexenyl (C 6 )), C 2-6 alkyl (e.g.,
  • each occurrence of R A1’ and R A2’ is independently hydrogen or C 1-6 alkyl. [0062] In certain embodiments, each occurrence of R A1’ and R A2’ is hydrogen. [0063] In certain embodiments, a' is 0. In certain embodiments, a' is 1. In certain embodiments, a' is 2. [0064] In certain embodiments, a'' is 0. In certain embodiments, a'' is 1. In certain embodiments, a'' is 2. [0065] In certain embodiments, one of a' and a'' is 0. [0066] In certain embodiments, each of a' and a'' is 1.
  • each R A is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ),
  • each R A is independently 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, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R A is independently 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, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R A is independently 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, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R A is independently oxo, halogen, -CN, -NO 2 , -OH, - NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • a is 0. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4, as valency permits.
  • a is 5, as valency permits. In certain embodiments, a is 6, as valency permits. In certain embodiments, a is 7, as valency permits. In certain embodiments, a is 8. In certain embodiments, a is 8, as valency permits. [0074] In certain embodiments, a is 0. [0075] In certain embodiments, each R A may be present on either Ring A I or Ring A II . [0076] In certain embodiments, Ring A is:
  • the compound of Formula II is a compound of Formula II-1
  • Ring A is wherein: Ring A III and Ring A IV are independently C4-8 carbocycle or 4- to 8-membered heterocycle; wherein at least one of Ring A III and Ring A IV is 4- to 8-membered heterocycle; A 3 and A 4 are independently C, CR Ax , or N; R Ax is hydrogen, 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 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
  • Ring A III and Ring A IV are independently C4-8 carbocycle (e.g., cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), or cyclooctenyl (C 8 )) or 4- to 8- membered heterocycle (e.g., heterocycle comprising one or two 4- to 8-membered rings and 1- 3 heteroatoms selected from N, O, and S).
  • C 4 C 4
  • Ring A IV is 5- to 8-membered heterocycle comprising at least two nitrogen atoms. In certain embodiments, Ring A IV is 5- to 8-membered heterocycle comprising two nitrogen atoms.
  • a 3 and A 4 are independently C, CR Ax , or N.
  • one of A 3 and A 4 is CR Ax , and the other one of A 3 and A 4 is N.
  • each R Ax is independently hydrogen, halogen, -CN, -NO 2 , - OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i- butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ), i-propoxy (C 3 ), n-butoxy (C 4 ), i-butoxy (C 4 ), s-butoxy (C 4 ), t- butoxy (C 4 ), pentoxy (C 5 ), or hexyl (C 6 )
  • each R Ax is independently hydrogen, 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 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C 6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R Ax is independently hydrogen, 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 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R Ax is independently hydrogen, halogen, -CN, -NO 2 , - OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R Ax is hydrogen.
  • the compound of Formula II is a compound of Formula II-3
  • R A5 is hydrogen, C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n- propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexeny
  • R A5 is an amino-protecting group.
  • R A6 is hydrogen, C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n- propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexenyl (
  • R A6 is hydrogen or C 1-6 alkyl.
  • R A6 is an amino-protecting group.
  • each R A is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ), i-propoxy (C 3 ), n-butoxy (
  • each R A is independently 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, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R A is independently 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, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C 6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R A is independently 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, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R A is independently oxo, halogen, -CN, -NO 2 , -OH, - NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • a is 0. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4, as valency permits.
  • a is 5, as valency permits. In certain embodiments, a is 6, as valency permits. In certain embodiments, a is 7, as valency permits. In certain embodiments, a is 8, as valency permits. [0107] In certain embodiments, a is 0.
  • Ring A’ is C4-12 fused carbocyclyl or 4- to 12-membered fused heterocyclyl (e.g., heterocyclyl comprising two 3- to 6-membered fused rings and 1-3 heteroatoms selected from N, O, and S). [0110] In certain embodiments, Ring A’ is 4- to 12-membered fused heterocyclyl. [0111] In certain embodiments, Ring A’ is 5- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • each R A’ is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ), i-propoxy (C 3 ), n-butoxy (C 4 ), i-butoxy (C 4 ), s- butoxy (C 6 )), C
  • each R A’ is independently 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, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R A’ is independently 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, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R A’ is independently 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, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R A’ is independently oxo, halogen, -CN, -NO 2 , -OH, - NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • at least one R A’ is halogen.
  • at least one R A’ is -F.
  • m is 0. In certain embodiments, m is 1.
  • m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. [0119] In certain embodiments, m is an integer selected from 0 to 3.
  • R D is hydrogen, deuterium, or C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )) optionally substituted with one or more R u .
  • R D is hydrogen.
  • q is 0. In certain embodiments, q is 1.
  • each R D1 is independently halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n- butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ), i-propoxy (C 3 ), n-butoxy (C
  • each R D1 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 3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R D1 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 3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R D1 is independently halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R u .
  • d is 0. In certain embodiments, d is 1. In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4. In certain embodiments, d is 5.
  • each R a is independently C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexenyl (C 6 ), C 2-6 alkenyl (e.g., ethenyl (C 2 ),
  • each R a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 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, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R a is independently C 1-6 alkyl, C 3-6 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 (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexenyl (C 6 ), C 2-6 alkynyl (e.g., methyl (C 1 ),
  • each R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.
  • each R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R b is independently hydrogen, C 1-6 alkyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or 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 (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t- butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2- propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexenyl (C 6 ), C 2-6 alkynyl (e.g., methyl (
  • each R c and each R d is independently hydrogen, C 1-6 alkyl, C 3- 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 u .
  • R a , R b , R c , and R d is independently and optionally substituted with one or more R z .
  • R z is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or 3- to 6- membered heterocyclyl.
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1-6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ), i-propoxy (C 3 ), n-butoxy (C 4 ), i-butoxy (C 4 ), s-butoxy (C 4 ), t-butoxy (C 4 ), pentoxy (C 5 ), or
  • each R u is independently 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, 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, C 3-6
  • each R u is independently 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, C 3-6 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 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, C 3-6 carb
  • each R u is independently 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, C 3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more 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, C 3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more 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, C 3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.
  • two R u together with the carbon atom(s) to which they are attached, form C 3-6 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), or cyclohexadienyl (C 6 )) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).
  • C 3 cyclopropyl
  • C 3 cyclopropenyl
  • C 4 cyclobutyl
  • C 4 cyclobutenyl
  • C 4 cyclopentyl
  • C 5 cyclopentenyl
  • two geminal R u together with the carbon atom to which they are attached, form C 3-6 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), or cyclohexadienyl (C 6 )) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).
  • C 3 cyclopropyl
  • C 3 cyclopropenyl
  • C 4 cyclobutyl
  • C 4 cyclobutenyl
  • C 4 cyclopentyl
  • C 5 cyclopentenyl
  • Ring A is optionally substituted with one or more R u .
  • R u is R i . In certain embodiments, R u is R 5 . In certain embodiments, R u is R X1 . In certain embodiments, R u is R X2 . In certain embodiments, R u is R Z1 . In certain embodiments, R u is R Z2 .
  • Ring A is optionally substituted 7-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 8-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 9-membered fused heterocycle.
  • Ring A is optionally substituted 10-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 11-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 12-membered fused heterocycle. [0156] In certain embodiments, Ring A is optionally substituted 7- to 12-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 11-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 10-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 9-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 8-membered fused heterocycle.
  • Ring A is optionally substituted 8- to 12-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 11-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 10-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 9-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 12-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 11-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 10-membered fused heterocycle.
  • the compound of Formula I is a compound of Formula I-1 or I-2 [0159]
  • each R i is independently 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, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8. [0161] In certain embodiments, Ring A is optionally substituted 7-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 8-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 9-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 10-membered spiro heterocycle.
  • Ring A is optionally substituted 11-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 12-membered spiro heterocycle. [0162] In certain embodiments, Ring A is optionally substituted 7- to 12-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 11-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 10-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 9-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 8-membered spiro heterocycle.
  • Ring A is optionally substituted 8- to 12-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 11-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 10-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 9-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 12-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 11-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 10-membered spiro heterocycle.
  • Ring A is: wherein o is 0 or 1. [0165] In certain embodiments, Ring A is: wherein o is 0 or 1. [0166] In certain embodiments, Ring A is: [0167] In certain embodiments, o is 0. In certain embodiments, o is 1.
  • the compound of Formula I is a compound of Formula I-3 or I-4 [0169]
  • each R i is independently 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, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • Ring A 2 is C 3 carbocycle. In certain embodiments, Ring A 2 is C 4 carbocycle. In certain embodiments, Ring A 2 is C 5 carbocycle. In certain embodiments, Ring A 2 is C 6 carbocycle. In certain embodiments, Ring A 2 is C 7 carbocycle. In certain embodiments, Ring A 2 is C8 carbocycle. [0171] In certain embodiments, Ring A 2 is C 3-8 carbocycle. In certain embodiments, Ring A 2 is C 3-7 carbocycle. In certain embodiments, Ring A 2 is C 3-6 carbocycle. In certain embodiments, Ring A 2 is C 3-5 carbocycle. In certain embodiments, Ring A 2 is C 3-4 carbocycle.
  • Ring A 2 is C 4-8 carbocycle. In certain embodiments, Ring A 2 is C 4-7 carbocycle. In certain embodiments, Ring A 2 is C 4-6 carbocycle. In certain embodiments, Ring A 2 is C 4-5 carbocycle. In certain embodiments, Ring A 2 is C 5-8 carbocycle. In certain embodiments, Ring A 2 is C 5-7 carbocycle. In certain embodiments, Ring A 2 is C 5-8 carbocycle. In certain embodiments, Ring A 2 is C 6-8 carbocycle. In certain embodiments, Ring A 2 is C 6-7 carbocycle. [0172] In certain embodiments, Ring A 2 is 3-membered heterocycle. In certain embodiments, Ring A 2 is 4-membered heterocycle.
  • Ring A 2 is 5-membered heterocycle. In certain embodiments, Ring A 2 is 6-membered heterocycle. In certain embodiments, Ring A 2 is 7-membered heterocycle. In certain embodiments, Ring A 2 is 8- membered heterocycle. [0173] In certain embodiments, Ring A 2 is 3- to 8-membered heterocycle. In certain embodiments, Ring A 2 is 3- to 7-membered heterocycle. In certain embodiments, Ring A 2 is 3- to 6-membered heterocycle. In certain embodiments, Ring A 2 is 3- to 5-membered heterocycle. In certain embodiments, Ring A 2 is 3- to 4-membered heterocycle. In certain embodiments, Ring A 2 is 4- to 8-membered heterocycle.
  • Ring A 2 is 4- to 7-membered heterocycle. In certain embodiments, Ring A 2 is 4- to 6-membered heterocycle. In certain embodiments, Ring A 2 is 4- to 5-membered heterocycle. In certain embodiments, Ring A 2 is 5- to 8-membered heterocycle. In certain embodiments, Ring A 2 is 5- to 7-membered heterocycle. In certain embodiments, Ring A 2 is 5- to 6-membered heterocycle. In certain embodiments, Ring A 2 is 6- to 8-membered heterocycle. In certain embodiments, Ring A 2 is 6- to 7-membered heterocycle. [0174] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3.
  • R B5 is wherein Ring A’ is C 4-12 fused carbocyclyl or 4- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • the compound of Formula I is a compound of Formula I-5
  • R B5 is wherein Ring A’ is 4- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • Ring A’ is 4-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 5-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 6-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 7-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 8-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 9- membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • Ring A’ is 10-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 11-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. [0178] In certain embodiments, Ring A’ is 4-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 5-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 6-membered fused heterocyclyl comprising 1 nitrogen atom.
  • Ring A’ is 7-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 8-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 9- membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 10-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 11-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 12-membered fused heterocyclyl comprising 1 nitrogen atom. [0179] In certain embodiments, Ring A’ is 4-membered fused heterocyclyl comprising 2 nitrogen atoms.
  • Ring A’ is 5-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 6-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 7-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 8-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 9- membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 10-membered fused heterocyclyl comprising 2 nitrogen atoms.
  • Ring A’ is 11-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 12-membered fused heterocyclyl comprising 2 nitrogen atoms. [0180] In certain embodiments, Ring A’ is 4- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 10-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 8- membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 6-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • Ring A’ is 6- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 6- to 10-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 6- to 8-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 8- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 8- to 10- membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. [0181] In certain embodiments, Ring A’ is 4- to 12-membered fused heterocyclyl comprising 1 nitrogen atom.
  • Ring A’ is 4- to 10-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 4- to 8-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 4- to 6-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 6- to 12- membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 6- to 10-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 6- to 8-membered fused heterocyclyl comprising 1 nitrogen atom.
  • Ring A’ is 8- to 12-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 8- to 10-membered fused heterocyclyl comprising 1 nitrogen atom. [0182] In certain embodiments, Ring A’ is 4- to 12-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 10-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 8-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 6- membered fused heterocyclyl comprising 2 nitrogen atoms.
  • Ring A’ is 6- to 12-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 6- to 10-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 6- to 8-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 8- to 12-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 8- to 10-membered fused heterocyclyl comprising 2 nitrogen atoms. [0183] In certain embodiments, R B5 is wherein Ring A’ is C 4-12 fused carbocyclyl.
  • Ring A’ is C 4 fused carbocyclyl. In certain embodiments, Ring A’ is C 5 fused carbocyclyl. In certain embodiments, Ring A’ is C 6 fused carbocyclyl. In certain embodiments, Ring A’ is C 7 fused carbocyclyl. In certain embodiments, Ring A’ is C 8 fused carbocyclyl. In certain embodiments, Ring A’ is C 9 fused carbocyclyl. In certain embodiments, Ring A’ is C 10 fused carbocyclyl. In certain embodiments, Ring A’ is C 11 fused carbocyclyl. In certain embodiments, Ring A’ is C 12 fused carbocyclyl.
  • Ring A’ is C 4-12 fused carbocyclyl. In certain embodiments, Ring A’ is C 4-10 fused carbocyclyl. In certain embodiments, Ring A’ is C 4-8 fused carbocyclyl. In certain embodiments, Ring A’ is C 4-6 fused carbocyclyl. In certain embodiments, Ring A’ is C 6-12 fused carbocyclyl. In certain embodiments, Ring A’ is C 6-10 fused carbocyclyl. In certain embodiments, Ring A’ is C 6-8 fused carbocyclyl. In certain embodiments, Ring A’ is C 8-12 fused carbocyclyl. In certain embodiments, Ring A’ is C 8-10 fused carbocyclyl.
  • each R A’ is independently 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, C 6-10 aryl, 5- to 10- membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • At least one R A’ is halogen.
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. [0189] In certain embodiments, m is an integer selected from 0 to 7. In certain embodiments, m is an integer selected from 0 to 5. In certain embodiments, m is an integer selected from 0 to 3. In certain embodiments, m is 0 or 1.
  • R B5 is [0191]
  • R B1 and R B2 are independently hydrogen, 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, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • R B1 and R B2 are independently hydrogen, halogen, or C 1-6 alkyl.
  • R B3 and R B4 are independently hydrogen, 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, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • R B3 and R B4 are independently hydrogen, halogen, or C 1-6 alkyl.
  • X’ is O.
  • X’ is -NR X’ -.
  • R X’ is hydrogen.
  • R D is hydrogen.
  • q is 1.
  • the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the compounds in Table 1. Table 1. *Note: the compounds below are enantiomerically pure but the absolute configuration of any of the stereogenic centers is not determined.
  • the present disclosure provides conjugates comprising a compound disclosed herein being connected to a ligand for a protein (e.g., via a linker).
  • the present disclosure provides conjugates of Formula II: and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: B 1 is N or CR B1 ; B 2 is N or CR B2 ; B 3 is N or CR B3 ; B 4 is N or CR B4 ; B 5 is N or CR B5 ; wherein: i) B 5 is CR B5 , either R B1 and R B5 or R B4 and R B5 , together with the carbon atoms to which they are bonded, form Ring A attached to -L-T, wherein Ring A is optionally substituted C 5-16 fused or spiro carbocycle or 5- to 16-membered fused or spiro heterocycle; R B2 , R B3 , and R
  • Ring A attached to -L-T is wherein each of the variables is defined herein.
  • Ring A attached to -L-T is wherein each of the variables is defined herein.
  • Ring A attached to -L-T is wherein each of the variables is defined herein.
  • Ring A attached to -L-T is wherein each of the variables is defined herein.
  • the conjugate of Formula II is a conjugate of Formula II-2 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.
  • the conjugate of Formula II is a conjugate of Formula II-4 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.
  • the conjugate of Formula II is a conjugate of Formula II-6 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.
  • L a linker, is a divalent chemical moiety that connects the ligand of a protein with the cereblon ligand disclosed herein.
  • L configures the ligand and the cereblon ligand such that the construct functions as a bifunctional degrader which binds the cereblon ligand and selectively degrads the target protein.
  • each L ’ is independently C 1-6 alkylene (e.g., methylene (-CH 2 - ), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), and hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -)), C 2-6 alkenylene (e.g., ethenylene (C 2 ), 1-propenylene (C 3 ), 2-propenylene (C 3 ), 1-butenylene (C 4 ), 2-butenylene (C 4 ), butadienylene (C 4 ), pentenylene (C 5 ), pentadienylene (C 5 ), or hexenylene (C 6 )), C 2-6 alkynylene (e.g., ethynylene (C 2 ), ethylene (-CH 2 CH 2
  • each occurrence of R L’ is independently hydrogen, C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 2-6 alkenyl (e.g., ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), or hexenyl (C 6 )), C 2-6 alkynyl (e.g., methyl (C
  • l is 0.
  • t is 1.
  • T a ligand of a protein, is a chemical entity that competitively or non-competitively binds a protein.
  • the protein is B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo- oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5 -lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase
  • Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channels. Still further target proteins include Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate- phosphate synthase.
  • the protein is an androgen receptor (AR), an estrogen receptor (ER), signal transducer and activator of transcription 3 (STAT3), signal transducer and activator of transcription 5 (STAT5), CREB-binding protein/EP300(E1A) binding protein (CBP/p300), SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2/4 (SMARCA2/4), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS G12D), Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), bromodomain-containing protein 4 (BRD4), or BRD9.
  • AR androgen receptor
  • ER estrogen receptor
  • STAT5 signal transducer and activator of transcription 3
  • STAT5 signal transducer and activator of transcription 5
  • CBP/p300 CREB-binding protein/EP300(E1A) binding protein
  • T is a small molecule.
  • T is an antibody.
  • T is a peptide.
  • the peptide has about 5 amino acids. In certain embodiments, the peptide has about 10 amino acids. In certain embodiments, the peptide has about 15 amino acids. In certain embodiments, the peptide has about 20 amino acids. In certain embodiments, the peptide has about 25 amino acids. In certain embodiments, the peptide has about 30 amino acids. In certain embodiments, the peptide has about 35 amino acids. In certain embodiments, the peptide has about 40 amino acids. In certain embodiments, the peptide has about 45 amino acids.
  • the peptide has about 50 amino acids.
  • T is a ligand for an estrogen receptor. In certain embodiments, T is ligand for an androgen receptor. In certain embodiments, T is ligand for a STAT3 protein. [0226] In certain embodiments, T is an estrogen receptor inhibitor. In certain embodiments, T is an androgen receptor inhibitor. In certain embodiments, T is a STAT3 protein inhibitor.
  • R B1 and R B5 or R B4 and R B5 together with the intervening atoms, form Ring A, wherein Ring A is optionally substituted C 3-12 carbocycle or 3- to 12- membered heterocycle attached to -L-T.
  • Ring A is optionally substituted with one or more R u .
  • R u is R i . In certain embodiments, R u is R 5 . In certain embodiments, R u is R X1 . In certain embodiments, R u is R X2 . In certain embodiments, R u is R Z1 . In certain embodiments, R u is R Z2 .
  • Ring A is optionally substituted 7-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 8-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 9-membered fused heterocycle.
  • Ring A is optionally substituted 10-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 11-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 12-membered fused heterocycle. [0233] In certain embodiments, Ring A is optionally substituted 7- to 12-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 11-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 10-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 9-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 8-membered fused heterocycle.
  • Ring A is optionally substituted 8- to 12-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 11-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 10-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 9-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 12-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 11-membered fused heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 10-membered fused heterocycle.
  • the conjugate of Formula I’ is a conjugate of Formula I’-1 or I’-2
  • each R i is independently 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, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8. [0238] In certain embodiments, Ring A is optionally substituted 7-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 8-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 9-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 10-membered spiro heterocycle.
  • Ring A is optionally substituted 11-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 12-membered spiro heterocycle. [0239] In certain embodiments, Ring A is optionally substituted 7- to 12-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 11-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 10-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 9-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 7- to 8-membered spiro heterocycle.
  • Ring A is optionally substituted 8- to 12-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 11-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 10-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 8- to 9-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 12-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 11-membered spiro heterocycle. In certain embodiments, Ring A is optionally substituted 9- to 10-membered spiro heterocycle.
  • Ring A is: wherein o is 0 or 1.
  • Ring A is: wherein o is 0 or 1.
  • Ring A is: [0244] In certain embodiments, o is 0. In certain embodiments, o is 1.
  • the conjugate of Formula I’ is a conjugate of Formula I’-3 or I’-4
  • each R i is independently 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, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • Ring A 2 is C 3 carbocycle. In certain embodiments, Ring A 2 is C 4 carbocycle. In certain embodiments, Ring A 2 is C 5 carbocycle. In certain embodiments, Ring A 2 is C 6 carbocycle. In certain embodiments, Ring A 2 is C 7 carbocycle. In certain embodiments, Ring A 2 is C 8 carbocycle. [0248] In certain embodiments, Ring A 2 is C 3-8 carbocycle. In certain embodiments, Ring A 2 is C 3-7 carbocycle. In certain embodiments, Ring A 2 is C 3-6 carbocycle. In certain embodiments, Ring A 2 is C 3-5 carbocycle. In certain embodiments, Ring A 2 is C 3-4 carbocycle.
  • Ring A 2 is C 4-8 carbocycle. In certain embodiments, Ring A 2 is C 4-7 carbocycle. In certain embodiments, Ring A 2 is C 4-6 carbocycle. In certain embodiments, Ring A 2 is C 4-5 carbocycle. In certain embodiments, Ring A 2 is C 5-8 carbocycle. In certain embodiments, Ring A 2 is C 5-7 carbocycle. In certain embodiments, Ring A 2 is C 5-8 carbocycle. In certain embodiments, Ring A 2 is C6-8 carbocycle. In certain embodiments, Ring A 2 is C 6-7 carbocycle. [0249] In certain embodiments, Ring A 2 is 3-membered heterocycle. In certain embodiments, Ring A 2 is 4-membered heterocycle.
  • Ring A 2 is 5-membered heterocycle. In certain embodiments, Ring A 2 is 6-membered heterocycle. In certain embodiments, Ring A 2 is 7-membered heterocycle. In certain embodiments, Ring A 2 is 8- membered heterocycle. [0250] In certain embodiments, Ring A 2 is 3- to 8-membered heterocycle. In certain embodiments, Ring A 2 is 3- to 7-membered heterocycle. In certain embodiments, Ring A 2 is 3- to 6-membered heterocycle. In certain embodiments, Ring A 2 is 3- to 5-membered heterocycle. In certain embodiments, Ring A 2 is 3- to 4-membered heterocycle. In certain embodiments, Ring A 2 is 4- to 8-membered heterocycle.
  • Ring A 2 is 4- to 7-membered heterocycle. In certain embodiments, Ring A 2 is 4- to 6-membered heterocycle. In certain embodiments, Ring A 2 is 4- to 5-membered heterocycle. In certain embodiments, Ring A 2 is 5- to 8-membered heterocycle. In certain embodiments, Ring A 2 is 5- to 7-membered heterocycle. In certain embodiments, Ring A 2 is 5- to 6-membered heterocycle. In certain embodiments, Ring A 2 is 6- to 8-membered heterocycle. In certain embodiments, Ring A 2 is 6- to 7-membered heterocycle. [0251] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3.
  • R B5 is wherein Ring A is C 4-12 fused carbocyclyl or 4- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • the conjugate of Formula I’ is a conjugate of Formula I’-5
  • R B5 is wherein Ring A’ is 4- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • Ring A’ is 4-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 5-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 6-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 7-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 8-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 9- membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • Ring A’ is 10-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 11-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. [0255] In certain embodiments, Ring A’ is 4-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 5-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 6-membered fused heterocyclyl comprising 1 nitrogen atom.
  • Ring A’ is 7-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 8-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 9- membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 10-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 11-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 12-membered fused heterocyclyl comprising 1 nitrogen atom. [0256] In certain embodiments, Ring A’ is 4-membered fused heterocyclyl comprising 2 nitrogen atoms.
  • Ring A’ is 5-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 6-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 7-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 8-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 9- membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 10-membered fused heterocyclyl comprising 2 nitrogen atoms.
  • Ring A’ is 11-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 12-membered fused heterocyclyl comprising 2 nitrogen atoms. [0257] In certain embodiments, Ring A’ is 4- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 10-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 8- membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 6-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms.
  • Ring A’ is 6- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 6- to 10-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 6- to 8-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 8- to 12-membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring A’ is 8- to 10- membered fused heterocyclyl comprising 1 or 2 nitrogen atoms. [0258] In certain embodiments, Ring A’ is 4- to 12-membered fused heterocyclyl comprising 1 nitrogen atom.
  • Ring A’ is 4- to 10-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 4- to 8-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 4- to 6-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 6- to 12- membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 6- to 10-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 6- to 8-membered fused heterocyclyl comprising 1 nitrogen atom.
  • Ring A’ is 8- to 12-membered fused heterocyclyl comprising 1 nitrogen atom. In certain embodiments, Ring A’ is 8- to 10-membered fused heterocyclyl comprising 1 nitrogen atom. [0259] In certain embodiments, Ring A’ is 4- to 12-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 10-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 8-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 4- to 6- membered fused heterocyclyl comprising 2 nitrogen atoms.
  • Ring A’ is 6- to 12-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 6- to 10-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 6- to 8-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 8- to 12-membered fused heterocyclyl comprising 2 nitrogen atoms. In certain embodiments, Ring A’ is 8- to 10-membered fused heterocyclyl comprising 2 nitrogen atoms. [0260] In certain embodiments, R B5 is wherein Ring A’ is C 4-12 fused carbocyclyl.
  • Ring A’ is C 4 fused carbocyclyl. In certain embodiments, Ring A’ is C 5 fused carbocyclyl. In certain embodiments, Ring A’ is C 6 fused carbocyclyl. In certain embodiments, Ring A’ is C7 fused carbocyclyl. In certain embodiments, Ring A’ is C 8 fused carbocyclyl. In certain embodiments, Ring A’ is C 9 fused carbocyclyl. In certain embodiments, Ring A’ is C 10 fused carbocyclyl. In certain embodiments, Ring A’ is C 11 fused carbocyclyl. In certain embodiments, Ring A’ is C 12 fused carbocyclyl.
  • Ring A’ is C 4-12 fused carbocyclyl. In certain embodiments, Ring A’ is C 4-10 fused carbocyclyl. In certain embodiments, Ring A’ is C 4-8 fused carbocyclyl. In certain embodiments, Ring A’ is C 4-6 fused carbocyclyl. In certain embodiments, Ring A’ is C 6-12 fused carbocyclyl. In certain embodiments, Ring A’ is C 6-10 fused carbocyclyl. In certain embodiments, Ring A’ is C 6-8 fused carbocyclyl. In certain embodiments, Ring A’ is C 8-12 fused carbocyclyl. In certain embodiments, Ring A’ is C8-10 fused carbocyclyl.
  • each R A’ is independently 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, C 6-10 aryl, 5- to 10- membered heteroaryl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. [0266] In certain embodiments, m is an integer selected from 0 to 7. In certain embodiments, m is an integer selected from 0 to 5. In certain embodiments, m is an integer selected from 0 to 3. In certain embodiments, m is 0 or 1.
  • R B5 is [0268]
  • R B1 and R B2 are independently hydrogen, 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, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • R B3 and R B4 are independently hydrogen, 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, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • X’ is O. [0273] In certain embodiments, X’ is -NR X’ -. [0274] In certain embodiments, R X’ is hydrogen. [0275] In certain embodiments, R D is hydrogen. [0276] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [0277] L, a linker, is a divalent chemical moiety that connects the ligand of a protein with the cereblon ligand disclosed herein. L configures the ligand and the cereblon ligand such that the construct functions as a bifunctional degrader which binds the cereblon ligand and selectively degrads the target protein.
  • L is a linker comprising 6- to 10-membered heteroarylene, C 6- 10 arylene, C 3-12 membered carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the arylene, heteroarylene, carbocyclylene, or heterocyclylene is optionally substituted by one or more R u , and is directly attached to T.
  • T a ligand of a protein
  • the protein is B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo- oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5 -lipoxygenase, tryptase serine protease, thymidylate syntha
  • Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channels. Still further target proteins include Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate- phosphate synthase.
  • the protein is an androgen receptor (AR), an estrogen receptor (ER), signal transducer and activator of transcription 3 (STAT3), signal transducer and activator of transcription 5 (STAT5), CREB-binding protein/EP300(E1A) binding protein (CBP/p300), SMARCA2/4, Kirsten rat sarcoma viral oncogene homolog G12D (KRAS G12D), Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), or bromodomain- containing protein 4 (BRD4).
  • AR androgen receptor
  • ER estrogen receptor
  • STAT5 signal transducer and activator of transcription 3
  • STAT5 signal transducer and activator of transcription 5
  • CBP/p300 CREB-binding protein/EP300(E1A) binding protein
  • SMARCA2/4 Kirsten rat sarcoma viral oncogene homolog G12D
  • SHP2 Src homology region 2-containing protein tyros
  • T is a peptide. In certain embodiments, the peptide has about 5 amino acids. In certain embodiments, the peptide has about 10 amino acids. In certain embodiments, the peptide has about 15 amino acids. In certain embodiments, the peptide has about 20 amino acids. In certain embodiments, the peptide has about 25 amino acids. In certain embodiments, the peptide has about 30 amino acids. In certain embodiments, the peptide has about 35 amino acids. In certain embodiments, the peptide has about 40 amino acids. In certain embodiments, the peptide has about 45 amino acids. In certain embodiments, the peptide has about 50 amino acids. [0288] In certain embodiments, T is a ligand for an estrogen receptor.
  • T is ligand for an androgen receptor. In certain embodiments, T is ligand for a STAT3 protein. [0289] In certain embodiments, T is an estrogen receptor inhibitor. In certain embodiments, T is an androgen receptor inhibitor. In certain embodiments, T is a STAT3 protein inhibitor. [0290]
  • the compounds of the present disclosure possess advantageous characteristics, as compared to known compounds, such as known cereblon-binding agents or known degraders comprising such cereblon-binding agents.
  • the compounds of the present disclosure display more potent cereblon-binding activity or more potent degradation activity against certain proteins, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and/or AUC), and/or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction).
  • beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein.
  • the compounds of the present disclosure may be 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) is a hydrate.
  • the compounds disclosed herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • suitable acid or base such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4, and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [0300] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”.
  • Solvates are within the scope of the invention. [0301] It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present invention. [0302] In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods of treating diseases by administering such solvates. The present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [0303] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like.
  • a solvent such as water, ethanol, and the like.
  • Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent.
  • Tautomers [0308]
  • 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.
  • compositions [0310]
  • the compound described herein is administered as a pure chemical.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • an appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration.
  • Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for intravenous injection.
  • the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.
  • the pharmaceutical composition is formulated as a tablet.
  • the compounds of the present disclosure can be 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)
  • a stereocenter exists in the compounds of the present dislosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L.
  • the reaction was conducted with addition of His tagged (e.g., CRBN+DDB- DLS7+CXU4) followed by addition of fluorescent probe (e.g., Cy5-labeled Thalidomide), and MAb Anti-6HIS Tb cryptate Gold in the assay buffer. After certain period of incubation at room temperature, the HTRF signals were read on a reader.
  • His tagged e.g., CRBN+DDB- DLS7+CXU4
  • fluorescent probe e.g., Cy5-labeled Thalidomide
  • MAb Anti-6HIS Tb cryptate Gold e.g., Cy5-labeled Thalidomide
  • CRBN E3 ubiquitin ligase protein complex is art recognized and refers to an association of proteins in which CRBN, a 442-amino acid protein, forms a Cullin-4-RING E3 ubiquitin ligase (CRL4) complex and interacts with the adaptor protein damaged DNA–binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). Within the CRL4 complex, CRBN acts as a substrate-specificity receptor.
  • DDB1 DNA–binding protein 1
  • CUL4A Cullin-4A
  • ROC1 regulator of cullins 1
  • provided herein are methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.
  • methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.
  • compounds described herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample are compounds described herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.
  • provided herein are methods of degrading a protein in a subject or biological sample comprising administering a conjugate described herein to the subject or contacting the biological sample with a compound described herein. [0327] In certain aspects, provided herein are uses of a conjugate described herein in the manufacture of a medicament for degrading a protein in a subject or biological sample. [0328] In certain aspects, provided herein are conjugates described herein for use in degrading a protein in a subject or biological sample.
  • the protein is an androgen receptor (AR), an estrogen receptor (ER), signal transducer and activator of transcription 3 (STAT3), STAT5, CREB- binding protein/EP300(E1A) binding protein (CBP/p300), SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2/4 (SMARCA2/4), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS G12D), Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), bromodomain- containing protein 4 (BRD4), or BRD9.
  • AR androgen receptor
  • ER estrogen receptor
  • STAT3 signal transducer and activator of transcription 3
  • STAT5 STAT5
  • CBP/p300 CREB- binding protein/EP300(E1A) binding protein
  • SWI/SNF Related SWI/SNF Related
  • Matrix Associated Actin Dependent Regul
  • provided herein are methods of treating or preventing a disease or disorder a subject in need thereof, comprising administering to the subject a conjugate described herein.
  • methods of treating or preventing a disease or disorder a subject in need thereof comprising administering to the subject a conjugate described herein.
  • uses of a conjugate described herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof are uses of a conjugate described herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • the disease or disorder is an estrogen receptor-mediated disease or disorder, an androgen receptor-mediated disease or disorder, or a STAT1/3 protein- mediated disease or disorder.
  • the protein is an androgen receptor (AR)-mediated disease or disorder, an estrogen receptor (ER)-mediated disease or disorder, signal transducer and activator of transcription 3-mediated disease or disorder (STAT3-mediated disease or disorder), STAT5-mediated disease or disorder, CREB-binding protein/EP300(E1A) binding protein-mediated disease or disorder (CBP/p300)-mediated disease or disorder, SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2/4-mediated disease or disorder (SMARCA2/4-mediated disease or disorder), Kirsten rat sarcoma viral oncogene homolog G12D-mediated disease or disorder (KRAS G12D-mediated disease or disorder), Src homology region 2-containing protein tyrosine phosphatase 2- mediated disease or disorder (SHP2-mediated disease or disorder), bromodomain-containing protein 4-mediated disease or disorder (BRD4-mediated disease or disorder), or BRD9-
  • AR androgen receptor
  • the subject is a mammal.
  • the subject is a human.
  • Definitions [0337] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions [0338] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • the following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1-20 alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1-10 alkyl”).
  • an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”).
  • an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like.
  • each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH 3 ).
  • the alkyl group is substituted C 1- 10 alkyl.
  • Alkylene refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • alkelene may be substituted or unsubstituted with one or more substituents as described herein.
  • exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (- CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (- CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Exemplary substituted divalent alkylene groups include but are not limited to, substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -,-CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -,-CH 2 C(CH 3 ) 2 -), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 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) (“C 2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2- 9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 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 (“C 2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C 2-10 alkenyl.
  • the alkenyl group is substituted C 2-10 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.
  • An “alkenylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C 2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2- 8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“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 2-5 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 carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • 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 2-10 alkynyl.
  • the alkynyl group is substituted C 2-10 alkynyl.
  • Alkynylene refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical.
  • alkynylene refers to the range or number of carbons in the linear carbon divalent chain.
  • An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.
  • heteroalkyl refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-10 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1- 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 (“heteroC 1-7 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 (“heteroC 1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC 1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC 1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC 1-2 alkyl”).
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“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 heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 alkyl.
  • heteroalkenyl refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 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 (“heteroC 2-8 alkenyl”).
  • a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC 2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC 2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“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 heteroC 2-10 alkenyl.
  • the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
  • heteroalkynyl refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • one or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkynyl”).
  • a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-5 alkynyl”).
  • a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC 2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC 2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“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 heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
  • heteroalkylene refers to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively.
  • heteroalkylene refers to the range or number of carbons in the linear divalent chain.
  • Heteroalkylene, “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has six ring carbon atoms (“C 6 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 (“C 14 aryl”; e.g., anthracyl).
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C 6-14 aryl.
  • the aryl group is substituted C 6- 14 aryl.
  • Alkyl is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.
  • Heteroaryl refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”).
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”).
  • a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”).
  • a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”).
  • a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”).
  • the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl.
  • the heteroaryl group is substituted 5- to 14-membered heteroaryl.
  • Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6- membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7- membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6- bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Heteroaralkyl is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
  • Carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3- 10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 12 ring carbon atoms (“C 5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C 5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C 5-6 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“ C 3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“ C 3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C 5-12 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C 5-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C 5-6 carbocyclyl”). Examples of C 5-6 carbocyclyl include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3-6 carbocyclyl examples include the aforementioned C 5-6 carbocyclyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 carbocyclyl include the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C 3-12 carbocyclyl. [0363] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3-12 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-12 carbocyclyl.
  • “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share one common bond with, 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 embeded.
  • the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embeded.
  • 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 one 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 embeded.
  • the number of carbons designates the total number of carbons of the bridged rings.
  • Heterocyclyl refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 10- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”).
  • a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”).
  • the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3- to 12- membered heterocyclyl. 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 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 carbons 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 embeded.
  • the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embeded.
  • “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 one 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 embeded.
  • the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embeded.
  • substitution can occur on any of the bridged rings.
  • “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, sulfur, boron, phosphorus, and silicon heteroatom, as valency permits. Hetero may be applied to any of the hydrocarbyl groups described above having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Acyl refers to a radical -C(O)R, wherein R is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein.
  • acylamino groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl- carbonylamino, benzoylamino and benzylcarbonylamino.
  • 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 -NR 2 , wherein each R is independently alkyl, as defined herein.
  • C 1-6 alkylamino refers to the group -NHR or -NR 2 , 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.
  • “Azido” refers to the radical -N 3 .
  • “Amino” refers to the radical -NH 2 .
  • “Hydroxy” refers to the radical -OH.
  • “Cyano” refers to the radical -CN.
  • “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.
  • “Nitro” refers to the radical -NO 2 .
  • Protecting group as used herein is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction.
  • a functional group e.g., hydroxyl, amino, thio, and carboxylic acid
  • hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), ⁇ -Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri- iso-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid
  • MOM methoxymethyl
  • MEM ⁇ -Methoxyethoxymethyl
  • THP tetrahydropyranyl
  • PMP p- methoxyphenyl
  • amino-protecting groups include but not limited to carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), p- methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2- nitro
  • thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-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-t-butyl ester, silyl esters, and orthoesters) and oxazoline.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulf
  • Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • an “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect 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”, “prevention” or “prophylactic treatment” 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).
  • the term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • “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 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.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is termed a “racemic mixture”.
  • “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons.
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)-compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound.
  • the weights are based upon total weight of compound.
  • the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound. [0408] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound.
  • the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure (S)- compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound.
  • the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range.
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
  • the phrase “at least one,” in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • Step A tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step B tert-butyl 7,7-difluoro-6-(4-nitrophenyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate [0420] To a solution of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (6 g, 1 eq, 19.7 mmol) and sodium iodide (2.95 g, 1 eq, 19.7 mmol) in THF (60 mL) was added trifluoromethyltrimethylsilane (29.5 mL, 10 eq, 197 mmol) at room temperature. The mixture was stirred at 65 o C overnight under N 2 atmosphere.
  • Step C tert-butyl (1R,6R)-6-(4-aminophenyl)-7,7-difluoro-3-azabicyclo[4.1.0]heptane-3- carboxylate & tert-butyl (1S,6S)-6-(4-aminophenyl)-7,7-difluoro-3-azabicyclo[4.1.0]heptane- 3-carboxylate [0421] A mixture of tert-butyl 7,7-difluoro-6-(4-nitrophenyl)-3-azabicyclo[4.1.0]heptane-3- carboxylate (5 g, 1 eq, 14.1 mmol) and 10% Pd-C (0.50 g) in EtOH (50 mL) was stirred at room temperature under hydrogen atmosphere for 2 h.
  • Step B 1'-benzyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-2H-spiro[benzofuran-3,4'-piperidine]
  • 1-benzyl-4-((2-bromo-5-((tetrahydro-2H-pyran-2- yl)oxy)phenoxy)methyl)-1,2,3,6-tetrahydropyridine (3.53 g, 1 eq, 7.7 mmol) in toluene (60 mL) was added tributylstannane (6.2 mL, 3 eq, 23.1 mmol) and then AIBN (253 mg, 0.2 eq, 1.54 mmol).
  • Step C 1'-benzyl-2H-spiro[benzofuran-3,4'-piperidin]-6-ol [0441] To the solution of 1'-benzyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-2H-spiro[benzofuran- 3,4'-piperidine] (2.83 g, 1 eq, 7.46 mmol) in MeOH (30 mL) was added 8 mL of 4N HCl/dioxane. The mixture was stirred at 50 °C for 5 h.
  • Step D (R)-3-((1'-benzyl-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)oxy)piperidine-2,6-dione & (S)-3-((1'-benzyl-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)oxy)piperidine-2,6-dione [0442] To a solution of 1'-benzyl-2H-spiro[benzofuran-3,4'-piperidin]-6-ol (350 mg, 1 eq, 1.18 mmol) in THF (5 mL) was added sodium hydride (60% in mineral oil; 57 mg, 1.2 eq, 1.42 mmol) at 60 o C.
  • Step F (S)-3-((2H-spiro[benzofuran-3,4'-piperidin]-6-yl)oxy)piperidine-2,6-dione
  • (S)-3-((1'-benzyl-2H-spiro[benzofuran-3,4'-piperidin]-6- yl)oxy)piperidine-2,6-dione 80 mg, 1 eq, 0.197 mmol
  • 10% Pd/C (16 mg) in DMF 5 mL
  • the reaction was monitored by LCMS.
  • the mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure.
  • Step A tert-butyl 4-(4-(ethoxycarbonyl)-3-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate
  • Step B tert-butyl 6-(4-(ethoxycarbonyl)-3-methylphenyl)-7,7-difluoro-3- azabicyclo[4.1.0]heptane-3-carboxylate [0449] To a solution of tert-butyl 4-(4-(ethoxycarbonyl)-3-methylphenyl)-3,6- dihydropyridine-1(2H)-carboxylate (5 g, 1 eq, 14.5 mmol) and Sodium iodide (2.17 g, 1 eq, 14.5 mmol) in THF (60 mL) was added trifluoromethyltrimethylsilane (21.7 mL, 10 eq, 145 mmol) at room temperature.
  • Step C 4-(3-(tert-butoxycarbonyl)-7,7-difluoro-3-azabicyclo[4.1.0]heptan-6-yl)-2- methylbenzoic acid
  • Step D tert-butyl 6-(4-(((benzyloxy)carbonyl)amino)-3-methylphenyl)-7,7-difluoro-3- azabicyclo[4.1.0]heptane-3-carboxylate
  • 4-(3-(tert-butoxycarbonyl)-7,7-difluoro-3-azabicyclo[4.1.0]heptan-6-yl)- 2-methylbenzoic acid 600 mg, 1 eq, 1.63 mmol
  • diphenylphosphoryl azide 539 mg, 1.2 eq, 1.96 mmol
  • Step E tert-butyl (1R,6R)-6-(4-amino-3-methylphenyl)-7,7-difluoro-3- azabicyclo[4.1.0]heptane-3-carboxylate & tert-butyl (1S,6S)-6-(4-amino-3-methylphenyl)- 7,7-difluoro-3-azabicyclo[4.1.0]heptane-3-carboxylate [0452] A mixture of tert-butyl 6-(4-(((benzyloxy)carbonyl)amino)-3-methylphenyl)-7,7- difluoro-3-azabicyclo[4.1.0]heptane-3-carboxylate (600 mg, 1.27 mmol) and 10% Pd/C (120 mg) in TFE (10 mL) was stirred at room temperature under hydrogen atmosphere for 2 h.
  • the mixture was stirred at 80 o C under N 2 atmosphere for 48 h.
  • the mixture was diluted with water (10 mL) and extracted with EA (20 mL x 3).
  • the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step B tert-butyl 4-((2-bromo-5-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)- carboxylate
  • 2-bromo-5-nitrophenol (12.0 g, 55.0 mmol, 1 eq.)
  • tert-butyl 4- (hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (12.9 g, 60.5 mmol, 1.1 eq.)
  • triphenylphosphane (17.3 g, 66.1 mmol, 1.2 eq.) in THF (200 mL) was slowly added DIAD (13 mL, 66.1 mmol, 1.2 eq.) at 0 °C.
  • Step C tert-butyl 6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'- carboxylate
  • Step D tert-butyl 6-amino-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate
  • a mixture of tert-butyl 6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]- 1'-carboxylate (6 g, 18.1 mmol) and 10% Pd/C (800 mg) in CF 3 CH 2 OH (60 mL) was stirred at room temperature under H 2 atmosphere (1 atm) for 16 hours. The mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure.
  • Step E tert-butyl (R)-6-((2,6-dioxopiperidin-3-yl)amino)-2H-spiro[benzofuran-3,4'- piperidine]-1'-carboxylate & tert-butyl (S)-6-((2,6-dioxopiperidin-3-yl)amino)-2H- spiro[benzofuran-3,4'-piperidine]-1'-carboxylate [0478] A solution of tert-butyl 6-amino-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (4 g, 13.1 mmol, 1 eq.), 3-bromopiperidine-2,6-dione (4.54 g, 23.7 mmol, 1.8 eq.) and Sodium bicarbonate (3.31 g, 39.4 mmol, 3 eq.) in MeCN (70 mL) was stir
  • Step G (S)-3-((2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)piperidine-2,6-dione HCl salt
  • a solution of tert-butyl (S)-6-((2,6-dioxopiperidin-3-yl)amino)-2H-spiro[benzofuran- 3,4'-piperidine]-1'-carboxylate 650 mg, 1.56 mmol
  • HCl/dioxane 4 M, 20 mL
  • Step B tert-butyl (R)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine- 3(4H)-carboxylate
  • tert-butyl (R)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2- d][1,4]oxazine-3(4H)-carboxylate 2.5 g, 7.4 mmol, 1 eq.
  • Step C tert-butyl (4aR)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5- tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate
  • tert-butyl (R)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2- d][1,4]oxazine-3(4H)-carboxylate 0.7 g, 2.3 mmol 1 eq.
  • 3-bromopiperidine-2,6-dione 440 mg, 2.3 mmol, 1 eq.
  • Step D 3-(((R)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8- yl)amino)piperidine-2,6-dione hydrochloride salt
  • a mixture of tert-butyl (4aR)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5- tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (50.0 mg, 0.12 mmol, 1.0 eq.) in HCl/dioxane (1 mL) was stirred at room temperature for 2h.
  • Step A (2-bromo-5-nitrophenyl)methanol
  • 2-bromo-5-nitrobenzoic acid (2 g, 8.13 mmol, 1.0 eq.) in THF (5 mL)
  • BH 3 (1 M in THF, 16.3 mL, 16.3 mmol, 2.0 eq.
  • the mixture solution was stirred at 60 °C for 2 hours.
  • water (10 mL) at room temperature the solution was adjusted to pH ⁇ 1 with 6 N HCl aq. and extracted with EA (20 x 3 mL).
  • the combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step B tert-butyl 4-(2-(hydroxymethyl)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate
  • Step C tert-butyl 3'-bromo-5-nitro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylate
  • Step D tert-butyl 5-amino-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylate
  • a mixture of tert-butyl 3'-bromo-5-nitro-3H-spiro[isobenzofuran-1,4'-piperidine]-1'- carboxylate (200 mg, 484 ⁇ mol) and 10% Pd/C (103 mg) in EtOH (5 mL) was stirred at 25 °C under H2 atmosphere (1 atm) for 5 hours. The mixture solution was filtrated through a Celite pad and the filtrate was concentrated under reduced pressure.
  • Step E tert-butyl 5-((2,6-dioxopiperidin-3-yl)amino)-3H-spiro[isobenzofuran-1,4'- piperidine]-1'-carboxylate
  • Step F 3-((3H-spiro[isobenzofuran-1,4'-piperidin]-5-yl)amino)piperidine-2,6-dione HCO 2 H salt
  • a mixture of tert-butyl 5-((2,6-dioxopiperidin-3-yl)amino)-3H-spiro[isobenzofuran- 1,4'-piperidine]-1'-carboxylate 25 mg, 60.2 ⁇ mol
  • 4 M HCl in dioxane (1 mL) in DCM (2 mL) was stirred at 25 °C for 1 hour.
  • Step C tert-butyl 3',3'-difluoro-6-nitro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate
  • Step E tert-butyl 6-((2,6-dioxopiperidin-3-yl)amino)-3',3'-difluoro-2H-spiro[benzofuran-3,4'- piperidine]-1'-carboxylate
  • a mixture of tert-butyl 6-amino-3',3'-difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'- carboxylate 300 mg, 881 ⁇ mol, 1 eq.
  • 3-bromopiperidine-2,6-dione (254 mg, 1.32 mmol, 1.5 eq.
  • sodium bicarbonate 222 mg, 2.64 mmol, 3 eq.
  • Step F 3-((3',3'-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)piperidine-2,6- dione HCOOH salt
  • Step A 8-((2-bromo-5-nitrophenoxy)methyl)-1,4-dioxaspiro[4.5]dec-7-ene
  • Step B 6-nitro-2H-dispiro[benzofuran-3,1'-cyclohexane-4',2''-[1,3]dioxolan]-2'-ene
  • Step C 2H-dispiro[benzofuran-3,1'-cyclohexane-4',2''-[1,3]dioxolan]-6-amine
  • Step D 3-((2H-dispiro[benzofuran-3,1'-cyclohexane-4',2''-[1,3]dioxolan]-6- yl)amino)piperidine-2,6-dione
  • a mixture of 2H-dispiro[benzofuran-3,1'-cyclohexane-4',2''-[1,3]dioxolan]-6-amine 100 mg, 383 ⁇ mol, 1 eq.
  • 3-bromopiperidine-2,6-dione 110 mg, 574 ⁇ mol, 1.5 eq.
  • sodium bicarbonate 96 mg, 1.15 mmol, 3.0 eq.
  • Step E 3-((4'-oxo-2H-spiro[benzofuran-3,1'-cyclohexan]-6-yl)amino)piperidine-2,6-dione [0509] A solution of 3-((2H-dispiro[benzofuran-3,1'-cyclohexane-4',2''-[1,3]dioxolan]-6- yl)amino)piperidine-2,6-dione (60 mg, 161 ⁇ mol, 1 eq.) and 3 N HCl aq. in acetone (3 mL) was stirred at 25 °C for 1 hour.
  • Step A tert-butyl 4-((2-bromo-4-fluoro-5-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)- carboxylate
  • 2-bromo-4-fluoro-5-nitrophenol 500 mg, 2.12 mmol, 1 eq.
  • tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate 587 mg, 2.75 mmol, 1.3 eq.
  • PPh3 (1.67 g, 6.36 mmol, 3 eq.
  • Step B tert-butyl 5-fluoro-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'- carboxylate
  • a mixture of tert-butyl 4-((2-bromo-4-fluoro-5-nitrophenoxy)methyl)-3,6- dihydropyridine-1(2H)-carboxylate 500 mg, 1.16 mmol, 1 eq.), tetraethylammonium chloride (211 mg, 1.28 mmol, 1.1 eq.), sodium acetate (238 mg, 2.9 mmol, 2.5 eq.), sodium formate (86 mg, 1.28 mmol, 1.1 eq.) and palladium diacetate (26 mg, 0.1 eq.
  • Step C tert-butyl 6-amino-5-fluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate [0513] A mixture of tert-butyl 5-fluoro-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'- pyridine]-1'-carboxylate (220 mg, 628 ⁇ mol) and 10% Pd/C (44 mg) in TFE (10 mL) was stirred at 25 °C under H2 atmosphere (1 atm) for 16 hours.
  • Step D tert-butyl 6-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-fluoro-2H-spiro[benzofuran- 3,4'-piperidine]-1'-carboxylate
  • a mixture of tert-butyl 6-amino-5-fluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'- carboxylate 160 mg, 496 ⁇ mol, 1 eq.
  • 2,6-bis(benzyloxy)-3-bromopyridine (276 mg, 744 ⁇ mol, 1.5 eq.
  • Pd 2 (dba) 3 45 mg, 49.6 ⁇ mol, 0.1 eq.
  • X-Phos 23 mg, 49.6 ⁇ mol, 0.1 eq.
  • Cs2CO3 485 mg, 1.49 mmol, 3 eq.
  • Step E tert-butyl 6-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2H-spiro[benzofuran-3,4'- piperidine]-1'-carboxylate
  • tert-butyl 6-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-fluoro-2H- spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (170 mg, 278 ⁇ mol) and 10% Pd/C (33 mg) in TFE (10 mL) was stirred at 25 °C under H 2 atmosphere (1 atm) for 16 hours.
  • Step F 3-((5-fluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)piperidine-2,6-dione HCl salt
  • a mixture of tert-butyl 6-((2,6-dioxopiperidin-3-yl)amino)-5-fluoro-2H- spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (20 mg, 46.1 ⁇ mol) and 4 M HCl/Dioxane (0.3 mL) in MeCN (3 mL) was stirred at 25 °C for 3 hours.
  • Step B 5-amino-2-bromo-3-fluorophenol [0520] To a solution of 4-bromo-3-fluoro-5-methoxyaniline (3.2 g, 14.5 mmol, 1 eq.) in DCM (30 mL) was added BBr 3 (6.9 mL, 72.7 mmol, 5 eq.) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After quenched with water (10 mL) at 0 °C, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with sat. NaHCO 3 aq.
  • Step C tert-butyl 4-((5-amino-2-bromo-3-fluorophenoxy)methyl)-3,6-dihydropyridine-1(2H)- carboxylate
  • 5-amino-2-bromo-3-fluorophenol (483 mg, 2.34 mmol, 1 eq.)
  • tert- butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate 500 mg, 2.34 mmol, 1 eq.
  • triphenylphosphine 922 mg, 3.52 mmol, 1.5 eq.
  • DIAD 0.7 mL, 3.52 mmol, 1.5 eq.
  • Step D tert-butyl 6-amino-4-fluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate
  • Step E tert-butyl 6-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-4-fluoro-2H-spiro[benzofuran- 3,4'-piperidine]-1'-carboxylate
  • a mixture of tert-butyl 6-amino-4-fluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'- carboxylate (90 mg, 279 ⁇ mol, 1 eq.), 2,6-bis(benzyloxy)-3-bromopyridine (124 mg, 335 ⁇ mol, 1.2 eq.), Pd2(dba)3 (26 mg, 27.9 ⁇ mol, 0.1 eq.), 2-(dicyclohexylphosphanyl)-2',4',6'- tris(isopropyl)-2',4',6'- tris(isopropyl)-2',4',6'- tris(is
  • Step F tert-butyl 6-((2,6-dioxopiperidin-3-yl)amino)-4-fluoro-2H-spiro[benzofuran-3,4'- piperidine]-1'-carboxylate
  • tert-butyl 6-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-4-fluoro-2H- spiro[benzofuran-3,4'-piperidine]-1'-carboxylate 100 mg, 163 ⁇ mol
  • 10% Pd-C 150 mg
  • Step G 3-((4-fluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)amino)piperidine-2,6-dione HCl salt
  • the reaction was conducted in total volume of 20 ⁇ L with addition of 2 nM His tagged CRBN+DDB-DLS7+CXU4 (Wuxi, catalogue # RP210521GA) to compounds followed by addition of 60 nM Fluorescent probe Cy5-labeled Thalidomide (Tenova Pharma, catalogue # T52461), and 0.4 nM of MAb Anti-6HIS Tb cryptate Gold (Cisbio, catalogue # 61HI2TLA in the assay buffer (50 mM HEPES pH 7.5, 1 mM TCEP, 0.01% Brij-35, 50 mM NaCl, and 0.1% BSA).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés et des conjugués de formules I et II et leurs sels, solvates ou stéréoisomères pharmaceutiquement acceptables, ainsi que leurs utilisations (par exemple, en tant qu'agents de liaison au céréblon et agents de dégradation bifonctionnels pour certaines protéines).
PCT/US2023/027353 2022-07-12 2023-07-11 Ligands de céréblon et leurs utilisations WO2024015346A1 (fr)

Applications Claiming Priority (22)

Application Number Priority Date Filing Date Title
US202263388300P 2022-07-12 2022-07-12
US202263388302P 2022-07-12 2022-07-12
US202263388299P 2022-07-12 2022-07-12
US202263388297P 2022-07-12 2022-07-12
US63/388,300 2022-07-12
US63/388,297 2022-07-12
US63/388,299 2022-07-12
US63/388,302 2022-07-12
US202263408633P 2022-09-21 2022-09-21
US202263408744P 2022-09-21 2022-09-21
US202263408601P 2022-09-21 2022-09-21
US202263408758P 2022-09-21 2022-09-21
US63/408,744 2022-09-21
US63/408,633 2022-09-21
US63/408,758 2022-09-21
US63/408,601 2022-09-21
US202263412346P 2022-09-30 2022-09-30
US63/412,346 2022-09-30
US202263427277P 2022-11-22 2022-11-22
US63/427,277 2022-11-22
US202363460734P 2023-04-20 2023-04-20
US63/460,734 2023-04-20

Publications (1)

Publication Number Publication Date
WO2024015346A1 true WO2024015346A1 (fr) 2024-01-18

Family

ID=87556269

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/027353 WO2024015346A1 (fr) 2022-07-12 2023-07-11 Ligands de céréblon et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2024015346A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019074824A1 (fr) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs procédés d'utilisation
WO2019136244A1 (fr) * 2018-01-04 2019-07-11 G1 Therapeutics, Inc. Composés hétérocycliques pour le traitement d'une prolifération cellulaire anormale
WO2022082876A1 (fr) * 2020-10-20 2022-04-28 苏州大学 Agent dégradant c-met basé sur la dégradation ciblée de protéine, son procédé de préparation et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019074824A1 (fr) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs procédés d'utilisation
WO2019136244A1 (fr) * 2018-01-04 2019-07-11 G1 Therapeutics, Inc. Composés hétérocycliques pour le traitement d'une prolifération cellulaire anormale
WO2022082876A1 (fr) * 2020-10-20 2022-04-28 苏州大学 Agent dégradant c-met basé sur la dégradation ciblée de protéine, son procédé de préparation et son utilisation

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Organic Reactions", vol. 55, 1942, JOHN WILEY & SONS
"Remington: The Science and Practice of Pharmacy", 2005, MACK PUB. CO.
CARRUTHERS: "Some Modern Methods of Organic Synthesis", 1987, CAMBRIDGE UNIVERSITY PRESS
CHEMICAL COMMUNICATIONS, vol. 19, 2009, pages 2756 - 2758
E. L. ELIELS. H. WILENL. N. MANDER: "Organic Synthesis: Concepts, Methods, Starting Materials", 1994, WILEY-INTERSCIENCE
ELIEL: "Stereochemistry of Carbon Compounds", 1962, MCGRAW-HILL
H. O. HOUSEW. A. BENJAMIN, INC. MENLO PARK: "Tables of Resolving Agents and Optical Resolutions", 1972, E.F. ELIEL, ED., 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
LAROCK, COMPREHENSIVE ORGANIC TRANSFORMATIONS, VCH PUBLISHERS, INC., 1989
S. R. SANDLER ET AL.: "Organic Functional Group Preparations", 1983, JOHN WILEY & SONS, INC.
SCIENCE, vol. 343, 2014, pages 305
SMITHMARCH: "March's Advanced Organic Chemistry", vol. 73, 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, article "Patai's 1992 Guide to the Chemistry of Functional Groups"
THOMAS SORRELL: "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia", vol. 8, 1999, UNIVERSITY SCIENCE BOOKS
WILEN ET AL., TETRAHEDRON, vol. 33, 1977, pages 2725

Similar Documents

Publication Publication Date Title
US20210198277A1 (en) Amine-substituted aryl or heteroaryl compounds
JP5116660B2 (ja) Ｈｉｖインテグラーゼ阻害剤
JP5759471B2 (ja) Ｊａｋ３キナーゼ阻害剤としての窒素含有ヘテロアリール誘導体
AU2019318543B2 (en) Transglutaminase 2 (TG2) inhibitors
AU2015240518A1 (en) Inhibitors of cyclin-dependent kinase 7 (CDK7)
JP2009507070A (ja) Ｃｃｒ８介在疾患の処置のための新規ジアザスピロアルカン類およびそれらの使用
CA2961186A1 (fr) Derive tricyclique
EP2307418A1 (fr) Nouvelles phénylimidazopyrazines
US11691981B2 (en) Heterocyclic compounds, preparation methods therefor, and methods of uses thereof
JP2022521536A (ja) イミダゾピリジニル化合物及び神経変性障害の処置のためのその使用
WO2021259815A1 (fr) Dérivés d'amidopyrimidone
JP2024510274A (ja) アミノヘテロアリール化合物および組成物
WO2023183607A1 (fr) Ligands du céréblon et leurs utilisations
WO2018038667A1 (fr) Inhibiteurs du virus respiratoire syncytial
WO2024015346A1 (fr) Ligands de céréblon et leurs utilisations
EP4251613A1 (fr) Inhibiteurs de kinases de type aminohétéroaryle
WO2024073475A1 (fr) Ligands de cereblon et utilisations associées
WO2024086644A1 (fr) Ligands de céréblon et leurs utilisations
US20240059704A1 (en) Cereblon Ligands and Uses Thereof
US20240059711A1 (en) Cereblon Ligands and Uses Thereof
WO2024015340A1 (fr) Ligands de céréblon et leurs utilisations
WO2023201012A1 (fr) Agents de dégradation d'ikzf2 et leurs utilisations
WO2024103069A1 (fr) Composés et compositions en tant qu'inhibiteurs d'eif4e et leurs utilisations
WO2024103067A1 (fr) Composés et compositions en tant qu'inhibiteurs de eif4e et leurs utilisations
CA3215491A1 (fr) Composes amino aza-heteroaryles a substitution halo utilises en tant qu'inhibiteurs de la kinase des progeniteurs hematopoietiques 1 (hpk1)

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: 23751161

Country of ref document: EP

Kind code of ref document: A1