WO2024073475A1 - Cereblon ligands and uses thereof - Google Patents

Cereblon ligands and uses thereof Download PDF

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Publication number
WO2024073475A1
WO2024073475A1 PCT/US2023/075207 US2023075207W WO2024073475A1 WO 2024073475 A1 WO2024073475 A1 WO 2024073475A1 US 2023075207 W US2023075207 W US 2023075207W WO 2024073475 A1 WO2024073475 A1 WO 2024073475A1
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Prior art keywords
carbocyclyl
alkyl
alkynyl
alkenyl
compound
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PCT/US2023/075207
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French (fr)
Inventor
Guozhang Xu
Xuqing Zhang
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Oncopia Therapeutics, Inc. D/B/A Proteovant Therapeutics, Inc.
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Publication of WO2024073475A1 publication Critical patent/WO2024073475A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—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

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 PROTAC molecules based on CRBN ligands have been developed.
  • the present disclosure provides compounds of Formula II or conjugates of Formula II’: wherein each of the variables in Formula II or Formula II’ is described, embodied, and exemplified herein. [0006] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound or a conjugate disclosed herein, and a pharmaceutically acceptable excipient.
  • the present disclosure provides methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering the compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein. [0008] In certain aspects, the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. [0009] In certain aspects, the present disclosure provides compounds disclosed herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.
  • the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering the conjugate disclosed herein to the subject. [0011] In certain aspects, the present disclosure provides uses of the conjugate disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0012] In certain aspects, the present disclosure provides conjugates disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. Attorney Docket No.
  • the present disclosure relates to compounds that show cereblon-binding activity, or conjugates in degrading certain proteins, and pharmaceutical compositions comprising such compounds or conjugates.
  • heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R u , together with the one or more intervening atoms, form C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each R a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; each R b is independently hydrogen
  • the compound of Formula II is a compound of Formula II-1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the compound of Formula II is a compound of Formula II-2 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the compound of Formula II is a compound of Formula II-1-i or II-2-i Attorney Docket No. PRSC-074/001WO 343170-2268 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • Ring A is C 3-12 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), 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 ), cyclononyl (C 9 ),
  • Ring A is piperidinyl, 3-azaspiro[5.5]undecanyl, 2- azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, or 5-oxa-2- azaspiro[3.4]octyl.
  • 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 (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-
  • PRSC-074/001WO 343170-2268 pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cyclo
  • each R A is independently oxo, halogen, -CN, -NO2, -OH, - NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 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, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R A is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • m is an integer selected from 0 to 10, as valency permits. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.
  • m is 4. In certain embodiments, m is 5, as valency permits. In certain embodiments, m is 6, as valency permits. In certain Attorney Docket No. PRSC-074/001WO 343170-2268 embodiments, m is 7, as valency permits. In certain embodiments, m is 8, as valency permits. In certain embodiments, m is 9, as valency permits. In certain embodiments, m is 10, as valency permits.
  • R B1 and R B2 are independently hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )), C 1- 6 alkoxy (e.g., methoxy (C 1 ), ethoxy (C 2 ), propoxy (C 3 ), i-propoxy (C 3 ), n-butoxy (C 4 ), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), t-butoxy
  • R B1 and R B2 are independently hydrogen, halogen, -CN, -NO 2 , -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R B1 and R B2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 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 and R B2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • R B1 is hydrogen.
  • R B2 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy.
  • the bond between Y and U is absent, then: r is 0 or 1; X is O or N; wherein when X is O, then U is absent; when X is N, then U is hydrogen or C 1-6 alkyl optionally substituted with one or more R u ; Y is CR Y .
  • R Y is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -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 (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C 4 ), pentoxy (C 5
  • PRSC-074/001WO 343170-2268 butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g.
  • R Y is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C 6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • R Y 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 3-6 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 Y is hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the Attorney Docket No. PRSC-074/001WO 343170-2268 alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • R Y is hydrogen.
  • R D is hydrogen, deuterium, C1-6 haloalkyl (e.g., C1-6 alkyl comprising 1 to 8 halogen atoms selected from -F, -Cl, -Br, and -I), or C1-6 alkyl (e.g., methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), i-propyl (C 3 ), n-butyl (C 4 ), i-butyl (C 4 ), s-butyl (C 4 ), t-butyl (C 4 ), pentyl (C 5 ), or hexyl (C 6 )).
  • C1-6 haloalkyl e.g., C1-6 alkyl comprising 1 to 8 halogen atoms selected from -F, -Cl, -Br, and -I
  • C1-6 alkyl e.g., methyl (C 1 ), ethyl (
  • R D is hydrogen.
  • each R D1 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 (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), s- butoxy
  • halogen
  • PRSC-074/001WO 343170-2268 heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • each R D1 is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, 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 D1 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 D1 is independently oxo, halogen, -CN, -NO 2 , -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • d is an integer selected from 0 to 5. In certain embodiments, 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.
  • d is 5.
  • q is an integer from 0 to 2.
  • q is 0.
  • q is 1.
  • q is 2.
  • the compound of Formula I is a compound of Formula I-1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • Attorney Docket No. PRSC-074/001WO 343170-2268 [0048]
  • U is -CH2-.
  • the compound of Formula I is a compound of Formula I-2 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • R Y is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, 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 Y is hydrogen.
  • Ring A is 3-membered heterocyclyl. In certain embodiments, Ring A is 4-membered heterocyclyl. In certain embodiments, Ring A is 5-membered heterocyclyl. In certain embodiments, Ring A is 6-membered heterocyclyl. In certain embodiments, Ring A is 7-membered heterocyclyl. In certain embodiments, Ring A is 8- membered heterocyclyl. In certain embodiments, Ring A is 9-membered heterocyclyl. In certain embodiments, Ring A is 10-membered heterocyclyl. In certain embodiments, Ring A is 11-membered heterocyclyl. In certain embodiments, Ring A is 12-membered heterocyclyl.
  • Ring A is 3- to 12-membered heterocyclyl. In certain embodiments, Ring A is 3- to 11-membered heterocyclyl. In certain embodiments, Ring A is 3- to 10-membered heterocyclyl. In certain embodiments, Ring A is 3- to 9-membered heterocyclyl. In certain embodiments, Ring A is 3- to 8-membered heterocyclyl. In certain embodiments, Ring A is 3- to 7-membered heterocyclyl. In certain embodiments, Ring A is 3- to 6-membered heterocyclyl. In certain embodiments, Ring A is 3- to 5-membered heterocyclyl. In certain embodiments, Ring A is 3- to 4-membered heterocyclyl.
  • Ring A is 4- to 12-membered heterocyclyl. In certain embodiments, Ring A is 4- to 11-membered heterocyclyl. In certain embodiments, Ring A is 4- to 10-membered heterocyclyl. In certain embodiments, Ring A is 4- to 9-membered heterocyclyl. In certain embodiments, Ring A is 4- to 8-membered heterocyclyl. In certain embodiments, Ring A is 4- to 7-membered heterocyclyl. In certain embodiments, Ring A is 4- to 6-membered Attorney Docket No. PRSC-074/001WO 343170-2268 heterocyclyl. In certain embodiments, Ring A is 4- to 5-membered heterocyclyl.
  • Ring A is 5- to 12-membered heterocyclyl. In certain embodiments, Ring A is 5- to 11-membered heterocyclyl. In certain embodiments, Ring A is 5- to 10-membered heterocyclyl. In certain embodiments, Ring A is 5- to 9-membered heterocyclyl. In certain embodiments, Ring A is 5- to 8-membered heterocyclyl. In certain embodiments, Ring A is 5- to 7-membered heterocyclyl. In certain embodiments, Ring A is 5- to 6-membered heterocyclyl. In certain embodiments, Ring A is 6- to 12-membered heterocyclyl. In certain embodiments, Ring A is 6- to 11-membered heterocyclyl.
  • Ring A is 6- to 10-membered heterocyclyl. In certain embodiments, Ring A is 6- to 9-membered heterocyclyl. In certain embodiments, Ring A is 6- to 8-membered heterocyclyl. In certain embodiments, Ring A is 6- to 7-membered heterocyclyl. In certain embodiments, Ring A is 8- to 12-membered heterocyclyl. In certain embodiments, Ring A is 8- to 11-membered heterocyclyl. In certain embodiments, Ring A is 8- to 10-membered heterocyclyl. In certain embodiments, Ring A is 8- to 9-membered heterocyclyl. In certain embodiments, Ring A is 9- to 12-membered heterocyclyl.
  • Ring A is 9- to 11-membered heterocyclyl. In certain embodiments, Ring A is 9- to 10-membered heterocyclyl. In certain embodiments, Ring A is 10- to 12-membered heterocyclyl. In certain embodiments, Ring A is 10- to 11-membered heterocyclyl. In certain embodiments, Ring A is 11- to 12-membered heterocyclyl. [0054] In certain embodiments, Ring A is heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring A is heterocyclyl comprising 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring A is heterocyclyl comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring A is heterocyclyl comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring A is heterocyclyl comprising 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring A is heterocyclyl comprising 2 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring A is heterocyclyl comprising 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring A is heterocyclyl comprising 3 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Attorney Docket No. PRSC-074/001WO 343170-2268 [0056] In certain embodiments, Ring A is C3 carbocyclyl. In certain embodiments, Ring A is C4 carbocyclyl. In certain embodiments, Ring A is C5 carbocyclyl. In certain embodiments, Ring A is C 6 carbocyclyl. In certain embodiments, Ring A is C 7 carbocyclyl. In certain embodiments, Ring A is C8 carbocyclyl. In certain embodiments, Ring A is C9 carbocyclyl. In certain embodiments, Ring A is C10 carbocyclyl.
  • Ring A is C11 carbocyclyl. In certain embodiments, Ring A is C 12 carbocyclyl. [0057] In certain embodiments, Ring A is C 3-12 carbocyclyl. In certain embodiments, Ring A is C3-11 carbocyclyl. In certain embodiments, Ring A is C3-10 carbocyclyl. In certain embodiments, Ring A is C 3-9 carbocyclyl. In certain embodiments, Ring A is C 3-8 carbocyclyl. In certain embodiments, Ring A is C 3-7 carbocyclyl. In certain embodiments, Ring A is C 3-6 carbocyclyl. In certain embodiments, Ring A is C3-5 carbocyclyl. In certain embodiments, Ring A is C3-4 carbocyclyl.
  • Ring A is C4-12 carbocyclyl. In certain embodiments, Ring A is C 4-11 carbocyclyl. In certain embodiments, Ring A is C 4-10 carbocyclyl. In certain embodiments, Ring A is C4-9 carbocyclyl. In certain embodiments, Ring A is C4-8 carbocyclyl. In certain embodiments, Ring A is C4-7 carbocyclyl. In certain embodiments, Ring A is C 4-6 carbocyclyl. In certain embodiments, Ring A is C 4-5 carbocyclyl. In certain embodiments, Ring A is C 5-12 carbocyclyl. In certain embodiments, Ring A is C 5-11 carbocyclyl. In certain embodiments, Ring A is C5-10 carbocyclyl.
  • Ring A is C5-9 carbocyclyl. In certain embodiments, Ring A is C 5-8 carbocyclyl. In certain embodiments, Ring A is C 5-7 carbocyclyl. In certain embodiments, Ring A is C 5-6 carbocyclyl. In certain embodiments, Ring A is C6-12 carbocyclyl. In certain embodiments, Ring A is C6-11 carbocyclyl. In certain embodiments, Ring A is C 6-10 carbocyclyl. In certain embodiments, Ring A is C 6-9 carbocyclyl. In certain embodiments, Ring A is C 6-8 carbocyclyl. In certain embodiments, Ring A is C6-7 carbocyclyl. In certain embodiments, Ring A is C7-12 carbocyclyl.
  • Ring A is C7-11 carbocyclyl. In certain embodiments, Ring A is C7-10 carbocyclyl. In certain embodiments, Ring A is C 7-9 carbocyclyl. In certain embodiments, Ring A is C 7-8 carbocyclyl. In certain embodiments, Ring A is C8-12 carbocyclyl. In certain embodiments, Ring A is C8-11 carbocyclyl. In certain embodiments, Ring A is C8-10 carbocyclyl. In certain embodiments, Ring A is C 8-9 carbocyclyl. In certain embodiments, Ring A is C 9-12 carbocyclyl. In certain embodiments, Ring A is C 9-11 carbocyclyl. In certain embodiments, Ring A is C 9-10 carbocyclyl.
  • Ring A is C10-12 carbocyclyl. In certain embodiments, Ring A is C 10-11 carbocyclyl. In certain embodiments, Ring A is C 11-12 carbocyclyl. [0058] In certain embodiments, Ring A is piperidinyl. Attorney Docket No. PRSC-074/001WO 343170-2268 [0059] In certain embodiments, the compound of Formula I is a compound of Formula I-1-i or I-2-i or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • each R A is independently oxo, halogen, -CN, -NO 2 , -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10- membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • At least one R A is oxo. In certain embodiments, at least one R A is halogen. In certain embodiments, at least one R A is -CN. In certain embodiments, at least one R A is -NO 2 . In certain embodiments, at least one R A is -OH. In certain embodiments, at least one R A is -NH2. In certain embodiments, at least one R A is C1-6 alkyl optionally substituted with one or more R u . In certain embodiments, at least one R A is C 1-6 alkoxy optionally substituted with one or more R u . In certain embodiments, at least one R A is C 1-6 alkylamino optionally substituted with one or more R u .
  • At least one R A is C2-6 alkenyl. In certain embodiments, at least one R A is C2-6 alkynyl. In certain embodiments, at least one R A is C 3-6 carbocyclyl optionally substituted with one or more R u . In certain embodiments, at least one R A is 3- to 6-membered heterocyclyl optionally substituted with one or more R u . [0062] In certain embodiments, 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.
  • m is 9. In certain embodiments, m is 10. [0063] In certain embodiments, m is an integer selected from 0 to 10. In certain embodiments, m is an integer selected from 0 to 8. In certain embodiments, m is an integer selected from 0 to 6. In certain embodiments, m is an integer selected from 0 to 4. In certain embodiments, m is an integer selected from 0 to 2. In certain embodiments, m is an integer selected from 2 to 10. In certain embodiments, m is an integer selected from 2 to 8. In certain embodiments, m is an integer selected from 2 to 6. In certain embodiments, m is an integer selected from 2 to 4. In Attorney Docket No.
  • m is an integer selected from 4 to 10. In certain embodiments, m is an integer selected from 4 to 8. In certain embodiments, m is an integer selected from 4 to 6. In certain embodiments, m is an integer selected from 6 to 10. In certain embodiments, m is an integer selected from 6 to 8. In certain embodiments, m is an integer selected from 8 to 10.
  • R B1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 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 is hydrogen.
  • R B2 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, 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 B2 is hydrogen.
  • R D is hydrogen. In certain embodiments, R D is deuterium. In certain embodiments, R D is C1-6 haloalkyl. In certain embodiments, R D is C1-6 alkyl. [0069] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [0070] In certain embodiments, q is an integer selected from 0 to 2. In certain embodiments, q is 0 or 1. In certain embodiments, q is 1 or 2.
  • each R a is independently C 1-6 alkyl (e.g., methyl (C 1 ), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 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., ethynyl (C2), 1-propynyl (C3), n
  • PRSC-074/001WO 343170-2268 comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R u .
  • 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 C1-6 alkyl, C2-6 alkenyl, C2-6 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 (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (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., ethynyl (C 2 ), 1-
  • each R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C3-6 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, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.
  • each R b is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • each R c and each R d is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (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 (C6), C2-6 alkynyl (e.g., ethyl (C2), n-
  • each R c and each R d is independently hydrogen, C1-6 alkyl, C3- 6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more R u .
  • R c and R d together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more R 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, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl.
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), Attorney Docket No.
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- Attorney Docket No.
  • 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, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl
  • each R u is independently oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 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 (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).
  • C 3 cyclopropyl
  • C 3 cyclopropenyl
  • C 4 cyclobutyl
  • C4 cyclobutenyl
  • C4 cyclobutenyl
  • C5 cyclopentyl
  • C5 cyclopen
  • two geminal R u together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (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).
  • C3-6 carbocyclyl e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C 4 ), cyclopentyl (C 5
  • C1-6 alkyl is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the corresponding (R)-isomers of the compounds in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the corresponding (S)-isomers of the compounds in Table 1 and pharmaceutically acceptable salts thereof. [0097] In certain embodiments, the compound is selected from the compounds in Table 1. [0098] In certain embodiments, the compound is selected from the corresponding (R)-isomers of the compounds in Table 1. [0099] In certain embodiments, the compound is selected from the corresponding (S)-isomers of the compounds in Table 1. Table 1. *Note: the compounds below are enantiomerically pure but the absolute configuration of the stereogenic center at glutarimide is not determined. Attorney Docket No. PRSC-074/001WO 343170-2268 Attorney Docket No.
  • 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: each variable referenced in Formula II’ (e.g., Ring A, R A , m, R B1 , R B2 , etc.) are described for Formula II above.
  • L is a linker
  • T is a ligand for a protein.
  • the conjugate of Formula II’ is a conjugate of Formula II’-1 or II’-2 Attorney Docket No. PRSC-074/001WO 343170-2268 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • 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 degrades the target protein.
  • each L ’ is independently C1-6 alkylene (e.g., methylene (-CH2- ), 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 CH 2 -)), C 1-6 heteroalkylene (e.g., C1-6 alkylene comprising 1-7 heteroatoms selected from N, O, and S), C2-6 alkenylene (e.g., ethenylene (C2), 1-propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2- butenylene (C 4 ), butadienylene (C 4 ), pentenylene (C 5 ), pentadienylene (C 5 ), or hexenylene (C6)
  • C1-6 heteroalkylene
  • 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 (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C 5 ), or hexenyl (C 6 )), C 2-6 alkynyl (e.g., ethynyl (
  • l is 0. In certain embodiments, l is 1. In certain embodiments, l is 2.
  • l is 3. In certain embodiments, l is 4. In certain embodiments, l is 5. In certain embodiments, l is 6.
  • 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 Attorney Docket No.
  • T is a small molecule.
  • T is an antibody.
  • T is a peptide. In certain embodiments, the peptide has about 5 amino acids.
  • 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. [0115] In certain embodiments, 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.
  • T is an estrogen receptor inhibitor. In certain embodiments, T is an androgen receptor inhibitor. In certain embodiments, T is a STAT3 protein inhibitor. EXEMPLARY EMBODIMENTS EXEMPLARY EMBODIMENT 1.
  • PRSC-074/001WO 343170-2268 selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R u , together with the one or more intervening atoms, form C 6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each R a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; each R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C
  • EXEMPLARY EMBODIMENT 3 The compound or conjugate of any one of the preceding compound or conjugate, wherein the compound of Formula II is a compound of Formula II-1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the conjugate of Formula II’ is a conjugate of Formula II’-1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • EXEMPLARY EMBODIMENT 4 The compound or conjugate of any one of the preceding compound or conjugate, wherein U is -CH2-.
  • R Y is hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • EXEMPLARY EMBODIMENT 7 The compound or conjugate of any one of the preceding compound or conjugate, wherein R Y is hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-4 carbocyclyl, or 3- to 4-membered heterocyclyl.
  • R Y is hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-4 carbocyclyl, or 3- to 4-membered heterocyclyl.
  • EXEMPLARY EMBODIMENT 8 The compound or conjugate of any one of the preceding compound or conjugate, wherein R Y is hydrogen.
  • EXEMPLARY EMBODIMENT 9 The compound or conjugate of any one of the preceding compound or conjugate, wherein Ring A is 3-
  • EXEMPLARY EMBODIMENT 10 The compound or conjugate of any one of the preceding compound or conjugate, wherein Ring A is piperidinyl, 3-azaspiro[5.5]undecanyl, 2- Attorney Docket No. PRSC-074/001WO 343170-2268 azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, or 5-oxa-2- azaspiro[3.4]octyl.
  • Ring A is piperidinyl, 3-azaspiro[5.5]undecanyl, 2- Attorney Docket No. PRSC-074/001WO 343170-2268 azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, or 5-oxa-2- azaspiro[3.4]octyl.
  • Ring A is piperidinyl, 3-azas
  • each R A is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10- membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • EXEMPLARY EMBODIMENT 12 The compound or conjugate of any one of the preceding compound or conjugate, wherein each R A is independently oxo, halogen, -CN, -NO 2 , -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl.
  • EXEMPLARY EMBODIMENT 13 The compound or conjugate of any one of the preceding compound or conjugate, wherein m is 0.
  • R B1 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 6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R u .
  • EXEMPLARY EMBODIMENT 15 The compound or conjugate of any one of the preceding compound or conjugate, wherein R B1 is hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-4 carbocyclyl, or 3- to 4-membered heterocyclyl.
  • R B1 is hydrogen, halogen, -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-4 carbocyclyl, or 3- to 4-membered heterocyclyl.
  • EXEMPLARY EMBODIMENT 16 The compound or conjugate of any one of the preceding compound or conjugate, wherein R B1 is hydrogen.
  • R B2 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, 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 .
  • EXEMPLARY EMBODIMENT 18 is optionally substituted with one or more R u .
  • EXEMPLARY EMBODIMENT 21 The compound or conjugate of any one of the preceding compound or conjugate, wherein each R D1 is independently oxo, halogen, -CN, -NO 2 , -OH, - NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-4 carbocyclyl, or 3- to 4-membered heterocyclyl.
  • EXEMPLARY EMBODIMENT 22 The compound or conjugate of any one of the preceding compound or conjugate, wherein d is 0.
  • EXEMPLARY EMBODIMENT 23 The compound or conjugate of any one of the preceding compound or conjugate, wherein d is 0.
  • EXEMPLARY EMBODIMENT 24 A compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure may 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 may 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
  • is a solvate in another Attorney Docket No.
  • 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
  • PRSC-074/001WO 343170-2268 monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.
  • 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.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Attorney Docket No. PRSC-074/001WO 343170-2268 Solvates [0127] 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”.
  • a complex with water is known as a “hydrate”.
  • Solvates are within the scope of the invention.
  • crystalline form may vary from solvate to solvate.
  • all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present invention.
  • the compounds described herein exist as solvates.
  • the present disclosure provides for methods of treating diseases by administering such solvates.
  • the present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • 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 Attorney Docket No. PRSC-074/001WO 343170-2268 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 [0135]
  • 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 [0137]
  • the compound described herein is administered as a pure chemical.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutically suitable or acceptable carrier also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier
  • 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 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)
  • PRSC-074/001WO 343170-2268 a solvent (e.g., DMSO) and transferred to multi-well plate.
  • the reaction is conducted with addition of His-tagged cereblon E3 ligase (e.g., CRBN+DDB-DLS7+CXU4) followed by addition of a fluorescent probe (e.g., Cy5-labeled Thalidomide) at a certain concentration (e.g., 60 nM), and MAb Anti-6HIS Tb cryptate Gold in an assay buffer (e.g., 50 mM HEPES pH 7.5, 1 mM TCEP, 0.01% Brij-35, 50 mM NaCl, and 0.1% BSA).
  • His-tagged cereblon E3 ligase e.g., CRBN+DDB-DLS7+CXU4
  • a fluorescent probe e.g., Cy5-labeled Thalidomide
  • MAb Anti-6HIS Tb cryptate Gold
  • the present disclosure provides methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering the compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein.
  • the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. [0151] In certain aspects, the present disclosure provides compounds disclosed herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. [0152] In certain aspects, the present disclosure provides a compound disclosed herein for use in preparing a conjugate disclosed herein.
  • 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 adaptor protein damaged DNA–binding protein 1
  • CUL4A Cullin-4A
  • ROC1 regulator of cullins 1
  • CRBN acts as a substrate-specificity receptor.
  • the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering the conjugate disclosed herein to the subject.
  • the present disclosure provides uses of the conjugate disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides conjugates disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • Attorney Docket No. PRSC-074/001WO 343170-2268 [0157]
  • the disease or disorder is an estrogen receptor-mediated disease or disorder, STAT3-mediated disease or disorder, SMARCA2/4-mediated disease or disorder, CBP/p300-mediated disease or disorder, an androgen receptor-mediated disease or disorder, or a BRD9-mediated disease or disorder.
  • the subject is a mammal.
  • the subject is a human.
  • 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.
  • C1-6 alkyl is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • the following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated.
  • 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 (“C1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1-10 alkyl”). In certain embodiments, 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 (“C1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”).
  • C 1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), 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 (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is Attorney Docket No. PRSC-074/001WO 343170-2268 independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3).
  • the alkyl group is substituted C1- 10 alkyl.
  • Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), i-Pr (-CH(CH3)2), n- Pr (-CH 2 CH 2 CH 3 ), n-Bu (-CH 2 CH 2 CH 2 CH 3 ), or i-Bu (-CH 2 CH(CH 3 ) 2 ).
  • 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 (-CH2-), ethylene (- CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (- CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), 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(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH 2 C(CH3) 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 (“C2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2- 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 (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“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 (“C2-3 alkenyl”).
  • 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 C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- Attorney Docket No. PRSC-074/001WO 343170-2268 butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C8), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C2-10 alkenyl.
  • the alkenyl group is substituted C2-10 alkenyl.
  • Alkenylene refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical.
  • alkenylene When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C2- 8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“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 (“C2-4 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 C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • C2-6 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 (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, 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. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.
  • 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.
  • 1 or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • 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”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“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 (“heteroC1-7 alkyl”).
  • a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC 1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated Attorney Docket No.
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”).
  • a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”).
  • each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • heteroalkyl group is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl.
  • heteroalkenyl refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • one or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“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 (“heteroC2-8 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 (“heteroC2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC 2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl.
  • the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
  • heteroalkynyl refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, Attorney Docket No. PRSC-074/001WO 343170-2268 nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • one or more heteroatoms e.g., oxygen, sulfur, Attorney Docket No. PRSC-074/001WO 343170-2268 nitrogen, boron, silicon, phosphorus
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 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 (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-5 alkynyl”).
  • a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC 2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”).
  • each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl.
  • the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
  • heteroalkylene refers to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively.
  • heteroalkylene refers to the range or number of carbons in the linear divalent chain.
  • Heteroalkylene, “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.
  • “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“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.
  • 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 Attorney Docket No. PRSC-074/001WO 343170-2268 attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”).
  • a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”).
  • a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”).
  • a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”).
  • the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl.
  • Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6- membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7- Attorney Docket No. PRSC-074/001WO 343170-2268 membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6- bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Heteroarylene refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group.
  • a “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C3- 10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“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 (“C5-8 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 (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
  • Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned 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 (C10), spiro[4.5]decanyl (C10), and the like.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon Attorney Docket No. PRSC-074/001WO 343170-2268 atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“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 ).
  • Examples of C 3-6 carbocyclyl include the aforementioned C 5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (C 8 ).
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3-12 carbocyclyl.
  • the carbocyclyl group is substituted C 3-12 carbocyclyl.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C3-12 carbocyclyl.
  • the carbocyclyl group is a substituted C3-12 carbocyclyl.
  • “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.
  • “Spiro carbocyclyl” or or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on Attorney Docket No. PRSC-074/001WO 343170-2268 the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embedded.
  • Bridged carbocyclyl or or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded.
  • the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded.
  • Carbocyclylene refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical.
  • the divalent radical may be present on different atoms or the same atom of the carbocyclylene group.
  • a “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Heterocyclyl refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- Attorney Docket No. PRSC-074/001WO 343170-2268 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 C 6 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 Attorney Docket No.
  • PRSC-074/001WO 343170-2268 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.
  • substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3- to 12- membered heterocyclyl.
  • the heterocyclyl group is substituted 3- to 12- membered heterocyclyl.
  • “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings.
  • the number of ring members designates the total number of ring members in the fused ring system.
  • “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.
  • the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.
  • “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.
  • the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.
  • substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.
  • “Heterocyclylene” as used herein refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocyclylene group.
  • heterocyclylene refers to the number of ring members in the heterocyclylene group.
  • a “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Alkoxy refers to the group -OR, wherein R is alkyl as defined herein.
  • C1-6 alkoxy refers to the group -OR, wherein each R is C1-6 alkyl, as defined herein. Exemplary C 1-6 alkyl is set forth above.
  • Alkylamino refers to the group -NHR or -NR 2 , wherein each R is independently alkyl, as defined herein.
  • C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, as defined herein.
  • Exemplary C1-6 alkyl is set forth above.
  • heteroaryl When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.
  • Halo or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
  • Protecting group refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction.
  • a functional group e.g., hydroxyl, amino, thio, and carboxylic acid
  • Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.
  • hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), ⁇ -Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri- Attorney Docket No.
  • ethers e.g., methoxymethyl (MOM), ⁇ -Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn
  • PRSC-074/001WO 343170-2268 iso-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)).
  • TOM iso-propylsilyloxymethyl
  • TDMS t-butyldimethylsilyl
  • esters e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)
  • amino-protecting groups include but not limited to carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), p- methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2- nitro
  • Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).
  • Common types of carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulf
  • PRSC-074/001WO 343170-2268 [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.
  • a metal ion e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion
  • 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 effect such treatment or prevention.
  • the “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • a “therapeutically effective amount” refers to the effective amount for therapeutic treatment.
  • a “prophylatically effective amount” refers to the effective amount for prophylactic treatment.
  • “Preventing”, “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 Attorney Docket No.
  • 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. [0222] 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 Attorney Docket No. PRSC-074/001WO 343170-2268 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. [0228] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • 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.
  • any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.
  • the claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed.
  • “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. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid
  • PRSC-074/001WO 343170-2268 hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.
  • a metal ion e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion
  • coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.
  • Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • “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).
  • Attorney Docket No. PRSC-074/001WO 343170-2268 [0237]
  • 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 Attorney Docket No. PRSC-074/001WO 343170-2268 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. [0245] 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 Attorney Docket No. PRSC-074/001WO 343170-2268 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. [0251] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • 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 B tert-butyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate
  • Step C tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-oxopyridin-1(2H)-yl)piperidine-1- carboxylate & tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate [0260] To a solution of tert-butyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)piperidine-1- carboxylate (500 mg, 1 eq, 1.7 mmol) in DMF (10 mL) was added sodium hydride (60% in mineral oil, 82 mg, 1.2 eq, 2.04 mmol) at 60 o C.
  • Step E (S)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)oxy)piperidine-2,6-dione
  • Step B tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate & tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- oxopyridin-1(2H)-yl)piperidine-1-carboxylate [0268] A mixture of tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-oxopyridin- 1(2H)-yl)piperidine-1-carboxylate (600 mg, 1 eq, 1.03 mmol) and 10% Pd/C (70 mg) in CF3CH2OH (20 mL) was stirred at room temperature under H2 atmosphere for 16 h.
  • Step D (S)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)amino)piperidine-2,6-dione [0272] To a solution of tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- oxopyridin-1(2H)-yl)piperidine-1-carboxylate (170 mg, 1 eq, 0.42 mmol) in DCM (5 mL) was added 5 mL of 4N HCl/dioxane. The mixture was stirred at room temperature overnight. The Attorney Docket No.
  • Step B 3-hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one [0275] To a solution of N-isopropyl-2-methoxyisonicotinamide (20.0 g, 103 mmol, 1.0 eq) in MTBE (250 mL) was added TMEDA (29.95 g, 258 mmol, 2.5 eq) at room temperature, which was then cooled to -78 °C.
  • n-BuLi solution 2.5 M in hexane
  • n-BuLi solution 124 mL, 309 mmol, 3.0 eq
  • DMF 27.7 mL, 361 mmol, 3.5 eq
  • the resulting suspension was quenched with saturated aqueous NH 4 Cl solution (200 mL) and extracted with dichloromethane (150 mL x 3).
  • Step C 4-methoxyfuro[3,4-c]pyridin-1(3H)-one [0276] To a solution of 3-hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-1-one (10 g, 45 mmol, 1.0 eq) in 2-propanol (100 mL) and water (30 mL) was added NaBH 4 (2.57 g, 67.5 mmol, 1.5 eq) in portions at room temperature and the reaction mixture was stirred for 3 h. The rection mixture was quenched by addition of acetone (30 mL) at 0 °C and stirred for 35 min at room temperature.
  • Step E tert-butyl 4-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)piperidine-1- carboxylate
  • 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione 8 g, 53 mmol, 1.0 eq
  • tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate 17.7 g, 63.6 mmol, 1.2 eq
  • cesium carbonate (17.3 g, 59.6 mmol, 1.0 eq) at room temperature.
  • the reaction mixture was stirred at 80 o C for 16 h.
  • the reaction mixture was cooled to room temperature, poured into water (300ml) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step G 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-2-oxo-1,2-dihydropyridine-4- carboxylic acid [0280] To a solution of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-2-oxo- 1,2-dihydropyridine-4-carboxylic acid (8 g, 22.7 mmol, 1.0 eq) in DCM (50 mL) was added MnO 2 (19.8 g, 227mmol, 10 eq) and the mixture was stirred at 50 o C for 10 h.
  • Step H tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate [0281] To a solution of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid (6 g, 17.1 mmol, 1.0 eq) and 3-aminopiperidine-2,6-dione hydrochloride (3.4 g, 20.6 mmol, 1.2 eq) in DCM (50 mL) was added AcOH (10 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 1 h.
  • Sodium triacetoxyborohydride (10.9 g, 51.4 mmol, 3.0 eq) was added to above mixture and the resulting reaction mixture was stirred at room temperature overnight.
  • the reaction mixture was quenched with water (50 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step K (R)-2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridine-1,4(2H)-dione [0284] To a solution of tert-butyl (R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (30 mg, 0.07 mmol, 1.0 eq) was added HCl/dioxane (4M, 3mL) at room temperature.
  • Step B 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid [0286] To a solution of methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2- dihydropyridine-4-carboxylate (5.3 g, 15.7 mmol, 1.0 eq) in MeOH (50 mL), and H 2 O (50 mL) was added NaOH (0.95 g, 23.6 mmol, 1.5 eq).
  • Step C tert-butyl (S)-4-(4-((2,4-dioxocyclohexyl)carbamoyl)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate [0287] To a solution of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine- 4-carboxylic acid (100 mg, 0.31 mmol, 1.0 eq) in DMF (5 mL) was added Et3N (94 mg, 0.93 mmol, 3.0 eq) and T3P (148 mg, 0.47 mmol, 1.5 eq) under N2 at 0 o C.
  • Step D (S)-N-(2,6-dioxopiperidin-3-yl)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridine-4- carboxamide
  • S tert-butyl
  • S-4-(4-((2,4-dioxocyclohexyl)carbamoyl)-2-oxopyridin- 1(2H)-yl)piperidine-1-carboxylate 80 mg, 0.185 mmol, 1.0 eq
  • DCM tert-butyl
  • trifluoroacetic acid 2 mL
  • Step B 3-methoxy-4-(methoxycarbonyl)pyridine 1-oxide
  • mCPBA 1-methyl g, 2 eq, 64.6 mmol
  • the mixture was stirred for 16h at 50°C, then added with Na 2 CO 3 (100 mL, 1 M), stirred for another 1h at rt.
  • the resulting mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated reduced pressure.
  • Step C methyl 5-methoxy-2-oxo-1,2-dihydropyridine-4-carboxylate [0292] A mixture of 3-methoxy-4-(methoxycarbonyl)pyridine 1-oxide (0.90 g, 1 eq, 4.9 mmol) in TFAA (10.0 mL) was stirred for 16 h at 80°C. The mixture was concentrated under reduced pressure and H2O (10 mL) was added.
  • Step D methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo-1,2- dihydropyridine-4-carboxylate
  • Cs2CO3 3.0 g, 2 eq, 9.3 mmol
  • tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (1.6 g, 1.2 eq, 5.6 mmol).
  • Step E 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo-1,2-dihydropyridine-4- carboxylic acid [0294] To a mixture of methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo- 1,2-dihydropyridine-4-carboxylate (1.20 g, 1 eq, 3.28 mmol) in MeOH/THF/H 2 O (20.0 mL) was added NaOH (524 mg, 4 eq, 13.1 mmol).
  • Step F tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxy-2-oxopyridin- 1(2H)-yl)piperidine-1-carboxylate
  • HATU 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo-1,2- dihydropyridine-4-carboxylic acid (0.95 g, 1 eq, 2.7 mmol) in DMA (10.0 mL) was added HATU (1.2 g, 1.2 eq, 3.2 mmol), TEA (0.82 g, 1.1 mL, 3 eq, 8.1 mmol), (S)-3-aminopiperidine- 2,6-dione (0.41 g, 1.2 Eq, 3.2 mmol).
  • Step G (S)-N-(2,6-dioxopiperidin-3-yl)-5-methoxy-2-oxo-1-(piperidin-4-yl)-1,2- dihydropyridine-4-carboxamide Attorney Docket No.
  • Step B tert-butyl 9-((methylsulfonyl)oxy)-3-azaspiro[5.5]undecane-3-carboxylate [0299] To a solution tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (4.00 g, 1 eq, 14.8 mmol) in DCM (50.0 mL)) was added MsCl (2.55 g, 1.74 mL, 1.5 eq, 22.3 mmol) in portions at room temperature and the reaction mixture was stirred for 2 hours.
  • Step C tert-butyl 9-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-3- azaspiro[5.5]undecane-3-carboxylate [0300] To a solution of tert-butyl 9-((methylsulfonyl)oxy)-3-azaspiro[5.5]undecane-3- carboxylate (5.00 g, 1.0 eq, 14.4 mmol) and 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (3.26 g, 1.5 eq, 21.6 mmol) in DMF (50 mL) was added Cs 2 CO 3 (9.38 g, 2.0 eq, 28.8 mmol) at room temperature, the reaction mixture was stirred at 80 o C for 16 hours.
  • Cs 2 CO 3 9.38 g, 2.0 eq, 28.8 mmol
  • Step D 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3-(hydroxymethyl)-2-oxo- 1,2-dihydropyridine-4-carboxylic acid [0301]
  • tert-butyl 9-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-3- azaspiro[5.5]undecane-3-carboxylate (4.00 g, 1.0 eq, 9.94 mmol) in THF (20 mL) and water( 30 mL)was added NaOH (1.59 g, 4.0 eq, 39.8 mmol) at 70 °C for 2 hours.
  • Step E 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0302] To a solution of 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (4.00 g, 1.0 eq, 9.51 mmol) in DCM (50 mL) was added manganese(IV) oxide (8.27 g, 10.0 eq, 95.1 mmol) and the mixture was stirred at 50 o C for 10 hours.
  • Step F tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate [0303] To a solution of 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3-formyl-2- oxo-1,2-dihydropyridine-4-carboxylic acid (4.00 g, 1.0 eq, 9.56 mmol) and3-aminopiperidine- 2,6-dione (1.47 g, 1.2 eq, 11.5 mmol) in DCM (50 mL) was added AcOH (10 mL) at room temperature,
  • PRSC-074/001WO 343170-2268 SFC to afford compound tert-butyl (R)-9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (P1) (650 mg,) as a white solid and tert-butyl (S)-9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (P2) (630 mg ) as a white solid.
  • Step I (S)-2-(2,6-dioxopiperidin-3-yl)-5-(3-azaspiro[5.5]undecan-9-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione hydrochloride (Example 10) [0307] To a solution of tert-butyl (S)-9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 1.0 eq, 195 ⁇ mol) was added HCl/dioxane (4M, 3.0 mL) at room temperature.
  • Step B tert-butyl 6-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.3]heptane-2-carboxylate [0310] To a solution of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate (5.50 g, 1.0 eq, 18.9 mmol) and 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (3.42 g, 1.2 eq, 22.7 mmol) in DMF (50 mL) was added Cs2CO3 (8.00 g, 1.3 eq, 24.5 mmol) at room temperature, the reaction mixture was stirred at 80 o C for 16 hours.
  • reaction mixture was cooled to room temperature, poured into water (300 ml) and extracted with EtOAc (100 mL x Attorney Docket No. PRSC-074/001WO 343170-2268 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step C 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(hydroxymethyl)-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0311] To a solution of tert-butyl 6-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.3]heptane-2-carboxylate (2.50 g, 1.0 eq, 7.22 mmol) in THF (20 mL) and water( 30 mL)was added sodium hydroxide (1.15 g, 4.0 eq, 28.9 mmol) at 70 °C for 2 hours.
  • Step D 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0312] To a solution of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.60 g, 1.0 eq, 7.14 mmol) in DCM (50 mL) was added manganese(IV) oxide (6.20 g, 10 eq, 71.4 mmol) and the mixture was stirred at 50 o C for 10 hours.
  • Step E tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate [0313] To a solution of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-2- oxo-1,2-dihydropyridine-4-carboxylic acid (2.50 g, 1.0 eq, 6.90 mmol) and 3-aminopiperidine- 2,6-dione (972 mg, 1.1 eq, 7.59 mmol) in DCM (50 mL) was added AcOH (10 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 1 h.
  • Sodium triacetoxyborohydride (2.19 g, 10.3 mmol, 1.5 eq) was added to above mixture and the resulting reaction mixture was stirred at room temperature overnight.
  • the reaction mixture was Attorney Docket No. PRSC-074/001WO 343170-2268 quenched with water (50 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step F tert-butyl (R)-6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl (S)-6-(2- (2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2- azaspiro[3.3]heptane-2-carboxylate [0314] The tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,
  • Step B tert-butyl 2-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-7- azaspiro[3.5]nonane-7-carboxylate [0321] To a solution of tert-butyl 2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7- carboxylate (3.8 g, 11.9 mmol, 1.2 eq) in DMA (50 mL) was added 3,5-dihydrofuro[3,4- c]pyridine-1,4-dione (1.5 g, 9.93 mmol, 1.0 eq), Cs2CO3 (3.23 g, 9.93 mmol, 1.0 eq) at room Attorney Docket No.
  • Step D 1-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0323] To a solution of 1-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.1 g , 2.8 mmol, 1.0 eq) in DCM (20 mL) was added DMP (1.78 g, 4.2 mmol, 1.5 eq) at 0 o C.
  • PRSC-074/001WO 343170-2268 (1.1 g, 5.4 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 20 o C for 12 hours. The reaction mixture was poured into water (30 ml) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step F tert-butyl (R)-2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate and tert-butyl (S)-2-(2-(2,6- dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-7- azaspiro[3.5]nonane-7-carboxylate [0325] The tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)
  • Step H (S)-2-(2,6-dioxopiperidin-3-yl)-5-(7-azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0327] To a solution of tert-butyl (S)-2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (10 mg, 1.0 eq, 19.5 ⁇ mol) was added HCl/dioxane (4M, 1.0 mL) at room temperature.
  • Step B tert-butyl 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate
  • tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate 2.0 g, 1 eq, 8.29 mmol
  • DCM 5.00 mL
  • MsCl 1. g, 1.5 eq, 12.4 mmol
  • Triethylamine 2.5 g, 3.47 mL, 3 eq, 24.9 mmol
  • Step C tert-butyl 7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.5]nonane-2-carboxylate [0330] To a mixture of tert-butyl 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2- carboxylate (3.00 g, 1 eq, 9.39 mmol), 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (1.70 g, 1.2 eq, 11.3 mmol) in DMF (20.0 mL) was added Cs 2 CO 3 (3.98 g, 1.3 eq, 12.2 mmol).
  • Step D 3-(4-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione hydrochloride [0331] To a mixture of tert-butyl 7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.5]nonane-2-carboxylate (720 mg, 1 eq, 1.92 mmol) in THF (10.0 mL), H 2 O (2.0 mL) was added NaOH (308 mg, 4 eq, 7.69 mmol), the mixture was stirred at 50°C for 4 h.
  • Step E 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0332] To a mixture of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (770 mg, 1 eq, 1.96 mmol) in DCM (30 mL) was added manganese(IV) oxide (1.71 g, 10 eq, 19.6 mmol), the mixture was stirred at 50°C for 10 h.
  • Step F tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate [0333] To a mixture of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-3-formyl-2- oxo-1,2-dihydropyridine-4-carboxylic acid (770 mg, 1 eq, 1.97 mmol), AcOH (10 mL) and 3- aminopiperidine-2,6-dione (328 mg, 1.3 eq, 2.56 mmol) in DCM (50 mL) was added sodium triacetoxyborohydride (2.19 g, 10.3 mmol, 1.5 eq
  • Step G tert-butyl (R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate and tert-butyl (S)-7-(2-(2,6- dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2- azaspiro[3.5]nonane-2-carboxylate
  • R tert-butyl
  • S tert-butyl (S)-7-(2-(2,6- dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-
  • Step H (R)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.5]nonan-7-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione formate [0336] To a mixture of tert-butyl (R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate (65.0 mg, 134 ⁇ mol) in FA (5.00 mL).
  • Step I (S)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.5]nonan-7-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione formate [0338] To a mixture of tert-butyl (S)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate (15 mg, 31 ⁇ mol) in HCOOH (2.00 mL) . The reaction was stirred at 25 °C for 4 h, the reaction was concentrated to afford (S)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.5]nonan-7
  • Step B tert-butyl 6-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.3]heptane-2-carboxylate [0341] To a mixture of tert-butyl 6-(7-bromo-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)-2-azaspiro[3.3]heptane-2-carboxylate (4.14 g, 9.73 mmol), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (1.83 g, 14.6 mmol), K 2 CO 3 (4.04 g, 29.2 mmol) and 1,1'- Attorney Dock
  • Step C 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(hydroxymethyl)-5- methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid
  • Step D 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-5-methyl-2-oxo- 1,2-dihydropyridine-4-carboxylic acid [0343] To a mixture of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (hydroxymethyl)-5-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (3.0 g, 7.93 mmol) and Manganese dioxide (27.6 g, 317 mmol) in DCM (30.0 mL) was stirred at 50°C for 3 h.
  • Step E tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate [0344] To a mixture of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-5- methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.5 g, 3.99 mmol), 3-aminopiperidine- 2,6-dione (0.56 g, 4.38 mmol), TEA (0.8 g, 7.97 mmol), AcOH (1.44 g, 23.9 mmol) and Sodium triacetoxyborohydride (2.53 g, 12.0 mmol) in DCM (20.0 mL)
  • Step F tert-butyl (R)-6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate & tert-butyl (S)-6-(2- (2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5- yl)-2-azaspiro[3.3]heptane-2-carboxylate [0345] The tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-7
  • Step H (S)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0348] To a mixture of tert-butyl (S)-6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (5 Attorney Docket No.
  • Step B tert-butyl 7-((methylsulfonyl)oxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [0351] To a mixture of tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (3.53 g, 15.4 mmol) and TEA (4.67 g, 46.2 mmol) in DCM (40.0 mL) was added Methanesulfonyl chloride (2.65 g, 23.1 mmol) at room temperature. The mixture was stirred at room temperature for 16 h.
  • Step C tert-butyl 7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-5-oxa-2- azaspiro[3.4]octane-2-carboxylate [0352] To a mixture of tert-butyl 7-((methylsulfonyl)oxy)-5-oxa-2-azaspiro[3.4]octane-2- carboxylate (3.24 g, 10.5 mmol), 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (1.33 g, 8.78 mmol) and Cs 2 CO 3 (5.72 g, 17.6 mmol) in DMF (75.0 mL) was stirred at 80 o C for 16h.
  • Step F (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0355] To a mixture of (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.0 g, 1 eq, 2.63 mmol) and manganese(IV) oxide (2.3 g, 10 eq, 26.3 mmol) in DCM (15.0 mL)THF (15.0 mL) was stirred at 50 °C for 2 h.
  • Step G tert-butyl (7R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [0356] To a mixture of (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3- formyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.1 g, 1 eq, 2.91 mmol), 3- aminopiperidine-2,6-dione (376 mg, 1.01 eq, 2.94 mmol), Triethylamine (88.3 mg, 122 ⁇ L, 0.3 eq, 872 ⁇ mol) and Acetic acid (87.3 mg
  • Step H tert-butyl (R)-7-(2-((R)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate & tert-butyl (R)-7-(2- ((S)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5- oxa-2-azaspiro[3.4]octane-2-carboxylate [0357] The tert-butyl (7R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-
  • PRSC-074/001WO 343170-2268 tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (320 mg) as a white solid.
  • Step I 2-((R)-2,6-dioxopiperidin-3-yl)-5-((R)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0359] To a mixture of tert-butyl (R)-7-(2-((R)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (20 mg, 1 eq, 42.3 ⁇ mol)in FA (2.5 mL).
  • Step J 2-((S)-2,6-dioxopiperidin-3-yl)-5-((R)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0361] To a mixture of tert-butyl (R)-7-(2-((S)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (20.
  • Compound 21 and Compound 22 (R)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5- (piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione and (S)-2-(2,6- dioxopiperidin-3-yl)-7-methyl-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine- 1,4(2H)-dione Attorney Docket No.
  • Step B tert-butyl 4-(7-bromo-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)piperidine- 1-carboxylate
  • tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate 6.32 g, 1.3 eq, 22.6 mmol.
  • Step C tert-butyl 4-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)piperidine- 1-carboxylate
  • tert-butyl 4-(7-bromo-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)piperidine-1-carboxylate (3.80 g, 1 eq, 9.19 mmol)
  • K 2 CO 3 (2.54 g, 2 eq, 18.4 mmol)
  • 2,4,6- trimethyl-1,3,5,2,4,6-trioxatriborinane (2.31 g, 2 eq, 18.4 mmol) in 1,4-Dioxane (20.0 mL) was added [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalla
  • Step D 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-5-methyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0366] To a mixture of tert-butyl 4-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)piperidine-1-carboxylate (2.70 g, 1 eq, 7.75 mmol) in THF (20.0 mL) and H 2 O (5.00 mL) was added NaOH (1.24 g, 4 eq, 31.0 mmol).The resultant mixture was then stirred at 50°C for 16 h.
  • Step E 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-5-methyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0367] To a mixture of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-5- methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (3.60 g, 1 eq, 9.83 mmol) in DCM (40.0 mL)was added manganese dioxide (8.54 g, 1.70 mL, 10 eq, 98.3 mmol). The resultant mixture was stirred at 50°C for 8 h.
  • Step F tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate [0368] To a mixture of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-5-methyl-2-oxo- 1,2-dihydropyridine-4-carboxylic acid (4.00 g, 1 eq, 11.0 mmol), 3-aminopiperidine-2,6-dione (1.69 g, 1.2 eq, 13.2 mmol),acetic acid (1.32 g, 1.26 mL, 2 eq, 22.0 mmol) in DCM (50.0 mL) was added sodium triacetoxyborohydride (6.98 g, 4.88
  • Step G tert-butyl (R)-4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate and tert-butyl (S)-4-(2-(2,6- dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5- yl)piperidine-1-carboxylate [0369] The tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (2
  • Step H (R)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(piperidin-4-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0370] To a mixture of tert-butyl (R)-4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (20.0 mg, 1 eq, 43.6 ⁇ mol) in HCl/dioxane (2.50 mL).
  • Step I (S)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(piperidin-4-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0372] To a mixture of tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (20.0 mg, 1 eq, 43.6 ⁇ mol) in HCl/dioxane (2.50 mL).
  • 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).
  • an agent includes a plurality of such agents
  • the cell includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.

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Abstract

Described herein are compounds of Formula II or conjugates of Formula II' and their pharmaceutically acceptable salts, solvates, or stereoisomers thereof, as well as their uses (e.g., as cereblon-binding agents or degraders for certain proteins).

Description

Attorney Docket No. PRSC-074/001WO 343170-2268 CEREBLON LIGANDS AND USES THEREOF RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/410,448, filed September 27, 2022; and U.S. Provisional Application No.63/484,264, filed February 10, 2023, the contents of each of which are incorporated herein by reference in their entireties. BACKGROUND [0002] Cereblon (CRBN), 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. [0003] The discovery process of CRBN type E3 ligase ligand is related to the study of thalidomide's mechanism of action. In 2010, while studying the toxicity of thalidomide, scientists discovered that cereblon is a binding protein of thalidomide (Science 2010, 327, 1345). 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. Subsequent studies found that 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 groundbreaking 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). [0004] On this basis, CRBN ligands are widely used in protein degradation, and a series of PROTAC molecules based on CRBN ligands have been developed. Due to the influence of CRBN ligand itself on the target point, it may additionally degrade zinc finger domain protein. Attorney Docket No. PRSC-074/001WO 343170-2268 Therefore, the design and synthesis of new and highly selective CRBN ligands is also particularly important in the synthesis of PROTACs molecules. SUMMARY [0005] In certain aspects, the present disclosure provides compounds of Formula II or conjugates of Formula II’:
Figure imgf000003_0001
wherein each of the variables in Formula II or Formula II’ is described, embodied, and exemplified herein. [0006] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound or a conjugate disclosed herein, and a pharmaceutically acceptable excipient. [0007] In certain aspects, the present disclosure provides methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering the compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein. [0008] In certain aspects, the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. [0009] In certain aspects, the present disclosure provides compounds disclosed herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. [0010] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering the conjugate disclosed herein to the subject. [0011] In certain aspects, the present disclosure provides uses of the conjugate disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0012] In certain aspects, the present disclosure provides conjugates disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. Attorney Docket No. PRSC-074/001WO 343170-2268 DETAILED DESCRIPTION [0013] The present disclosure relates to compounds that show cereblon-binding activity, or conjugates in degrading certain proteins, and pharmaceutical compositions comprising such compounds or conjugates. Compounds of the Present Disclosure Cereblon Ligands [0014] The present disclosure provides compounds of Formula II:
Figure imgf000004_0001
and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: Ring A is C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each RA is independently amino-protecting group, oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRbS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; m is an integer selected from 0 to 10, as valency permits; RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; denotes an optional covalent bond between Y and U; i) when the bond between Y and U is present: Attorney Docket No. PRSC-074/001WO 343170-2268 r is 1; X is N; U is -CH2- or -C(=O)-; Y is C; ii) when the bond between Y and U is absent: r is 0 or 1; X is O or N; wherein when X is O, then U is absent; when X is N, then U is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Y is CRY; RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD1 is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; each RD is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 5; and q is an integer from 0 to 2, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, Attorney Docket No. PRSC-074/001WO 343170-2268 heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0015] In certain embodiments, the compound of Formula II is a compound of Formula II-1
Figure imgf000006_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0016] In certain embodiments, the compound of Formula II is a compound of Formula II-2
Figure imgf000006_0002
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0017] In certain embodiments, the compound of Formula II is a compound of Formula II-1-i or II-2-i Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000007_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0018] In certain embodiments, Ring A is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) or 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S). [0019] In certain embodiments, Ring A is piperidinyl, 3-azaspiro[5.5]undecanyl, 2- azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, or 5-oxa-2- azaspiro[3.4]octyl. [0020] In certain embodiments, each RA is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), Attorney Docket No. PRSC-074/001WO 343170-2268 pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0021] In certain embodiments, each RA is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0022] In certain embodiments, each RA is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0023] In certain embodiments, each RA is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0024] In certain embodiments, m is an integer selected from 0 to 10, as valency permits. In certain embodiments, 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, as valency permits. In certain embodiments, m is 6, as valency permits. In certain Attorney Docket No. PRSC-074/001WO 343170-2268 embodiments, m is 7, as valency permits. In certain embodiments, m is 8, as valency permits. In certain embodiments, m is 9, as valency permits. In certain embodiments, m is 10, as valency permits. [0025] In certain embodiments, RB1 and RB2 are independently hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1- 6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, Attorney Docket No. PRSC-074/001WO 343170-2268 alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0026] In certain embodiments, RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0027] In certain embodiments, RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0028] In certain embodiments, RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0029] In certain embodiments, RB1 is hydrogen. [0030] In certain embodiments, RB2 is hydrogen, C1-6 alkyl, or C1-6 alkoxy. [0031] In certain embodiments, the bond between Y and U is present, then r is 1; X is N; U is -CH2- or -C(=O)-; and Y is C. [0032] In certain embodiments, the bond between Y and U is absent, then: r is 0 or 1; X is O or N; wherein when X is O, then U is absent; when X is N, then U is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Y is CRY. [0033] In certain embodiments, RY is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- Attorney Docket No. PRSC-074/001WO 343170-2268 butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0034] In certain embodiments, RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0035] In certain embodiments, RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0036] In certain embodiments, RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the Attorney Docket No. PRSC-074/001WO 343170-2268 alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0037] In certain embodiments, RY is hydrogen. [0038] In certain embodiments, RD is hydrogen, deuterium, C1-6 haloalkyl (e.g., C1-6 alkyl comprising 1 to 8 halogen atoms selected from -F, -Cl, -Br, and -I), or C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)). [0039] In certain embodiments, RD is hydrogen. [0040] In certain embodiments, each RD1 is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., Attorney Docket No. PRSC-074/001WO 343170-2268 heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0041] In certain embodiments, each RD1 is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0042] In certain embodiments, each RD1 is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0043] In certain embodiments, each RD1 is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0044] In certain embodiments, d is an integer selected from 0 to 5. In certain embodiments, 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. [0045] In certain embodiments, q is an integer from 0 to 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [0046] In certain embodiments, the present disclosure provides compounds of Formula I:
Figure imgf000013_0001
and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: Ring A is C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each RA is independently amino-protecting group, oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - Attorney Docket No. PRSC-074/001WO 343170-2268 NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; m is an integer selected from 0 to 10, as valency permits; RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; denotes an optional covalent bond between Y and U; i) when the bond between Y and U is present: r is 1; X is N; U is -CH2- or -C(=O)-; Y is C; ii) when the bond between Y and U is absent: r is 0 or 1; X is O or N; wherein when X is O, then U is absent; when X is N, then U is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Y is CRY; RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; and q is an integer from 0 to 2, Attorney Docket No. PRSC-074/001WO 343170-2268 wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0047] In certain embodiments, the compound of Formula I is a compound of Formula I-1
Figure imgf000015_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Attorney Docket No. PRSC-074/001WO 343170-2268 [0048] In certain embodiments, U is -CH2-. In certain embodiments, U is -C(=O)-. [0049] In certain embodiments, the compound of Formula I is a compound of Formula I-2
Figure imgf000016_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0050] In certain embodiments, RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0051] In certain embodiments, RY is hydrogen. [0052] In certain embodiments, Ring A is 3-membered heterocyclyl. In certain embodiments, Ring A is 4-membered heterocyclyl. In certain embodiments, Ring A is 5-membered heterocyclyl. In certain embodiments, Ring A is 6-membered heterocyclyl. In certain embodiments, Ring A is 7-membered heterocyclyl. In certain embodiments, Ring A is 8- membered heterocyclyl. In certain embodiments, Ring A is 9-membered heterocyclyl. In certain embodiments, Ring A is 10-membered heterocyclyl. In certain embodiments, Ring A is 11-membered heterocyclyl. In certain embodiments, Ring A is 12-membered heterocyclyl. [0053] In certain embodiments, Ring A is 3- to 12-membered heterocyclyl. In certain embodiments, Ring A is 3- to 11-membered heterocyclyl. In certain embodiments, Ring A is 3- to 10-membered heterocyclyl. In certain embodiments, Ring A is 3- to 9-membered heterocyclyl. In certain embodiments, Ring A is 3- to 8-membered heterocyclyl. In certain embodiments, Ring A is 3- to 7-membered heterocyclyl. In certain embodiments, Ring A is 3- to 6-membered heterocyclyl. In certain embodiments, Ring A is 3- to 5-membered heterocyclyl. In certain embodiments, Ring A is 3- to 4-membered heterocyclyl. In certain embodiments, Ring A is 4- to 12-membered heterocyclyl. In certain embodiments, Ring A is 4- to 11-membered heterocyclyl. In certain embodiments, Ring A is 4- to 10-membered heterocyclyl. In certain embodiments, Ring A is 4- to 9-membered heterocyclyl. In certain embodiments, Ring A is 4- to 8-membered heterocyclyl. In certain embodiments, Ring A is 4- to 7-membered heterocyclyl. In certain embodiments, Ring A is 4- to 6-membered Attorney Docket No. PRSC-074/001WO 343170-2268 heterocyclyl. In certain embodiments, Ring A is 4- to 5-membered heterocyclyl. In certain embodiments, Ring A is 5- to 12-membered heterocyclyl. In certain embodiments, Ring A is 5- to 11-membered heterocyclyl. In certain embodiments, Ring A is 5- to 10-membered heterocyclyl. In certain embodiments, Ring A is 5- to 9-membered heterocyclyl. In certain embodiments, Ring A is 5- to 8-membered heterocyclyl. In certain embodiments, Ring A is 5- to 7-membered heterocyclyl. In certain embodiments, Ring A is 5- to 6-membered heterocyclyl. In certain embodiments, Ring A is 6- to 12-membered heterocyclyl. In certain embodiments, Ring A is 6- to 11-membered heterocyclyl. In certain embodiments, Ring A is 6- to 10-membered heterocyclyl. In certain embodiments, Ring A is 6- to 9-membered heterocyclyl. In certain embodiments, Ring A is 6- to 8-membered heterocyclyl. In certain embodiments, Ring A is 6- to 7-membered heterocyclyl. In certain embodiments, Ring A is 8- to 12-membered heterocyclyl. In certain embodiments, Ring A is 8- to 11-membered heterocyclyl. In certain embodiments, Ring A is 8- to 10-membered heterocyclyl. In certain embodiments, Ring A is 8- to 9-membered heterocyclyl. In certain embodiments, Ring A is 9- to 12-membered heterocyclyl. In certain embodiments, Ring A is 9- to 11-membered heterocyclyl. In certain embodiments, Ring A is 9- to 10-membered heterocyclyl. In certain embodiments, Ring A is 10- to 12-membered heterocyclyl. In certain embodiments, Ring A is 10- to 11-membered heterocyclyl. In certain embodiments, Ring A is 11- to 12-membered heterocyclyl. [0054] In certain embodiments, Ring A is heterocyclyl comprising 1 heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 4 heteroatoms selected from nitrogen, oxygen, and sulfur. [0055] In certain embodiments, Ring A is heterocyclyl comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 2 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, Ring A is heterocyclyl comprising 3 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Attorney Docket No. PRSC-074/001WO 343170-2268 [0056] In certain embodiments, Ring A is C3 carbocyclyl. In certain embodiments, Ring A is C4 carbocyclyl. In certain embodiments, Ring A is C5 carbocyclyl. In certain embodiments, Ring A is C6 carbocyclyl. In certain embodiments, Ring A is C7 carbocyclyl. In certain embodiments, Ring A is C8 carbocyclyl. In certain embodiments, Ring A is C9 carbocyclyl. In certain embodiments, Ring A is C10 carbocyclyl. In certain embodiments, Ring A is C11 carbocyclyl. In certain embodiments, Ring A is C12 carbocyclyl. [0057] In certain embodiments, Ring A is C3-12 carbocyclyl. In certain embodiments, Ring A is C3-11 carbocyclyl. In certain embodiments, Ring A is C3-10 carbocyclyl. In certain embodiments, Ring A is C3-9 carbocyclyl. In certain embodiments, Ring A is C3-8 carbocyclyl. In certain embodiments, Ring A is C3-7 carbocyclyl. In certain embodiments, Ring A is C3-6 carbocyclyl. In certain embodiments, Ring A is C3-5 carbocyclyl. In certain embodiments, Ring A is C3-4 carbocyclyl. In certain embodiments, Ring A is C4-12 carbocyclyl. In certain embodiments, Ring A is C4-11 carbocyclyl. In certain embodiments, Ring A is C4-10 carbocyclyl. In certain embodiments, Ring A is C4-9 carbocyclyl. In certain embodiments, Ring A is C4-8 carbocyclyl. In certain embodiments, Ring A is C4-7 carbocyclyl. In certain embodiments, Ring A is C4-6 carbocyclyl. In certain embodiments, Ring A is C4-5 carbocyclyl. In certain embodiments, Ring A is C5-12 carbocyclyl. In certain embodiments, Ring A is C5-11 carbocyclyl. In certain embodiments, Ring A is C5-10 carbocyclyl. In certain embodiments, Ring A is C5-9 carbocyclyl. In certain embodiments, Ring A is C5-8 carbocyclyl. In certain embodiments, Ring A is C5-7 carbocyclyl. In certain embodiments, Ring A is C5-6 carbocyclyl. In certain embodiments, Ring A is C6-12 carbocyclyl. In certain embodiments, Ring A is C6-11 carbocyclyl. In certain embodiments, Ring A is C6-10 carbocyclyl. In certain embodiments, Ring A is C6-9 carbocyclyl. In certain embodiments, Ring A is C6-8 carbocyclyl. In certain embodiments, Ring A is C6-7 carbocyclyl. In certain embodiments, Ring A is C7-12 carbocyclyl. In certain embodiments, Ring A is C7-11 carbocyclyl. In certain embodiments, Ring A is C7-10 carbocyclyl. In certain embodiments, Ring A is C7-9 carbocyclyl. In certain embodiments, Ring A is C7-8 carbocyclyl. In certain embodiments, Ring A is C8-12 carbocyclyl. In certain embodiments, Ring A is C8-11 carbocyclyl. In certain embodiments, Ring A is C8-10 carbocyclyl. In certain embodiments, Ring A is C8-9 carbocyclyl. In certain embodiments, Ring A is C9-12 carbocyclyl. In certain embodiments, Ring A is C9-11 carbocyclyl. In certain embodiments, Ring A is C9-10 carbocyclyl. In certain embodiments, Ring A is C10-12 carbocyclyl. In certain embodiments, Ring A is C10-11 carbocyclyl. In certain embodiments, Ring A is C11-12 carbocyclyl. [0058] In certain embodiments, Ring A is piperidinyl. Attorney Docket No. PRSC-074/001WO 343170-2268 [0059] In certain embodiments, the compound of Formula I is a compound of Formula I-1-i or I-2-i
Figure imgf000019_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0060] In certain embodiments, each RA is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10- membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0061] In certain embodiments, at least one RA is oxo. In certain embodiments, at least one RA is halogen. In certain embodiments, at least one RA is -CN. In certain embodiments, at least one RA is -NO2. In certain embodiments, at least one RA is -OH. In certain embodiments, at least one RA is -NH2. In certain embodiments, at least one RA is C1-6 alkyl optionally substituted with one or more Ru. In certain embodiments, at least one RA is C1-6 alkoxy optionally substituted with one or more Ru. In certain embodiments, at least one RA is C1-6 alkylamino optionally substituted with one or more Ru. In certain embodiments, at least one RA is C2-6 alkenyl. In certain embodiments, at least one RA is C2-6 alkynyl. In certain embodiments, at least one RA is C3-6 carbocyclyl optionally substituted with one or more Ru. In certain embodiments, at least one RA is 3- to 6-membered heterocyclyl optionally substituted with one or more Ru. [0062] In certain embodiments, 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. [0063] In certain embodiments, m is an integer selected from 0 to 10. In certain embodiments, m is an integer selected from 0 to 8. In certain embodiments, m is an integer selected from 0 to 6. In certain embodiments, m is an integer selected from 0 to 4. In certain embodiments, m is an integer selected from 0 to 2. In certain embodiments, m is an integer selected from 2 to 10. In certain embodiments, m is an integer selected from 2 to 8. In certain embodiments, m is an integer selected from 2 to 6. In certain embodiments, m is an integer selected from 2 to 4. In Attorney Docket No. PRSC-074/001WO 343170-2268 certain embodiments, m is an integer selected from 4 to 10. In certain embodiments, m is an integer selected from 4 to 8. In certain embodiments, m is an integer selected from 4 to 6. In certain embodiments, m is an integer selected from 6 to 10. In certain embodiments, m is an integer selected from 6 to 8. In certain embodiments, m is an integer selected from 8 to 10. [0064] In certain embodiments, RB1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0065] In certain embodiments, RB1 is hydrogen. [0066] In certain embodiments, RB2 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0067] In certain embodiments, RB2 is hydrogen. [0068] In certain embodiments, RD is hydrogen. In certain embodiments, RD is deuterium. In certain embodiments, RD is C1-6 haloalkyl. In certain embodiments, RD is C1-6 alkyl. [0069] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [0070] In certain embodiments, q is an integer selected from 0 to 2. In certain embodiments, q is 0 or 1. In certain embodiments, q is 1 or 2. [0071] In certain embodiments, each Ra is independently C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl Attorney Docket No. PRSC-074/001WO 343170-2268 comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0072] In certain embodiments, each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl. [0073] In certain embodiments, each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. [0074] In certain embodiments, each Ra is independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0075] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0076] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl. [0077] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. Attorney Docket No. PRSC-074/001WO 343170-2268 [0078] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0079] In certain embodiments, each Rc and each Rd is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0080] In certain embodiments, each Rc and each Rd is independently hydrogen, C1-6 alkyl, C3- 6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more Ru. [0081] In certain embodiments, Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more Ru. [0082] In certain embodiments, Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz. [0083] In certain embodiments, Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1- 6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl. [0084] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), Attorney Docket No. PRSC-074/001WO 343170-2268 s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl- i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRbS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0085] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- Attorney Docket No. PRSC-074/001WO 343170-2268 membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl. [0086] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl. [0087] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0088] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl. [0089] In certain embodiments, two Ru, together with the carbon atom(s) to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S). [0090] In certain embodiments, two geminal Ru, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S). Attorney Docket No. PRSC-074/001WO 343170-2268 [0091] Embodiments of the variables in any of the Formulae described herein, e.g., Formulae I and I’, as applicable, are described below. Any of the variables can be any moiety as described in the embodiments below. In addition, the combination of any moieties described for any of the variables, as applicable, with any moieties described for any of the remaining variables, is also contemplated. [0092] Without wishing to be limited by this statement, while various options for variables are described herein, it is understood that the present disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options. [0093] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0094] In certain embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof. [0095] In certain embodiments, the compound is selected from the corresponding (R)-isomers of the compounds in Table 1 and pharmaceutically acceptable salts thereof. [0096] In certain embodiments, the compound is selected from the corresponding (S)-isomers of the compounds in Table 1 and pharmaceutically acceptable salts thereof. [0097] In certain embodiments, the compound is selected from the compounds in Table 1. [0098] In certain embodiments, the compound is selected from the corresponding (R)-isomers of the compounds in Table 1. [0099] In certain embodiments, the compound is selected from the corresponding (S)-isomers of the compounds in Table 1. Table 1. *Note: the compounds below are enantiomerically pure but the absolute configuration of the stereogenic center at glutarimide is not determined.
Figure imgf000025_0001
Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000026_0001
Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000027_0001
Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000028_0003
Bifunctional Degraders [0100] In certain aspects, the present disclosure provides conjugates comprising a compound disclosed herein being connected to a ligand for a protein (e.g., via a linker). [0101] In certain aspects, the present disclosure provides conjugates of Formula II’:
Figure imgf000028_0001
and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: each variable referenced in Formula II’ (e.g., Ring A, RA, m, RB1, RB2, etc.) are described for Formula II above. L is a linker, and T is a ligand for a protein. [0102] In certain embodiments, the conjugate of Formula II’ is a conjugate of Formula II’-1 or II’-2
Figure imgf000028_0002
Attorney Docket No. PRSC-074/001WO 343170-2268 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0103] 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 degrades the target protein. [0104] In certain embodiments, L is of Formula
Figure imgf000029_0001
wherein: * denotes attachment to T and ** denotes attachment to C; each L’ is independently C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru; each occurrence of RL’ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and l is an integer selected from 0 to 6. [0105] In certain embodiments, each L’ is independently C1-6 alkylene (e.g., methylene (-CH2- ), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-)), C1-6 heteroalkylene (e.g., C1-6 alkylene comprising 1-7 heteroatoms selected from N, O, and S), C2-6 alkenylene (e.g., ethenylene (C2), 1-propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2- butenylene (C4), butadienylene (C4), pentenylene (C5), pentadienylene (C5), or hexenylene (C6)), C2-6 alkynylene (e.g., ethynylene (C2), 1-propynylene (C3), 2-propynylene (C3), 1- butynylene (C4), 2-butynylene (C4), pentynylene (C5), or hexynylene (C6)), C3-12 carbocyclylene (e.g., cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), cyclobutenylene (C4), cyclopentylene (C5), cyclopentenylene (C5), cyclohexylene (C6), cyclohexenylene (C6), cyclohexadienylene (C6), cycloheptylene (C7), cycloheptenylene (C7), cycloheptadienylene (C7), cycloheptatrienylene (C7), cyclooctylene (C8), cyclooctenylene (C8), bicyclo[2.2.1]heptanylene (C7), bicyclo[2.2.2]octanylene (C8), cyclononylene (C9), Attorney Docket No. PRSC-074/001WO 343170-2268 cyclononenylene (C9), cyclodecylene (C10), cyclodecenylene (C10), octahydro-1H-indenylene (C9), decahydronaphthalenylene (C10), or spiro[4.5]decanylene (C10)), 3- to 12-membered heterocyclylene (e.g., heterocyclylene comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 arylene (e.g., phenylene or naphthylene), 5- to 10-membered heteroarylene (e.g., heteroarylene comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -C(=O)-, -C(=O)N(RL2)-, -C(=O)O-, -N(RL2)- , -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru. [0106] In certain embodiments, each occurrence of RL’ is independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1- butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. [0107] In certain embodiments, each occurrence of RL’ is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. [0108] In certain embodiments, l is 0. In certain embodiments, l is 1. In certain embodiments, l is 2. In certain embodiments, l is 3. In certain embodiments, l is 4. In certain embodiments, l is 5. In certain embodiments, l is 6. Attorney Docket No. PRSC-074/001WO 343170-2268 [0109] T, a ligand of a protein, is a chemical entity that competitively or non-competitively binds a protein. [0110] In certain embodiments, 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, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR), protein P- glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-l receptor, TNF-alphaR, ICAM1, Cat+ channels, VC AM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RaslRaflMEWERK pathway, interleukin- 1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-l (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, estrogen receptors, androgen receptors (AR), adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk- IIKDR, vitronectin receptor, integrin receptor, Her-2l neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase. 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. [0111] In certain embodiments, 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 Attorney Docket No. PRSC-074/001WO 343170-2268 (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), or bromodomain-containing protein 4 (BRD4). [0112] In certain embodiments, T is a small molecule. [0113] In certain embodiments, T is an antibody. [0114] In certain embodiments, 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. [0115] In certain embodiments, 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. [0116] 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. EXEMPLARY EMBODIMENTS EXEMPLARY EMBODIMENT 1. A compound of Formula II:
Figure imgf000032_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring A is C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each RA is independently amino-protecting group, oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRbS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - Attorney Docket No. PRSC-074/001WO 343170-2268 OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; m is an integer selected from 0 to 10, as valency permits; RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; denotes an optional covalent bond between Y and U; i) when the bond between Y and U is present: r is 1; X is N; U is -CH2- or -C(=O)-; Y is C; ii) when the bond between Y and U is absent: r is 0 or 1; X is O or N; wherein when X is O, then U is absent; when X is N, then U is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Y is CRY; RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; each RD1 is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 Attorney Docket No. PRSC-074/001WO 343170-2268 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 5; and q is an integer from 0 to 2, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. EXEMPLARY EMBODIMENT 2. A conjugate of Formula II’: Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000035_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring A is C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each RA is independently amino-protecting group, oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRbS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; m is an integer selected from 0 to 10, as valency permits; RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; denotes an optional covalent bond between Y and U; i) when the bond between Y and U is present: r is 1; X is N; U is -CH2- or -C(=O)-; Y is C; ii) when the bond between Y and U is absent: r is 0 or 1; Attorney Docket No. PRSC-074/001WO 343170-2268 X is O or N; wherein when X is O, then U is absent; when X is N, then U is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Y is CRY; RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; each RD1 is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 5; and q is an integer from 0 to 2, L is a linker, and T is a ligand for a protein, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents Attorney Docket No. PRSC-074/001WO 343170-2268 selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. EXEMPLARY EMBODIMENT 3. The compound or conjugate of any one of the preceding compound or conjugate, wherein the compound of Formula II is a compound of Formula II-1
Figure imgf000037_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the conjugate of Formula II’ is a conjugate of Formula II’-1
Figure imgf000037_0002
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Attorney Docket No. PRSC-074/001WO 343170-2268 EXEMPLARY EMBODIMENT 4. The compound or conjugate of any one of the preceding compound or conjugate, wherein U is -CH2-. EXEMPLARY EMBODIMENT 5. The compound or conjugate of any one of the preceding compound or conjugate, wherein the compound of Formula II is a compound of Formula II-2
Figure imgf000038_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the conjugate of Formula II’ is a conjugate of Formula II’-2
Figure imgf000038_0002
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. EXEMPLARY EMBODIMENT 6. The compound or conjugate of any one of the preceding compound or conjugate, wherein RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. EXEMPLARY EMBODIMENT 7. The compound or conjugate of any one of the preceding compound or conjugate, wherein RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. EXEMPLARY EMBODIMENT 8. The compound or conjugate of any one of the preceding compound or conjugate, wherein RY is hydrogen. EXEMPLARY EMBODIMENT 9. The compound or conjugate of any one of the preceding compound or conjugate, wherein Ring A is 3- to 12-membered heterocyclyl. EXEMPLARY EMBODIMENT 10. The compound or conjugate of any one of the preceding compound or conjugate, wherein Ring A is piperidinyl, 3-azaspiro[5.5]undecanyl, 2- Attorney Docket No. PRSC-074/001WO 343170-2268 azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, or 5-oxa-2- azaspiro[3.4]octyl. EXEMPLARY EMBODIMENT 11. The compound or conjugate of any one of the preceding compound or conjugate, wherein each RA is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10- membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. EXEMPLARY EMBODIMENT 12. The compound or conjugate of any one of the preceding compound or conjugate, wherein each RA is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. EXEMPLARY EMBODIMENT 13. The compound or conjugate of any one of the preceding compound or conjugate, wherein m is 0. EXEMPLARY EMBODIMENT 14. The compound or conjugate of any one of the preceding compound or conjugate, wherein RB1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. EXEMPLARY EMBODIMENT 15. The compound or conjugate of any one of the preceding compound or conjugate, wherein RB1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. EXEMPLARY EMBODIMENT 16. The compound or conjugate of any one of the preceding compound or conjugate, wherein RB1 is hydrogen. EXEMPLARY EMBODIMENT 17. The compound or conjugate of any one of the preceding compound or conjugate, wherein RB2 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. EXEMPLARY EMBODIMENT 18. The compound or conjugate of any one of the preceding compound or conjugate, wherein RB2 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. Attorney Docket No. PRSC-074/001WO 343170-2268 EXEMPLARY EMBODIMENT 19. The compound or conjugate of any one of the preceding compound or conjugate, wherein RB2 is hydrogen, C1-6 alkyl, or C1-6 alkoxy. EXEMPLARY EMBODIMENT 20. The compound or conjugate of any one of the preceding compound or conjugate, wherein RD is hydrogen. EXEMPLARY EMBODIMENT 21. The compound or conjugate of any one of the preceding compound or conjugate, wherein each RD1 is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. EXEMPLARY EMBODIMENT 22. The compound or conjugate of any one of the preceding compound or conjugate, wherein d is 0. EXEMPLARY EMBODIMENT 23. The compound or conjugate of any one of the preceding compound or conjugate, wherein q is 1. EXEMPLARY EMBODIMENT 24. A compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. [0117] The compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known cereblon-binding agents or known degraders comprising such cereblon-binding agents. For example, the compounds of the present disclosure may 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). These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein. [0118] Due to the existence of double bonds, the compounds of the present disclosure may be in cis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration. [0119] In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another Attorney Docket No. PRSC-074/001WO 343170-2268 embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate. [0120] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Forms of Compounds Disclosed Herein Pharmaceutically acceptable salts [0121] In certain embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [0122] In certain embodiments, 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. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [0123] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, Attorney Docket No. PRSC-074/001WO 343170-2268 monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate. [0124] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4- methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3- hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. [0125] In certain embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. [0126] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Attorney Docket No. PRSC-074/001WO 343170-2268 Solvates [0127] 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. [0128] 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. [0129] 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. [0130] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Isomers/Stereoisomers [0131] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” [0132] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. [0133] In certain embodiments, the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the Attorney Docket No. PRSC-074/001WO 343170-2268 corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. [0134] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In certain embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers [0135] In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. [0136] Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Pharmaceutical Compositions [0137] In certain embodiments, the compound described herein is administered as a pure chemical. In certain embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Attorney Docket No. PRSC-074/001WO 343170-2268 [0138] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. [0139] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [0140] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [0141] In certain embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection. In certain embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In certain embodiments, the pharmaceutical composition is formulated as a tablet. Preparation and Characterization of the Compounds [0142] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of Attorney Docket No. PRSC-074/001WO 343170-2268 the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The compounds of the present disclosure (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and/or synthesis described herein (e.g., Examples). General Synthetic Scheme Scheme 1
Figure imgf000046_0001
[0143] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present dislosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994). [0144] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Attorney Docket No. PRSC-074/001WO 343170-2268 Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [0145] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022- 9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0- 471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645- Attorney Docket No. PRSC-074/001WO 343170-2268 X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. Analytical Methods, Materials, and Instrumentation [0146] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC/MS) were collected using a SHIMADZU LCMS- 2020EV or Agilent 1260-6125B LCMS. Purity and low resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C182.7 μm 4.6 X 100 mm; Flow rate 0.8 mL/min; Solvent A (100/0.1 water/formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C181.7 µm 2.1 X 50 mm; Flow rate 0.5 mL/min; Solvent A (0.1%formic acid water), Solvent B (acetonitrile); gradient: hold 5%B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min. Biological Assays [0147] The biological activities of the compounds of the present disclosure can be assessed with methods and assays known in the art. [0148] The CRBN-DDB1 binding potency of the present disclosure may be determined using HTRF assay technology (Perkin Elmer). In a typical assay, compounds are serially diluted in Attorney Docket No. PRSC-074/001WO 343170-2268 a solvent (e.g., DMSO) and transferred to multi-well plate. The reaction is conducted with addition of His-tagged cereblon E3 ligase (e.g., CRBN+DDB-DLS7+CXU4) followed by addition of a fluorescent probe (e.g., Cy5-labeled Thalidomide) at a certain concentration (e.g., 60 nM), and MAb Anti-6HIS Tb cryptate Gold in an assay buffer (e.g., 50 mM HEPES pH 7.5, 1 mM TCEP, 0.01% Brij-35, 50 mM NaCl, and 0.1% BSA). After incubation for a certain period of time (e.g., one hour) at a certain temperature (e.g., room temperature), the HTRF signals are read from a reader (e.g., Envision reader (Perkin Elemer)). Data may be analyzed using XLfit using four parameters dose response curve to determine IC50s. Methods of Use [0149] In certain aspects, the present disclosure provides methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering the compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein. [0150] In certain aspects, the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. [0151] In certain aspects, the present disclosure provides compounds disclosed herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. [0152] In certain aspects, the present disclosure provides a compound disclosed herein for use in preparing a conjugate disclosed herein. [0153] “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. [0154] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering the conjugate disclosed herein to the subject. [0155] In certain aspects, the present disclosure provides uses of the conjugate disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. [0156] In certain aspects, the present disclosure provides conjugates disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. Attorney Docket No. PRSC-074/001WO 343170-2268 [0157] In certain embodiments, the disease or disorder is an estrogen receptor-mediated disease or disorder, STAT3-mediated disease or disorder, SMARCA2/4-mediated disease or disorder, CBP/p300-mediated disease or disorder, an androgen receptor-mediated disease or disorder, or a BRD9-mediated disease or disorder. [0158] In certain embodiments, the subject is a mammal. [0159] In certain embodiments, the subject is a human. Definitions [0160] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions [0161] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. [0162] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Attorney Docket No. PRSC-074/001WO 343170-2268 [0163] The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0164] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0165] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. [0166] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is Attorney Docket No. PRSC-074/001WO 343170-2268 independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1- 10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), i-Pr (-CH(CH3)2), n- Pr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2). [0167] “Alkylene” as used herein, refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkelene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (- CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like. [0168] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2- 9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- Attorney Docket No. PRSC-074/001WO 343170-2268 butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl. [0169] “Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkenylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH- ) and propenylene (e.g., - CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., - C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)- CH=CH-,-C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like. [0170] “Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2- 8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Attorney Docket No. PRSC-074/001WO 343170-2268 Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl. [0171] “Alkynylene” as used herein, refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like. [0172] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1- 8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7 alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated Attorney Docket No. PRSC-074/001WO 343170-2268 group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl. [0173] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl. [0174] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, Attorney Docket No. PRSC-074/001WO 343170-2268 nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl. [0175] Analogous to “alkylene,” “alkenylene,” and “alkynylene” as defined above, “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” as used herein, refer to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. “Heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein. [0176] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In Attorney Docket No. PRSC-074/001WO 343170-2268 some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). [0177] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14 aryl. In certain embodiments, the aryl group is substituted C6- 14 aryl. [0178] “Arylene” as used herein, refers to an aryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “arylene” group, it is understood that the range or number refers to the range or number of carbons in the aryl group. An “arylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0179] “Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. [0180] “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 Attorney Docket No. PRSC-074/001WO 343170-2268 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). [0181] In certain embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In certain embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl. [0182] 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- Attorney Docket No. PRSC-074/001WO 343170-2268 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. [0183] “Heteroarylene” as used herein, refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group. A “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0184] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3- 10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. [0185] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon Attorney Docket No. PRSC-074/001WO 343170-2268 atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Examples of C5-6 carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 carbocyclyl include the aforementioned C5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-12 carbocyclyl. [0186] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-12 carbocyclyl. [0187] “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings. [0188] “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 Attorney Docket No. PRSC-074/001WO 343170-2268 the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embedded. [0189] “Bridged carbocyclyl” or or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embedded. [0190] “Carbocyclylene” as used herein, refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the carbocyclylene group. When a range or number of carbons is provided for a particular “carbocyclyl” group, it is understood that the range or number refers to the range or number of carbons in the carbocyclyl group. A “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein. [0191] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- Attorney Docket No. PRSC-074/001WO 343170-2268 membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. [0192] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [0193] As the foregoing examples illustrate, in certain embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment Attorney Docket No. PRSC-074/001WO 343170-2268 is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3- to 12- membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12- membered heterocyclyl. [0194] “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of ring members designates the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings. [0195] “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. [0196] “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. Attorney Docket No. PRSC-074/001WO 343170-2268 [0197] “Heterocyclylene” as used herein, refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocyclylene group. When a range or number of ring members is provided for a particular “heterocyclylene” group, it is understood that the range or number refers to the number of ring members in the heterocyclylene group. A “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein. [0198] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl as defined herein. C1-6 alkoxy refers to the group -OR, wherein each R is C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above. [0199] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R is independently alkyl, as defined herein. C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above. [0200] “Oxo” refers to =O. When a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure/tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical. [0201] “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. [0202] “Protecting group” as used herein is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively. [0203] Common types of hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), β-Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri- Attorney Docket No. PRSC-074/001WO 343170-2268 iso-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)). [0204] Common types of amino-protecting groups include but not limited to carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g, benzyl (Bn), p- methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2- nitrophenylsulfenyl (Nps)). [0205] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)). [0206] Common types of carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline. [0207] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions [0208] “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. [0209] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo Attorney Docket No. PRSC-074/001WO 343170-2268 [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. [0210] “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates. [0211] 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. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. [0212] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylatically effective amount” refers to the effective amount for prophylactic treatment. [0213] “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 Attorney Docket No. PRSC-074/001WO 343170-2268 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). [0214] 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. [0215] “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). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “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. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease. [0216] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that only differ in the arrangement of their atoms in space are termed “stereoisomers.” [0217] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is termed a “racemic mixture”. [0218] “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of it electrons and an atom (usually Attorney Docket No. PRSC-074/001WO 343170-2268 H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. [0219] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, 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. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [0220] As used herein and unless otherwise indicated, the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)-compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound. [0221] As used herein and unless otherwise indicated, the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound. [0222] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the Attorney Docket No. PRSC-074/001WO 343170-2268 compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)- compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. [0223] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. [0224] 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. [0225] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0226] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. [0227] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but Attorney Docket No. PRSC-074/001WO 343170-2268 also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0228] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. [0229] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. [0230] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or Attorney Docket No. PRSC-074/001WO 343170-2268 configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure. The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed. Other Definitions [0231] “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. [0232] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, Attorney Docket No. PRSC-074/001WO 343170-2268 hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. [0233] “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates. [0234] 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. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. [0235] 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. [0236] “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). Attorney Docket No. PRSC-074/001WO 343170-2268 [0237] 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. [0238] “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). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “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. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease. [0239] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that only differ in the arrangement of their atoms in space are termed “stereoisomers.” [0240] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is termed a “racemic mixture”. [0241] “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of pi electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the Attorney Docket No. PRSC-074/001WO 343170-2268 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. [0242] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, 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. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [0243] As used herein and unless otherwise indicated, the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)-compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound. [0244] As used herein and unless otherwise indicated, the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound. [0245] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)- compound can comprise, for example, about 90% excipient and about 10% enantiomerically Attorney Docket No. PRSC-074/001WO 343170-2268 pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. [0246] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. [0247] 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. [0248] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0249] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. [0250] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly Attorney Docket No. PRSC-074/001WO 343170-2268 one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0251] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. [0252] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. [0253] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize many equivalents to the specific Attorney Docket No. PRSC-074/001WO 343170-2268 inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure. [0254] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed. EXAMPLES [0255] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. I. Synthesis and Characterization [0256] The following abbreviations were used in descriptions and examples: [0257] ACN acetonitrile; DCM dichloromethane; DMA N,N-dimethylacetamide; DMP Dess- Martin periodinane; DMSO dimethylsulfoxide; EA ethyl acetate; FA formic acid; hr Hour; hrs Hours; m-CPBA 3-chlorobenzenecarboperoxoic acid; LC/MS liquid chromatography-mass spectrometry; MeOH methanol; MS mass spectrometry; mL milliliters; NBS N- bromosuccinimide; NMP N-methyl pyrrolidinone; NMR nuclear magnetic resonance; PE petroleum ether; ppm parts per million; T3P propanephosphonic acid anhydride; TEA triethylamine; TFA trifluoroacetic acid; TFAA trifluoroacetic anhydride; THF tetrahydrofuran; TMEDA tetramethylethylenediamine. Compound 1. (R)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)oxy)piperidine- 2,6-dione Attorney Docket No. PRSC-074/001WO 343170-2268 Compound 2. (S)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)oxy)piperidine- 2,6-dione
Figure imgf000078_0001
Step E Step A: tert-butyl 4-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate [0258] A mixture of 4-(benzyloxy)pyridin-2(1H)-one (4 g, 1 eq, 19.9 mmol), tert-butyl 4- (tosyloxy)piperidine-1-carboxylate (9.2 g, 1.3 eq, 25.9 mmol) and K2CO3 (4.12 g, 1.5 eq, 29.9 mmol) in DMF (50 mL) was stirred at 100oC under N2 atmosphere overnight. The mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography and eluted with 0-60% EA in PE to give tert-butyl 4-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (4.5 g, yield 59%) as a white solid. LC-MS (ESI): mass calcd. for C22H28N2O4, 384.20; m/z found, 385 [M+H]+. Step B: tert-butyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate [0259] A mixture of tert-butyl 4-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)piperidine-1- carboxylate (1.5 g, 1 eq, 3.9 mmol) and 10% Pd/C (300 mg) in EtOH (20 mL) was stirred at Attorney Docket No. PRSC-074/001WO 343170-2268 room temperature under H2 atmosphere for 5 h. The mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography and eluted with 0-10% MeOH in DCM to give tert-butyl 4-(4-hydroxy-2- oxopyridin-1(2H)-yl)piperidine-1-carboxylate (1.1 g, yield 96%) as a white solid. LC-MS (ESI): mass calcd. for C15H22N2O4, 294.16; m/z found, 295 [M+H]+. Step C: tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-oxopyridin-1(2H)-yl)piperidine-1- carboxylate & tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate [0260] To a solution of tert-butyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)piperidine-1- carboxylate (500 mg, 1 eq, 1.7 mmol) in DMF (10 mL) was added sodium hydride (60% in mineral oil, 82 mg, 1.2 eq, 2.04 mmol) at 60oC. After 20 min, a solution of 3-bromopiperidine- 2,6-dione (391 mg, 1.2 eq, 2.04 mmol) in DMF (2 mL) was added to the reaction mixture slowly at 60oC. The mixture was stirred at the same temperature for 1 h, then quenched with sat. NH4Cl aq. (10 mL). The mixture was diluted with water (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep- TLC (DCM / MeOH = 12 / 1) and SFC separation to afford tert-butyl (R)-4-(4-((2,6- dioxopiperidin-3-yl)oxy)-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (70 mg, yield 10%) as a white solid, LC-MS (ESI): mass calcd. for C20H27N3O6, 405.19; m/z found, 406 [M+H]+.; and tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-oxopyridin-1(2H)-yl)piperidine-1- carboxylate (50 mg, yield 7%) as a white solid, LC-MS (ESI): mass calcd. for C20H27N3O6, 405.19; m/z found, 406 [M+H]+. [0261] Preparative separation method: Instrument: Waters Thar 80 preparative SFC Column: (R,R)-WHELK, 250×21.2 mm I.D., 5 µm Mobile phase: A for CO2 and B for MEOH Gradient: B 30% Flow rate: 40 mL/min Back pressure: 100 bar Column temperature: 35 ℃ Wavelength: 220 nm Cycle-time: 15 min Eluted time：15 H Attorney Docket No. PRSC-074/001WO 343170-2268 Step D: (R)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)oxy)piperidine-2,6-dione [0262] A mixture of tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate (50 mg, 1 eq, 0.123 mmol) and HCl (4 M in dioxane; 0.3 mL, 10 eq, 1.2 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. The reaction was monitored by LCMS. Then the precipitate was collected by filtration to afford (R)-3-((2-oxo- 1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)oxy)piperidine-2,6-dione HCl salt (26 mg, yield 62%) as a blue solid. LC-MS (ESI): mass calcd. for C15H19N3O4, 305.14; m/z found, 306
Figure imgf000080_0001
7.84 (d, J = 7.7 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.34 (s, 1H), 5.39 (dd, J = 11.1, 5.3 Hz, 1H), 5.02 (t, J = 12.0 Hz, 1H), 3.70 – 3.58 (m, 2H), 3.24 (t, J = 12.0 Hz, 2H), 2.89 – 2.73 (m, 2H), 2.39 – 2.16 (m, 6H). Step E: (S)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)oxy)piperidine-2,6-dione [0264] A mixture of tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate (70 mg, 1 eq, 0.17 mmol) and HCl (4 M in dioxane; 0.5 mL, 11.6 eq, 2 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. The reaction was monitored by LCMS. Then the precipitate was collected by filtration to afford (S)-3-((2-oxo- 1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)oxy)piperidine-2,6-dione HCl salt (39 mg, yield 66%) as a blue solid. LC-MS (ESI): mass calcd. for C15H19N3O4, 305.14; m/z found, 306 [M+H]+. [0265] 1H NMR (400 MHz, MeOD-d4) δ 7.70 (d, J = 7.7 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 6.21 (s, 1H), 5.32 (dd, J = 11.0, 5.2 Hz, 1H), 4.97 (t, J = 11.8 Hz, 1H), 3.65 – 3.58 (m, 2H), 3.23 (t, J = 11.7 Hz, 2H), 2.85 – 2.73 (m, 2H), 2.35 – 2.11 (m, 6H). Compound 3. (R)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4- yl)amino)piperidine-2,6-dione Compound 4. (S)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)amino)piperidine- 2,6-dione Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000081_0001
Step A: tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate [0266] A mixture of tert-butyl 4-(4-amino-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (2.6 g, 1 eq, 8.86 mmol; Ref: WO2021003314), 2,6-bis(benzyloxy)-3-bromopyridine (4.59 g, 1.4 eq, 12.4 mmol), Pd2(dba)3 (812 mg, 0.1 eq, 0.886 mmol), X-Phos (423 mg, 0.1 eq, 0.886 mmol) and Cs2CO3 (8.66 g, 3 eq, 26.6 mmol) in 100 mL of 1,4-dioxane was stirred at 100 °C under N2 atmosphere for 16 h. The reaction was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (C18, 0.1%FA) to give tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate (2.4 g, yield 47%) as a yellow solid. LC-MS (ESI): mass calcd. for C34H38N4O5, 582.28; m/z found, 583 [M+H]+. [0267] 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 8.2 Hz, 1H), 7.45 – 7.28 (m, 12H), 6.47 (d, J = 8.2 Hz, 1H), 5.86 (dd, J = 7.6, 2.4 Hz, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 4.73 (t, J = 10.7 Hz, 1H), 4.14 – 4.01 (m, 2H), 2.83 (s, 2H), 1.67 – 1.56 (m, 4H), 1.42 (s, 9H). Step B: tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate & tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- oxopyridin-1(2H)-yl)piperidine-1-carboxylate [0268] A mixture of tert-butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-oxopyridin- 1(2H)-yl)piperidine-1-carboxylate (600 mg, 1 eq, 1.03 mmol) and 10% Pd/C (70 mg) in CF3CH2OH (20 mL) was stirred at room temperature under H2 atmosphere for 16 h. The Attorney Docket No. PRSC-074/001WO 343170-2268 reaction was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (C18, 0.1% FA) and separated by SFC to give tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-oxopyridin-1(2H)-yl)piperidine- 1-carboxylate (190 mg, yield 46%) as a yellow solid, LC-MS (ESI): mass calcd. for C20H28N4O5, 404.21; m/z found, 405 [M+H]+; and tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3- yl)amino)-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (170 mg, yield 41%) as a yellow solid, LC-MS (ESI): mass calcd. for C20H28N4O5, 404.21; m/z found, 405 [M+H]+. [0269] Preparative separation method Instrument: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IB, 250×21.2mm I.D., 5µm Mobile phase: A for CO2 and B for MEOH Gradient: B 30% Flow rate: 40 mL/min Back pressure: 100 bar Column temperature: 35℃ Wavelength: 220 nm Cycle-time: 5 min Eluted time:4 h Step C: (R)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)amino)piperidine-2,6-dione [0270] To a solution of tert-butyl (R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- oxopyridin-1(2H)-yl)piperidine-1-carboxylate (190 mg, 1 eq, 470 mmol) in DCM (5 mL) was added 5 mL of 4 N HCl/dioxane. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was triturated with MeCN (5 mL), then filtered to give (R)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4- yl)amino)piperidine-2,6-dione, HCl salt (110 mg, yield 69%) as a purple solid. LC-MS (ESI): mass calcd. for C15H20N4O3, 304.15; m/z found, 305 [M+H]+. [0271] 1H NMR (400 MHz, DMSO-d6, HCl salt) δ 10.94 (s, 1H), 9.25 (s, 2H), 7.95 – 7.75 (m, 2H), 6.36 (s, 1H), 5.94 (s, 1H), 4.92 – 4.82 (m, 1H), 4.52 (s, 1H), 3.44 – 3.34 (m, 2H), 3.13 – 3.02 (m, 2H), 2.82 – 2.70 (m, 1H), 2.65 – 2.55 (m, 1H), 2.19 – 2.13 (m, 2H), 2.13 – 2.03 (m, 1H), 2.03 – 1.88 (m, 3H). Step D: (S)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4-yl)amino)piperidine-2,6-dione [0272] To a solution of tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- oxopyridin-1(2H)-yl)piperidine-1-carboxylate (170 mg, 1 eq, 0.42 mmol) in DCM (5 mL) was added 5 mL of 4N HCl/dioxane. The mixture was stirred at room temperature overnight. The Attorney Docket No. PRSC-074/001WO 343170-2268 mixture was concentrated under reduced pressure, and the residue was triturated with MeCN (5 mL), then filtered to give (S)-3-((2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridin-4- yl)amino)piperidine-2,6-dione, HCl salt (110 mg, yield 77%) as a purple solid. LC-MS (ESI): mass calcd. for C15H20N4O3, 304.15; m/z found, 305 [M+H]+. [0273] 1H NMR (400 MHz, DMSO-d6, HCl salt) δ 10.93 (s, 1H), 9.16 (s, 2H), 7.82 – 7.22 (m, 2H), 6.28 (s, 1H), 5.84 (s, 1H), 4.87 – 4.81 (m, 1H), 4.52 (s, 1H), 3.43 – 3.33 (m, 2H), 3.12 – 2.98 (m, 2H), 2.82 – 2.67 (m, 1H), 2.63 – 2.55 (m, 1H), 2.18 - 2.11 (m, 2H), 2.11 – 2.04 (m, 1H), 2.02 – 1.88 (m, 3H). Compound 5. (R)-2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione Compound 6. (S)-2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione
Figure imgf000083_0001
Step A: N-isopropyl-2-methoxyisonicotinamide Attorney Docket No. PRSC-074/001WO 343170-2268 [0274] To a solution of 2-methoxyisonicotinic acid (30.0 g, 196 mmol, 1.0 eq) and isopropylamine (12.7 g, 216 mmol, 1.1 eq) in DMA (150 mL) was added TEA (39.6 g, 392 mmol, 2.0 eq) and TBTU (94.4 g, 294 mmol, 1.5 eq). The resulting mixture was stirred for 2h at room temperature. The mixture was poured into water (1000 mL) and extracted with EA (200 mL x 3). The organic phase was washed with brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried to give N-isopropyl-2- methoxyisonicotinamide (22 g, yield 57.9%) as a brown solid. LC-MS (ESI, m/z): mass calcd. For C10H14N2O2, 194.2; found, 195.4 [M+H]+. Step B: 3-hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one [0275] To a solution of N-isopropyl-2-methoxyisonicotinamide (20.0 g, 103 mmol, 1.0 eq) in MTBE (250 mL) was added TMEDA (29.95 g, 258 mmol, 2.5 eq) at room temperature, which was then cooled to -78 °C. Subsequently, n-BuLi solution (2.5 M in hexane) (124 mL, 309 mmol, 3.0 eq) was added to above mixture over 35 min and the resulting mixture was stirred at -78 oC for an additional 3 h, and subsequently at -22 °C for another 3 h. DMF (27.7 mL, 361 mmol, 3.5 eq) was added to above mixture at -78 °C and stirred for 3 h. The resulting suspension was quenched with saturated aqueous NH4Cl solution (200 mL) and extracted with dichloromethane (150 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was trituration with ethyl acetate (30 mL) and PE (150 mL) for 24 h at room temperature, filtered and dried to obtain 3-hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (12 g, yield 52.4%) as a pale-yellow solid. LC-MS (ESI, m/z): mass calcd. For C11H14N2O3, 222.2; found, 223.4 [M+H]+. Step C: 4-methoxyfuro[3,4-c]pyridin-1(3H)-one [0276] To a solution of 3-hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-1-one (10 g, 45 mmol, 1.0 eq) in 2-propanol (100 mL) and water (30 mL) was added NaBH4 (2.57 g, 67.5 mmol, 1.5 eq) in portions at room temperature and the reaction mixture was stirred for 3 h. The rection mixture was quenched by addition of acetone (30 mL) at 0 °C and stirred for 35 min at room temperature. The mixture was poured into aqueous HCl solution (1 N) (100 mL) at 0 °C and stirred at 50oC overnight. After evaporation, the residue was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with ethyl acetate (10 mL) and PE (50 mL) for 1 h at room temperature, filtered and dried to give 4-methoxyfuro[3,4-c]pyridin-1(3H)-one (6 g, yield 80.8%) as a light brown solid. LC-MS (ESI, m/z): mass calcd. For C8H7NO3, 165.1; found, 166.3 [M+H]+. Attorney Docket No. PRSC-074/001WO 343170-2268 Step D: 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione [0277] To a solution of 4-methoxyfuro[3,4-c]pyridin-1(3H)-one (13 g , 78.8 mmol, 1.0 eq) in HCl (50 mL) at 0 oC. The reaction mixture was stirred at 80 oC for 2 h. After evaporation, the residue was triturated with MeOH (30 mL) and DCM (100 mL) for 10 min at room temperature, filtered and dried to give 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (8 g, yield 67%) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C7H5NO3, 151.1; found, 152.3 [M+H]+ Step E: tert-butyl 4-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)piperidine-1- carboxylate [0278] To a solution of 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (8 g, 53 mmol, 1.0 eq) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (17.7 g, 63.6 mmol, 1.2 eq) in DMF (50 mL) was added cesium carbonate (17.3 g, 59.6 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at 80 oC for 16 h. The reaction mixture was cooled to room temperature, poured into water (300ml) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EA = 13/1) to give tert-butyl 4-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)piperidine-1-carboxylate (7 g, yield 71%) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C17H22N2O5, 334.4; found, 335.2 [M+H]+ Step F: 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0279] To a solution of tert-butyl 4-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)piperidine-1-carboxylate (7 g, 21 mmol, 1.0 eq) in THF (14 mL) and water（30 mL）was added NaOH (3.4 g, 83.8 mmol, 4 eq) at 70 °C for 2 h. The organic layer was concentrated to get 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-2-oxo-1,2-dihydropyridine- 4-carboxylic acid (8 g) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C17H24N2O6, 352.4; found, 353.2[M+H]+ Step G: 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-2-oxo-1,2-dihydropyridine-4- carboxylic acid [0280] To a solution of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-2-oxo- 1,2-dihydropyridine-4-carboxylic acid (8 g, 22.7 mmol, 1.0 eq) in DCM (50 mL) was added MnO2 (19.8 g, 227mmol, 10 eq) and the mixture was stirred at 50 oC for 10 h. After filtration, the filtrate was concentrated to get 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-2-oxo- 1,2-dihydropyridine-4-carboxylic acid (6 g) as a yellow solid. The crude product was directly Attorney Docket No. PRSC-074/001WO 343170-2268 used in next step without further purification. LC-MS (ESI, m/z): mass calcd. For C17H22N2O6, 350.4; found, 351.1[M+H]+ Step H: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate [0281] To a solution of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid (6 g, 17.1 mmol, 1.0 eq) and 3-aminopiperidine-2,6-dione hydrochloride (3.4 g, 20.6 mmol, 1.2 eq) in DCM (50 mL) was added AcOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (10.9 g, 51.4 mmol, 3.0 eq) was added to above mixture and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 10/1) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (3.5 g, yield 46%) as a yellow solid. LC- MS (ESI, m/z): mass calcd. For C22H28N4O6, 444.5; found, 445.1[M+H]+ Step I: (S)-2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridine-1,4(2H)-dione and (R)-2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0282] The 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridine-1,4(2H)-dione (1g, 2.25 mmol, 1.0 eq) was purified by SFC (the conditions were described as followed:
Figure imgf000086_0001
Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000087_0001
to afford compound (S)-2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione (400 mg, 0.9 mmol, 80%) as a white solid and (R)-2- (2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)- dione (400 mg, 0.9 mmol, 80%) as a white solid. LC-MS (ESI, m/z): mass calcd. For C22H28N4O6, 444.5; found, 445.1[M+H]+ Step J: (S)-2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridine-1,4(2H)-dione [0283] To a solution of tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (30 mg, 0.07 mmol, 1.0 eq) was added HCl/dioxane (4M, 3mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford (S)-2-(2,6- dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (27 mg) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C22H28N4O6, 344.4; found, 345.5[M+H]+ Step K: (R)-2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridine-1,4(2H)-dione [0284] To a solution of tert-butyl (R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (30 mg, 0.07 mmol, 1.0 eq) was added HCl/dioxane (4M, 3mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford (R)-2-(2,6- dioxopiperidin-3-yl)-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (27 mg) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C22H28N4O6, 344.4; found, 345.5[M+H]+. Compound 7. (S)-N-(2,6-dioxopiperidin-3-yl)-2-oxo-1-(piperidin-4-yl)-1,2- dihydropyridine-4-carboxamide Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000088_0001
6 Step A: methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4- carboxylate [0285] To a solution of methyl 2-hydroxyisonicotinate (5.0 g, 32.6 mmol, 1.0 eq) in DMF (100 mL) were added tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (10.94 g, 39.1 mmol, 1.2 eq) and Cs2CO3 (21.2 g, 65.2 mmol, 2.0 eq). The mixture was stirred under N2 at 80oC for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The separated organic phase was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50%) to afford methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2- dihydropyridine-4-carboxylate (5.3 g, yield 48.4 %) as a yellow oil. LC-MS (ESI): mass calcd. for C17H24N2O5, 336.39; m/z found, 281 [M+H-56]+. Step B: 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid [0286] To a solution of methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2- dihydropyridine-4-carboxylate (5.3 g, 15.7 mmol, 1.0 eq) in MeOH (50 mL), and H2O (50 mL) was added NaOH (0.95 g, 23.6 mmol, 1.5 eq). The mixture was stirred at 40 oC for 1 hour. After cooling to room temperature, the reaction mixture was evaporated to about 50 mL, adjusted to pH = 5 ~ 6 with AcOH, and extracted with EtOAc (50 mL x 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4- carboxylic acid (2.8 g, yield 55.3 %) as a colorless oil. The crude product was directly used in next step without purification. LC-MS (ESI): mass calcd. for C16H22N2O5, 322.36; m/z found, 321 [M-H]-. Attorney Docket No. PRSC-074/001WO 343170-2268 Step C: tert-butyl (S)-4-(4-((2,4-dioxocyclohexyl)carbamoyl)-2-oxopyridin-1(2H)- yl)piperidine-1-carboxylate [0287] To a solution of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine- 4-carboxylic acid (100 mg, 0.31 mmol, 1.0 eq) in DMF (5 mL) was added Et3N (94 mg, 0.93 mmol, 3.0 eq) and T3P (148 mg, 0.47 mmol, 1.5 eq) under N2 at 0 oC. The reaction was allowed to slowly warm to 25 oC and stirred at that temperature for 2 hours. Water (5 mL) was added to the mixture, then diluted with EtOAc (10 mL), washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40%) to afford tert-butyl (S)-4-(4-((2,4-dioxocyclohexyl)carbamoyl)-2-oxopyridin- 1(2H)-yl)piperidine-1-carboxylate (80 mg, yield 59.8 %) as a white oil. LC-MS (ESI): mass calcd. for C22H29N3O6, 431.49; m/z found, 376 [M+H-56]+. Step D: (S)-N-(2,6-dioxopiperidin-3-yl)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridine-4- carboxamide [0288] To a solution of tert-butyl (S)-4-(4-((2,4-dioxocyclohexyl)carbamoyl)-2-oxopyridin- 1(2H)-yl)piperidine-1-carboxylate (80 mg, 0.185 mmol, 1.0 eq) in DCM (5 mL) was added trifluoroacetic acid (2 mL) and the reaction was stirred at 25 oC for 1 hour. The mixture was concentrated and dried to afford (S)-N-(2,6-dioxopiperidin-3-yl)-2-oxo-1-(piperidin-4-yl)-1,2- dihydropyridine-4-carboxamide (58 mg, yield 94.3 %) as a white solid. LC-MS (ESI): mass calcd. for C16H20N4O4, 332.36; m/z found, 333.2 [M+H]+. [0289] 1H NMR (400M Hz, MeOD-d4) δ 8.24 (d, J = 8.0 Hz, 1H), 7.36-7.34 (m, 1H), 7.23 (s, 1H), 5.40-5.36 (m, 1H), 4.86-4.83 (m, 1H), 3.44-3.38 (m, 2H), 3.31-3.22 (m, 2H), 2.83-2.79 (m, 1H), 2.74-2.69 (m, 1H), 2.26-2.20 (m, 4H), 2.19-2.03 (m, 2H). Compound 8. (S)-N-(2,6-dioxopiperidin-3-yl)-5-methoxy-2-oxo-1-(piperidin-4-yl)-1,2- dihydropyridine-4-carboxamide
Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000090_0001
Step A: methyl 3-methoxyisonicotinate [0290] A mixture of 3-methoxyisonicotinic acid (5.00 g, 1 eq, 32.6 mmol) in HCl/MeOH (4M, 50.0 mL) was stirred for 5 h at 80°C. The mixture was concentrated under reduced pressure to afford methyl 3-methoxyisonicotinate (5.00 g, 29.9 mmol, 91.6 %) as a yellow solid. LC-MS (ESI): mass calcd. for C7H7NO3, 153.14; m/z found, 154.2 [M+H]+. Step B: 3-methoxy-4-(methoxycarbonyl)pyridine 1-oxide [0291] To a mixture of methyl 3-methoxyisonicotinate (5.40 g, 1 eq, 32.3 mmol) in DCM (20.0 mL) was added mCPBA (11.1 g, 2 eq, 64.6 mmol). The mixture was stirred for 16h at 50°C, then added with Na2CO3 (100 mL, 1 M), stirred for another 1h at rt. The resulting mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/10) to afford 3-methoxy-4-(methoxycarbonyl)pyridine 1-oxide (1.00 g, 5.46 mmol, 16.9 %) as a white solid. LC-MS (ESI): mass calcd. for C8H9NO4, 183.1; m/z found, 183.2 [M+H]+. Step C: methyl 5-methoxy-2-oxo-1,2-dihydropyridine-4-carboxylate [0292] A mixture of 3-methoxy-4-(methoxycarbonyl)pyridine 1-oxide (0.90 g, 1 eq, 4.9 mmol) in TFAA (10.0 mL) was stirred for 16 h at 80°C. The mixture was concentrated under reduced pressure and H2O (10 mL) was added. The mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 80% gradient in 20 min; detector, UV 254 nm to afford methyl 5-methoxy-2-oxo- 1,2-dihydropyridine-4-carboxylate (0.90 g, 4.9 mmol, 100 %) as a yellow solid. LC-MS (ESI): mass calcd. For C8H9NO4, 183.16; m/z found, 184.2 [M+H]+. Attorney Docket No. PRSC-074/001WO 343170-2268 Step D: methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo-1,2- dihydropyridine-4-carboxylate [0293] To a mixture of methyl 5-methoxy-2-oxo-1,2-dihydropyridine-4-carboxylate (0.85 g, 1 eq, 4.6 mmol) in DMA (10.0 mL) was added Cs2CO3 (3.0 g, 2 eq, 9.3 mmol), tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (1.6 g, 1.2 eq, 5.6 mmol). The mixture was stirred at 80°C for 16h. The resulting mixture was diluted with brine, extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA 2/1 to afford methyl 1-(1-(tert- butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo-1,2-dihydropyridine-4-carboxylate (1.20 g, 3.28 mmol, 71 %) as a white solid. LC-MS (ESI): mass calcd. for C18H26N2O6, 366.41; m/z found, 367.3 [M+H]+. Step E: 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo-1,2-dihydropyridine-4- carboxylic acid [0294] To a mixture of methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo- 1,2-dihydropyridine-4-carboxylate (1.20 g, 1 eq, 3.28 mmol) in MeOH/THF/H2O (20.0 mL) was added NaOH (524 mg, 4 eq, 13.1 mmol). The mixture was stirred at rt for 2h, acidified to pH =6 with 1N HCl, extracted with EA (50 Ml x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo-1,2- dihydropyridine-4-carboxylic acid (1.00 g, 2.84 mmol, 86.6 %) as a white solid. LC-MS (ESI): mass calcd. for C17H24N2O6, 352.39; m/z found, 353.3 [M+H]+. Step F: tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxy-2-oxopyridin- 1(2H)-yl)piperidine-1-carboxylate [0295] To a mixture of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methoxy-2-oxo-1,2- dihydropyridine-4-carboxylic acid (0.95 g, 1 eq, 2.7 mmol) in DMA (10.0 mL) was added HATU (1.2 g, 1.2 eq, 3.2 mmol), TEA (0.82 g, 1.1 mL, 3 eq, 8.1 mmol), (S)-3-aminopiperidine- 2,6-dione (0.41 g, 1.2 Eq, 3.2 mmol). The mixture was stirred for 2h at rt. The mixture was diluted with brine. The precipitates were collected by filtration, washed with water and dried to afford tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxy-2-oxopyridin- 1(2H)-yl)piperidine-1-carboxylate (1.00 g, 2.16 mmol, 80 %) as a white solid. LC-MS (ESI): mass calcd. for C22H30N4O7, 462.50; m/z found, 463.6 [M+H]+. Step G: (S)-N-(2,6-dioxopiperidin-3-yl)-5-methoxy-2-oxo-1-(piperidin-4-yl)-1,2- dihydropyridine-4-carboxamide Attorney Docket No. PRSC-074/001WO 343170-2268 [0296] A mixture of tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxy-2- oxopyridin-1(2H)-yl)piperidine-1-carboxylate (0.02 g, 1 eq, 0.04 mmol) in HCl/dioxane (1 mL) was stirred at rt for 1h. After the reaction was completed, the mixture was concentrated to afford (S)-N-(2,6-dioxopiperidin-3-yl)-5-methoxy-2-oxo-1-(piperidin-4-yl)-1,2- dihydropyridine-4-carboxamide (2.45 mg, 6.76 µmol, 20 %) as a yellow solid. LC-MS (ESI): mass calcd. for C17H22N4O5, 362.39; m/z found, 363.4 [M+H]+. [0297] 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.18 (s, 2H), 8.73 (s, 1H), 8.06 (s, 1H), 7.04 (s, 1H), 5.16 (s, 1H), 4.75 (s, 1H), 3.91 (s, 3H), 3.26 – 3.01 (m, 4H), 2.78 (s, 1H), 2.24 – 1.82 (m, 7H). Compound 9 and Compound 10：(R)-2-(2,6-dioxopiperidin-3-yl)-5-(3- azaspiro[5.5]undecan-9-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione and (S)-2-(2,6-dioxopiperidin-3-yl)-5-(3-azaspiro[5.5]undecan-9-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione
Figure imgf000092_0001
Step A: tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate [0298] To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (4.00 g, 1 eq, 15.0 mmol) in MeOH (40.0 mL) was added NaBH4 (283 mg, 0.5 eq, 7.48 mmol) in portions at room temperature and the reaction mixture was stirred for 3 h. The mixture was poured into aqueous HCl solution (1 N) (100 mL) at 0 °C for 30 min. After evaporation, the residue was Attorney Docket No. PRSC-074/001WO 343170-2268 diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. to give tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (4.00 g, 14.8 mmol, 99.3 %) as a white solid. LC-MS (ESI, m/z): mass calcd. For C15H27NO3, 269.20; found, 214.2 [M- 56+H]+. Step B: tert-butyl 9-((methylsulfonyl)oxy)-3-azaspiro[5.5]undecane-3-carboxylate [0299] To a solution tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (4.00 g, 1 eq, 14.8 mmol) in DCM (50.0 mL)) was added MsCl (2.55 g, 1.74 mL, 1.5 eq, 22.3 mmol) in portions at room temperature and the reaction mixture was stirred for 2 hours. After evaporation, the residue was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 9-((methylsulfonyl)oxy)-3-azaspiro[5.5]undecane-3- carboxylate (5.00 g, 14.4 mmol, 96.9 %) as a white solid. LC-MS (ESI, m/z): mass calcd. For C16H29NO5S, 347.17; found, 248.3 [M-100+H]+. Step C: tert-butyl 9-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-3- azaspiro[5.5]undecane-3-carboxylate [0300] To a solution of tert-butyl 9-((methylsulfonyl)oxy)-3-azaspiro[5.5]undecane-3- carboxylate (5.00 g, 1.0 eq, 14.4 mmol) and 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (3.26 g, 1.5 eq, 21.6 mmol) in DMF (50 mL) was added Cs2CO3 (9.38 g, 2.0 eq, 28.8 mmol) at room temperature, the reaction mixture was stirred at 80oC for 16 hours. The reaction mixture was cooled to room temperature, poured into water (300ml) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EA = 13/1) to give tert-butyl 9-(1,4-dioxo-1,4- dihydrofuro[3,4-c]pyridin-5(3H)-yl)-3-azaspiro[5.5]undecane-3-carboxylate (4.00 g, 9.94 mmol, 69.1 %) as a white solid. LC-MS (ESI, m/z): mass calcd. For C22H30N2O5, 402.21; found, 347.2 [M-56+H]+. Step D: 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3-(hydroxymethyl)-2-oxo- 1,2-dihydropyridine-4-carboxylic acid [0301] To a solution of tert-butyl 9-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-3- azaspiro[5.5]undecane-3-carboxylate (4.00 g, 1.0 eq, 9.94 mmol) in THF (20 mL) and water（ 30 mL）was added NaOH (1.59 g, 4.0 eq, 39.8 mmol) at 70 °C for 2 hours. The organic layer was concentrated to 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3- Attorney Docket No. PRSC-074/001WO 343170-2268 (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (4.00 g, 9.51 mmol, 95.7 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C22H32N2O6, 420.23; found, 406.3 [M- 56+41+H]+ Step E: 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0302] To a solution of 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (4.00 g, 1.0 eq, 9.51 mmol) in DCM (50 mL) was added manganese(IV) oxide (8.27 g, 10.0 eq, 95.1 mmol) and the mixture was stirred at 50oC for 10 hours. After filtration, the filtrate was concentrated to 1-(3-(tert- butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3-formyl-2-oxo-1,2-dihydropyridine-4- carboxylic acid (3.00 g, 7.17 mmol, 75.4 %) as a yellow solid. The crude product was directly used in next step without further purification. LC-MS (ESI, m/z): mass calcd. For C22H30N2O6, 418.21; found, 363.1[M-56+H]+ Step F: tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate [0303] To a solution of 1-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)-3-formyl-2- oxo-1,2-dihydropyridine-4-carboxylic acid (4.00 g, 1.0 eq, 9.56 mmol) and3-aminopiperidine- 2,6-dione (1.47 g, 1.2 eq, 11.5 mmol) in DCM (50 mL) was added AcOH (10 mL) at room temperature, the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (3.04 g, 14.3 mmol, 1.5 eq) was added to above mixture and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 10/1) to give tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1.60 g, 3.12 mmol, 32.7 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C27H36N4O6, 512.26; found, 457.3 [M-56+H]+ Step G: tert-butyl (R)-9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate and tert-butyl (S)-9-(2- (2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3- azaspiro[5.5]undecane-3-carboxylate [0304] The tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1.6 g) was purified by Attorney Docket No. PRSC-074/001WO 343170-2268 SFC to afford compound tert-butyl (R)-9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (P1) (650 mg,) as a white solid and tert-butyl (S)-9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (P2) (630 mg ) as a white solid. LC-MS (ESI, m/z): mass calcd. For C27H36N4O6, 512; found, 457.3 [M- 56+H]+ Step H: (R)-2-(2,6-dioxopiperidin-3-yl)-5-(3-azaspiro[5.5]undecan-9-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione hydrochloride (Example 9) [0305] To a solution of tert-butyl (R)-9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 1.0 eq, 195 µmol) was added HCl/dioxane (4M, 3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford (R)-2-(2,6-dioxopiperidin-3-yl)-5-(3-azaspiro[5.5]undecan-9-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione hydrochloride (80.0 mg, 176 µmol, 90.0 %, 98.5% Purity) as a white solid. LC-MS (ESI, m/z): mass calcd. For C22H28N4O4, 412.21; found, 413.3
Figure imgf000095_0001
11.01 (s, 1 H), 8.78 (s, 2 H), 8.31 (d, J = 5.2 Hz, 1 H), 7.30 (d, J = 5.2 Hz, 1 H), 5.23-5.08 (m, 2 H), 4.48-4.38 (m, 1 H), 4.33-4.21 (m, 1 H), 3.57 (s, 1 H), 3.07-2.96 (m, 4 H), 2.95-2.82 (m, 1 H), 2.64-2.56 (m, 1 H), 2.46-2.37 (m, 1 H), 2.04- 1.96 (m, 1 H), 1.87 (s, 2 H), 1.72-1.51 (m, 8 H), 1.43-1.32 (m, 2 H). Step I: (S)-2-(2,6-dioxopiperidin-3-yl)-5-(3-azaspiro[5.5]undecan-9-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione hydrochloride (Example 10) [0307] To a solution of tert-butyl (S)-9-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 1.0 eq, 195 µmol) was added HCl/dioxane (4M, 3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford (S)-2-(2,6-dioxopiperidin-3-yl)-5-(3-azaspiro[5.5]undecan-9-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione hydrochloride (75.0 mg, 166 µmol, 85.3 %, 99.6% Purity) as a yellow solid. LC-MS (ESI, m/z): mass calcd. ForC22H28N4O4, 412.21; found, 413.3
Figure imgf000095_0002
11.01 (s, 1 H), 8.78 (s, 2 H), 8.31 (d, J = 5.2 Hz, 1 H), 7.30 (d, J = 5.2 Hz, 1 H), 5.23-5.08 (m, 2 H), 4.48-4.38 (m, 1 H), 4.33-4.21 (m, 1 H), 3.57 (s, 1 H), 3.07-2.96 (m, 4 H), 2.95-2.82 (m, 1 H), 2.64-2.56 (m, 1 H), 2.46-2.37 (m, 1 H), 2.04- 1.96 (m, 1 H), 1.87 (s, 2 H), 1.72-1.51 (m, 8 H), 1.43-1.32 (m, 2 H). Attorney Docket No. PRSC-074/001WO 343170-2268 Compound 11 and Compound 12: (S)-2-(2,6-dioxopiperidin-3-yl)-5-(2- azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione and (R)- 2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridine-1,4(2H)-dione
Figure imgf000096_0001
Step A: tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate [0309] To a solution tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (4.00 g, 1.0 eq, 18.8 mmol) in DCM (50.0 mL)) was added MsCl (2.58 g, 1.75 mL, 1.2 eq, 22.5 mmol), TEA (2.85 g, 3.92 mL, 1.5 eq, 28.1 mmol) in portions at room temperature and the reaction mixture was stirred for 2 hours. After evaporation, the residue was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 6- ((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (5.50 g, crude) as a white solid. LC-MS (ESI, m/z): mass calcd. For C12H21NO5S, 291.11; found, 236.2 [M-56+H]+. Step B: tert-butyl 6-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.3]heptane-2-carboxylate [0310] To a solution of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate (5.50 g, 1.0 eq, 18.9 mmol) and 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (3.42 g, 1.2 eq, 22.7 mmol) in DMF (50 mL) was added Cs2CO3 (8.00 g, 1.3 eq, 24.5 mmol) at room temperature, the reaction mixture was stirred at 80oC for 16 hours. The reaction mixture was cooled to room temperature, poured into water (300 ml) and extracted with EtOAc (100 mL x Attorney Docket No. PRSC-074/001WO 343170-2268 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EA = 13/1) to give tert-butyl 6-(1,4-dioxo-1,4- dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2-azaspiro[3.3]heptane-2-carboxylate (2.50 g, 7.48 mmol, 39.6 %) as a white solid. LC-MS (ESI, m/z): mass calcd. For C18H22N2O5, 346.15; found, 347.2 [M+H]+. Step C: 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(hydroxymethyl)-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0311] To a solution of tert-butyl 6-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.3]heptane-2-carboxylate (2.50 g, 1.0 eq, 7.22 mmol) in THF (20 mL) and water（ 30 mL）was added sodium hydroxide (1.15 g, 4.0 eq, 28.9 mmol) at 70 °C for 2 hours. The organic layer was concentrated to 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.60 g, 7.14 mmol, 98.9 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C18H24N2O6, 364.16; found, 309.4 [M- 56+H]+ Step D: 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0312] To a solution of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.60 g, 1.0 eq, 7.14 mmol) in DCM (50 mL) was added manganese(IV) oxide (6.20 g, 10 eq, 71.4 mmol) and the mixture was stirred at 50oC for 10 hours. After filtration, the filtrate was concentrated to give 1-(2-(tert- butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-2-oxo-1,2-dihydropyridine-4- carboxylic acid (2.50 g, 6.90 mmol, 96.7 %) as a yellow solid. The crude product was directly used in next step without further purification. LC-MS (ESI, m/z): mass calcd. For C18H22N2O6, 362.15; found, 307.2 [M-56+H]+ Step E: tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate [0313] To a solution of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-2- oxo-1,2-dihydropyridine-4-carboxylic acid (2.50 g, 1.0 eq, 6.90 mmol) and 3-aminopiperidine- 2,6-dione (972 mg, 1.1 eq, 7.59 mmol) in DCM (50 mL) was added AcOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (2.19 g, 10.3 mmol, 1.5 eq) was added to above mixture and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was Attorney Docket No. PRSC-074/001WO 343170-2268 quenched with water (50 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=10/1) to give tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (1.00 g, 2.19 mmol, 31.8 %) as a white solid. LC-MS (ESI, m/z): mass calcd. For C23H28N4O6, 456.20; found, 401.2 [M-56+H]+ Step F: tert-butyl (R)-6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl (S)-6-(2- (2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2- azaspiro[3.3]heptane-2-carboxylate [0314] The tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g ) was purified by SFC (the conditions were described as followed: [0315] to afford compound tert-butyl (R)-6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (P1) (450 mg,) as a white solid and tert-butyl (S)-6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (P2) (430 mg ) as a white solid. LC-MS (ESI, m/z): mass calcd. For C23H28N4O6, 456.20; found, 401.2 [M- 56+H]+ Step G: (R)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0316] To a solution of tert-butyl (R)-6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (50.0 mg, 1.0 eq, 110 µmol) in FA (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford (R)-2-(2,6- dioxopiperidin-3-yl)-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine- 1,4(2H)-dione (40.0 mg, 110 µmol, 97.6% Purity) as a white solid. LC-MS (ESI, m/z): mass calcd. For C18H20N4O4, 356.15; found, 357.1 [M+H]+ [0317] 1H NMR (400 MHz, DMSO-d6) δ 11.35-8.97 (m, 1 H), 8.38-8.19 (m, 2 H), 7.33 (d, J = 5.2 Hz, 1 H), 5.33-5.03 (m, 2 H), 4.49-4.40 (m, 1 H), 4.32-4.25 (m, 1 H), 3.96 (s, 2 H), 3.87 (s, 2 H), 2.98-2.86 (m, 1 H), 2.81-2.69 (m, 2 H), 2.64-2.55 (m, 1 H), 2.47-2.38 (m, 1 H), 2.34- 2.25 (m, 2 H), 2.07-1.94 (m, 1 H). Attorney Docket No. PRSC-074/001WO 343170-2268 Step H: (S)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0318] To a solution of tert-butyl (S)-6-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (50.0 mg, 1.0 eq, 110 µmol) in FA (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford (S)-2-(2,6-dioxopiperidin- 3-yl)-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (40.0 mg, 112 µmol, 99.39% Purity) as a white solid. LC-MS (ESI, m/z): mass calcd. For C18H20N4O4, 356.15; found, 357.1 [M+H]+ [0319] 1H NMR (400 MHz, DMSO-d6) δ 11.35-8.97 (m, 1 H), 8.38-8.19 (m, 2 H), 7.33 (d, J = 5.2 Hz, 1 H), 5.33-5.03 (m, 2 H), 4.49-4.40 (m, 1 H), 4.32-4.25 (m, 1 H), 3.96 (s, 2 H), 3.87 (s, 2 H), 2.98-2.86 (m, 1 H), 2.81-2.69 (m, 2 H), 2.64-2.55 (m, 1 H), 2.47-2.38 (m, 1 H), 2.34- 2.25 (m, 2 H), 2.07-1.94 (m, 1 H). Compound 13 and Compound 14: (R)-2-(2,6-dioxopiperidin-3-yl)-5-(7- azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione and (S)- 2-(2,6-dioxopiperidin-3-yl)-5-(7-azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridine-1,4(2H)-dione
Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000100_0001
Step A: tert-butyl 2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate [0320] To a solution of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (4.5 g, 18.6 mmol, 1.0 eq) and TEA (4.72 g, 46.6 mmol, 2.5 eq) in DCM (50 mL) was added MsCl (2.56 g, 22.4 mmol, 1.2 eq) at 0oC and stirred at 20oC for 12 hours. The mixture was poured into NH4Cl (300 mL) and extracted with EA (200 mL x 3). The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried to give tert-butyl 2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7- carboxylate (6.2 g, crude) as a white solid. Step B: tert-butyl 2-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-7- azaspiro[3.5]nonane-7-carboxylate [0321] To a solution of tert-butyl 2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7- carboxylate (3.8 g, 11.9 mmol, 1.2 eq) in DMA (50 mL) was added 3,5-dihydrofuro[3,4- c]pyridine-1,4-dione (1.5 g, 9.93 mmol, 1.0 eq), Cs2CO3 (3.23 g, 9.93 mmol, 1.0 eq) at room Attorney Docket No. PRSC-074/001WO 343170-2268 temperature, the resulting mixture was stirred at 80oC for 12 hours. The resulting suspension was quenched with saturated aqueous water (200 mL) and extracted with EA (150 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified Prep-HPLC (Acetonitrile/0.05%Formate acid) and concentrated to give tert-butyl 4-(1,4-dioxo-1,4- dihydrofuro[3,4-c]pyridin-5(3H)-yl)piperidine-1-carboxylate (1.2 g, yield 36.2%) as a white solid. LC-MS (ESI, m/z): mass calcd. For C20H26N2O5, 374.18; found, 319.2 [M-56+H]+. Step C: 1-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3-(hydroxymethyl)-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0322] To a solution of tert-butyl 4-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)piperidine-1-carboxylate (1.0 g, 2.67 mmol, 1.0 eq) in THF (10 mL) and water (2 mL) was added sodium hydroxide (0.214 g, 5.34 mmol, 2 eq) in portions at room temperature and the reaction mixture was stirred for 3 h at 50°C. The mixture was poured into water (100 mL) and extracted with EA (100 mL x 3). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 1-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.1 g, crude) as a white solid. LC-MS (ESI, m/z): mass calcd. For C20H28N2O6, 392.19; found, 337.3 [M-56+H]+. Step D: 1-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0323] To a solution of 1-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.1 g , 2.8 mmol, 1.0 eq) in DCM (20 mL) was added DMP (1.78 g, 4.2 mmol, 1.5 eq) at 0oC. The reaction mixture was stirred at 20oC for 4 hours. The mixture was poured into NH4Cl (30 mL) and extracted with EA (20 mL x 3). The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The crude product was purified by Prep-HPLC (Acetonitrile/0.05%Formate acid) and concentrated to give 1-(7-(tert-butoxycarbonyl)-7- azaspiro[3.5]nonan-2-yl)-3-formyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.7 g, yield 77%) as a white solid. LC-MS (ESI, m/z): mass calcd. For C20H26N2O6, 390.18; found, 389.1 [M-H]-. Step E: tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate [0324] To a solution of 1-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3-formyl-2- oxo-1,2-dihydropyridine-4-carboxylic acid (0.7 g, 1.8 mmol, 1.0 eq) and 3-aminopiperidine- 2,6-dione (0.28 g, 2.2 mmol, 1.2 eq) in DCM (5 mL) was added Sodium triacetoxyborohydride Attorney Docket No. PRSC-074/001WO 343170-2268 (1.1 g, 5.4 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 20oC for 12 hours. The reaction mixture was poured into water (30 ml) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Acetonitrile/0.05%Formate acid) to give tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.45 g, 52% yield) as a white solid. LC-MS (ESI, m/z): mass calcd. For C25H32N4O6, 484.23; found, 429.2[M-56+H]+. Step F: tert-butyl (R)-2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate and tert-butyl (S)-2-(2-(2,6- dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-7- azaspiro[3.5]nonane-7-carboxylate [0325] The tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.45 g ) was purified by to afford compound tert-butyl (R)-2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (P1) (160 mg,) as a white solid and tert-butyl (S)-2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (P2) (170 mg ) as a white solid. LC-MS (ESI, m/z): mass calcd. For C25H32N4O6, 484.23; found, 429.2[M-56+H]+. Step G: (R)-2-(2,6-dioxopiperidin-3-yl)-5-(7-azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0326] To a solution of tert-butyl (R)-2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (10 mg, 1.0 eq, 19.5 µmol) was added HCl/dioxane (4M, 1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford (R)-2-(2,6-dioxopiperidin-3-yl)-5-(7-azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione (2.78 mg, 176 µmol, 89.0 %, Purity) as a white solid. LC-MS (ESI, m/z): mass calcd. For C20H24N4O4, 384.18; found, 385.3 [M+H]+. Step H: (S)-2-(2,6-dioxopiperidin-3-yl)-5-(7-azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0327] To a solution of tert-butyl (S)-2-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (10 mg, 1.0 eq, 19.5 µmol) was added HCl/dioxane (4M, 1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to Attorney Docket No. PRSC-074/001WO 343170-2268 afford (S)-2-(2,6-dioxopiperidin-3-yl)-5-(7-azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione (2.89 mg, 176 µmol, 99.0 %, Purity) as a white solid. LC-MS (ESI, m/z): mass calcd. For C20H24N4O4, 384.18; found, 385.3 [M+H]+. Compound 15 and Compound 16: (R)-2-(2,6-dioxopiperidin-3-yl)-5-(7- azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione and (S)- 2-(2,6-dioxopiperidin-3-yl)-5-(7-azaspiro[3.5]nonan-2-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridine-1,4(2H)-dione
Figure imgf000103_0001
Step A: tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate [0328] To a mixture of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (2.0 g, 1 eq, 8.36 mmol) in MeOH (20 mL). The mixture was stirred at room temperature for 2 h. The reaction solution was quenched with saturated aqueous NH4Cl solution (20 mL), extracted with EA (30 mL×2). The organic phase was washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated to afford tert-butyl 7-hydroxy-2- azaspiro[3.5]nonane-2-carboxylate (2.00 g, 99.2 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C13H23NO3, 241.2; found, 186.3 [M+H-56]+. Step B: tert-butyl 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate [0329] To a mixture of tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (2.0 g, 1 eq, 8.29 mmol) in DCM (5.00 mL) was added MsCl (1.4 g, 1.5 eq, 12.4 mmol), Triethylamine (2.5 g, 3.47 mL, 3 eq, 24.9 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction solution was quenched with saturated aqueous NH4Cl solution (20 mL), extracted with Attorney Docket No. PRSC-074/001WO 343170-2268 EA (30 mL×2). The organic phase was washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered. The mixture was direct concentrated to afford tert-butyl 7- ((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (2.30 g, 86.9 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C14H25NO5S, 319.1; found, 264.2 [M+H-56]+. Step C: tert-butyl 7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.5]nonane-2-carboxylate [0330] To a mixture of tert-butyl 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2- carboxylate (3.00 g, 1 eq, 9.39 mmol), 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (1.70 g, 1.2 eq, 11.3 mmol) in DMF (20.0 mL) was added Cs2CO3 (3.98 g, 1.3 eq, 12.2 mmol). The reaction solution was stirred at 90oC for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (60 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / Petroleum ether = 3:7) to give tert-butyl 7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.5]nonane-2-carboxylate (720 mg, 20.5 %). LC-MS (ESI, m/z): mass calcd. For C20H26N2O5, 374.2; found, 319.2 [M+H-56]+. Step D: 3-(4-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione hydrochloride [0331] To a mixture of tert-butyl 7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.5]nonane-2-carboxylate (720 mg, 1 eq, 1.92 mmol) in THF (10.0 mL), H2O (2.0 mL) was added NaOH (308 mg, 4 eq, 7.69 mmol), the mixture was stirred at 50°C for 4 h. The mixture was diluted with H2O (10 mL) and extracted with EA (15 mL×2). The combined organic layer was washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated to give 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (750 mg, crude) as a white solid. LC-MS (ESI, m/z): mass calcd. For C20H28N2O6, 392.2; found, 393.3 [M+H]+. Step E: 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0332] To a mixture of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (770 mg, 1 eq, 1.96 mmol) in DCM (30 mL) was added manganese(IV) oxide (1.71 g, 10 eq, 19.6 mmol), the mixture was stirred at 50°C for 10 h. The mixture was filtered and the filtrate was concentrated to 1-(2-(tert- butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-3-formyl-2-oxo-1,2-dihydropyridine-4- carboxylic acid (750 mg, 97.9 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C20H26N2O6, 390.2; found, 335.2 [M+H-56]+. Attorney Docket No. PRSC-074/001WO 343170-2268 Step F: tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate
Figure imgf000105_0001
[0333] To a mixture of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonan-7-yl)-3-formyl-2- oxo-1,2-dihydropyridine-4-carboxylic acid (770 mg, 1 eq, 1.97 mmol), AcOH (10 mL) and 3- aminopiperidine-2,6-dione (328 mg, 1.3 eq, 2.56 mmol) in DCM (50 mL) was added sodium triacetoxyborohydride (2.19 g, 10.3 mmol, 1.5 eq) at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL) and extracted with DCM (30 mL×3). The organic layer is washed with brine (30 mL×3), dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 10/1) to afford tert-butyl 7-(2-(2,6- dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2- azaspiro[3.5] Nonane-2-carboxylate (200 mg, 20.9 %) as a white solid. LC-MS (ESI, m/z): mass calcd. For C25H32N4O6, 484.2; found, 429.5 [M+H-56]+. Step G: tert-butyl (R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate and tert-butyl (S)-7-(2-(2,6- dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2- azaspiro[3.5]nonane-2-carboxylate Attorney Docket No. PRSC-074/001WO 343170-2268 [0334] The tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.5] Nonane-2-carboxylate (0.2 g) was purified by SFC (the conditions were described as followed: [0335] To afford tert-butyl (R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate (85 mg) and tert-butyl (S)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5- yl)-2-azaspiro[3.5]nonane-2-carboxylate (75 mg). Step H: (R)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.5]nonan-7-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione formate [0336] To a mixture of tert-butyl (R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate (65.0 mg, 134 μmol) in FA (5.00 mL). The mixture was stirred at room temperature for 5h. The mixture was concentrated to afford (R)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.5]nonan-7-yl)-3,5- dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione formate (50.0 mg, 87.7%) as a white solid. LC-MS (ESI, m/z): mass calcd. For C20H24N4O4, 384.18; found, 385.3 [M+H]+. [0337] 1H NMR (400 MHz, DMSO) δ 8.43 (s, 1 H), 8.31 (d, J = 5.2 Hz, 1 H), 7.30 (d, J = 5.20 Hz, 1H), 5.16 - 5.12 (m, 3H), 4.44-4.24 (m, 2H), 3.58 (d, J = 6.8 Hz, 4 H), 2.96 - 2.87 (m, 1H), 2.61- 2.57 (m, 1H), 2.45 - 2.39 (m, 1H), 2.02 - 1.85 (m, 6H), 1.90 - 1.87 (m, 2 H), 1.68 - 52 (m, 4H). Step I: (S)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.5]nonan-7-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione formate [0338] To a mixture of tert-butyl (S)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.5]nonane-2-carboxylate (15 mg, 31 μmol) in HCOOH (2.00 mL) .The reaction was stirred at 25 °C for 4 h, the reaction was concentrated to afford (S)-2-(2,6-dioxopiperidin-3-yl)-5-(2-azaspiro[3.5]nonan-7-yl)-3,5- dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione formate (10.39 mg, 80 %) as a white solid. LC-MS (ESI, m/z): mass calcd. For C20H24N4O4, 384.18; found, 385.3 [M+H]+. [0339] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1 H), 8.31 (d, J = 5.2 Hz, 1 H), 7.30 (d, J = 5.2 Hz, 1 H), 5.16-5.10 (m, 2 H), 4.44-4.23 (m, 2 H), 3.58 (d, J = 6.8 Hz, 4 H), 2.97-2.85 (m, 1 H), 2.63-2.56 (m, 1 H), 2.47-2.38 (m, 1 H), 2.05-1.82 (m, 6 H), 1.69-1.52 (m, 4 H). Compound 17 and Compound 18：(S)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(2- azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione and (R)- Attorney Docket No. PRSC-074/001WO 343170-2268 2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione
Figure imgf000107_0001
P2 Step A ：tert-butyl 6-(7-bromo-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.3]heptane-2-carboxylate [0340] To a mixture of 7-bromo-3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (5.0 g, 21.7 mmol), tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (6.97 g, 23.9 mmol), and Cs2CO3 (7.08 g, 21.7 mmol) in DMA (50.0 mL) was stirred at 90°C for 12 h. After the reaction was completed, the mixture was diluted with H2O (200 mL) and extracted with EA (150 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give tert-butyl 6-(7-bromo-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)-2-azaspiro[3.3]heptane-2-carboxylate (3.5 g, crude) as a white solid. LC-MS (ESI, m/z): mass calcd. For C18H21BrN2O5, 424.28; found, 410 [M-56+MeCN+H]+. Step B：tert-butyl 6-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-2- azaspiro[3.3]heptane-2-carboxylate [0341] To a mixture of tert-butyl 6-(7-bromo-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)-2-azaspiro[3.3]heptane-2-carboxylate (4.14 g, 9.73 mmol), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (1.83 g, 14.6 mmol), K2CO3 (4.04 g, 29.2 mmol) and 1,1'- Attorney Docket No. PRSC-074/001WO 343170-2268 Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (712 mg, 0.973 mmol) in 1,4- Dioxane (40.0 mL) was stirred at 90°C for 12 h. After the reaction was completed, the mixture was diluted with H2O (200 mL) and extracted with EA (150 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated and purified by column (PE:EA=0~50%) to give tert-butyl 6-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin- 5(3H)-yl)-2-azaspiro[3.3]heptane-2-carboxylate (2.65 g, 75.5%) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C19H24N2O5, 360.17; found, 361.0 [M+H]+. Step C：1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(hydroxymethyl)-5- methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid [0342] To a mixture of tert-butyl 6-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)-2-azaspiro[3.3]heptane-2-carboxylate (2.4 g, 6.66 mmol) and NaOH (1.07 mg, 26.6 mmol) in THF (20.0 mL), H2O (4.0 mL) was stirred at 50°C for 12 h. After the reaction was completed, the mixture was diluted with H2O (20 mL) and extracted with EA (15 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give 1-(2- (tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(hydroxymethyl)-5-methyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid (3.6 g, crude) as a white solid. LC-MS (ESI, m/z): mass calcd. For C19H26N2O6, 378.18; found, 379.1 [M+H]+. Step D：1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-5-methyl-2-oxo- 1,2-dihydropyridine-4-carboxylic acid [0343] To a mixture of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (hydroxymethyl)-5-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (3.0 g, 7.93 mmol) and Manganese dioxide (27.6 g, 317 mmol) in DCM (30.0 mL) was stirred at 50°C for 3 h. After the reaction was completed, the mixture was filtered and evaporated to give 1-(2-(tert- butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-5-methyl-2-oxo-1,2-dihydropyridine- 4-carboxylic acid (8.9 g, crude) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C19H24N2O6, 376.16; found, 362.1 [M-56+MeCN+H]+. Step E：tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate [0344] To a mixture of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-5- methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.5 g, 3.99 mmol), 3-aminopiperidine- 2,6-dione (0.56 g, 4.38 mmol), TEA (0.8 g, 7.97 mmol), AcOH (1.44 g, 23.9 mmol) and Sodium triacetoxyborohydride (2.53 g, 12.0 mmol) in DCM (20.0 mL) was stirred at room temperature Attorney Docket No. PRSC-074/001WO 343170-2268 for 12 h. After the reaction was completed, the mixture was evaporated and purified by column (PE： EA=0~100%) to give tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (1.21 g, 64.5%) as a white solid. LC-MS (ESI, m/z): mass calcd. For C24H30N4O6, 470.22; found, 456.1 [M-56+MeCN+H]+. Step F： tert-butyl (R)-6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate & tert-butyl (S)-6-(2- (2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5- yl)-2-azaspiro[3.3]heptane-2-carboxylate [0345] The tert-butyl 6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (1.21 g) was purified by SFC to afford tert-butyl (R)-6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (496 mg) as a white solid and tert-butyl (S)-6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (502 mg) as a white solid. LC-MS (ESI, m/z): mass calcd. For C24H30N4O6，470.22; found, 471.2 [M+H]+. Step G: (R)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0346] To a mixture of tert-butyl (R)-6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (5 mg, 0.01 mmol) in HCOOH (2.0 mL) was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated to give (R)-2-(2,6-dioxopiperidin-3-yl)-7- methyl-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (2.14 mg, crude) as a white solid. LC-MS (ESI, m/z): mass calcd. For C19H22N4O4，370.16; found, 371.1 [M+H]+. [0347] 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1 H), 8.06 (s, 1 H), 5.07-5.16 (m, 2 H), 4.19- 4.39 (dd, J = 61.2 Hz, J - 18.4 Hz, 2 H), 3.91-4.01 (d, J = 36.8 Hz, 4 H), 2.86-2.91 (m, 1 H), 2.74-.2.78 (m, 2 H), 2.57-2.61 (d, J = 16.0 Hz, 1 H), 2.50 (s, 3 H), 2.41-2.47 (m, 1 H), 2.25- 2.30 (m, 2 H), 1.97-2.00 (m, 1 H). Step H: (S)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0348] To a mixture of tert-butyl (S)-6-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate (5 Attorney Docket No. PRSC-074/001WO 343170-2268 mg, 0.01 mmol) in HCOOH (2.0 mL) was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated to give (S)-2-(2,6-dioxopiperidin-3-yl)-7- methyl-5-(2-azaspiro[3.3]heptan-6-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (2.05 mg, crude), (2.14 mg, crude) as a white solid. LC-MS (ESI, m/z): mass calcd. For C19H22N4O4，370.16; found, 371.1 [M+H]+. [0349] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 2 H), 8.06 (s, 1 H), 5.08-5.15 (m, 2 H), 4.19- 4.39 (dd, J = 61.2 Hz, J - 18.4 Hz, 2 H), 4.00 (s, 2 H), 3.92 (s, 2 H), 2.75-.2.78 (m, 2 H), 2.57- 2.61 (d, J = 16.0 Hz, 1 H), 2.52 (s, 3 H), 2.41-2.47 (m, 1 H), 2.25-2.30 (m, 2 H), 1.97-2.01 (m, 1 H). Compound 19 and Compound 20：2-((R)-2,6-dioxopiperidin-3-yl)-5-((R)-5-oxa-2- azaspiro[3.4]octan-7-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione and 2- ((S)-2,6-dioxopiperidin-3-yl)-5-((R)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione
Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000111_0001
Step A: tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [0350] To a mixture of tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (4.89 g, 21.5 mmol) in MeOH (60.0 mL) was added NaBH4 (1.22 g, 32.3 mmol) at 0 oC. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with H2O (70 mL), extracted with EA (70 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 7-hydroxy-5- oxa-2-azaspiro[3.4]octane-2-carboxylate (3.53 g, yield: 71.6 %) as brown oil. LC-MS (ESI, m/z): mass calcd. For C11H19NO4，229.13; found, 230.1 [M+H]+. Step B: tert-butyl 7-((methylsulfonyl)oxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [0351] To a mixture of tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (3.53 g, 15.4 mmol) and TEA (4.67 g, 46.2 mmol) in DCM (40.0 mL) was added Methanesulfonyl chloride (2.65 g, 23.1 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with Na2CO3 aqueous solution (60 mL), extracted with EA (100 mL×2). The combined organic layer was dried over Attorney Docket No. PRSC-074/001WO 343170-2268 anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 7-((methylsulfonyl)oxy)- 5-oxa-2-azaspiro[3.4]octane-2-carboxylate (4.44 g, yield: 93.8 %) as yellow oil. LC-MS (ESI, m/z): mass calcd. For C12H21NO6S，307.11; found, 308.1 [M+H]+. Step C: tert-butyl 7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-5-oxa-2- azaspiro[3.4]octane-2-carboxylate [0352] To a mixture of tert-butyl 7-((methylsulfonyl)oxy)-5-oxa-2-azaspiro[3.4]octane-2- carboxylate (3.24 g, 10.5 mmol), 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (1.33 g, 8.78 mmol) and Cs2CO3 (5.72 g, 17.6 mmol) in DMF (75.0 mL) was stirred at 80 oC for 16h. After the reaction was completed, the mixture was diluted with H2O (150 mL), extracted with EA (150 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=100/1) to give tert-butyl 7-(1,4-dioxo-1,4- dihydrofuro[3,4-c]pyridin-5(3H)-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (3.10 g, yield: 97.4 %) as a yellow oil. LC-MS (ESI, m/z): mass calcd. For C18H22N2O6，362.15; found, 363.1 [M+H]+. Step D: 2-(dimethoxymethyl)-7-(4-((1S,2S)-2-isobutyl-6-((2-methoxyethoxy)methoxy)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)-7-azaspiro[3.5]nonane & 2-(dimethoxymethyl)-7-(4- ((1R,2R)-2-isobutyl-6-((2-methoxyethoxy)methoxy)-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)-7-azaspiro[3.5]nonane [0353] The tert-butyl 7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-5-oxa-2- azaspiro[3.4]octane-2-carboxylate (3.1 g) was purified by SFC to afford tert-butyl (R)-7-(1,4- dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (1 g) as a yellow solid and tert-butyl (S)-7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-5- oxa-2-azaspiro[3.4]octane-2-carboxylate (1.38 g) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C18H22N2O6, 362.15; found, 363.1 [M+H]+. Step E: (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3-(hydroxymethyl)- 2-oxo-1,2-dihydropyridine-4-carboxylic acid. [0354] To a mixture of tert-butyl (R)-7-(1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)-5- oxa-2-azaspiro[3.4]octane-2-carboxylate (1.1 g, 1 eq, 3.04 mmol) in THF (10.0 mL) and H2O (2.0 mL) was was added NaOH, the mixture was stirred at 50 °C for 4 h. After the reaction was completed, the mixture was diluted with H2O (10 mL) and extracted with EA (15 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3-(hydroxymethyl)-2- Attorney Docket No. PRSC-074/001WO 343170-2268 oxo-1,2-dihydropyridine-4-carboxylic acid (1.1 g, crude) as a white solid. LC-MS (ESI, m/z): mass calcd. For C18H24N2O7, 380.16; found, 381.2 [M+H]+. Step F: (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0355] To a mixture of (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3- (hydroxymethyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.0 g, 1 eq, 2.63 mmol) and manganese(IV) oxide (2.3 g, 10 eq, 26.3 mmol) in DCM (15.0 mL)THF (15.0 mL) was stirred at 50 °C for 2 h. After the reaction was completed, the mixture was filtered and evaporated to give (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3-formyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid (1.0 g, crude) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C18H22N2O7, 378.14; found, 379.2 [M+H]+. Step G: tert-butyl (7R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [0356] To a mixture of (R)-1-(2-(tert-butoxycarbonyl)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3- formyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1.1 g, 1 eq, 2.91 mmol), 3- aminopiperidine-2,6-dione (376 mg, 1.01 eq, 2.94 mmol), Triethylamine (88.3 mg, 122 μL, 0.3 eq, 872 μmol) and Acetic acid (87.3 mg, 83.5 μL, 0.5 eq, 1.45 mmol) in DCM (10.0 mL) was added sodium triacetoxyborohydride (1.3 g, 862 μL, 2 eq, 5.81 mmol), then the mixture was stirred at 25 °C for 16 h. After the reaction was completed, the mixture was concentrated and the residue purified by flash column chromatography on silica gel (PE:EA=0~100%) to give tert-butyl (7R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (700 mg, 1.48 mmol, 51.0 %) as a white solid. LC-MS (ESI, m/z): mass calcd. For C23H28N4O7, 472.2; found, 473.3 [M+H]+. Step H: tert-butyl (R)-7-(2-((R)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate & tert-butyl (R)-7-(2- ((S)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5- oxa-2-azaspiro[3.4]octane-2-carboxylate [0357] The tert-butyl (7R)-7-(2-(2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (700 mg) was purified by SFC (the conditions were described as followed: [0358] to afford tert-butyl (R)-7-(2-((R)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (350 mg) as a white solid and tert-butyl (R)-7-(2-((S)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- Attorney Docket No. PRSC-074/001WO 343170-2268 tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (320 mg) as a white solid. Step I: 2-((R)-2,6-dioxopiperidin-3-yl)-5-((R)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0359] To a mixture of tert-butyl (R)-7-(2-((R)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (20 mg, 1 eq, 42.3 μmol)in FA (2.5 mL). The mixture was stirred at room temperature for 16 h. The mixture was direct concentration to afford 2-((R)-2,6-dioxopiperidin-3-yl)-5-((R)-5-oxa-2- azaspiro[3.4]octan-7-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (2.48 mg, 6.36 μmol, 15.0 %, 95.555% Purity). LC-MS (ESI, m/z): mass calcd. For C18H20N4O5, 372.14; found, 373.1 [M+H]+. [0360] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 4.80 Hz, 2 H), 7.35 (d, J = 5.20 Hz, 1 H), 5.69 (s, 1 H), 5.16-5.11 (m, 1 H), 4.44-4.40 (m, 1 H), 4.31-4.26 (m, 1 H), 4.11-4.08 (m, 1 H), 3.96-3.85 (m, 6 H), 2.98-2.91 (m, 1 H), 2.61-2.55 (m, 2 H), 2.48-2.40 (m, 2 H), 2.02-1.20 (m, 1 H), 1.24 (s, 1 H). Step J: 2-((S)-2,6-dioxopiperidin-3-yl)-5-((R)-5-oxa-2-azaspiro[3.4]octan-7-yl)-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0361] To a mixture of tert-butyl (R)-7-(2-((S)-2,6-dioxopiperidin-3-yl)-1,4-dioxo-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (20. mg, 1 eq, 42.3 μmol) in FA (2.5 mL). The mixture was stirred at room temperature for 16 h. The mixture was direct concentration to afford 2-((S)-2,6-dioxopiperidin-3-yl)-5-((R)-5-oxa- 2-azaspiro[3.4]octan-7-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (2.40 mg, 6.11 μmol, 14.4 %, 94.763% Purity). LC-MS (ESI, m/z): mass calcd. For C18H20N4O5, 372.14; found, 373.1 [M+H]+. [0362] 1H NMR (400 MHz, DMSO-d6) δ 8.36-8.33 (m, 2 H), 7.36 (d, J = 5.20 Hz, 1 H), 5.70- 5.67 (m, 1 H), 5.16-5.10 (m, 1 H), 4.42 (d, J = 18.00 Hz, 1 H), 4.28 (d, J = 12.00 Hz, 1 H), 4.12-4.08 (m, 2 H), 3.95 (d, J = 10.40 Hz, 3 H), 3.88-3.86 (m, 4 H), 2.97-2.84 (m, 1 H), 2.64- 2.54 (m, 1 H), 2.48-2.40 (m, 2 H), 2.03-1.98 (m, 1 H). Compound 21 and Compound 22：(R)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5- (piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione and (S)-2-(2,6- dioxopiperidin-3-yl)-7-methyl-5-(piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine- 1,4(2H)-dione Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000115_0001
Step A: 7-bromo-3,5-dihydrofuro[3,4-c]pyridine-1,4-dione [0363] To a mixture of 3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (6.50 g, 1 eq, 43.0 mmol) in MeCN (50.0 mL)was added NBS (8.42 g, 1.1 eq, 47.3 mmol). The resultant mixture was then stirred at 70°C for 16 h. The mixture was diluted with H2O (200 mL), extracted with EtOAc (50 mLx2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-30% EtOAc/hexane to afford 7-bromo-3,5-dihydrofuro[3,4- c]pyridine-1,4-dione (6.50 g, 28.3 mmol, 65.7 %)as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C7H4BrNO3, 228.9; found, 230.1[M+H]+. Step B: tert-butyl 4-(7-bromo-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)piperidine- 1-carboxylate [0364] To a mixture of 7-bromo-3,5-dihydrofuro[3,4-c]pyridine-1,4-dione (4.00 g, 1 eq, 17.4 mmol), Cs2CO3 (5.67 g, 1 eq, 17.4 mmol) in DMA (30.0 mL) was added tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (6.32 g, 1.3 eq, 22.6 mmol). The resultant mixture was stirred at 100°C for 16 h. The mixture was poured into H2O (200 mL), extracted with EtOAc (100 mLx2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-30% EtOAc/hexane to afford tert-butyl 4-(7-bromo-1,4- dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)piperidine-1-carboxylate (3.80 g, 9.19 mmol, Attorney Docket No. PRSC-074/001WO 343170-2268 52.9 %)as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C17H21BrN2O5, 412.1; found, 435.1[M+Na]+. Step C: tert-butyl 4-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)-yl)piperidine- 1-carboxylate [0365] To a mixture of tert-butyl 4-(7-bromo-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)piperidine-1-carboxylate (3.80 g, 1 eq, 9.19 mmol), K2CO3 (2.54 g, 2 eq, 18.4 mmol), 2,4,6- trimethyl-1,3,5,2,4,6-trioxatriborinane (2.31 g, 2 eq, 18.4 mmol) in 1,4-Dioxane (20.0 mL) was added [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (751 mg, 0.1 eq, 919 μmol). The resultant mixture was then stirred at 90 °C for 16 h. The mixture was poured into H2O (50 mL), extracted with EtOAc (20 mLx2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-30% EtOAc/hexane to afford tert-butyl 4-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4- c]pyridin-5(3H)-yl)piperidine-1-carboxylate (2.70 g, 7.75 mmol, 84.3 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C18H24N2O5, 348.2; found, 349.2[M+H]+. Step D: 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-5-methyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0366] To a mixture of tert-butyl 4-(7-methyl-1,4-dioxo-1,4-dihydrofuro[3,4-c]pyridin-5(3H)- yl)piperidine-1-carboxylate (2.70 g, 1 eq, 7.75 mmol) in THF (20.0 mL) and H2O (5.00 mL) was added NaOH (1.24 g, 4 eq, 31.0 mmol).The resultant mixture was then stirred at 50°C for 16 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to afford 1-(1- (tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-5-methyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid (2.80 g, 7.64 mmol, 98.6 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C18H26N2O6, 366.2; found, 367.2[M+H]+. Step E: 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-5-methyl-2-oxo-1,2- dihydropyridine-4-carboxylic acid [0367] To a mixture of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(hydroxymethyl)-5- methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (3.60 g, 1 eq, 9.83 mmol) in DCM (40.0 mL)was added manganese dioxide (8.54 g, 1.70 mL, 10 eq, 98.3 mmol). The resultant mixture was stirred at 50°C for 8 h. The mixture was filtered and concentrated in vacuum to afford 1- (1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-5-methyl-2-oxo-1,2-dihydropyridine-4- carboxylic acid (4 g, crude) as a black solid. LC-MS (ESI, m/z): mass calcd. For C18H24N2O6, 364.2; found, 387.2[M+Na]+. Attorney Docket No. PRSC-074/001WO 343170-2268 Step F: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate [0368] To a mixture of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-formyl-5-methyl-2-oxo- 1,2-dihydropyridine-4-carboxylic acid (4.00 g, 1 eq, 11.0 mmol), 3-aminopiperidine-2,6-dione (1.69 g, 1.2 eq, 13.2 mmol),acetic acid (1.32 g, 1.26 mL, 2 eq, 22.0 mmol) in DCM (50.0 mL) was added sodium triacetoxyborohydride (6.98 g, 4.88 mL, 3 eq, 32.9 mmol). The resultant mixture was then stirred at room temperature for 16 h. The mixture was poured into H2O (50 mL), extracted with DCM (20 mLx2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography using 0-60% EtOAc/hexane to afford tert-butyl 4-(2-(2,6- dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5- yl)piperidine-1-carboxylate (2.00 g, 4.36 mmol, 39.7 %) as a yellow solid. LC-MS (ESI, m/z): mass calcd. For C23H30N4O6, 458.2; found, 459.2[M+H]+. Step G: tert-butyl (R)-4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate and tert-butyl (S)-4-(2-(2,6- dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5- yl)piperidine-1-carboxylate [0369] The tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro- 5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (2 g) was purified by SFC to afford tert-butyl (R)-4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (1 g) as a purple solid and tert-butyl (S)- 4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- c]pyridin-5-yl)piperidine-1-carboxylate (1 g) as a purple solid. LC-MS (ESI, m/z): mass calcd. For C23H30N4O6, 458.2; found, 459.2[M+H]+. Step H: (R)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(piperidin-4-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0370] To a mixture of tert-butyl (R)-4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (20.0 mg, 1 eq, 43.6 μmol) in HCl/dioxane (2.50 mL). The mixture was stirred at room temperature for 1 h. The mixture was direct concentration to afford (R)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5- (piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (2.26 mg, 6.13 μmol, 14.1 %, 97.199% purity). LC-MS (ESI, m/z): mass calcd. For C18H22N4O4, 358.2; found, 359.1[M+H]+. Attorney Docket No. PRSC-074/001WO 343170-2268 [0371] 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1 H), 9.01-8.86 (m, 2H), 8.09 (s, 1 H), 5.37- 5.35 (m, 1 H), 5.14-5.10 (m, 1 H), 4.44-4.24 (m, 2 H), 3.23-3.13 (m, 4 H), 2.96-2.87 (m, 1 H), 2.61-2.57 (m, 1 H), 2.49 (s, 3 H), 2.45-2.41(m, 1 H), 2.18-2.13 (m, 2 H), 2.01-1.91 (m, 3 H). Step I: (S)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5-(piperidin-4-yl)-3,5-dihydro-1H- pyrrolo[3,4-c]pyridine-1,4(2H)-dione [0372] To a mixture of tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-1,4-dioxo- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)piperidine-1-carboxylate (20.0 mg, 1 eq, 43.6 μmol) in HCl/dioxane (2.50 mL). The mixture was stirred at room temperature for 1 h. The mixture was direct concentration to afford (S)-2-(2,6-dioxopiperidin-3-yl)-7-methyl-5- (piperidin-4-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-1,4(2H)-dione (2.20 mg, 5.81 μmol, 13.3 %, 94.699% Purity). LC-MS (ESI, m/z): mass calcd. For C18H22N4O4, 358.2; found, 359.1
Figure imgf000118_0001
11.01 (s, 1 H), 9.25-9.16 (m, 2H), 8.09 (s, 1 H), 5.38- 5.34 (m, 1 H), 5.13-5.08 (m, 1 H), 4.45-4.25 (m, 2 H), 3.23-3.12 (m, 4 H), 2.96-2.87 (m, 1 H), 2.62-2.58 (m, 1 H), 2.49 (s, 3 H), 2.45-2.41(m, 1 H), 2.18-2.13 (m, 2 H), 2.01-1.94 (m, 3 H). II. Biological Assessment In vitro Assay: IC50 Measurements for binding to CRBN/DDB1 [0374] The binding potency was determined using HTRF assay technology (Perkin Elmer). Compounds were serially diluted in DMSO and 0.2 µL volume was transferred to white 384- well plate. The reaction was conducted in total volume of 20 µL with addition of 2 nM His tagged CRBN+DDB-DLS7+CXU4 (Wuxi, catalogue # RP210521GA) to compounds followed by addition of 60 nM fluorescent probe Cy5-labeled thalidomide (Tenova Pharma, catalogue # T52461), and 0.4 nM of MAb Anti-6HIS Tb cryptate Gold (Cisbio, catalogue # 61HI2TLA in the assay buffer (50 mM HEPES pH 7.5, 1 mM TCEP, 0.01% Brij-35, 50 mM NaCl, and 0.1% BSA). After one hour incubation at room temperature, the HTRF signals were read on Envision reader (Perkin Elemer). Data was analyzed using XLfit using four parameters dose response curve to determine IC50s. Table E1. Binding IC50 to CRBN/DDB1
Figure imgf000118_0002
Attorney Docket No. PRSC-074/001WO 343170-2268
Figure imgf000119_0001
Note: IC50: "A": < 50 nM; "B": 50-500 nM; "C": > 500 and <5000 nM; "D": >=5000 nM.
Attorney Docket No. PRSC-074/001WO 343170-2268 INCORPORATION BY REFERENCE [0375] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS [0376] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. [0377] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

Attorney Docket No. PRSC-074/001WO 343170-2268 CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula II:
Figure imgf000121_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring A is C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each RA is independently amino-protecting group, oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRbS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; m is an integer selected from 0 to 10, as valency permits; RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; denotes an optional covalent bond between Y and U; i) when the bond between Y and U is present: r is 1; X is N; U is -CH2- or -C(=O)-; Y is C; Attorney Docket No. PRSC-074/001WO 343170-2268 ii) when the bond between Y and U is absent: r is 0 or 1; X is O or N; wherein when X is O, then U is absent; when X is N, then U is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Y is CRY; RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; each RD1 is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 5; and q is an integer from 0 to 2, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or Attorney Docket No. PRSC-074/001WO 343170-2268 two Ru, together with the one or more intervening atoms, form C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. 2. A conjugate of Formula II’:
Figure imgf000123_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring A is C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each RA is independently amino-protecting group, oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRbS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; m is an integer selected from 0 to 10, as valency permits; Attorney Docket No. PRSC-074/001WO 343170-2268 RB1 and RB2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; denotes an optional covalent bond between Y and U; i) when the bond between Y and U is present: r is 1; X is N; U is -CH2- or -C(=O)-; Y is C; ii) when the bond between Y and U is absent: r is 0 or 1; X is O or N; wherein when X is O, then U is absent; when X is N, then U is hydrogen or C1-6 alkyl optionally substituted with one or more Ru; Y is CRY; RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; each RD1 is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 5; and Attorney Docket No. PRSC-074/001WO 343170-2268 q is an integer from 0 to 2, L is a linker, and T is a ligand for a protein, wherein: each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz; and each Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl. 3. The compound or conjugate of claim 1 or 2, wherein Attorney Docket No. PRSC-074/001WO 343170-2268 the compound of Formula II is a compound of Formula II-1
Figure imgf000126_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the conjugate of Formula II’ is a conjugate of Formula II’-1
Figure imgf000126_0002
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 4. The compound or conjugate of claim 3, wherein U is -CH2-. 5. The compound or conjugate of claim 1 or 2, wherein the compound of Formula II is a compound of Formula II-2
Figure imgf000126_0003
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the conjugate of Formula II’ is a conjugate of Formula II’-2
Figure imgf000126_0004
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Attorney Docket No. PRSC-074/001WO 343170-2268 6. The compound or conjugate of claim 5, wherein RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. 7. The compound or conjugate of claim 6, wherein RY is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. 8. The compound or conjugate of claim 7, wherein RY is hydrogen. 9. The compound or conjugate of any one of claims 1-8, wherein Ring A is 3- to 12- membered heterocyclyl. 10. The compound or conjugate of claim 9, wherein Ring A is piperidinyl, 3- azaspiro[5.5]undecanyl, 2-azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2- azaspiro[3.5]nonanyl, or 5-oxa-2-azaspiro[3.4]octyl. 11. The compound or conjugate of any one of claims 1-10, wherein each RA is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. 12. The compound or conjugate of claim 11, wherein each RA is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. 13. The compound or conjugate of any one of claims 1-12, wherein m is 0. 14. The compound or conjugate of any one of claims 1-13, wherein RB1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered Attorney Docket No. PRSC-074/001WO 343170-2268 heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. 15. The compound or conjugate of claim 14, wherein RB1 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. 16. The compound or conjugate of claim 15, wherein RB1 is hydrogen. 17. The compound or conjugate of any one of claims 1-16, wherein RB2 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. 18. The compound or conjugate of claim 17, wherein RB2 is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. 19. The compound or conjugate of claim 18, wherein RB2 is hydrogen, C1-6 alkyl, or C1-6 alkoxy. 20. The compound or conjugate of any one of claims 1-18, wherein RD is hydrogen. 21. The compound or conjugate of any one of claims 1-20, wherein each RD1 is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl. 22. The compound or conjugate of any one of claims 1-21, wherein d is 0. 23. The compound or conjugate of any one of claims 1-22, wherein q is 1. 24. A compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. Attorney Docket No. PRSC-074/001WO 343170-2268 25. A pharmaceutical composition comprising the compound of any one of claims 1-24, or the conjugate of any one of claims 2-23, and a pharmaceutically acceptable excipient. 26. A method of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering the compound of any one of claims 1-24 to the subject or contacting the biological sample with the compound of any one of claims 1-24. 27. Use of the compound of any one of claims 1-24 in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. 28. A compound of any one of claims 1-24 for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. 29. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering the conjugate of any one of claims 2-23 to the subject. 30. Use of the conjugate of any one of claims 2-23 in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. 31. A conjugate of any one of claims 2-23 for use in treating or preventing a disease or disorder in a subject in need thereof.
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