Cereblon Ligands and Uses Thereof

Abstract

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

Description

BACKGROUND

Cereblon (CRBN), a component of the DDB1-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. 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).

On this basis, CRBN ligands are widely used in protein degradation, and a series of PROTACs 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. Therefore, the design and synthesis of new and highly selective CRBN ligands is also particularly important in the synthesis of PROTACs molecules.

SUMMARY

In certain aspects, the present disclosure provides compounds or conjugates of Formula II:

and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables in Formula II is described, embodied, and exemplified herein.

In certain aspects, the present disclosure provides compounds or conjugates of Formula I:

and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables in Formula I is described, embodied, and exemplified herein.

In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.

In certain aspects, provided herein are methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.

In certain aspects, provided herein are uses of a compound described herein in the manufacture of a medicament for binding cerebon E3 ubiquitin ligase protein complex in a subject or biological sample.

In certain aspects, provided herein are compounds described herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

In certain aspects, provided herein are methods of degrading a protein in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.

In certain aspects, provided herein are uses of a compound described herein in the manufacture of a medicament for degrading a protein in a subject or biological sample.

In certain aspects, provided herein are compounds described herein for use in degrading a protein in a subject or biological sample.

In certain aspects, provided herein are methods of reducing a protein in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.

In certain aspects, provided herein are uses of a compound described herein in the manufacture of a medicament for reducing a protein in a subject or biological sample.

In certain aspects, provided herein are compounds described herein for use in reducing a protein in a subject or biological sample.

In certain aspects, provided herein are methods of treating or preventing a disease or disorder a subject in need thereof, comprising administering to the subject a compound described herein.

In certain aspects, provided herein are uses of a compound described herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

In certain aspects, provided herein are compounds described herein for use in treating or preventing a disease or disorder in a subject in need thereof.

DETAILED DESCRIPTION

The present disclosure relates to compounds that show cereblon-binding activity, bifunctional degraders comprising a cereblon-binding moeity, and pharmaceutical compositions comprising such compounds or bifunctional degraders. The present disclosure further relates to methods of degrading a protein in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein. The present disclosure also relates to methods of treating or preventing a disease or disorder a subject in need thereof, comprising administering to the subject a compound described herein.

Compounds of the Present Disclosure

Cereblon Ligands

In certain aspects, the present disclosure provides compounds of Formula II:

and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein:

• • B² is N or CR^B2;
  • B³ is N or CR^B3;
  • B⁴ is N or CR^B4;
  • B⁵ is N or CR^B5;
  • one of R^B2 and R^B3, R^B3 and R^B4, and R^B4 and R^B5, together with the carbon atoms to which they are bonded, form Ring A, wherein Ring A is optionally substituted 7- to 16-membered spiro carbocycle or optionally substituted 7- to 16-membered spiro heterocycle; the remaining two of R^B2, R^B3, R^B4, and R^B5, when applicable, are independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • denotes an optional covalent bond between B¹ and C¹;
  • i) when the bond between B¹ and C¹ is present:
    • r is 1;
    • B¹ is C;
    • C¹ is —C(R^C1)₂—, —C(═O)—, —(C═O)—N(R^C1′)—*, or —N═C(R^C1′)—*;
    • each R^C1 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, 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; or
    • two R^C1, together with the carbon atom to which they are attached, form C_3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more R^u;
    • R^C1′ is H or C_1-6 alkyl optionally substituted with one or more R^u, and * denotes attachment to Ring B; and
    • C² is N;
  • ii) when the bond between B¹ and C¹ is absent:
    • r is 0 or 1;
    • B¹ is N or CR^B1;
    • R^B1 is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
    • C¹ is absent; or
    • C¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u;
    • C² is N or O;
    • wherein i) when C² is N, then C¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and ii) when C² is O, then C¹ is absent;
  • R^D1 is hydrogen, deuterium, or C_1-6 alkyl optionally substituted with one or more R^u;
  • q is an integer from 0 to 2,
  • each R^D is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • d is an integer selected from 0 to 5,
  • wherein:
  • each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^bS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- or 6-membered heteroaryl;
  • 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, 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; and
  • each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or
  • R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; wherein each of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z;
  • each R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- or 6-membered heteroaryl.

In certain embodiments, the bond between B¹ and C¹ is present.

In certain embodiments, the compound of Formula II is a compound of Formula II-1

In certain embodiments, when the bond between B¹ and C¹ is present, then B¹ is C.

In certain embodiments, when the bond between B¹ and C¹ is present, then r is 0 or 1.

In certain embodiments, when the bond between B¹ and C¹ is present, then C¹ is —C(R^C1)₂—, —C(═O)—, —(C═O)—N(R^C1′)—*, or —N═C(R^C1′)—*.

In certain embodiments, when the bond between B¹ and C¹ is present, then C² is N.

In certain embodiments, R^C1′ is H or C_1-6 alkyl optionally substituted with one or more R^u, and * denotes attachment to Ring B.

In certain embodiments, each R^C1 is independently hydrogen, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, 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)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 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-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-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, orpentylhexylamino), C_3-6 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), or cyclohexadienyl (C₆)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, two R^C1, together with the carbon atom to which they are attached, form C_3-6 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), or cyclohexadienyl (C₆)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, the bond between B¹ and C¹ is absent.

In certain embodiments, the compound of Formula II is a compound of Formula II-2

In certain embodiments, when the bond between B¹ and C¹ is present, then r is 0 or 1.

In certain embodiments, when the bond between B¹ and C¹ is absent, then B¹ is N or CR^B1.

In certain embodiments, R^B1 is hydrogen, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, 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)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 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-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-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), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, R^B1 is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, R^B1 is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_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.

In certain embodiments, R^B1 is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, 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.

In certain embodiments, R^B1 is hydrogen or halogen.

In certain embodiments, when the bond between B¹ and C¹ is absent, then C¹ is absent.

In certain embodiments, when the bond between B¹ and C¹ is absent, then C¹ is 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)), C_3-6 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), or cyclohexadienyl (C₆)), 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), —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, when the bond between B¹ and C¹ is absent, then C² is N or O. In certain embodiments, when the bond between B¹ and C¹ is absent, then C² is N. In certain embodiments, when the bond between B¹ and C¹ is absent, then C² is O.

In certain embodiments, when the bond between B¹ and C¹ is absent, and C² is N, then C¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, when the bond between B¹ and C¹ is absent, and C² is O, then C¹ is absent.

In certain embodiments, B² is N or CR^B2. In certain embodiments, B² is N. In certain embodiments, B² is CR^B2.

In certain embodiments, B³ is N or CR^B3. In certain embodiments, B³ is N. In certain embodiments, B³ is CR^B3.

In certain embodiments, B⁴ is N or CR^B4. In certain embodiments, B² is N. In certain embodiments, B⁴ is CR^B4.

In certain embodiments, B⁵ is N or CR^B5. In certain embodiments, B² is N. In certain embodiments, B⁵ is CR^B5.

In certain embodiments, one of B², B³, B⁴, and B⁵ is N. In certain embodiments, two of B², B³, B⁴, and B⁵ are N.

In certain embodiments, one of R^B2 and R^B3, R^B3 and R^B4, and R^B4 and R^B5, together with the carbon atoms to which they are bonded, form Ring A, wherein Ring A is optionally substituted 7- to 16-membered spiro carbocycle or optionally substituted 7- to 16-membered spiro heterocycle.

In certain embodiments, one of R^B2 and R^B3, R^B3 and R^B4, and R^B4 and R^B5, together with the carbon atoms to which they are bonded, form Ring A, wherein Ring A is optionally substituted 7- to 16-membered spiro heterocycle.

In certain embodiments, R^B1 and R^B2, together with the carbon atoms to which they are bonded, form Ring A.

In certain embodiments, R^B2 and R^B3, together with the carbon atoms to which they are bonded, form Ring A.

In certain embodiments, R^B3 and R^B4, together with the carbon atoms to which they are bonded, form Ring A.

In certain embodiments, the remaining two of R^B2, R^B3, R^B4, and R^B5, when applicable, are independently hydrogen, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, 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)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 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-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-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), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 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), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, the remaining two of R^B2, R^B3, R^B4, and R^B5, when applicable, are independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, the remaining two of R^B2, R^B3, R^B4, and R^B5, when applicable, are independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, the remaining two of R^B2, R^B3, R^B4, and R^B5, when applicable, are independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_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.

In certain embodiments, the remaining two of R^B2, R^B3, R^B4, and R^B5, when applicable, are independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, 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.

In certain embodiments, each of R^B4 and R^B5 is hydrogen. In certain embodiments, each R^B2 and R^B5 is hydrogen.

In certain embodiments, Ring A is optionally substituted 7- to 16-membered spiro heterocycle (e.g., heterocycle comprising two 4- to 8-membered spiro rings and 1-5 heteroatoms selected from N, O, and S).

In certain embodiments, Ring A is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, Ring A is optionally substituted with one or more R^u, R^A1, R^A1′, R^A2, or R^A2′.

In certain embodiments, R^u is R^A1. In certain embodiments, R^u is R^A1′. In certain embodiments, R^u is R^A2. In certain embodiments, R^u is R^A2′.

In certain embodiments,

• • Ring A is:

or

• • Ring A attached to -L-T is

wherein:

• • Ring A^II is C_3-8 carbocycle or 3- to 8-membered heterocycle;
  • each A¹ is independently —C(R^A1)₂—, —NR^A1′—, —O—, —S—, —S(═O)—, or —S(═O)₂—;
  • each A² is independently —C(R^A2)₂—, —NR^A2′—, —O—, —S—, —S(═O)—, or —S(═O)₂—;
  • each occurrence of R^A1 and R^A2 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • two geminal R^A1 or two geminal R^A2 together form oxo; or
  • two geminal R^A1 or two geminal R^A2, together with the carbon atom to which they are attached, form C_3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more R^u;
  • each occurrence of R^A1′ and R^A2′ is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • a′ and a″ are independently 1 or 2;
  • each R^A is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • a is an integer selected from 0 to 8, as valency permits,
  • wherein Ring A¹ is not carbocycle.

In certain embodiments, Ring A¹ is 5- to 8-membered heterocycle (e.g., heterocycle comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

In certain embodiments, Ring A¹ is 5- to 8-membered heterocycle comprising one oxygen atom.

In certain embodiments, Ring A¹ is 5- to 8-membered heterocycle comprising one oxygen atom and one double bond.

In certain embodiments, Ring A¹ is 5- to 8-membered heterocycle comprising two oxygen atoms.

In certain embodiments, Ring A¹ is 5- to 8-membered heterocycle comprising one nitrogen atom.

In certain embodiments, Ring A¹ is 5- to 8-membered heterocycle comprising two nitrogen atoms.

In certain embodiments, Ring A¹ is 5- to 8-membered heterocycle comprising one nitrogen atom and one oxygen atom.

In certain embodiments, Ring A^II is C_3-8 carbocycle (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), or bicyclo[2.2.2]octanyl (C₈)) or 3- to 8-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

In certain embodiments, each A¹ is independently —C(R^A1)₂—, —NR^A1′—, —O—, —S—, —S(═O)—, or —S(═O)₂—.

In certain embodiments, each A¹ is independently —C(R^A1)₂—, —NR^A1′—, or —O—.

In certain embodiments, each A² is independently —C(R^A2)₂—, —NR^A2′—, —O—, —S—, —S(═O)—, or —S(═O)₂—.

In certain embodiments, each A² is independently —C(R^A2)₂—, —NR^A2′—, or —O—.

In certain embodiments, each occurrence of R^A1 and R^A2 is independently hydrogen, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, 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)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 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-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-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), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₈), or hexynyl (C₆)), C_3-12 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), C_6-10 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), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^A1 and R^A2 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^A1 and R^A2 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^A1 and R^A2 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_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.

In certain embodiments, each occurrence of R^A1 and R^A2 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, 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.

In certain embodiments, each occurrence of R^A1 and R^A2 is hydrogen.

In certain embodiments, two geminal R^A1 or two geminal R^A2 together form oxo.

In certain embodiments, two geminal R^A1 or two geminal R^A2, together with the carbon atom to which they are attached, form C_3-6 carbocycle (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), or cyclohexadienyl (C₆)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^A1′ and R^A2′ 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)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 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)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^A1′ and R^A2′ is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, 5- to 6-membered heteroaryl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^A1′ and R^A2′ is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^A1′ and R^A2′ is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^A1′ and R^A2′ is independently hydrogen or C_1-6 alkyl.

In certain embodiments, each occurrence of R^A1′ and R^A2′ is hydrogen.

In certain embodiments, a′ is 1. In certain embodiments, a′ is 2.

In certain embodiments, a″ is 1. In certain embodiments, a″ is 2.

In certain embodiments, each of a′ and a″ is 1.

In certain embodiments, one of a′ and a″ is 1, and the other one of a′ and a″ is 2.

In certain embodiments, each R^A is independently oxo, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, 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)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 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-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-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), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 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), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^A is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^A is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^A is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_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.

In certain embodiments, each R^A is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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.

In certain embodiments, a is 0. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4, as valency permits. In certain embodiments, a is 5, as valency permits. In certain embodiments, a is 6, as valency permits. In certain embodiments, a is 7, as valency permits. In certain embodiments, a is 0. In certain embodiments, a is 8, as valency permits.

In certain embodiments, each R^A may independently be present on either Ring A^I or Ring A^II.

In certain embodiments, Ring A is:

In certain embodiments, the compound is a compound of Formula II-1-a-i, II-1-a-ii, II-1-a-iii, or II-1-a-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, the compound of Formula II-2 is a compound of Formula II-2-a-i, II-2-a-i, II-2-a-iii, or II-2-a-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, the compound of Formula II-1 is a compound of Formula II-1-a-v, II-1-a-vi, II-1-a-vii, or II-1-a-viii:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, the compound of Formula II-2 is a compound of Formula II-2-a-v, II-2-a-vi, II-2-a-vii, or II-2-a-viii:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, R^D1 is hydrogen, deuterium, or 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)) optionally substituted with one or more R^u.

In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

In certain embodiments, each R^D is independently halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO₂, —OH, —NH₂, 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)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 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-1-propylamino, methyl-n-butylamino, methyl-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-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), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^D is independently halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^D is independently halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_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.

In certain embodiments, each R^D is independently halogen, —CN, —NO₂, —OH, —NH₂, 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.

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.

In certain embodiments, each R^a is independently 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)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, 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, C₆ aryl, or 5- to 6-membered heteroaryl.

In certain embodiments, each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, 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.

In certain embodiments, 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)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C₂-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C_2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^c and each R^d 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)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^c and each R^d is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, 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.

In certain embodiments, R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z.

In certain embodiments, R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 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-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-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), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 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), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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.

In certain embodiments, each RU is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_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, —NO₂, —OH, —NH₂, 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.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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, —NO₂, —OH, —NH₂, 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.

In certain embodiments, two R^u, together with the carbon atom(s) to which they are attached, form C_3-6 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).

In certain embodiments, two geminal R^u, together with the carbon atom to which they are attached, form C_3-6 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).

In certain aspects, the present disclosure provides compounds of Formula I:

and pharmaceutically acceptable salts, solvates, or stereoisomers thereof,wherein:

• • R¹ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or
  • R¹ and R², together with the intervening carbon atoms, form optionally substituted 7- to 16-membered spiro heterocycle;
  • Y″ is N or CR³;
  • R³ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or
  • R² and R³, together with the intervening carbon atoms, form optionally substituted 7- to 16-membered spiro heterocycle; provided that either R¹ and R², or R² and R³ form optionally substituted 7- to 16-membered spiro heterocycle;
  • Y′ is N or CR^Y′;
  • R^Y′ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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;
  • denotes an optional covalent bond between Y and U;
  • when the bond between Y and U is absent:
  • r is 0 or 1;
  • Y is N or CR^Y;
  • R^Y is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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;
  • U is hydrogen or C_1-6 alkyl optionally substituted with one or more R^u;
  • when the bond between Y and U is present:
  • r is 1;
  • Y is C;
  • U is —CH₂—, —C(═O)—, —(C═O)—N(R^U)—*, —N═C(R^U)—*;
  • R^U is H or C_1-6 alkyl optionally substituted with one or more R^u, and * denotes attachment to Ring B;
  • R⁴ is hydrogen, deuterium, C_1-6 haloalkyl, or C_1-6 alkyl; and
  • q is an integer from 0 to 2,
  • wherein:
  • each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 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, C_3-12 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, 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; and
  • each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or
  • R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl,
  • wherein each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and
  • each R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, the compound of Formula I is a compound of Formula I-1

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, U is —CH₂— or —C(═O)—.

In certain embodiments, the compound of Formula I is a compound of Formula I-2

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, Y is N.

In certain embodiments, Y is CR^Y.

In certain embodiments, R^Y is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, R^Y is hydrogen, halogen, or C_1-6 alkoxy.

In certain embodiments, R¹ and R², together with the intervening carbon atoms, form optionally substituted 7- to 16-membered spiro heterocycle.

In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^u. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R¹. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^X1. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^Z1. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^X2. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^Z2.

In certain embodiments, R^u is Rⁱ. In certain embodiments, R^u is R^X1. In certain embodiments, R^u is R^X2. In certain embodiments, R^u is R^Z1. In certain embodiments, R^u is R^Z2. In certain embodiments, Rⁱ is R^X1. In certain embodiments, Rⁱ is R^X2. In certain embodiments, Rⁱ is R^Z1. In certain embodiments, Rⁱ is R^Z2.

In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, the 7- to 16-membered spiro heterocycle is of the following structure:

wherein:

• • Ring A² is C_3-12 carbocycle or 3- to 12-membered heterocycle;
  • each X is independently —C(R^X1)₂—, —NR^X2—, —O—, —S—, —S(═O)—, or —S(═O)₂—;
  • each Z is independently —C(R^Z1)₂—, —NR^Z2—, —O—, —S—, —S(═O)—, or —S(═O)₂—;
  • each occurrence of R^X1 and R^Z1 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • two geminal R^X1 or two geminal R^Z1 together form oxo; or two R^X1 or two R^Z1, together with the intervening carbon atom(s), form C_3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u;
  • each occurrence of R^X2 and R^Z2 is independently hydrogen or C_1-6 alkyl optionally substituted with one or more R^u;
  • m′ and n′ are independently an integer selected from 1 to 3;
  • each Rⁱ independently is oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • s is an integer selected from 0 to 10,
  • provided that Ring A¹ is 4- to 9-membered heterocycle.

In certain embodiments, the 7- to 16-membered spiro heterocycle is

In certain embodiments, the compound of Formula I-1 is a compound of Formula I-1-a-i, I-1-a-ii, I-1-a-iii, or I-1-a-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

• • R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or
  • R⁵ is an amino-protecting group; and
  • m and n are independently an integer selected from 0 to 2.

In certain embodiments, the compound of Formula I-2 is a compound of Formula I-2-a-i, I-2-a-ii, I-2-a-iii, or I-2-a-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

• • R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or
  • R⁵ is an amino-protecting group; and
  • m and n are independently an integer selected from 0 to 2.

In certain embodiments, each R⁵ is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, or —C(═O)R^a, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R⁵ is independently hydrogen or C_1-6 alkyl optionally substituted with one or more R^u.

In certain embodiments, Y″ is N.

In certain embodiments, Y″ is CR³.

In certain embodiments, R³ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R² and R³, together with the intervening carbon atoms, form optionally substituted 7- to 16-membered spiro heterocycle.

In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^u. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R¹. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^X1. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^Z1. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^X2. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^Z2.

In certain embodiments, R^u is Rⁱ. In certain embodiments, R^u is R^X1. In certain embodiments, R^u is R^X2. In certain embodiments, R^u is R^Z1. In certain embodiments, R^u is R^Z2. In certain embodiments, Rⁱ is R^X1. In certain embodiments, Rⁱ is R^X2. In certain embodiments, Rⁱ is R^Z1. In certain embodiments, Rⁱ is R^Z2.

In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, the compound of Formula I-1 is a compound of Formula I-1-b-i, I-1-b-ii, I-1-b-iii, or I-1-b-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

• • R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or
  • R⁵ is an amino-protecting group; and
  • m and n are independently an integer selected from 0 to 2.

In certain embodiments, the compound of Formula I-2 is a compound of Formula I-2-b-i, I-2-b-ii, I-2-b-iii, or I-2-b-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

• • R⁵ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; or
  • R⁵ is an amino-protecting group; and
  • m and n are independently an integer selected from 0 to 2.

In certain embodiments, each R⁵ is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, or —C(═O)R^a, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R⁵ is independently hydrogen or C_1-6 alkyl optionally substituted with one or more R^u.

In certain embodiments, R¹ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, X is —C(R^X1)₂—, —NR^X2—, or —O—, and Z is —C(R^Z1)₂—, —NR^Z2—, or —O—.

In certain embodiments, Y′ is N.

In certain embodiments, Y′ is CR^Y′.

In certain embodiments, R^Y′ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, R^Y′ is hydrogen.

In certain embodiments, each R¹ is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, s is an integer selected from 0 to 8, as valency permits. In certain embodiments, s is an integer selected from 0 to 7, as valency permits. In certain embodiments, s is an integer selected from 0 to 6, as valency permits. In certain embodiments, s is an integer selected from 0 to 5, as valency permits. In certain embodiments, s is an integer selected from 0 to 4, as valency permits. In certain embodiments, s is an integer selected from 0 to 3, as valency permits. In certain embodiments, s is an integer selected from 0 to 2, as valency permits. In certain embodiments, s is 0 or 1, as valency permits.

In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is deuterium. In certain embodiments, R⁴ is C_1-6 haloalkyl. In certain embodiments, R⁴ is C_1-6 alkyl.

In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 0 or 1. In certain embodiments, q is 0 or 2. In certain embodiments, q is 1 or 2.

In certain embodiments, each R^a is independently 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)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 carbocyclyl (e.g., cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₆), 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), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, 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, C₆ aryl, or 5- to 6-membered heteroaryl.

In certain embodiments, each R^a is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, 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.

In certain embodiments, 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)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6-membered heteroaryl.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C₂-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, each R^b is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C_2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, each R^c and each R^d 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)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₅), or hexynyl (C₆)), C_3-12 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), C_6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each R^c and each R^d is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, 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.

In certain embodiments, R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^Z.

In certain embodiments, R^Z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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)), C_1-6 alkoxy (e.g., methoxy (C₁), ethoxy (C₂), propoxy (C₃), i-propoxy (C₃), n-butoxy (C₄), i-butoxy (C₄), s-butoxy (C₄), t-butoxy (C₄), pentoxy (C₅), or hexoxy (C₆)), C_1-6 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-1-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-1-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-1-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-1-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), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₈), or hexynyl (C₆)), C_3-12 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), C_6-10 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), —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, each RU is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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.

In certain embodiments, each RU is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_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, —NO₂, —OH, —NH₂, 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.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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.

In certain embodiments, each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, 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, —NO₂, —OH, —NH₂, 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.

In certain embodiments, two R^u, together with the carbon atom(s) to which they are attached, form C_3-6 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).

In certain embodiments, two geminal R^u, together with the carbon atom to which they are attached, form C_3-6 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).

In certain embodiments, the compound is selected from the compounds in Tables 1-3, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is selected from the compounds in Table 3, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is selected from the compounds in Tables 1 and 2, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is selected from the compounds in Tables 1-3.

In certain embodiments, the compound is selected from the compounds in Table 1.

In certain embodiments, the compound is selected from the compounds in Table 2.

In certain embodiments, the compound is selected from the compounds in Table 3.

In certain embodiments, the compound is selected from the compounds in Tables 1 and 2.

TABLE 1
Compound
No.	Structure	Chemical Name
A1		3-(7′-oxo-7′,9′-dihydro-8′H- spiro[piperidine-4,2′- pyrano[2,3-e]isoindol]-8′- yl)piperidine-2,6-dione
A2		3-(7′-oxo-3′,4′,7′,9′-tetrahydro- 8′H-spiro[piperidine-4,2′- pyrano[2,3-e]isoindol]-8′- yl)piperidine-2,6-dione
A3		3-(7′-oxo-7′,9′-dihydro-8′H- spiro[azetidine-3,2′- pyrano[2,3-e]isoindol]-8′- yl)piperidine-2,6-dione hydrochloride
A4		3-(7′-oxo-3′,4′,7′,9′-tetrahydro- 8′H-spiro[azetidine-3,2′- pyrano[2,3-e]isoindol]-8′- yl)piperidine-2,6-dione hydrochloride

TABLE 2
Compound
No.	Structure	Chemical Name
B1		(S)-3-(7′-oxo-7′,9′-dihydro- 2′H,8′H-spiro[piperidine-4,3′- [1,4]dioxino[2,3-e]isoindol]- 8′-yl)piperidine-2,6-dione
B2		3-(7′-oxo-7′,9′-dihydro- 2′H,8′H-spiro[azetidine-3,3′- [1,4]dioxino[2,3-e]isoindol]- 8′-yl)piperidine-2,6-dione
B3		(S)-3-(5′-fluoro-6′-oxo-6′,8′- dihydro-3′H,7′H- spiro[piperidine-4,2′- [1,4]dioxino [2,3-f]isoindol]-7′- yl)piperidine-2,6-dione
B4		(S)-3-(6′-oxo-6′,8′-dihydro- 3′H,7′H-spiro[azetidine-3,2′- [1,4]dioxino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
B5		7′-(2,6-dioxopiperidin-3-yl)-7′- hydro-3′H,6′H-spiro[azetidine- 3,2′-[1,4]dioxino[2,3- f]isoindole]-6′,8′-dione

TABLE 3
No	Structure	Chemical name
C1		(S)-3-(7'-oxo-7',9'-dihydro- 3′H,8′H-spiro[piperidine-4,2′- [1,4]dioxino[2,3-e]isoindol]- 8′-yl)piperidine-2,6-dione
C2		(S)-3-(7′-oxo-7′,9′-dihydro- 3′H,8′H-spiro[azetidine-3,2′- [1,4]dioxino[2,3-e]isoindol]- 8′-yl)piperidine-2,6-dione
C3		(S)-3-(6′-oxo-6′,8′-dihydro- 3′H,7′H-spiro[piperidine-4,2′- [1,4]dioxino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
C4		(S)-3-(6′-oxo-6′,8′-dihydro- 3′H, 7′H-spiro[azetidine-3,2′- [1,4]dioxino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
C5		(S)-3-(8′-oxo-6′,8′-dihydro- 3′H,7′H-spiro[piperidine-4,2′- [1,4]dioxino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
C6		(S)-3-(8′-oxo-6′,8′-dihydro- 3′H, 7′H-spiro[azetidine-3,2′- [1,4]dioxino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
C7		(S)-3-(7′-oxo-1′,2′,7′,9′- tetrahydro-8′H- spiro[piperidine-4,3′- [1,4]oxazino[3,2-e]isoindol]- 8′-yl)piperidine-2,6-dione
C8		(S)-3-(7′-oxo-7′,9′-dihydro- 2′H-spiro[piperidine-4,3′- [1,4]oxazino[2,3-e]isoindol]- 8′(4′H)-yl)piperidine-2,6- dione
C9		(S)-3-(7′-oxo-1′,2′,7′,9′- tetrahydro-8'H- spiro[azetidine-3,3′- [1,4]oxazino[3,2-e]isoindol]- 8′-yl)piperidine-2,6-dione
C1		(S)-3-(7′-oxo-7′,9′-dihydro- 2′H-spiro[azetidine-3,3′- [1,4]oxazino[2,3-e]isoindol]- 8′(4′H)-yl)piperidine-2,6- dione
C10		(S)-3-(7′-oxo-7′,9′-dihydro- 3′H-spiro[piperidine-4,2′- [1,4]oxazino[3,2-e]isoindol]- 8′(1′H)-yl)piperidine-2,6- dione
C11		(S)-3-(7′-oxo-3′,4′,7′,9′- tetrahydro-8'H- spiro[piperidine-4,2′- [1,4]oxazino[2,3-e]isoindol]- 8′-yl)piperidine-2,6-dione
C12		(S)-3-(7′-oxo-7′,9′-dihydro- 3′H-spiro[azetidine-3,2′- [1,4]oxazino[3,2-e]isoindol]- 8′(1′H)-yl)piperidine-2,6- dione
C13		(S)-3-(7′-oxo-3′,4′,7′,9′- tetrahydro-8′H- spiro[azetidine-3,2′- [1,4]oxazino[2,3-e]isoindol]- 8′-yl)piperidine-2,6-dione
C14		(S)-3-(8′-oxo-6′,8′-dihydro- 2′H-spiro[piperidine-4,3′- [1,4]oxazino[2,3-f]isoindol]- 7′(4′H)-yl)piperidine-2,6- dione
C15		(S)-3-(6′-oxo-3′,4′,6′,8′- tetrahydro-7′H- spiro[piperidine-4,2′- [1,4]oxazino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
C16		(S)-3-(8′-oxo-6′,8′-dihydro- 2′H-spiro[azetidine-3,3′- [1,4]oxazino[2,3-f]isoindol]- 7′(4′H)-yl)piperidine-2,6- dione
C17		(S)-3-(6′-oxo-3′,4′,6′,8′- tetrahydro-7'H- spiro[azetidine-3,2′- [1,4]oxazino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
C18		(S)-3-(8′-oxo-3′,4′,6′,8′- tetrahydro-7′H- spiro[piperidine-4,2′- [1,4]oxazino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
C19		(S)-3-(6′-oxo-6′,8′-dihydro- 2′H-spiro[piperidine-4,3′- [1,4]oxazino[2,3-f]isoindol]- 7′(4′H)-yl)piperidine-2,6- dione
C20		(S)-3-(8′-oxo-3′,4′,6′,8′- tetrahydro-7′H- spiro[azetidine-3,2′- [1,4]oxazino[2,3-f]isoindol]- 7′-yl)piperidine-2,6-dione
C21		(S)-3-(6′-oxo-6′,8′-dihydro- 2′H-spiro[azetidine-3,3′- [1,4]oxazino[2,3-f]isoindol]- 7′(4′H)-yl)piperidine-2,6- dione
C22		(S)-3-(6′-oxo-3′,4′,6′,8′- tetrahydro-7′H- spiro[piperidine-4,2′- pyrano[2,3-f]isoindol]-7′- yl)piperidine-2,6-dione
C23		(S)-3-(6′-oxo-3′,4′,6′,8′- tetrahydro-7′H- spiro[azetidine-3,2′- pyrano[2,3-f]isoindol]-7′- yl)piperidine-2,6-dione
C24		(S)-3-(8′-oxo-6′,8′-dihydro- 2′H-spiro[piperidine-4,3′- pyrano[2,3-f]isoindol]- 7′(4′H)-yl)piperidine-2,6- dione
C25		(S)-3-(8′-oxo-6′,8′-dihydro- 2′H-spiro[azetidine-3,3′- pyrano[2,3-f]isoindol]- 7′(4′H)-yl)piperidine-2,6- dione
C26		(S)-3-(7′-oxo-7′,9′-dihydro- 2′H-spiro[piperidine-4,3′- pyrano[2,3-e]isoindol]- 8′(4′H)-yl)piperidine-2,6- dione
C27		(S)-3-(3′-oxo-1′,3′,8′,9′- tetrahydro-2′H- spiro[piperidine-4,7′- pyrano[3,2-e]isoindol]-2′- yl)piperidine-2,6-dione
C28		(S)-3-(7′-oxo-7′,9′-dihydro- 2′H-spiro[azetidine-3,3′- pyrano[2,3-e]isoindol]- 8′(4′H)-yl)piperidine-2,6- dione
C29		(S)-3-(3′-oxo-11,3′,8′,9′- tetrahydro-2′H- spiro[azetidine-3,7′- pyrano[3,2-e]isoindol]-2′- yl)piperidine-2,6-dione
C30		7′-(2,6-dioxopiperidin-3-yl)- 3′,4′-dihydro-6′H- spiro[piperidine-4,2′- pyrano[2,3-f]isoindole]- 6′,8′(7′H)-dione
C31		7′-(2,6-dioxopiperidin-3-y1)- 3′,4′-dihydro-6′H- spiro[azetidine-3,2′- pyrano[2,3-f]isoindole]- 6′,8′(7′H)-dione
C32		7′-(2,6-dioxopiperidin-3-yl)- 2′H-spiro[piperidine-4,3′- pyrano[2,3-f]isoindole]- 6′,8′(4′H,7′H)-dione
C33		7′-(2,6-dioxopiperidin-3-yl)- 2′H-spiro[azetidine-3,3′- pyrano[2,3-f]isoindole]- 6′,8′(4′H,7′H)-dione
C34		8′-(2,6-dioxopiperidin-3-yl)- 2′H-spiro[piperidine-4,3′- pyrano[2,3-e]isoindole]- 7′,9′(4′H,8′H)-dione
C35		2'-(2,6-dioxopiperidin-3-yl)- 8′,9′-dihydro-1′H- spiro[piperidine-4,7′- pyrano[3,2-e]isoindole]- 1′,3′(2′H)-dione
C36		8′-(2,6-dioxopiperidin-3-yl)- 2′H-spiro[azetidine-3,3′- pyrano[2,3-e]isoindole]- 7′,9′(4′H,8′H)-dione
C37		2′-(2,6-dioxopiperidin-3-yl)- 8′,9′-dihydro-1′H- spiro[azetidine-3,7′- pyrano[3,2-e]isoindole]- 1′,3′(2′H)-dione
C38		8′-(2,6-dioxopiperidin-3-yl)- 8′-hydro-2′H,7′H- spiro[piperidine-4,3′- [1,4]dioxino[2,3-e]isoindole]- 7′,9′-dione
C39		7′-(2,6-dioxopiperidin-3-yl)- 7′-hydro-3′H,6′H- spiro[piperidine-4,2′- [1,4]dioxino[2,3-f]isoindole]- 6′,8′-dione
C40		8′-(2,6-dioxopiperidin-3-yl)- 8′-hydro-3′H,7′H- spiro[piperidine-4,2′- [1,4]dioxino[2,3-e]isoindole]- 7′,9′-dione
C41		8′-(2,6-dioxopiperidin-3-yl)- 2′H-spiro[piperidine-4,3′- [1,4]oxazino[2,3-e]isoindole]- 7′,9′(4′H,8′H)-dione
C42		7′-(2,6-dioxopiperidin-3-yl)- 2′H-spiro[piperidine-4,3′- [1,4]oxazino[2,3-f]isoindole]- 6′,8′(4′H,7′H)-dione
C43		8′-(2,6-dioxopiperidin-3-yl)- 4-methyl-2′H- spiro[piperidine-4,3′- [1,4]oxazino[2,3-e]isoindole]- 7′,9′(4′H,8′H)-dione
C44		7′-(2,6-dioxopiperidin-3-yl)- 4′-methyl-2′H- spiro[piperidine-4,3′- [1,4]oxazino[2,3-f]isoindole]- 6′,8′(4′H,7′H)-dione
C45		8′-(2,6-dioxopiperidin-3-yl)- 8′-hydro-2′H,7′H- spiro[azetidine-3,3′- [1,4]dioxino[2,3-e]isoindole]- 7′,9′-dione
C46		7′-(2,6-dioxopiperidin-3-yl)- 7′-hydro-3′H,6′H- spiro[azetidine-3,2′- [1,4]dioxino[2,3-f]isoindole]- 6′,8′-dione
C47		8′-(2,6-dioxopiperidin-3-yl)- 8′-hydro-3′H,7′H- spiro[azetidine-3,2′- [1,4]dioxino[2,3-e]isoindole]- 7′,9′-dione
C48		8′-(2,6-dioxopiperidin-3-yl)- 2′H-spiro[azetidine-3,3′- [1,4]oxazino[2,3-e]isoindole]- 7′,9′(4′H,8′H)-dione
C49		7′-(2,6-dioxopiperidin-3-yl)- 2′H-spiro[azetidine-3,3′- [1,4]oxazino[2,3-f]isoindole]- 6′,8′(4′H,7′H)-dione
C50		8′-(2,6-dioxopiperidin-3-yl)- 4′-methyl-2′H-spiro[azetidine- 3,3′-[1,4]oxazino[2,3- e]isoindole]-7′,9′(4′H,8′H)- dione
C51		7′-(2,6-dioxopiperidin-3-yl)- 4′-methyl-2′H-spiro[azetidine- 3,3′-[1,4]oxazino[2,3- f]isoindole]-6′,8′(4′H,7′H)- dione
C52		3-(5-oxo-5,7- dihydrospiro[furo[2,3- f]isoindole-2,4′-piperidin]- 6(3H)-yl)piperidine-2,6-dione
C53		3-(5′-oxo-5′,7′- dihydrospiro[azetidine-3,2′- furo[2,3-f]isoindol]-6′(3′H)- y1)piperidine-2,6-dione
C54		3-(6-oxo-6,8- dihydrospiro[furo[2,3- e]isoindole-2,4-piperidin]- 7(3H)-yl)piperidine-2,6-dione
C55		3-(6-oxo-6,8- dihydrospiro[furo[2,3- e]isoindole-2,4′-piperidin]- 7(3H)-yl)piperidine-2,6-dione
C56		3-(7-oxo-5,7- dihydrospiro[furo[2,3- f]isoindole-2,4′-piperidin]- 6(3H)-yl)piperidine-2,6-dione
C57		3-(7′-oxo-5′,7′- dihydrospiro[azetidine-3,2′- furo[2,3-f]isoindol]-6′(3′H)- yl)piperidine-2,6-dione
C58		3-(3-oxo-1,8- dihydrospiro[furo[3,2- e]isoindole-7,4′-piperidin]- 2(3H)-yl)piperidine-2,6-dione
C59		3-(3-oxo-1,8- dihydrospiro[furo[3,2- e]isoindole-7,4′-piperidin]- 2(3H)-yl)piperidine-2,6-dione

Bifunctional Degraders

In certain aspects, the present disclosure provides a conjugate comprising a compound disclosed herein being connected to a ligand for a protein (e.g., via a linker).

In certain aspects, provided herein are conjugates of Formula II:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

• • B² is N or CR^B2;
  • B³ is N or CR^B3;
  • B⁴ is N or CR^B4;
  • B⁵ is N or CR^B5;
  • one of R^B2 and R^B3, R^B3 and R^B4, and R^B4 and R^B5, together with the carbon atoms to which they are bonded, form Ring A attached to -L-T, wherein Ring A is optionally substituted 7- to 16-membered spiro carbocycle or optionally substituted 7- to 16-membered spiro heterocycle; the remaining two of R^B2, R^B3, R^B4, and R^B5, when applicable, are independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • denotes an optional covalent bond between B¹ and C¹;
  • i) when the bond between B¹ and C¹ is present:
    • r is 1;
    • B¹ is C;
    • C¹ is —C(R^C1)₂— or —C(═O)—;
    • each R^C1 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, 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; or
    • two R^C1, together with the carbon atom to which they are attached, form C_3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more R^u; and
    • C² is N;
  • ii) when the bond between B¹ and C¹ is absent:
    • r is 0 or 1;
    • B¹ is N or CR^B1;
    • R^B1 is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
    • C¹ is absent; or
    • C¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u;
    • C² is N or O;
    • wherein i) when C² is N, then C¹ is hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u; and ii) when C² is O, then C¹ is absent;
  • R^D1 is hydrogen, deuterium, or C_1-6 alkyl optionally substituted with one or more R^u;
  • q is an integer from 0 to 2,
  • each R^D is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • d is an integer selected from 0 to 5,
  • L is linker; and
  • T is a ligand for a protein,
  • wherein:
  • each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^bS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, and 5- or 6-membered heteroaryl;
  • 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, 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; and
  • each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or
  • R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl;
  • wherein each of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z;
  • each R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C₆ aryl, or 5- or 6-membered heteroaryl.

In certain embodiments, the conjugate of Formula II is a conjugate of Formula II-1

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.

In certain embodiments, the conjugate of Formula II is a conjugate of Formula II-2

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.

In certain embodiments, Ring A attached to -L-T is

wherein each of the variables is defined herein.

In certain embodiments, Ring A attached to -L-T is

wherein each of the variables is defined herein.

In certain embodiments, the conjugate of Formula II-1 is a conjugate of Formula II-1-b-i, II-1-b-ii, II-1-b-iii, or II-1-b-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.

In certain embodiments, the conjugate of Formula II-2 is a conjugate of Formula II-2-b-i, II-2-b-ii, II-2-b-iii, or II-2-b-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.

In certain embodiments, the conjugate of Formula II-1 is a conjugate of Formula II-1-b-v, II-1-b-vi, II-1-b-vii, or II-1-b-viii:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.

In certain embodiments, the conjugate of Formula II-2 is a conjugate of Formula II-2-b-v, II-2-b-vi, II-2-b-vii, or II-2-b-viii:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of the variables is defined herein.

L, a linker, is a divalent chemical moiety that connects the ligand of a protein with the cereblon ligand disclosed herein. L configures the ligand and the cereblon ligand such that the construct functions as a bifunctional degrader which binds the cereblon ligand and selectively degrads the target protein.

In certain embodiments, L is a linker comprising C_1-6 alkylene, C_2-6 alkenylene, C_2-6 alkynylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, —C(═O)—, —C(═O)N(R^L′)—, —C(═O)O—, —N(R^L′)—, —O—, —S—, or —S(═O)₂—, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted by one or more R^u.

In certain embodiments, L is of Formula II-X

wherein:

• • * denotes attachment to T and ** denotes attachment to C;
  • each L′ is independently C_1-6 alkylene, C_2-6 alkenylene, C_2-6 alkynylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, —C(═O)—, —C(═O)N(R^L′)—, —C(═O)O—, —N(R^L′)—, —O—, —S—, or —S(═O)₂—, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u;
  • each occurrence of R^L′ is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • l is an integer selected from 0 to 6.

In certain embodiments, each L′ is independently C_1-6 alkylene (e.g., methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—), and hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—)), C_2-6 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)), C_2-6 alkynylene (e.g., ethynylene (C₂), 1-propynylene (C₃), 2-propynylene (C₃), 1-butynylene (C₄), 2-butynylene (C₄), pentynylene (C₅), or hexynylene (C₆)), C_3-12 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), 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), C_6-10 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(R^L2)—, —C(═O)O—, —N(R^L2)—, —O—, —S—, or —S(═O)₂—, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u.

In certain embodiments, each L′ is independently C_1-6 alkylene, C_3-12 carbocyclylene, 3- to 12-membered heterocyclylene, —C(═O)—, —C(═O)N(R^L′)—, —C(═O)O—, —N(R^L′)—, —O—, —S—, or —S(═O)₂—, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^L′ 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)), C_2-6 alkenyl (e.g., ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), pentenyl (C₅), pentadienyl (C₅), or hexenyl (C₆)), C_2-6 alkynyl (e.g., ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), pentynyl (C₈), or hexynyl (C₆)), C_3-12 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), C_6-10 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)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u.

In certain embodiments, each occurrence of R^L′ is independently hydrogen, C_1-6 alkyl, C_3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R^u.

In certain embodiments, 1 is 0. In certain embodiments, t is 1. In certain embodiments, 1 is 2. In certain embodiments, 1 is 3. In certain embodiments, 1 is 4. In certain embodiments, 1 is 5. In certain embodiments, 1 is 6.

T, a ligand of a protein, is a chemical entity that competitively or non-competitively binds a protein.

In certain embodiments, the protein is B7.1 and B7, TINFR1m, 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-1 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-1 (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-21 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.

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 (CBP/p300), SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2/4 (SMARCA2/4), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS G12D), Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), bromodomain-containing protein 4 (BRD4), or BRD9.

In certain embodiments, T is a small molecule.

In certain embodiments, T is an antibody.

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.

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.

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.

In certain aspects, the present disclosure provides conjugates of Formula I′:

and pharmaceutically acceptable salts, solvates, or stereoisomers thereof,wherein:

• • R¹ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • R¹ and R², together with the intervening carbon atoms, form optionally substituted 7- to 16-membered spiro heterocycle attached to -L-T;
  • Y″ is N or CR³;
  • R³ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • R² and R³, together with the intervening carbon atoms, form optionally substituted 7- to 16-membered spiro heterocycle attached to -L-T;
  • provided that either R¹ and R², or R² and R³ form optionally substituted 7- to 16-membered spiro heterocycle attached to -L-T;
  • Y′ is N or CR^Y′;
  • R^Y′ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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;
  • - - - denotes an optional covalent bond between Y and U;
  • when the bond between Y and U is absent:
  • r is 0 or 1;
  • Y is N or CR^Y;
  • R^Y is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.
  • U is hydrogen or C_1-6 alkyl optionally substituted with one or more R^u;
  • when the bond between Y and U is present:
  • r is 1;
  • Y is C;
  • U is —CH₂—, —C(═O)—, —(C═O)—N(R^U)—*, —N═C(R^U)—*;
  • R^U is H or C_1-6 alkyl optionally substituted with one or more R^u, and * denotes attachment to Ring B;
  • R⁴ is hydrogen, deuterium, C_1-6 haloalkyl, or C_1-6 alkyl; and
  • q is an integer from 0 to 2,
  • L is a linker; and
  • T is a ligand for a protein,
  • wherein:
  • each R^u is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 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, C_3-12 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, 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; and
  • each R^c and R^d is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C_6-10 aryl, or 5- to 10-membered heteroaryl; or
  • R^c and R^d, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl,
  • wherein each occurrence of R^a, R^b, R^c, and R^d is independently and optionally substituted with one or more R^z; and
  • each R^z is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

In certain embodiments, the conjugate of Formula I′ is a conjugate of Formula I′-1

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, U is —CH₂— or —C(═O)—.

In certain embodiments, the conjugate of Formula I′ is a conjugate of Formula I′-2

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, Y is N.

In certain embodiments, Y is CR^Y.

In certain embodiments, R^Y is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, R^Y is hydrogen, halogen, or C_1-6 alkoxy.

In certain embodiments, R¹ and R², together with the intervening carbon atoms, form optionally substituted 7- to 16-membered spiro heterocycle attached to -L-T.

In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^u. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R¹. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^X1. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^Z1. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^X2. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^Z2.

In certain embodiments, R^u is Rⁱ. In certain embodiments, R^u is R^X1. In certain embodiments, R^u is R^X2. In certain embodiments, R^u is R^Z1. In certain embodiments, R^u is R^Z2. In certain embodiments, Rⁱ is R^X1. In certain embodiments, Rⁱ is R^X2. In certain embodiments, Rⁱ is R^Z1. In certain embodiments, Rⁱ is R^Z2.

In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, the 7- to 16-membered spiro heterocycle is of the following structure:

wherein:

• • Ring A² is C_3-12 carbocycle or 3- to 12-membered heterocycle;
  • each X is independently —C(R^X1)₂—, —NR^X2—, —O—, —S—, —S(═O)—, or —S(═O)₂—;
  • each Z is independently —C(R^Z1)₂—, —NR^Z2—, —O—, —S—, —S(═O)—, or —S(═O)₂—;
  • each occurrence of R^X1 and R^Z1 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • two geminal R^X1 or two geminal R^Z1 together form oxo; or
  • two R^X1 or two R^Z1, together with the intervening carbon atom(s), form C_3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u;
  • each occurrence of R^X2 and R^Z2 is independently hydrogen or C_1-6 alkyl optionally substituted with one or more R^u;
  • m′ and n′ are independently an integer selected from 1 to 3;
  • each Rⁱ independently is oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • s is an integer selected from 0 to 10,
  • provided that Ring A¹ is 4- to 9-membered heterocycle.

In certain embodiments, the 7- to 16-membered spiro heterocycle is

In certain embodiments, the conjugate of Formula I′-1 is a conjugate of Formula I′-1-a-i, I′-1-a-ii, I′-1-a-iii, or I′-1-a-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

• • R⁵ is -L-T; and
  • m and n are independently an integer selected from 0 to 2.

In certain embodiments, the conjugate of Formula I′-2 is a conjugate of Formula I′-2-a-i, I′-2-a-ii, I′-2-a-iii, or I′-2-a-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

• • R⁵ is -L-T; and
  • m and n are independently an integer selected from 0 to 2.

In certain embodiments, Y″ is N.

In certain embodiments, Y″ is CR³.

In certain embodiments, R³ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R² and R³, together with the intervening carbon atoms, form optionally substituted 7- to 16-membered spiro heterocycle attached to -L-T.

In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^u. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more Rⁱ. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^X1. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^Z1. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^X2. In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more R^Z2.

In certain embodiments, R^u is Rⁱ. In certain embodiments, R^u is R^X1. In certain embodiments, R^u is R^X2. In certain embodiments, R^u is R^Z1. In certain embodiments, R^u is R^Z2. In certain embodiments, Rⁱ is R^X1. In certain embodiments, Rⁱ is R^X2. In certain embodiments, Rⁱ is R^Z1. In certain embodiments, Rⁱ is R^Z2.

In certain embodiments, the 7- to 16-membered spiro heterocycle is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

In certain embodiments, the 7- to 16-membered spiro heterocycle is of the following structure:

wherein:

• • Ring A² is C_3-12 carbocycle or 3- to 12-membered heterocycle;
  • each X is independently —C(R^X1)₂—, —NR^X2—, —O—, —S—, —S(═O)—, or —S(═O)₂—;
  • each Z is independently —C(R^Z1)₂—, —NR^Z2—, —O—, —S—, —S(═O)—, or —S(═O)₂—;
  • each occurrence of R^X1 and R^Z1 is independently hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u;
  • two geminal R^X1 or two geminal R^Z1 together form oxo; or
  • two R^X1 or two R^Z1, together with the intervening carbon atom(s), form C_3-12 carbocyclyl or 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more R^u;
  • each occurrence of R^X2 and R^Z2 is independently hydrogen or C_1-6 alkyl optionally substituted with one or more R^u;
  • m′ and n′ are independently an integer selected from 1 to 3;
  • each Rⁱ independently is oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, C_3-12 carbocyclyl, 3- to 12-membered heterocyclyl, —SR^b, —S(═O)R^a, —S(═O)₂R^a, —S(═O)₂OR^b, —S(═O)₂NR^cR^d, —NR^cS(═O)₂R^a, —NR^cS(═O)R^a, —NR^cS(═O)₂OR^b, —NR^cS(═O)₂NR^cR^d, —NR^bC(═O)NR^cR^d, —NR^bC(═O)R^a, —NR^bC(═O)OR^b, —OS(═O)₂R^a, —OS(═O)₂OR^b, —OS(═O)₂NR^cR^d, —OC(═O)R^a, —OC(═O)OR^b, —OC(═O)NR^cR^d, —C(═O)R^a, —C(═O)OR^b, or —C(═O)NR^cR^d, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • s is an integer selected from 0 to 10,
  • provided that Ring A¹ is 4- to 9-membered heterocycle.

In certain embodiments, the 7- to 16-membered spiro heterocycle is

In certain embodiments, the conjugate of Formula I′-1 is a conjugate of Formula I′-1-b-i, I′-1-b-ii, I′-1-b-iii, or I′-1-b-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

• • R⁵ is -L-T; and
  • m and n are independently an integer selected from 0 to 2.

In certain embodiments, the conjugate of Formula I′-2 is a conjugate of Formula I′-2-b-i, I′-2-b-ii, I′-2-b-iii, or I′-2-b-iv:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

• • R⁵ is -L-T; and
  • m and n are independently an integer selected from 0 to 2.

In certain embodiments, R¹ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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

In certain embodiments, R¹ is hydrogen.

In certain embodiments, X is —C(R^X1)₂—, —NR^X2—, or —O—, and Z is —C(R^Z1)₂—, —NR^Z2—, or —O—.

In certain embodiments, Y′ is N.

In certain embodiments, Y′ is CR^Y′.

In certain embodiments, R^Y′ is hydrogen, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, R^Y′ is hydrogen.

In certain embodiments, each Rⁱ is independently oxo, halogen, —CN, —NO₂, —OH, —NH₂, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylamino, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, 5- to 10-membered heteroaryl, 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.

In certain embodiments, s is an integer selected from 0 to 8, as valency permits. In certain embodiments, s is an integer selected from 0 to 7, as valency permits. In certain embodiments, s is an integer selected from 0 to 6, as valency permits. In certain embodiments, s is an integer selected from 0 to 5, as valency permits. In certain embodiments, s is an integer selected from 0 to 4, as valency permits. In certain embodiments, s is an integer selected from 0 to 3, as valency permits. In certain embodiments, s is an integer selected from 0 to 2, as valency permits. In certain embodiments, s is 0 or 1, as valency permits.

In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is deuterium. In certain embodiments, R⁴ is C_1-6 haloalkyl. In certain embodiments, R⁴ is C_1-6 alkyl.

In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 0 or 1. In certain embodiments, q is 0 or 2. In certain embodiments, q is 1 or 2.

L, the linker, is a chemical moiety that connects the ligand of a protein with the cereblon ligand disclosed herein. L configures the ligand and the cereblon ligand such that the construct functions as a bifunctional degrader which binds the cereblon ligand and selectively degrads the target protein.

In certain embodiments, L is a linker comprising 6- to 10-membered heteroarylene, C_6-10 arylene, C_3-12 membered carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the arylene, heteroarylene, carbocyclylene, or heterocyclylene is optionally substituted by one or more R^u, and is directly attached to T.

In certain embodiments, L is of formula

wherein:

• • * denotes attachment to T and ** denotes attachment to C;
  • each occurrence of —W′— is independently C_1-3 alkylene, C₂ alkenylene, C₂ alkynylene, C_3-12 carbocycylene, 3- to 12-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, —C(═O)—, —N(R^L)—, —O—, —S—, or —S(═O)₂—, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more R^u;
  • each occurrence of R^L is independently hydrogen, C_1-6 alkyl, 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, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^u; and
  • t is an integer selected from 1 to 15.

In certain embodiments, L is of formula

wherein:

• • W′¹ is 6- to 10-membered heteroarylene, C_6-10 arylene, C_3-12 membered carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the arylene, heteroarylene, carbocyclylene, or heterocyclylene is optionally substituted by one or more R^u; and
  • each —W′— is independently C_1-3 alkylene, —C(═O)—, —N(R^L)_, —O—, C_3-12 carbocycylene, or 3- to 12-membered heterocyclylene, wherein the alkylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more R^u.

In certain embodiments, L is of Formula:

wherein:

• • W is absent; or
  • W is C_1-3 alkylene, —O—, —NR^W—, or —(C═O)—, wherein the alkylene is optionally substituted by one or more R^u;
  • Cy¹ is absent; or
  • Cy¹ is 6-membered heteroarylene, C₆ arylene, C_3-12 membered carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the arylene, heteroarylene, carbocyclylene, or heterocyclylene is optionally substituted by one or more R^u;
  • Z′ is absent; or
  • each Z′ is independently C_1-3 alkylene, —O—, —NR^W—, —(C═O)—, C_3-12 membered carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the alkylene, carbocyclylene, or heterocyclylene is optionally substituted by one or more R^u;
  • R^W is hydrogen or C_1-6 alkyl optionally substituted with one or more R^u; and
  • p is an integer selected from 0 to 8.

T, a ligand for a protein, is a chemical entity that competitively or non-competitively binds a protein.

In certain embodiments, T is a small molecule.

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.

In certain embodiments, T is an antibody.

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 STAT1/3 protein.

In certain embodiments, T is an estrogen receptor inhibitor. In certain embodiments, T is an androgen receptor inhibitor. In certain embodiments, T is a STAT1/3 protein inhibitor.

The compounds of the present disclosure possess advantageous characteristics, as compared to known compounds, such as known cereblon-binding agents or known degraders comprising such cereblon-binding agents. For example, the compounds of the present disclosure display more potent cereblon-binding activity or more potent degradation activity against certain proteins, more favorable pharmacokinetic properties (e.g., as measured by C_max, T_max, 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.

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.

In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate.

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

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.

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.

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, 7-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

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.

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⁺(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.

Solvates

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.

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.

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.

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

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.”

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.

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 corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the invention.

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

In certain embodiments, 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.

Pharmaceutical Compositions

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, 21^st Ed. Mack Pub. Co., Easton, PA (2005)).

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.

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.

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.

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

The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The compounds of the present disclosure (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and/or synthesis described herein (e.g., Examples).

General Synthetic Scheme

The compounds of the present disclosure can generally be prepared by first preparing pools of intermediates, including a pool of cereblon ligands, a pool of linkers, and a pool of inhibitors, as detailed in the Example section, then followed by subsequent reactions to connect a linker to an inhibitor and a cereblon ligand via metal-catalyzed coupling reactions and reductive amination. Large pool of compounds can be prepared by selecting different combinations of cereblon ligands, linkers, and inhibitors from each pool. General synthetic routes for preparing inhibitor-linker conjugate via metal-catalyzed coupling reactions, which is further coupled to cerebon ligand via reductive amination, are summarize below.

Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure (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).

The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Analytical Methods, Materials, and Instrumentation

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-C18 2.7 μm 4.6×100 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 C18 1.7 μm 2.1×50 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

The biological activities of the compounds of the present disclosure can be assessed with methods and assays known in the art.

The CRBN-DDB1 binding potency of the present disclosure was determined using HTRF assay technology (Perkin Elmer). Compounds are serially diluted and are transferred multi-well plate. The reaction was conducted with addition of His tagged (e.g., CRBN+DDB-DLS7+CXU4) followed by addition of 60 nM fluorescent probe (e.g., Cy5-labeled Thalidomide), and MAb Anti-6HIS Tb cryptate Gold in the assay buffer. After one hour incubation at room temperature, the HTRF signals were read on Envision reader (Perkin Elemer).

ERa degradative activity of compounds can be assessed in MCF-7 and T47D Cells. MCF-7 and T47D cell are seeded and are subsequently treated with the compounds at certain concentrations (e.g., 0.02 to 300 nM). DMSO can be used as vehicle control. Cells are fixed and are blocked with Intercept (PBS) Blocking Buffer (e.g., Li-COR, Odyssey Blocking Buffer), and are stained with ER (e.g., 1:500, Cell signaling) primary antibody for overnight at cold room. Secondary Antibody (e.g., IRDye 800CW Goat anti-Rabbit IgG) and CellTag 700 Stain are added in Intercept (PBS) Blocking Buffer. Finally, cell plate is placed in incubator to dry. Image and signal were captured on Odyssey® DLx Imaging System.

In vitro assay can be accomplished by MCF-7 and T47D Cell Titer Glo (CTG) assay. MCF-7 and T47D cell (From HDB) are cultured in multi-well white plate with phenol red-free RPMI1640+10% CS-FBS+1% P/S medium (e.g., at 1,000 cells/well). On day 0: Cells were treated with compound at certain concentrations (e.g., 0.5 to 10000 nM) (DMSO and Staurosporine as control). On day 0 and day 6: add Cell Titer Glo reagent and read on EnVision after 30 min incubation for data generation.

In-cell western blot analysis. Cells are seeded in multi-well plates (e.g., at 40,000 or 10,000 cells/well). Diluted compounds at certain concentration are added (final 0.5% DMSO) and cells are incubated for certain period of time (e.g., 16 hours). Formaldehyde (e.g., PBS:FA=9:1) is added and followed by washing with PBS. The cells are blocked with Licor blocking buffer (Li-Cor). The relative ER percentage in treated cells were obtained by comparing the values of treated wells to those in untreated and DMSO-treated wells as 100%.

Western Blot Analysis. The cells that are treated with the compounds are lysed in Radioimmunoprecipitation Assay Protein Lysis and Extraction Buffer (e.g., 25 mmol/L Tris.HCl, pH 7.6, 150 mmol/L NaCl, 1% Nonidet P-40, 1% sodium deoxycholate, and 0.1% sodium dodecyl sulfate) containing proteinase inhibitor cocktail. Equal amounts of total protein are electrophoresed through 10% SDS-polyacrylamide gels after determination of protein concentration by BCA assay. The separated protein bands were transferred onto PVDF membranes and blotted against different antibodies. The blots are scanned, and the band intensities were quantified (e.g., by using GelQuant.NET software provided by biochemlabsolutions.com). The relative mean intensity of target proteins is expressed after normalization to the intensity of glyceraldehyde-3-phosphate dehydrogenase bands.

Cell Growth Assay. The cells were seeded at certain concentration (e.g., at 1500/well) in multi-well plates overnight. Cells are subsequently treated with the compounds. A certain period of time (e.g., 4 days) after the compound treatment, 10% WST-8 reagent was added to the culture medium and incubate under certain condition (e.g., in a CO₂ incubator at 37° C. for 2.5 hours). The absorbance is measured on each sample using a microplate reader at certain wavelength (e.g., 450 nm). The relative absorbance is calculated against the vehicle control from three individually repeats.

In vivo pharmacodynamic and efficacy studies. To develop breast cancer cell line xenografts, mice is given 17β-Estradiol in drinking water for certain period of time. Certain number (e.g., five million) of cells in 50% Matrigel are injected subcutaneously into SCID mice to induce tumor formation. When tumors reach certain size (e.g., 100-400 mm³), mice are treated with vehicle control (e.g., 5% DMSO, 10% solutol, 85% Water) or the compound, and sacrificed at indicated time points. Tumor tissue is harvested for analysis. Tumor sizes and animal weights were measured 2-3 times per week. Tumor volume (mm³)=(length×width2)/2. Tumor growth inhibition is calculated using TGI (%)=(Vc−Vt)/(Vc−Vo)×100, where Vc, Vt are the median of control and treated groups at the end of the study and Vo at the start.

Methods of Use

“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.

In certain aspects, provided herein are methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering a compound described herein to the subject or contacting the biological sample with a compound described herein.

In certain aspects, provided herein are uses of a compound described herein in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

In certain aspects, provided herein are compounds described herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

In certain aspects, provided herein are methods of degrading a protein in a subject or biological sample comprising administering a conjugate described herein to the subject or contacting the biological sample with a compound described herein.

In certain aspects, provided herein are uses of a conjugate described herein in the manufacture of a medicament for degrading a protein in a subject or biological sample.

In certain aspects, provided herein are conjugates described herein for use in degrading a protein in a subject or biological sample.

In certain embodiments, the protein is an androgen receptor (AR), an estrogen receptor (ER), signal transducer and activator of transcription 3 (STAT3), STAT5, CREB-binding protein/EP300(E1A) binding protein (CBP/p300), SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2/4 (SMARCA2/4), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS G12D), Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), bromodomain-containing protein 4 (BRD4), or BRD9.

In certain aspects, provided herein are methods of treating or preventing a disease or disorder a subject in need thereof, comprising administering to the subject a conjugate described herein.

In certain aspects, provided herein are uses of a conjugate described herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

In certain aspects, provided herein are conjugates described herein for use in treating or preventing a disease or disorder in a subject in need thereof.

In certain embodiments, the disease or disorder is an estrogen receptor-mediated disease or disorder, an androgen receptor-mediated disease or disorder, or a STAT1/3 protein-mediated disease or disorder.

In certain embodiments, the protein is an androgen receptor (AR)-mediated disease or disorder, an estrogen receptor (ER)-mediated disease or disorder, signal transducer and activator of transcription 3-mediated disease or disorder (STAT3-mediated disease or disorder), STAT5-mediated disease or disorder, CREB-binding protein/EP300(E1A) binding protein-mediated disease or disorder (CBP/p300)-mediated disease or disorder, SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2/4-mediated disease or disorder (SMARCA2/4-mediated disease or disorder), Kirsten rat sarcoma viral oncogene homolog G12D-mediated disease or disorder (KRAS G12D-mediated disease or disorder), Src homology region 2-containing protein tyrosine phosphatase 2-mediated disease or disorder (SHP2-mediated disease or disorder), bromodomain-containing protein 4-mediated disease or disorder (BRD4-mediated disease or disorder), or BRD9-mediated disease or disorder.

In certain embodiments, the subject is a mammal.

In certain embodiments, the subject is a human.

Definitions

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

Chemical Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. 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, 5^th 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, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

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, N Y, 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).

The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C_1-6 alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1-3, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6 alkyl.

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. 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 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.

“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 (“C_1-12 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 (“C_1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C_1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C_1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C_1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). Examples of 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 (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C_1-10 alkyl (e.g., —CH₃). In certain embodiments, the alkyl group is substituted C_1-10 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).

“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.

“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) (“C_2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C_2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C_2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C_2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C_2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C_2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C_2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C_2-4 alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 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 C_2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C_2-10 alkenyl.

“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.

“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 (“C_2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C_2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C_2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C_2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C_2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C_2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C_2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C_2-4 alkynyl groups include, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 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 C_2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C_2-10 alkynyl.

“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.

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 (“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 (“heteroC_1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC_1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC_1-7 alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC_1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC_1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“heteroC_1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC_1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC_1-2 alkyl”). 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 (“heteroC_2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC_1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC_1-10 alkyl.

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 (“heteroC_2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-8 alkenyl”). In certain embodiments, 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 1 or 2 heteroatoms (“heteroC_2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC_2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC_2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC_2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC_2-10 alkenyl.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is 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 (“heteroC_2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-8 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 (“heteroC_2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC_2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC_2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC_2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC_2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC_2-6 alkynyl”). 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 heteroC_2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC_2-10 alkynyl.

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.

“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 (“C_6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl).

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 C_6-14 aryl. In certain embodiments, the aryl group is substituted C_6-14 aryl.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

“Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 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.

“Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl/heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

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.

Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

“Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C_3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C_3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3-6 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 (“C_5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C_5-6 carbocyclyl”). Exemplary C_3-6 carbocyclyl include, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3-8 carbocyclyl include, without limitation, the aforementioned C_3-6 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 C_3-10 carbocyclyl include, without limitation, the aforementioned C_3-8 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.

In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C_3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C_3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C_3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C_3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C_5-12 carbocyclyl”). 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 (C₅) and cyclohexyl (C₅). Examples of C_3-6 carbocyclyl include the aforementioned C_5-6 carbocyclyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3-8 carbocyclyl include the aforementioned C_3-6 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 C_3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C_3-12 carbocyclyl.

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 C_3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C_3-12 carbocyclyl.

“Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share one common bond with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

“Spiro carbocyclyl” or or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embeded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embeded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embeded.

“Bridged carbocyclyl” or or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than one atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embeded. In such instances, the number of carbons designates the total number of carbons of the bridged rings. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embeded.

“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 5 membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred to herein as a 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.

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.

As the foregoing examples illustrate, in certain embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12-membered heterocyclyl.

“Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share one common bond with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons 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.

“Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embeded. 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 embeded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embeded.

“Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than one atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embeded. 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 embeded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the bridged rings.

“Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, sulfur, boron, phosphorus, and silicon heteroatom, as valency permits. Hetero may be applied to any of the hydrocarbyl groups described above having from 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” as used herein, refers to a radical —C(O)R, wherein R is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. Representative acyl groups include, but are not limited to, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), and benzylcarbonyl (—C(═O)CH₂Ph).

“Acylamino” as used herein, refers to a radical —NRC(═O)R, wherein each instance of R is independently hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. Exemplary “acylamino” groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.

“Acyloxy” as used herein, refers to a radical —OC(═O)R, wherein R is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.

“Alkoxy” as used herein, refers to the group —OR, wherein R is alkyl as defined herein. C_1-6 alkoxy refers to the group —OR, wherein each R is C_1-6 alkyl, as defined herein. Exemplary C_1-6 alkyl is set forth above.

“Alkylamino” as used herein, refers to the group —NHR or —NR₂, wherein each R is independently alkyl, as defined herein. C_1-6 alkylamino refers to the group —NHR or —NR₂, wherein each R is independently C_1-6 alkyl, as defined herein. Exemplary C_1-6 alkyl is set forth above.

“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.

“Azido” refers to the radical —N₃.

“Amino” refers to the radical —NH₂.

“Hydroxy” refers to the radical —OH.

“Thioketo” refers to the group ═S.

“Carboxy” refers to the radical —C(═O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (C₁), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

“Nitro” refers to the radical —NO₂.

“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.

Common types of hydroxyl-protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), β-Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p-methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g. t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri-iso-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz)).

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)).

Common types of thiol-protecting groups include but not limited to sulfide (e.g., p-methylbenzyl (Meb), t-butyl, acetamidoethyl (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.

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

“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. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

“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.

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.

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 “prophylactically effective amount” refers to the effective amount for prophylactic treatment.

“Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or in a subject who is predisposed to the disease in advance of disease onset).

The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

“Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). 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.

“Cereblon 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.

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.”

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”.

“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 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.

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.

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.

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.

In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range.

The term “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.

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.

As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

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.

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.

While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

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

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. Cereblon Ligands

Synthetic and Characterization

Compound A1: 3-(7′-oxo-7′,9′-dihydro-8′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

Step A: 1′-benzyl 7-methyl 8-methyl-4-oxospiro[chromane-2,4′-piperidine]-1′,7-dicarboxylate

To a solution of methyl 4-acetyl-3-hydroxy-2-methylbenzoate (2.9 g, 13.93 mmol, 1.0 eq) in MeOH (30 mL) were added benzyl 4-oxopiperidine-1-carboxylate (4.113 mL, 20.9 mmol, 1.5 eq) and pyrrolidine (1.72 mL, 20.9 mmol, 1.5 eq). The reaction mixture was stirred at 80° C. in a sealed tube overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 17%) to afford 1′-benzyl 7-methyl 8-methyl-4-oxospiro[chromane-2,4′-piperidine]-1′,7-dicarboxylate (5.88 g, yield 99%) as a yellow solid. LC-MS (ESI): mass calcd. for C₂₄H₂₅NO₆, 423.1; m/z found, 424.4 [M+H]⁺.

Step B: 1-benzyl 7′-methyl 8′-methyldispiro[piperidine-4,2′-chromane-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate

To a solution of 1′-benzyl 7-methyl 8-methyl-4-oxo-3,4-dihydrospiro[l-benzopyran-2,4′-piperidine]-1′,7-dicarboxylate (5.88 g, 13.89 mmol, 1.0 eq) in DCM (40 mL) were added 2,2,7,7-tetramethyl-3,6-dioxa-2,7-disilaoctane (23.887 mL, 97.2 mmol, 7.0 eq) and trimethylsilyl trifluoromethanesulfonate (0.25 mL, 1.4 mmol, 0.1 eq) and the reaction mixture was stirred under N2 at 50° C. overnight. After cooled to room temperature, the reaction mixture was diluted with EA (150 mL), washed with saturated aqueous NaHCO₃ solution (25 mL×3) and brine (25 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, from 0% to 16%) to afford 1″-benzyl 7′-methyl 8′-methyl-3′H-dispiro[1,3-dioxolane-2,4′-[1]benzopyran-2′,4″-piperidine]-1″,7′-dicarboxylate (6.1 g, yield 94%) as a yellow solid. LC-MS (ESI): mass calcd. for C₂₆H₂₉NO₇, 467.2; m/z found, 468.2 [M+H]⁺.

Step C: 1-(tert-butyl) 7′-methyl 8′-methyldispiro[piperidine-4,2′-chromane-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate

To a solution of 1″-benzyl 7′-methyl 8′-methyl-3′H-dispiro[1,3-dioxolane-2,4′-benzopyran-2′,4″-piperidine]-1″,7′-dicarboxylate (6.1 g, 13.05 mmol, 1.0 eq) in MeOH (100 mL) was added 100% Pd/C (0.14 g) and the reaction mixture was stirred under H₂ atmosphere (1 atm) at 70° C. overnight. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford methyl 8′-methyl-3′H-dispiro[1,3-dioxolane-2,4′-[1]benzopyran-2′,4″-piperidine]-7′-carboxylate (4.1 g, yield 94%) as a yellow solid. LC-MS (ESI): mass calcd. for C₁₈H₂₃NO₅, 333.2; m/z found, 334.2 [M+H]⁺.

Step D: 1-(tert-butyl) 7′-methyl 8′-methyldispiro[piperidine-4,2′-chromane-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate

To a solution of methyl 8′-methyl-3′H-dispiro[1,3-dioxolane-2,4′-[1]benzopyran-2′,4″-piperidine]-7′-carboxylate (4.1 g, 12.3 mmol, 1.0 eq) in DCM (40 mL) were added di-tert-butyl dicarbonate (4.03 g, 18.45 mmol, 1.5 eq) and TEA (5.13 mL, 36.9 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 3 h. After evaporation, the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 16%) to afford 1″-tert-butyl 7′-methyl 8′-methyl-3′H-dispiro[1,3-dioxolane-2,4′-[1]benzopyran2′,4″-piperidine]-1″,7′-dicarboxylate (5.0 g, yield 93%) as a yellow solid. LC-MS (ESI): mass calcd. for C₂₃H₃₁NO₇, 433.2; m/z found, 434.2 [M+H]⁺.

Step E: 1-(tert-butyl) 7′-methyl 8′-(bromomethyl)dispiro[piperidine-4,2′-chromane-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate

To a solution of 1″-tert-butyl 7′-methyl 8′-methyl-3′H-dispiro[1,3-dioxolane-2,4′-[1]benzopyran2′,4″-piperidine]-1″,7′-dicarboxylate (5.0 g, 11.53 mmol, 1.0 eq) in CCl₄ (50 mL) were added NBS (2.16 g, 12.1 mmol, 1.1 eq) and benzoyl benzenecarboperoxoate (0.56 g, 2.3 mmol, 0.2 eq). The reaction mixture was stirred at 80° C. overnight. After evaporation, the residue was purified by flash column chromatography (ethyl acetate in petroleum ether, from 10% to 30%) to afford 1-(tert-butyl) 7′-methyl 8′-(bromomethyl)dispiro[piperidine-4,2′-chromane-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate (1.24 g, yield 21%) as a yellow solid. LC-MS (ESI): mass calcd. for C₂₃H₃₀BrNO₇, 511.1; m/z found, 512.1 [M+H]⁺.

Step F: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-3′H,7′H-dispiro[piperidine-4,2′-pyrano[2,3-e]isoindole-4′,2″-[1,3]dioxolane]-1-carboxylate

To a solution of 1-(tert-butyl) 7′-methyl 8′-(bromomethyl)dispiro[piperidine-4,2′-chromane-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate (1.24 g, 2.42 mmol, 1.0 eq) in MeCN (8 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (0.47 g, 3.63 mmol, 1.5 eq) and DIEA (1.20 mL, 7.26 mmol, 3.0 eq). The reaction mixture was stirred at 80° C. in a sealed tube for 4 h. After cooled to room temperature, the reaction solution was filtered and the cake was dried to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-3′H,7′H-dispiro[piperidine-4,2′-pyrano[2,3-e]isoindole-4′,2″-[1,3]dioxolane]-1-carboxylate (1.1 g, yield 85.9%) as an off-white solid. LC-MS (ESI): mass calcd. for C₂₇H₃₃N₃O₈, 527.2; m/z found, 528.2 [M+H]⁺.

Step G: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′,7′-dioxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-3′H,7′H-dispiro[piperidine-4,2′-pyrano[2,3-e]isoindole-4′,2″-[1,3]dioxolane]-1-carboxylate (1.1 g, 2.9 mmol, 1.0 eq) in acetone (30 mL) was added aqueous HCl solution (4 N) (1 mL, 4.0 mmol, 1.4 eq) and the reaction mixture was stirred at room temperature for 30 min. The reaction solution was diluted with EA (50 mL), washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′,7′-dioxo-4′,7′,8′,9′-tetrahydro3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (1.0 g, yield 87%) as a gray white solid. LC-MS (ESI): mass calcd. for C₂₅H₂₉N₃O₇, 483.2; m/z found, 484.2 [M+H]⁺.

Step H: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′-hydroxy-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′,7′-dioxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (1.01 g, 2.09 mmol, 1.0 eq) in THF (25.0 mL) was added NaBH₄ (198 mg, 5.22 mmol, 2.5 eq) in portions. The mixture was stirred at 10° C. for 5 h. The reaction solution was diluted with EA (50 mL), quenched with saturated aqueous NH₄C₁ solution (20 mL), and washed with brine (20 mL×2). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0 to 100%) to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′-hydroxy-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (693 mg, yield 68%) as a white solid. LC-MS (ESI): mass calcd. for C₂₅H₃₁N₃O₇, 485.2; m/z found, 486.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (d, J=3.6 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 5.12-5.07 (m, 1H), 4.78 (t, J=6.8 Hz, 1H), 4.46-4.30 (m, 1H), 4.29-4.14 (m, 1H), 3.85-3.65 (m, 2H), 3.28-2.99 (m, 2H), 2.97 (m, 2.84 (m, 1H), 2.63-2.54 (m, 1H), 2.47-2.37 (m, 1H), 2.23-2.12 (m, 1H), 1.99-1.93 (m, 1H), 1.87-1.77 (m, 2H), 1.68-1.51 (m, 3H), 1.40 (s, 9H).

Step I: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-7′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate

To a mixture of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′-hydroxy-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (300 mg, 618 μmol, 1.0 eq) and TEA (625 mg, 861 μL, 6.18 mmol, 10 eq) in DCM (15.0 mL) was added methanesulfonic anhydride (538 mg, 3.09 mmol, 5.0 eq) and the reaction mixture was stirred at 12° C. for 18 h. The reaction solution was diluted with EA (50 mL), washed with brine (10 mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 50% to 100%) to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-7′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (213 mg, yield 74%) as a yellow solid. LC-MS (ESI): mass calcd. for C₂₅H₂₉N₃O₆, 467.2; m/z found, 468.2 [M+H]⁺.

Step J: 3-(7′-oxo-7′,9′-dihydro-8′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-7′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (50.0 mg, 107 μmol, 1.0 eq) in MeCN (4.00 mL) was added HCl-dioxane (4 N) (1.00 mL, 4.00 mmol, 37.4 eq) and the mixture was stirred at 12° C. for 1 h. The reaction solution was concentrated under reduced pressure to obtain 3-(7′-oxo-7′,9′-dihydro-8′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione hydrochloride (20.6 mg, yield 52%) as a powder white solid. LC-MS (ESI): mass calcd. for C₂₀H₂₁N₃O₄, 367.1; m/z found, 368.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.96-8.88 (m, 2H), 7.29 (s, 2H), 6.70 (d, J=10.0 Hz, 1H), 5.94 (d, J=10.0 Hz, 1H), 5.15-5.10 (m, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.30 (d, J=17.2 Hz, 1H), 3.24-3.12 (m, 4H), 2.98-2.88 (m, 1H), 2.65-2.56 (m, 1H), 2.44-2.36 (m, 1H), 2.16-2.05 (m, 2H), 2.03-1.91 (m, 3H).

Compound A2: 3-(7′-oxo-3′,4′,7′,9′-tetrahydro-8′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

Step A: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-7′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (60.0 mg, 128 μmol, 1.0 eq) in EA (5.00 mL) was added 10% Pd/C (13.7 mg) and the mixture was stirred under H₂ atmosphere (1 atm) at 12° C. for 18 h. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (60.0 mg, yield 99%) as an off-white solid. LC-MS (ESI): mass calcd. for C₂₅H₃₁N₃O₆, 469.2; m/z found, 470.2 [M+H]⁺.

Step B: 3-(7′-oxo-3′,4′,7′,9′-tetrahydro-8′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindole]-1-carboxylate (75.0 mg, 160 μmol, 1.0 eq) in MeCN (4.00 mL) was added HCl-dioxane (4 N) (1.00 mL, 4.00 mmol, 25.0 eq) at 12° C. and the mixture was stirred for 1 h. The reaction solution was concentrated under reduced pressure and dried to obtain 3-(7′-oxo-3′,4′,7′,9′-tetrahydro-8′H-spiro[piperidine-4,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione hydrochloride (47.9 mg, yield 81%) as an off-white solid. LC-MS (ESI): mass calcd. for C₂₀H₂₃N₃O₄, 369.2; m/z found, 370.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.93-8.87 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 5.14-5.09 (m, 1H), 4.41 (d, J=17.4 Hz, 1H), 4.24 (d, J=17.4 Hz, 1H), 3.25-3.07 (m, 4H), 2.99-2.90 (m, 1H), 2.90-2.85 (m, 2H), 2.65-2.56 (m, 1H), 2.49-2.40 (m, 1H), 2.03-1.81 (m, 7H).

Compound A3: 3-(7′-oxo-7′,9′-dihydro-8′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione hydrochloride

Step A: 1-benzyl 7′-methyl 8′-methyl-4′-oxo-3′,4′-dihydrospiro[azetidine-3,2′-[1]benzopyran]-1,7′-dicarboxylate

To a solution of methyl 4-acetyl-3-hydroxy-2-methylbenzoate (4.8 g, 23.05 mmol, 1.0 eq) in MeOH (50 mL) were added benzyl 3-oxoazetidine-1-carboxylate (7.10 g, 34.580 mmol, 1.5 eq) and pyrrolidine (2.8 mL, 34.58 mmol, 1.5 eq). The reaction mixture was stirred at 80° C. in a sealed tube overnight. After cooled to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 20%) to afford 1-benzyl 7′-methyl 8′-methyl-4′-oxo-3′,4′-dihydrospiro[azetidine-3,2′-[1]benzopyran]-1,7′-dicarboxylate (2.2 g, yield 24%) as a red oil. LC-MS (ESI): mass calcd. for C₂₂H₂₁NO₆, 395.14; m/z found, 396.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.38-7.31 (m, 5H), 5.12 (s, 2H), 4.19-4.05 (m, 4H), 3.92 (s, 3H), 3.06 (s, 2H), 2.47 (s, 3H).

Step B: 1-benzyl 7′-methyl 8′-methyl-3′H-dispiro[azetidine-3,2′-[1]benzopyran-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate

To a solution of 1-benzyl 7′-methyl 8′-methyl-4′-oxo-3′,4′-dihydrospiro[azetidine-3,2′-[1]benzopyran]-1,7′-dicarboxylate (2.2 g, 5.56 mmol, 0.0 eq) in anhydrous DCM (20 mL) were added 1,2-bis(trimethylsiloxy)ethane (10.9 mL, 44.5 mmol, 8.0 eq) and TMSOTf (0.10 mL, 0.55 mmol, 0.1 eq). The reaction mixture was stirred at 50° C. overnight. After cooled to room temperature, the reaction was diluted with EA (150 mL), washed with saturated aqueous NaHCO₃ solution (30 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 5%) to afford 1-benzyl 7′-methyl 8′-methyl-3′H-dispiro[azetidine-3,2′-[1]benzopyran-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate (1.88 g, yield 77%) as a light yellow solid: LC-MS (ESI): mass calcd. for C₂₄H₂₅NO₇, 439.2; m/z found, 440.3 [M+H]⁺.

Step C: 1-(tert-butyl) 7′-methyl 8′-methyldispiro[azetidine-3,2′-chromane-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate

To a solution of 1-benzyl 7′-methyl 8′-methyl-3′H-dispiro[azetidine-3,2′-[1]benzopyran-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate (2.1 g, 4.78 mmol, 1.0 eq) in 2,2,2-trifluoroethanol (30 mL) was added 10% Pd/C (200 mg). The reaction was stirred under H₂ (1 atm) at 70° C. overnight. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and TEA (0.656 mL, 4.72 mmol, 1.2 eq) and Di-tert-butyldicarbonate (1.3 mL, 5.89 mmol, 1.5 eq) were added to above mixture. The resulting reaction mixture was stirred at room temperature for 2 h. After evaporation, the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10%) to afford 1-tert-butyl 7′-methyl 8′-methyl-3′H-dispiro[azetidine-3,2′-[1]benzopyran-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate (1.5 g, yield 94%) as a light yellow oil. LC-MS (ESI): mass calcd. for C₂₁H₂₇NO₇, 405.2; m/z found, 350.1 [M+H-56]⁺.

Step D: 1-tert-butyl 7′-methyl 8′-(bromomethyl)-3′H-dispiro[azetidine-3,2′-[1]benzopyran-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate

A solution of 1-tert-butyl 7′-methyl 8′-methyl-3′H-dispiro[azetidine-3,2′-[1]benzopyran-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate (1.3 g, 3.20 mmol, 1.0 eq), NBS (0.68 g, 3.84 mmol, 1.2 eq), and BPO (20 mg, 0.059 mmol, 0.2 eq) in CCl₄ (30 mL) was stirred at 80° C. overnight. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30%) to afford 1-tert-butyl 7′-methyl 8′-(bromomethyl)-3′H-dispiro[azetidine-3,2′-[1]benzopyran-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate (1 g, yield 64%) as a colorless oil. LC-MS (ESI): mass calcd. for C₂₁H₂₆BrNO₇, 485.1; m/z found, 430.1 [M+H-56]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 5.03 (s, 2H), 4.26-4.09 (m, 8H), 3.93 (s, 3H), 2.42 (s, 2H), 1.46 (s, 9H).

Step E: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-3′H,7′H-dispiro[azetidine-3,2′-pyrano[2,3-e]isoindole-4′,2′″-[1,3]dioxolane]-1-carboxylate

To a solution of 1-(tert-butyl) 7′-methyl 8′-(bromomethyl)dispiro[azetidine-3,2′-chromane-4′,2″-[1,3]dioxolane]-1,7′-dicarboxylate (1.00 g, 2.06 mmol, 1.0 eq) and 3-aminopiperidine-2,6-dione hydrochloride (510 mg, 3.10 mmol, 1.5 eq) in MeCN (20.0 mL) was added Diisopropylethylamine (801 mg, 1.06 mL, 6.19 mmol, 3.0 eq). The reaction was stirred at 80° C. in a sealed tube for 16 h. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolve with EA (100 mL), washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 90%) to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-3′H,7′H-dispiro[azetidine-3,2′-pyrano[2,3-e]isoindole-4′,2″-[1,3]dioxolane]-1-carboxylate (0.85 g, yield 82%) as a purple solid. LC-MS (ESI): mass calcd. for C₂₅H₂₉N₃O₈, 499.2; m/z found, 444.3 [M+H-56]⁺.

Step F: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′,7′-dioxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-3′H,7′H-dispiro[azetidine-3,2′-pyrano[2,3-e]isoindole-4′,2″-[1,3]dioxolane]-1-carboxylate (200 mg, 400 μmol, 1.0 eq) in DCM (10.0 mL) and was added dropwise HCl-dioxane (4 N) (4.0 mL, 16.0 mmol, 40.0 eq) at room temperature and the reaction mixture was stirred at room temperature for 2 h. After evaporation, the residue was dissolved in DCM (10.0 mL), TEA (111 mg, 1.10 mmol, 3.0 eq) and di-tert-butyl dicarbonate (120 mg, 549 μmol, 1.5 eq) were added to above mixture and the reaction mixture was stirred at room temperature for 2 h. After evaporation, the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 90%) to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′,7′-dioxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (150 mg, yield 90%) as a white solid. LC-MS (ESI): mass calcd. for C₂₃H₂₅N₃O₇, 455.1; m/z found, 454.1 [M−H]—. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 5.18-5.13 (m, 1H), 4.58 (d, J=17.4 Hz, 1H), 4.41 (d, J=17.4 Hz, 1H), 4.23-3.98 (m, 4H), 3.29 (d, J=3.4 Hz, 2H), 2.99-2.88 (m, 1H), 2.63-2.59 (m, 1H), 2.49-2.40 (m, 1H), 2.07-2.01 (m, 1H), 1.39 (s, 9H).

Step G: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′-hydroxy-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′,7′-dioxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (335 mg, 736 μmol, 1.0 eq) in THF (30.0 mL) was added NaBH₄ (27.8 mg, 736 μmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH₄Cl solution (20 mL) and extracted with EtOAc (40 mL×3). The organic layer was washed with brine (40 mL×3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 100%) to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′-hydroxy-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (270 mg, yield 80%) as a white powder. LC-MS (ESI): mass calcd. for C₂₃H₂₇N₃O₇, 457.2; m/z found, 456.1 [M−H]⁻.

Step H: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-7′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-4′-hydroxy-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (63.0 mg, 138 μmol, 1.0 eq) in DCM (20.0 mL) were added TEA (0.36 g, 0.50 mL, 3.6 mmol, 26.0 eq) and methanesulfonic anhydride (240 mg, 1.38 mmol, 10.0 eq). The reaction mixture was stirred at 40° C. for 36 h. After cooled to room temperature, the reaction solution was diluted with EA (50 mL), washed with brine (10 mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (100% EA) to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-7′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (30.0 mg, yield 49%) as a white solid. LC-MS (ESI): mass calcd. for C₂₃H₂₅N₃O₆, 439.2; m/z found, 438.1 [M−H]⁻.

Step I: 3-(7′-oxo-7′,9′-dihydro-8′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione hydrochloride

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-7′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (30.0 mg, 68.3 μmol, 1 eq) in DCM (4.00 mL) was added dropwise HCl-dioxane (4 N) (4.0 mL, 16.0 mmol, 117 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After evaporation, the residue was slurried with MTBE (2 mL), filtered, and dried to afford 3-(7′-oxo-7′,9′-dihydro-8′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione hydrochloride (20.0 mg, yield 78%) as a light yellow solid. LC-MS (ESI): mass calcd. for C₁₈H₁₇N₃O₄, 339.1; m/z found, 340.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.53-9.45 (m, 2H), 7.33 (s, 2H), 6.83 (d, J=10.0 Hz, 1H), 6.36 (d, J=10.0 Hz, 1H), 5.16-5.11 (m, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.40-4.11 (m, 5H), 2.99-2.86 (m, 1H), 2.63-2.58 (m, 1H), 2.46-2.37 (m, 1H), 2.09-1.96 (m, 1H).

Compound A4: 3-(7′-oxo-3′,4′,7′,9′-tetrahydro-8′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione hydrochloride

Step A: tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-8′,9′-dihydro-7′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (60.0 mg, 137 μmol, 1.0 eq) in 2,2,2-Trifluoroethanol was added 10% Pd/C (60.0 mg) and the mixture was stirred under H₂ atmosphere (1 atm) at 55° C. for 18 h. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (100% EA) to afford tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (40.0 mg, yield 66%) as a white powder. LC-MS (ESI): mass calcd. for C₂₃H₂₇N₃O₆, 441.2; m/z found, 440.1 [M−H]⁻.

Step B: 3-(7′-oxo-3′,4′,7′,9′-tetrahydro-8′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

To a solution of tert-butyl 8′-(2,6-dioxopiperidin-3-yl)-7′-oxo-4′,7′,8′,9′-tetrahydro-3′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindole]-1-carboxylate (30.0 mg, 68.0 μmol, 1.0 eq) in MeCN (10.0 mL) was added dropwise HCl-dioxane (4 N) (2.0 mL, 8.0 mmol, 88 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and dried to afford 3-(7′-oxo-3′,4′,7′,9′-tetrahydro-8′H-spiro[azetidine-3,2′-pyrano[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione (15.0 mg, yield 64%) as a light yellow solid. LC-MS (ESI): mass calcd. for C₁₈H₁₉N₃O₄, 341.1; m/z found, 342.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 9.08-8.93 (m, 2H), 7.30-7.25 (m, 2H), 5.15-5.10 (m, 1H), 4.37 (d, J=17.2 Hz, 1H), 4.25 (d, J=17.2 Hz, 1H), 4.13-4.11 (m, 4H), 3.00-2.85 (m, 3H), 2.62-2.57 (m, 1H), 2.42-2.38 (m, 1H), 2.27-2.16 (m, 2H), 2.03-1.96 (m, 1H).

Compound B1: (S)-3-(7′-oxo-7′,9′-dihydro-2′H,8′H-spiro[piperidine-4,3′-[1,4]dioxino[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

Step 1: 5-bromo-4-iodoisobenzofuran-1(3H)-one

To a solution of 1 (10 g, 1.0 equiv) in CF₃SO₃H (50 mL) was added NIS (1.5 equiv) potionwise at 0° C. The reaction was stirred at rt overnight. Then the reaction mixture was poured into ice-water, and gray solid was precipitated, which is collected by filtration and washed with water. The filter cake was dissolved in DCM, washed with aquous Na₂S₂O₃, brine, dried over Na₂SO₄ and concentrated to afford a crude product. Further purification by silica gel column chromatography to give the desired product as a white solid 6.55 g.

Step 2: 5-bromo-4-hydroxyisobenzofuran-1(3H)-one

A mixture of 2 (6.55 g, 1.0 equiv), Cu₂O (553 mg, 0.2 equiv) and NaOH (3.86 g, 5.0 equiv) in DMA/H₂O (40 mL/20 mL) was degassed with N2 and stirred at 80° C. under N2 atmosphere overnight. Then the reaction mixture was cooled to rt, neutralized with 2N aq. HCl, extracted with EA, washed with brine, dried over Na₂SO₄, and concentrated to give the crude product, which is purified by silica gel column chromatography to provide compound 3 as a yellow solid 3.67 g (yield=83%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 5.34 (s, 2H).

Step 3: tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-4-hydroxypiperidine-1-carboxylate

To a solution of 3 (500 mg, 1.0 equiv) and 4 (931 mg, 2.0 equiv) in DMF (15 mL) was added DIPEA (3.8 mL, 10.0 equiv), which was stirred at 100° C. for 2 days. Then the reaction mixture was cooled to rt, diluted with EA, washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by silica gel column chromatography to give compound 5 as a brown oil 1.03 g, yield>95%. LC-MS: 344.01 [M+H]⁺.

Step 4: tert-butyl 7′-oxo-7′,9′-dihydro-2′H-spiro[piperidine-4,3′-[1,4]dioxino[2,3-e]isobenzofuran]-1-carboxylate

A mixture of 5 (870 mg, 1.0 equiv), Pd(OAc)₂ (51 mg, 0.2 equiv), 2-[Di(tert-butyl)phosphino]-1,1′-binaphthyl (135 mg, 0.3 equiv) and K₃PO₄ (719 mg, 3.0 equiv) in Toluene (12 mL) was degassed with N2 and then was stirred at 110° C. under N2 atmosphere overnight. The reaction mixture was filtered through celite, and the filtration was concentrated under reduced pressure. The result mixture was purified by silica gel column chromatography to give compound 6 as a white solid 540 mg, yield=73%. LC-MS: 362.21 [M+H]⁺.

Step 5: 1′-(tert-butoxycarbonyl)-5-(hydroxymethyl)-3H-spiro[benzo[b][1,4]dioxine-2,4′-piperidine]-6-carboxylic acid

To a solution of 6 (298 mg, 1.0 equiv) in THF/MeOH/H₂O (5 mL/5 mL/3 mL) was added NaOH (330 mg, 10 equiv). The reaction was stirred at rt for 8 h, then concentrated to remove most of the THF/MeOH. The residue was diluted with 4 mL water, followed by neutralization with 2 N aq HCl to PH 4-6, then extracted with DCM. Then combined organic layer was washed with brine, dried with Na₂SO₄, and concentrated to give the desired product 7 as a white solid 284 mg, which was directly used in the next step.

Step 6: 1′-(tert-butoxycarbonyl)-5-formyl-3H-spiro[benzo[b][1,4]dioxine-2,4′-piperidine]-6-carboxylic acid

To a solution of 7 (284 mg, 1.0 equiv) in DCM (15 mL) was added DMP (475 mg, 1.5 equiv) potionwise at 0° C. 5 h Later, the reaction mixture was washed with brine, dried over Na₂SO₄, and concentrated to give the crude product 8, which was directly used in the next step.

Step 7: (S)-3-(7′-oxo-7′,9′-dihydro-2′H,8′H-spiro[piperidine-4,3′-[1,4]dioxino[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

To a suspension of 9 (46 mg, 2.0 equiv) in DMF (4 mL) was added DIPEA (49 uL, 2.0 equiv), which was stirred at rt for 10 min, followed by addition of AcOH (423 uL, 10.0 equiv). 10 min Later, crude compound 8 (53 mg, 1.0 equiv) was added, and the resulted mixture was stirred at rt for 15 min. Subsequently, NaBH(OAc)₃ (119 mg, 4.0 equiv) was added, and the reaction mixture was stirred overnight. Then the reaction mixture was heated to 50° C. and kept stirring for 12 h. Next, the reaction mixture was concentrated to remove AcOH, and purified by pre-HPLC to give a light purple solid 33 mg. LC-MS: 472.17 [M+H]⁺. Finally, Compound B1 was obtained after treatment with TFA. LC-MS: 372.17 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 7.37 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.51-4.35 (m, 2H), 4.17 (d, J=2.0 Hz, 2H), 3.42-3.35 (m, 4H), 2.96-2.84 (m, 1H), 2.82-2.72 (m, 1H), 2.56-2.42 (m, 1H), 2.21-2.06 (m, 3H), 2.01-1.88 (m, 2H). ¹³C NMR (101 MHz, MeOD) δ 174.64, 172.26, 171.11, 145.75, 138.95, 131.85, 126.85, 119.67, 118.32, 71.56, 53.74, 46.27, 40.52, 40.49, 32.37, 28.91, 28.85, 24.05.

Compound B2: 3-(7′-oxo-7′,9′-dihydro-2′H,8′H-spiro[azetidine-3,3′-[1,4]dioxino[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

Step 1 and Step 2 are Same as in the Synthesis of Compound B1

Step 3: tert-butyl 3-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3-hydroxyazetidine-1-carboxylate

To a solution of 3 (1 equiv) in DMF (c1=0.2 mol/L). DIPEA (10 equiv) and epoxide (1.5 equiv) was added into the flask. The reaction was heated to 100° C. The reaction was detected by UPLC-MS. Concentrated directly and purify by silica gel chromatography to give 4 (96% yield).

Step 4: tert-butyl 7′-oxo-7′,9′-dihydro-2′H-spiro[azetidine-3,3′-[1,4]dioxino[2,3-e]isobenzofuran]-1-carboxylate

To a solution of 4 (1 equiv) in toluene (c1=0.1 mol/L). Pd(OAc)₂ (0.1 equiv), Ligand (0.11 equiv) and K3PO4 (3 equiv) was added into the flask under N2. The reaction was heated to 140° C. under N2 for 4h. TLC showed reaction was completed. Quenched with saturated NaHCO₃, The organic phase was separated. EA was added to the mixture, the resulting mixture was washed by brine. The combined organic phase was dried by MgSO4. Filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (90% yield).

Step 5: tert-butyl 6′-(diethylcarbamoyl)-5′-(hydroxymethyl)-3′H-spiro[azetidine-3,2′-benzo[b][1,4]dioxine]-1-carboxylate

To a suspension of aluminium trichloride (1.3 equiv.) in DCM (c_AlCl3=0.5 mol/L), diethylamine (2.5 equiv.) was added at 0° C. and the mixture was stirred for additional 30 min. A solution of 5 (1.0 eq.) in DCM (c₁₀=1 mol/L), was added and the resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was poured into 300 mL saturated aqueous NH₄Cl. The organic layers were combined and washed with 200 mL saturated aqueous NH₄Cl, dried over anhydrous MgSO4, and concentrated in vacuum. The obtained residue was purified by silica gel chromatography to give 6 (85% yield).

Step 6: tert-butyl 6′-(diethylcarbamoyl)-5′-formyl-3′H-spiro[azetidine-3,2′-benzo[b][1,4]dioxine]-1-carboxylate

To a solution of 6 (1 equiv) in DCM (c₁=0.1 mol/L). DMP (1.1 equiv) was added into the flask at room temperature. Reaction was detected by UPLM-MS. Quenched with saturated NaHCO₃. EA was added to the mixture, The organic phase was separated. the resulting mixture was washed by brine. The combined organic phase was dried by MgSO₄. Filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 7 (90%).

Step 7 to Step 9: 3-(7′-oxo-7′,9′-dihydro-2′H,8′H-spiro[azetidine-3,3′-[1,4]dioxino[2,3-e]isoindol]-8′-yl)piperidine-2,6-dione

To a solution of 7 (1 equiv) in MeOH (c₁=0.2 mol/L). NaOAc (1.0 equiv) and (S)-3-Amino-piperidine-2,6-dione hydrochloride NaOAc (1.0 equiv), NaCNBH₃ (1.0 equiv) was added into the flask at room temperature. Reaction was detected by UPLM-MS (about 3 hours). Remove solvent under vacuum. The residue was dissolved in toluene. HOAc (15 equiv) was added into flask. The reaction was heated at 110° C. and stirred for 12 hour. 9 was purified by HPLC (TFA condition). 1.0 equiv TFA was added and concentrated 9 to get de-Boc Compound B2 (70% yield in three steps).

Compound B3. (S)-3-(5′-fluoro-6′-oxo-6′,8′-dihydro-3′H,7′H-spiro[piperidine-4,2′-[1,4]dioxino[2,3-f]isoindol]-7′-yl)piperidine-2,6-dione

Step 1: 5-bromo-7-fluoro-6-methoxyisobenzofuran-1(3H)-one

To a 100 mL round-bottom flask, Eaton's reagent (30 mL), compound 4-bromo-3-methoxybenzoic acid (1, 5 gm, 21.83 mmol) and Paraformaldehyde (1.96 g, 65 mmol) were added in an ice bath. The resulting mixture was stirred and heated to 50° C. for overnight. After being cooled to room temperature, the reaction mixture was poured into ice-cold water (100 mL) and extracted with dichloromethane (3×60 mL). The combined organic layer was washed with water, saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo, followed purification by silica gel chromatography to give compound 2 in 70% yield.

Step 2: 5-bromo-7-fluoro-6-hydroxyisobenzofuran-1(3H)-one

Over a solution of 5-bromo-6-methoxyisobenzofuran-1(3H)-one (2 g, 8.29 mmol) in dry CH₂Cl₂ (36 mL) under N2 atmosphere at −20° C. was added boron tribromide (16.6 mL 1M DCM, 16.6 mmol). Then the solution was stirred at rt for overnight. Next, the reaction was quenched adding a saturated solution of NaHCO₃ (15 mL). The aqueous phase was extracted with CH₂Cl₂ (3×30 mL), and the organic phases were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The reaction crude was purified by flash chromatography (20% EtOAc/hexane) affording 3 as a white solid (1.32 g, 70% yield).

Step 3: benzyl 4-(((6-bromo-4-fluoro-3-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)methyl)-4-hydroxypiperidine-1-carboxylate

To a solution of 3 (1 eq.) in DMF (5 mL/mmol), 10 eq. of DIPEA and 1.5 eq. of epoxide were added into the flask. The reaction was heated to 100° C. The reaction was monitored by UPLC-MS. Concentrated directly and purify by silica gel chromatography to give 4 (96% yield). LC/MS (ESI) m/z: 494.09 (M+H)

Step 4: benzyl 5′-fluoro-6′-oxo-6′,8′-dihydro-3′H-spiro[piperidine-4,2′-[1,4]dioxino[2,3-f]isobenzofuran]-1-carboxylate

To a solution of 4 (1 eq.) in toluene (5 mL/mmol), Pd(OAc)₂ (0.1 eq.), [1,1′-binaphthalen]-2-yldi-tert-butylphosphane (0.1 eq.) and K₃PO₄ (3 eq.) was added into the flask under N2. The reaction was heated to 140° C. under N2 for 4h. TLC showed reaction was completed. Quenched with saturated NaHCO₃, the organic phase was separated. Ethyl acetate was added to the mixture, the resulting mixture was washed by brine. The combined organic phase was dried by MgSO4. Filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 5 in (70% yield). LC/MS (ESI) m/z: 414.12 (M+H)

Step 5: 1′-((benzyloxy)carbonyl)-5-fluoro-7-(hydroxymethyl)-3H-spiro[benzo[b][1,4]dioxine-2,4′-piperidine]-6-carboxylic acid

To a solution of (S)-2-((benzyloxy)methyl)-2,3-dihydro-[1,4]dioxino[2,3-f]isobenzofuran-6(8H)-one (5, eq.) in tetrahydrofuran and water (1:1) was added sodium hydroxide (5 eq.). The mixture was stirred at 20° C. for 16 h. TLC (ethyl acetate:hexane=1:1) showed reaction was complete. The mixture was adjusted to pH=5 with aq. hydrochloric acid (1 M) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine (10×2 mL) and dried over sodium sulfate. The crude material (6) was not further purified and used as crude for the next steps. LC/MS (ESI) m/z: 432.12 (M+H)

Step 6: benzyl 5′-fluoro-8′-hydroxy-6′-oxo-6′,8′-dihydro-3′H-spiro[piperidine-4,2′-[1,4]dioxino[2,3-f]isobenzofuran]-1-carboxylate

To a solution of 6 (1.0 eq) in DCM (10 mL) was added DMP (1.2 eq.) at 0° C. and stirred it for 30 mins. TLC (ethyl acetate:hexane=1:1) showed reaction was complete. The reaction mixture was then diluted with DCM, washed with brine, dried over and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 7 in (70% yield). LC/MS (ESI) m/z: 430.12 (M+H).

Step 7&8: benzyl (S)-7′-(2,6-dioxopiperidin-3-yl)-5′-fluoro-6′-oxo-7′,8′-dihydro-3′H,6′H-spiro[piperidine-4,2′-[1,4]dioxino[2,3-f]isoindole]-1-carboxylate

A mixture of 7 (1.0 eq, (S)-3-aminopiperidine-2,6-dione (1.5 eq) and NaOAc (3 eq) was dissolved in methanol:DCM (1:1), and kept stirring at rt for 20 min. Then NaBH₃CN (2.0 eq) was added. 2 h Later, UPLC-MS showed the starting material 7 was completely conversion and a new main peak 8 with desired MS formed. LC/MS (ESI) m/z: 542.16 (M+H). The crude compound 8 (1.0 eq., 440 mg) was dissolved in CH₃CN (4 mL) and was treated with HOAc (15 eq.). The reaction was heated at 60° C. and stirred for 2h. Next, the reaction mixture was quenched with water and concentrated under reduced pressure to give a residue which was purified by pre-HPLC to give 8 in (70% yield).

¹H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.47-7.32 (m, 5H), 6.81 (s, 1H), 5.18 (s, 3H), 4.48-4.20 (m, 2H), 4.02 (s, 2H), 3.33 (t, J=12.5 Hz, 2H), 3.05-2.75 (m, 4H), 2.45-2.15 (m, 2H), 1.85 (s, 2H), 1.67 (s, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 171.47, 169.73, 166.88, 155.37, 149.27, 147.61, 146.68, 136.42, 134.67, 131.63, 131.50, 128.56 (two peaks), 128.19, 127.99 (two peaks), 112.12, 112.02, 107.52, 72.74, 70.78, 67.52, 51.79, 46.71, 39.06, 31.44, 23.24. LC/MS (ESI) m/z: 523.15 (M+H).

Step 9: (S)-3-(5′-fluoro-6′-oxo-6′,8′-dihydro-3′H,7′H-spiro[piperidine-4,2′-[1,4]dioxino[2,3-f]isoindol]-7′-yl)piperidine-2,6-dione

To a stirred solution of compound 8 in methanol at room temperature Pd—C was added and the reaction was stirred for another 1 h. UPLC mass chromatography showed the completion of the reaction. Catalyst was filtered out and washed with MeOH. Organic solvent was evaporated, and Compound B3 was obtained. LC/MS (ESI) m/z: 390.12 (M+H).

Compound B4. (S)-3-(6′-oxo-6′,8′-dihydro-3′H,7′H-spiro[azetidine-3,2′-[1,4]dioxino[2,3-f]isoindol]-7′-yl)piperidine-2,6-dione

Step 1: 5-bromo-6-methoxyisobenzofuran-1(3H)-one

To a 100 mL round-bottom flask, Eaton's reagent (30 mL), compound 4-bromo-3-methoxybenzoic acid (1, 5 gm, 21.83 mmol) and Paraformaldehyde (1.96 g, 65 mmol) were added in an ice bath. The resulting mixture was stirred and heated to 50° C. for overnight. After being cooled to room temperature, the reaction mixture was poured into ice-cold water (100 mL) and extracted with dichloromethane (3×60 mL). The combined organic layer was washed with water, saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo, followed purification by silica gel chromatography to give compound 2 in 70% yield.

Step 2: 5-bromo-6-hydroxyisobenzofuran-1(3H)-one

Over a solution of 5-bromo-6-methoxyisobenzofuran-1(3H)-one (2 g, 8.29 mmol) in dry CH₂Cl₂ (36 mL) under N2 atmosphere at −20° C. was added boron tribromide (16.6 mL 1M DCM, 16.6 mmol). Then the solution was stirred at rt for overnight. Next, the reaction was quenched adding a saturated solution of NaHCO₃ (15 mL). The aqueous phase was extracted with CH₂Cl₂ (3×30 mL), and the organic phases were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The reaction crude was purified by flash chromatography (20% EtOAc/hexane) affording 3 as a white solid (1.32 g, 70% yield).

Step 3: tert-butyl 3-(((6-bromo-3-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)methyl)-3-hydroxyazetidine-1-carboxylate

To a solution of 3 (1 eq.) in DMF (5 mL/mmol), 10 eq. of DIPEA and 1.5 eq. of epoxide were added into the flask. The reaction was heated to 100° C. The reaction was monitored by UPLC-MS. Concentrated directly and purify by silica gel chromatography to give 4 (96% yield). LC/MS (ESI) m/z: 414.12 (M+H)

Step 4: tert-butyl 6′-oxo-6′,8′-dihydro-3′H-spiro[azetidine-3,2′-[1,4]dioxino[2,3-f]isobenzofuran]-1-carboxylate

To a solution of 4 (1 eq.) in toluene (5 mL/mmol), Pd(OAc)₂ (0.1 eq.), [1,1′-binaphthalen]-2-yldi-tert-butylphosphane (0.1 eq.) and K₃PO₄ (3 eq.) was added into the flask under N2. The reaction was heated to 140° C. under N2 for 4h. TLC showed reaction was completed. Quenched with saturated NaHCO₃, the organic phase was separated. Ethyl acetate was added to the mixture, the resulting mixture was washed by brine. The combined organic phase was dried by MgSO₄. Filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 5 in (70% yield). LC/MS (ESI) m/z: 334.15 (M+H)

Step 5: 1-(tert-butoxycarbonyl)-7′-(hydroxymethyl)-3′H-spiro[azetidine-3,2′-benzo[b][1,4]dioxine]-6′-carboxylic acid

To a solution of (S)-2-((benzyloxy)methyl)-2,3-dihydro-[1,4]dioxino[2,3-f]isobenzofuran-6(8H)-one (5, 1 eq.) in tetrahydrofuran and water (1:1) was added sodium hydroxide (5 eq.). The mixture was stirred at 20° C. for 16 h. TLC (ethyl acetate:hexane=1:1) showed reaction was complete. The mixture was adjusted to pH=5 with aq. hydrochloric acid (1 M) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine (10×2 mL) and dried over sodium sulfate. The crude material (6) was not further purified and used as crude for the next steps. LC/MS (ESI) m/z: 352.12 (M+H)

Step 6: tert-butyl 8′-hydroxy-6′-oxo-6′,8′-dihydro-3′H-spiro[azetidine-3,2′-[1,4]dioxino[2,3-f]isobenzofuran]-1-carboxylate

To a solution of 6 (1.0 eq) in DCM (10 mL) was added DMP (1.2 eq.) at 0° C. and stirred it for 30 mins. TLC (ethyl acetate:hexane=1:1) showed reaction was complete. The reaction mixture was then diluted with DCM, washed with brine, dried over and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 7 in (70% yield). LC/MS (ESI) m/z: 350.15 (M+H).

Step 7&8: tert-butyl (S)-7′-(2,6-dioxopiperidin-3-yl)-6′-oxo-7′,8′-dihydro-3′H,6′H-spiro[azetidine-3,2′-[1,4]dioxino[2,3-f]isoindole]-1-carboxylate

A mixture of 7 (1.0 eq), (S)-3-aminopiperidine-2,6-dione (1.5 e eq) and NaOAc (3.0 eq) was dissolved in methanol:DCM (1:1), and kept stirring at rt for 20 min. Then NaBH₃CN (2.0 eq.) was added. 2 h Later, UPLC-MS showed the starting material 7 was completely conversion and a new main peak 8 with desired MS formed. LC/MS (ESI) m/z: 462.16 (M+H). The crude compound 8 (1.0 eq) was dissolved in CH₃CN (4 mL) and was treated with HOAc (15 eq.). The reaction was heated at 60° C. and stirred for 2h. Next, the reaction mixture was quenched with water and concentrated under reduced pressure to give a residue which was purified by pre-HPLC to give I-39 in (70% yield). ¹H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.43 (s, 1H), 7.01 (d, J=0.8 Hz, 1H), 5.20 (dd, J=13.2, 5.2 Hz, 1H), 4.45-4.21 (m, 4H), 4.14-3.94 (m, 5H), 3.07-2.71 (m, 2H), 2.52-2.16 (m, 2H), 1.57 (s, 9H).

LC/MS (ESI) m/z: 444.15 (M+H).

Step 9: (S)-3-(6′-oxo-6′,8′-dihydro-3′H,7′H-spiro[azetidine-3,2′-[1,4]dioxino[2,3-f]isoindol]-7′-yl)piperidine-2,6-dione

To a stirred solution of compound 8 in DCM at room temperature TFA was added and the reaction was stirred for another 1 h. UPLC mass chromatography showed the completion of the reaction. Organic solvent was evaporated, and Compound B4 was obtained. LC/MS (ESI) m/z: 344.12 (M+H)

Compound B5. 7′-(2,6-dioxopiperidin-3-yl)-7′-hydro-3′H,6′H-spiro[azetidine-3,2′-[1,4]dioxino[2,3-f]isoindole]-6′,8′-dione

Step 1

Compound 1 (1.0 eq) and 2 (1.05 eq) DIPEA (3.0 eq) were dissolved in DMF (10 X). The reaction was stirred at 90° C. for 4 h. The reaction was cooled to rt, and partitioned with EtOAc and H2O. The organic layer was dried, concentrated and purified with Combiflash with hexane and EtOAc to give 3 in 70% yield. LC/MS (ESI) m/z: 412.18 (M+H).

Step 2

PPh3 (1.3 eq) and DIAD 1.3 eq) were dissolved in THF (10×) and stirred at rt for 10 min. Compound 3 (1.0 eq) was added and the mixture was stirred at rt overnight. The reaction was concentrated and purified with Combiflash using Hexane and EtOAc to give 4 in 85%. LC/MS (ESI) m/z: 394.15 (M+H).

Step 3 and step 4

Compound 4 (1.0 eq) and NaOH (10 N, 20.0 eq) were dissolved in MeOH (5×) and THF (5×). The mixture was stirred at rt overnight. The pH was adjusted to pH 1, and EtOAc (20×) was added. The organic layer was separated, dried and concentrated. The result residue was added with Ac2O (20×) and stirred at 80° C. for 2 h. The reaction was cooled and directly purified with Combiflash using Hexane ane EtOAc to give 6 in 70% for two steps. LC/MS (ESI) m/z: 5: 366.20 (M+H); 6: 348.26 (M+H).

Step 5 and 6

Compound 6 (1.0 eq) and 7 (1.1 eq) and DIPEA (4.0 eq) were dissolved in acetonitrile (15×). The reaction was refluxed overnight. The organic solvent was removed and the residue was purified with Combiflash using DCM and MeOH. The result compound 8 was dissolved in dioxane and HCL (4N in dioxane) was added at 0° C. The deprotection was finished in around 6 h. The suspension was filtered and dried to give Compound B5 as white powder in 60% for two steps. LC/MS (ESI) m/z: 8: 458.24 (M+H); 9: 358.19 (M+H).

Biological Activity of Cereblon Ligands

For Compound A1 to A4

In Vitro Assay: IC₅₀ Measurements for Binding to CRBN/DDB1

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 were analyzed using XLfit using four parameters dose response curve to determine IC₅₀s.

TABLE E1
CRBN binding IC50
             CRBN Binding
Compound No. IC50 (μM)
A1           1.1
A2           0.62
A3           1.3
A4           5.2

For Compound B1 to B5

Cereblon Binding Assay

The binding to cereblon (CRBN) was determined using the Cereblon Binding Kit (Cisbio, #64BDCRBNPEG) following the manufacturer's instruction. Briefly, serially diluted compounds were incubated with GST-tagged wild-type human CRBN protein, XL665-labelled Thalidomide and Europium Cryptate labelled GST antibody at room temperature for about 3 hours. Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) measurements were acquired on a CALRIOstar plate reader with MARS data analysis software (BMG Labtech), with the following settings: 665/10 nm and 620/10 nm emission, 60 s delay and 400 s integration. The TR-FRET ratio was taken as the 665/620 nm intensity ratio. The readings were normalized to the control (0.5%) and the IC₅₀ was calculated by nonlinear regression (four parameters sigmoid fitted with variable slope) analysis using the GraphPad Prism 8 software.

TABLE E2
Example CRBN TR-FRET IC50 (μM)
B1      0.33
B2      0.259
B3      1.73
B4      4.33
B5      4.63

II. Bifunctional Degrader

Synthesis and Characterization

1. ER Degrader

Compound THP-B383. (S)-3-(5′-fluoro-1-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-6′-oxo-6′,8′-dihydro-3′H,7′H-spiro[piperidine-4,2′-[1,4]dioxino[2,3-f]isoindol]-7′-yl)piperidine-2,6-dione

To a solution of B3 (1.2 equiv) in Methanol:DCM (4:1) was added NaOAc (2 equiv) and the mixture was stirred at room temperature for 5 mins. The aldehyde 9 (1 equiv) in MeOH: DCM (4:1) was then added to the reaction mixture and stirred for another 10 mins. Sodiumcyanoborohydride (2 equiv) and Acetic acis was then added to the reaction sequentially and stirred for another 15 minutes. UPLC chromatography showed the completion of the reaction, and the product was purified using preparative HPLC. LC/MS (ESI) m/z: 785.41 (M+H).

Compound THP-B394. (S)-3-(1-((7-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-6′-oxo-6′,8′-dihydro-3′H,7′H-spiro[azetidine-3,2′-[1,4]dioxino[2,3-f]isoindol]-7′-yl)piperidine-2,6-dione

To a solution of B4 (1.2 equiv) in Methanol:DCM (4:1) was added NaOAc (2 equiv) and the mixture was stirred at room temperature for 5 mins. The aldehyde 9 (1 equiv) in MeOH: DCM (4:1) was then added to the reaction mixture and stirred for another 10 mins. Sodiumcyanoborohydride (2 equiv) and Acetic acid was then added to the reaction sequentially and stirred for another 15 minutes. UPLC chromatography showed the completion of the reaction, and the product THP-B394 was purified using preparative HPLC. LC/MS (ESI) m/z: 779.42 (M+H).

The compounds in the table below are synthesized in a similar manner as compounds THP-B383 and THP-B394 via reductive animation.

TABLE E3
Compound
No.	Structure	[M + H]+
THP-B367		739.25
THP-B368		779.3
THP-B369		766.99
THP-B371		807.30
THP-B372		823.40
THP-B373		823.31
THP-B374		839.32
THP-B376		779.35
THP-B377		811.28
THP-B384		825.39
THP-B385		793.35
THP-B386		809.29
THP-B395		767.37

Biological Activity of Degraders

In-cell western blot analysis. a. seed cells in black-sided/clear bottom 96- or 384-well plates at 40,000 or 10,000 cells/well, overnight; b. add diluted compounds (final 0.5% DMSO), 16 hours. 16 h later, remove medium, add 100 μL or 25 μL of 3.7-4.0% formaldehyde (PBS:FA=9:1), RT 20 min, no shaking; c. wash with PBS, and permeabilized with 100 μL or 25 μL/well of 1×PBS+0.1% Triton X-100 10 minutes; d. block with 100 μL or 25 μL Licor blocking buffer (Li-Cor), RT 1h, moderate shaking; d. Add 100 μL or 25 μL of anti-ER (cs-8644, 1:500-1,000)+GAPDH (Millipore MAB374, 1:1000) in Block+0.05% Tween 20. RT 2h, gentle shaking. Negative control: cells plus secondary antibodies (no primary antibodies); e. wash×4 with PBS+0.05-0.1% Tween 20, gentel shaking; f. anti-rabbit-680 and anti-mouse-800 (both 1:1000 in LiCor block+0.05% Tween20, RT 1h, gentle shaking, no light. LI-COR: 0.2% to reduce background; g. wash×4 with PBS+0.05% Tween 20, gental shaking; h. add 100 μL or 25 μL of PBS to each well and read on CLX plate reader. The relative ER percentage in treated cells were obtained by comparing the values of treated wells to those in untreated and DMSO-treated wells as 100%.

Western Blot Analysis. Western blot analysis was performed essentially as described previously. The cells treated with indicated compounds were lysed in Radioimmunoprecipitation Assay Protein Lysis and Extraction Buffer (25 mmol/L Tris.HCl, pH 7.6, 150 mmol/L NaCl, 1% Nonidet P-40, 1% sodium deoxycholate, and 0.1% sodium dodecyl sulfate) containing proteinase inhibitor cocktail (Roche Diagnostics, Mannheim, Germany). Equal amounts of total protein were electrophoresed through 10% SDS-polyacrylamide gels after determination of protein concentration by BCA assay (Fisher Scientific, Pittsburgh, PA). The separated protein bands were transferred onto PVDF membranes (GE Healthcare Life Sciences, Marlborough, MA) and blotted against different antibodies, as indicated. The blots were scanned, and the band intensities were quantified using GelQuant.NET software provided by biochemlabsolutions.com. The relative mean intensity of target proteins was expressed after normalization to the intensity of glyceraldehyde-3-phosphate dehydrogenase bands.

	TABLE E4
		ICW	Cell growth Inhibition in
	Compound No.	DC50 (nM)	T47D cell line IC50 (μM)
	THP-B367	C	B
	THP-B368	C	B
	THP-B369	B	A
	THP-B371	A	A
	THP-B372	B	B
	THP-B373	A	A
	THP-B374	A	A
	THP-B376	B	A
	THP-B377	B	A
	THP-B383	C	C
	THP-B384	C	B
	THP-B385	C	B
	THP-B386	C	B
	THP-B394		B
	THP-B395		B
	DC50: “A”: <10 nM; “B”: 10-100 nM; “C”: >100 nM.
	IC50: “A”: <1 nM; “B”: 1-10 nM; “C”: >10 nM.

INCORPORATION BY REFERENCE

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

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.

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

1. A compound of Formula II:

2. A conjugate of Formula II:

3. The conjugate of claim 2, wherein the conjugate of Formula II is a conjugate of Formula II-1

4. (canceled)

5. The conjugate of claim 2, wherein the conjugate of Formula II is a conjugate of Formula II-2

6. (canceled)

7. The conjugate of claim 5, wherein B1 is N or CRB1, wherein RB1 is hydrogen or halogen.

8.-9. (canceled)

10. The conjugate of claim 2, wherein Ring A attached to -L-T is

11. The conjugate of claim 10, wherein Ring AI is 5- to 8-membered heterocycle.

12. The conjugate of claim 10, wherein Ring AI is 5- to 8-membered heterocycle comprising one oxygen atom, 5- to 8-membered heterocycle comprising one oxygen atom and one double bond, 5- to 8-membered heterocycle comprising two oxygen atoms, 5- to 8-membered heterocycle comprising one nitrogen atom, 5- to 8-membered heterocycle comprising two nitrogen atoms, or 5- to 8-membered heterocycle comprising one nitrogen atom and one oxygen atom.

13. The conjugate of claim 10, wherein each A1 is independently —C(RA1)2—, —NRA1′—, or —O—, and each A2 is independently —C(RA2)2—, —NRA2′—, or —O—.

14.-16. (canceled)

17. The conjugate of claim 10, wherein Ring A attached to -L-T is

18.-19. (canceled)

20. The conjugate of claim 10, wherein the conjugate of Formula II-1 is a conjugate of Formula II-1-b-i, II-1i-b-ii, II-1-b-iii, II-1-b-iv, II-2-b-i, II-2-b-ii, II-2-b-iii, or II-2-b-iv:

21. (canceled)

22. The conjugate of claim 20, wherein B4 is CRB4 and B5 is CRB5, wherein RB4 and RB5 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.

23.-24. (canceled)

25. The conjugate of claim 10, wherein the conjugate of Formula II-1 is a conjugate of Formula II-1-b-v, II-1-b-vi, II-1-b-vii, II-1-b-viii, II-2-b-v, II-2-b-vi, II-2-b-vii, or II-2-b-viii:

26. (canceled)

27. The conjugate of claim 25, wherein B2 is CRB2 and B5 is CRB5, wherein RB2 and RB5 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.

28.-31. (canceled)

32. A compound selected from the compounds in Tables 1 and 2 or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising the conjugate of claim 2, and a pharmaceutically acceptable excipient.

32.-34. (canceled)

35. A method of degrading a protein in a subject or biological sample comprising administering the conjugate of claim 2 to the subject or contacting the biological sample with the conjugate of claim 2.

36.-37. (canceled)

38. The method of claim 35, wherein the protein is an estrogen receptor, a STAT3 protein, an androgen receptor, a SMARCA2 protein, a SMARCA4 protein, a BRD4 protein, a BRD9 protein, or a CBP/p300 protein.

39. A method of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering the compound of claim 1 to the subject or contacting the biological sample with the compound of claim 1.

40. The conjugate of claim 2, wherein T is a ligand for an estrogen receptor, a STAT3 protein, an androgen receptor, a SMARCA2 protein, a SMARCA4 protein, a BRD4 protein, a BRD9 protein, or a CBP/p300 protein.