CEREBLON LIGANDS AND USES THEREOF RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/417,198, filed October 18, 2022, the contents of which are incorporated herein by reference in their entireties. BACKGROUND [0002] Cereblon (CRBN), a component of the DDBl-CUL4a-Rocl ubiquitin ligase complex, is a molecular target of immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide. Inhibition of CRBN ubiquitination by these agents may allow CRBN to accumulate, leading to the increased cullin-4 RING E3 ligase-mediated degradation of target proteins. [0003] The discovery process of CRBN type E3 ligase ligand is related to the study of thalidomide's mechanism of action. In 2010, while studying the toxicity of thalidomide, scientists discovered that cereblon is a binding protein of thalidomide (Science 2010, 327, 1345). Cerebellar protein is part of the E3 ubiquitin ligase protein complex, which acts as a substrate receptor to select ubiquitinated proteins. The study shows that thalidomide-cerebellar protein binding in vivo may be the cause of thalidomide teratogenicity. Subsequent studies found that the compound and related structures can be used as anti-inflammatory agents, anti- angiogenic agents and anti-cancer agents. Lenalidomide and pomalidomide obtained by further modification of the structure of thalidomide have greatly improved their safety and significantly reduced their teratogenic effects. Lenalidomide has been approved by the FDA in 2006 for marketing. Two groundbreaking papers published in Science in 2014 pointed out that lenalidomide works by degrading two special B cell transcription factors, Ikaros family zinc finger structural proteins 1 and 3 (IKZF1 and IKZF3), which further reveals the structure of thalidomide may be combined with the E3 ubiquitin ligase protein complex of the cerebellar protein to further play a role in degrading the target protein (Science, 2014, 343, 301; Science, 2014, 343, 305). [0004] On this basis, CRBN ligands are widely used in protein degradation, and a series of 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. 1 275501297 v3 SUMMARY [0005] 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 are defined, described, and exemplified herein. [0006] 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. [0007] 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. [0008] 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. [0009] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a conjugate disclosed herein, and a pharmaceutically acceptable excipient. [00010] 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 conjugate described herein. [00011] 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. [00012] In certain aspects, provided herein are conjugates described herein for use in degrading a protein in a subject or biological sample. [00013] 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. [00014] 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. 2 275501297 v3 [00015] 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. DETAILED DESCRIPTION [00016] The present disclosure relates to compounds that show cereblon-binding activity, and compounds that bifunctional degraders comprising such compound, as well as pharmaceutical compositions thereof. 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 Application Cereblon Ligands [00017] In certain aspects, the present disclosure provides compounds of Formula I: and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: R ¹ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 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) ₂ R ^a , -S(=O) ₂ OR ^b , -S(=O) ₂ NR ^c R ^d , - NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , - NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , -OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; R ¹ and R ² , together with the intervening carbon atoms, form Ring A; Y” is N or CR ³ ; R ³ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 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 ^c R ^d , - 3 275501297 v3 NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , - NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O)2R ^a , -OS(=O)2OR ^b , -OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; or R ² and R ³ , together with the intervening carbon atoms, form Ring A; provided that either R ¹ and R ² or R ² and R ³ form Ring A, Y’ is N or CR ^Y’ ; R ^Y’ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _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; X is O or N; wherein when X is O, then U is absent; Y is N or CR ^Y ; R ^Y is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 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 ; and U is absent, hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -S(=O)R ^a , -S(=O)2R ^a , - S(=O)2OR ^b , -S(=O)2NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; when the bond between Y and U is present: r is 1; X is N; Y is C; and U is -CH ₂ - or -C(=O)- R ⁴ is hydrogen, deuterium, C _1-6 haloalkyl, or C _1-6 alkyl; q is an integer from 0 to 2, 4 275501297 v3 Ring A is wherein: each R ⁱ independently is oxo, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SR ^b , -S(=O)R ^a , -S(=O)2R ^a , -S(=O)2OR ^b , - S(=O) ₂ NR ^c R ^d , -NR ^c S(=O) ₂ R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O) ₂ OR ^b , -NR ^c S(=O) ₂ NR ^c R ^d , - NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , - OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or - C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; s is an integer selected from 0 to 5; m is an integer selected from 0 to 2; R ^cp is , wherein: R ^end is -OR ^H1 , -N(R ^H2 )2, -SR ^H3 , or -C(=O)OR ^H4 ; R ^H1 is hydrogen, C1-6 alkyl, -S(=O)2R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , or a hydroxyl- protecting group, wherein the C _1-6 alkyl is optionally substituted with one or more R ^u ; R ^H2 is hydrogen, C1-6 alkyl, -S(=O)2R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , or an amino- protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u ; R ^H3 is hydrogen, C _1-6 alkyl, -C(=O)R ^a , or a thiol-protecting group, wherein the C _1-6 alkyl is optionally substituted with one or more R ^u ; R ^H4 is hydrogen, C1-6 alkyl, or a carboxylic acid-protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u ; each occurrence of G is independently -C(R ^G1 ) ₂ -, -O-, -NR ^G2 -, -C(=O)-, -S-, or -S(=O) ₂ -; each R ^G1 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u ; 5 275501297 v3 each R ^G2 is independently hydrogen or C1-6 alkyl optionally substituted with one or more R ^u ; and p is an integer selected from 0 to 5, wherein: each R ^u is independently oxo, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _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) ₂ NR ^c R ^d , -NR ^c S(=O) ₂ R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O) ₂ OR ^b , -NR ^c S(=O) ₂ NR ^c R ^d , - NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , - OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or - C(=O)NR ^c R ^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, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R ^u , together with the one or more intervening atoms, form C _6-10 aryl, 5- to 10-membered heteroaryl, C _3-12 carbocyclyl or 3- to 12-membered heterocyclyl; each R ^a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C _6-10 aryl, or 5- to 10-membered heteroaryl; each R ^b is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl. [00018] In certain embodiments, Ring A is 6 275501297 v3 or , [00019] In certain embodiments, the compound is not or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00021] In certain embodiments, the compound of Formula I is a compound of Formula I-2 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00022] In certain embodiments, U is hydrogen or C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C ₆ )). [00023] In certain embodiments, Y is N. [00024] In certain embodiments, Y is CR ^Y . [00025] In certain embodiments, R ^Y is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . [00026] In certain embodiments, R ^Y is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C ₄ ), s-butyl (C ₄ ), t-butyl (C ₄ ), pentyl (C ₅ ), or hexyl (C ₆ )), C _1-6 alkoxy (e.g., methoxy (C ₁ ), ethoxy (C ₂ ), n-propoxy (C ₃ ), i-propoxy (C ₃ ), n-butoxy (C ₄ ), i-butoxy (C ₄ ), s-butoxy (C ₄ ), 7 275501297 v3 t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C ₆ )), C _2-6 alkynyl (e.g., ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), or spiro[4.5]decanyl (C ₁₀ )), 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 ^c R ^d , -NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , - NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , - OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , -OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , - C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u . [00027] In certain embodiments, R ^Y is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C _6-10 aryl, 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 . 8 275501297 v3 [00028] In certain embodiments, R ^Y is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C ₆ aryl, 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 . [00029] In certain embodiments, R ^Y is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00030] In certain embodiments, R ^Y is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00031] In certain embodiments, R ^Y is hydrogen. [00032] In certain embodiments, R ¹ and R ² , together with the intervening carbon atoms, form Ring A. [00033] In certain embodiments, the compound of Formula I-1 is a compound of Formula I-1- I’, I-1-ii’, I-1-iii’, or I-1-iv’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00034] In certain embodiments, the compound of Formula I-1 is a compound of Formula I-1- i, I-1-ii, I-1-iii, or I-1-iv: 9 275501297 v3 (I-1-i), (I-1-ii), (I-1-iii), or (I-1-iv), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00035] In certain embodiments, the compound of Formula I-2 is a compound of Formula I- 2-i’, I-2-ii’, I-2-iii’, or I-2-iv’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00036] In certain embodiments, the compound of Formula I-2 is a compound of Formula I- 2-i, I-2-ii, I-2-iii, or I-2-iv: iv), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00037] In certain embodiments, Y” is N. [00038] In certain embodiments, Y” is CR ³ . [00039] In certain embodiments, R ³ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered 10 275501297 v3 heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . [00040] In certain embodiments, R ³ is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C ₄ ), s-butyl (C ₄ ), t-butyl (C ₄ ), pentyl (C ₅ ), or hexyl (C ₆ )), C _1-6 alkoxy (e.g., methoxy (C ₁ ), ethoxy (C ₂ ), n-propoxy (C ₃ ), i-propoxy (C ₃ ), n-butoxy (C ₄ ), i-butoxy (C ₄ ), s-butoxy (C ₄ ), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), or hexenyl (C ₆ )), C _2-6 alkynyl (e.g., ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptenyl (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 (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), 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 ^c R ^d , -NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , - NR ^c S(=O) ₂ OR ^b , -NR ^c S(=O) ₂ NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , - OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , -OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , - C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, 11 275501297 v3 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u . [00041] In certain embodiments, R ³ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 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 . [00042] In certain embodiments, R ³ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C ₆ aryl, 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 . [00043] In certain embodiments, R ³ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00044] In certain embodiments, R ³ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00045] In certain embodiments, R ³ is hydrogen. [00046] In certain embodiments, R ² and R ³ , together with the intervening carbon atoms, form Ring A. [00047] In certain embodiments, the compound of Formula I-1 is a compound of Formula I-1- v’, I-1-vi’, I-1-vii’, or I-1-viii’: 12 275501297 v3 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00048] In certain embodiments, the compound of Formula I-1 is a compound of Formula I-1- v, I-1-vi, I-1-vii, or I-1-viii: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00049] In certain embodiments, the compound of Formula I-2 is a compound of Formula I- 2-v’, I-2-vi’, I-2-vii’, or I-2-viii’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00050] In certain embodiments, the compound of Formula I-2 is a compound of Formula I- 2-v, I-2-vi, I-2-vii, or I-2-viii: 13 275501297 v3 (I-2-v), (I-2-vi), (I-2-vii), or (I-2-viii), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00051] In certain embodiments, R ¹ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . [00052] In certain embodiments, R ¹ is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C ₄ ), s-butyl (C ₄ ), t-butyl (C ₄ ), pentyl (C ₅ ), or hexyl (C ₆ )), C _1-6 alkoxy (e.g., methoxy (C ₁ ), ethoxy (C ₂ ), n-propoxy (C ₃ ), i-propoxy (C ₃ ), n-butoxy (C ₄ ), i-butoxy (C ₄ ), s-butoxy (C ₄ ), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), or hexenyl (C ₆ )), C _2-6 alkynyl (e.g., ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), 14 275501297 v3 cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (C ₈ ), cyclononyl (C ₉ ), cyclononenyl (C ₉ ), 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) ₂ R ^a , -S(=O) ₂ OR ^b , -S(=O) ₂ NR ^c R ^d , -NR ^c S(=O) ₂ R ^a , -NR ^c S(=O)R ^a , - NR ^c S(=O) ₂ OR ^b , -NR ^c S(=O) ₂ NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , - OS(=O)2R ^a , -OS(=O)2OR ^b , -OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , - C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u . [00053] In certain embodiments, R ¹ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C _6-10 aryl, 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 . [00054] In certain embodiments, R ¹ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C ₆ aryl, 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 . [00055] In certain embodiments, R ¹ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _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 . [00056] In certain embodiments, R ¹ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00057] In certain embodiments, R ¹ is hydrogen. [00058] In certain embodiments, Y’ is N. 15 275501297 v3 [00059] In certain embodiments, Y’ is CR ^Y’ . [00060] In certain embodiments, R ^Y’ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . [00061] In certain embodiments, R ^Y’ is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO ₂ , -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C ₄ ), s-butyl (C ₄ ), t-butyl (C ₄ ), pentyl (C ₅ ), or hexyl (C ₆ )), C _1-6 alkoxy (e.g., methoxy (C ₁ ), ethoxy (C ₂ ), n-propoxy (C ₃ ), i-propoxy (C ₃ ), n-butoxy (C ₄ ), i-butoxy (C ₄ ), s-butoxy (C ₄ ), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), or hexenyl (C ₆ )), C _2-6 alkynyl (e.g., ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), 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 (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), or spiro[4.5]decanyl (C ₁₀ )), 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 ^c R ^d , -NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , - 16 275501297 v3 NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , - OS(=O)2R ^a , -OS(=O)2OR ^b , -OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , - C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u . [00062] In certain embodiments, R ^Y’ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 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 . [00063] In certain embodiments, R ^Y’ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C ₆ aryl, 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 . [00064] In certain embodiments, R ^Y’ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00065] In certain embodiments, R ^Y’ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00066] In certain embodiments, R ^Y’ is hydrogen. [00067] In certain embodiments, Ring A is 5- to 7-membered heterocycle comprising one oxygen atom. [00068] In certain embodiments, Ring A is 5- to 7-membered heterocycle comprising one oxygen atom and no double bond. [00069] In certain embodiments, Ring A is 5- to 7-membered heterocycle comprising one oxygen atom and a double bond. [00070] In certain embodiments, Ring A is 17 275501297 v3 wherein: each R ⁱ independently is oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 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 ^c R ^d , -NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , - NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , - OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or - C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; s is an integer selected from 0 to 5; m is an integer selected from 0 to 2; R ^cp is , wherein: R ^end is -OR ^H1 , -N(R ^H2 ) ₂ , -SR ^H3 , or -C(=O)OR ^H4 ; R ^H1 is hydrogen, C1-6 alkyl, -S(=O)2R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , or a hydroxyl- protecting group, wherein the C _1-6 alkyl is optionally substituted with one or more R ^u ; R ^H2 is hydrogen, C _1-6 alkyl, -S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , or an amino- protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u ; R ^H3 is hydrogen, C1-6 alkyl, -C(=O)R ^a , or a thiol-protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u ; R ^H4 is hydrogen, C1-6 alkyl, or a carboxylic acid-protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u ; each occurrence of G is independently -C(R ^G1 ) ₂ -, -O-, -NR ^G2 -, -C(=O)-, -S-, or -S(=O) ₂ -; each R ^G1 is independently hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u ; each R ^G2 is independently hydrogen or C1-6 alkyl optionally substituted with one or more R ^u ; and p is an integer selected from 0 to 5. 18 275501297 v3 [00071] In certain embodiments, Ring A is [00072] In certain embodiments, R ^end is -OR ^H1 or -N(R ^H2 ) ₂ . [00073] In certain embodiments, R ^H1 is hydrogen, C _1-6 alkyl (e.g., methyl (C ₁ ), ethyl (C ₂ ), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C ₆ )), -S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , or a hydroxyl-protecting group, wherein the C _1-6 alkyl is optionally substituted with one or more R ^u . [00074] In certain embodiments, R ^H1 is hydrogen. [00075] In certain embodiments, R ^H2 is hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C ₃ ), i-propyl (C ₃ ), n-butyl (C ₄ ), i-butyl (C ₄ ), s-butyl (C ₄ ), t-butyl (C ₄ ), pentyl (C ₅ ), or hexyl (C6)), -S(=O)2R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , or an amino-protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u . [00076] In certain embodiments, R ^H2 is hydrogen. [00077] In certain embodiments, R ^H3 is hydrogen, C _1-6 alkyl (e.g., methyl (C ₁ ), ethyl (C ₂ ), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C ₆ )), -C(=O)R ^a , or a thiol-protecting group, wherein the C _1-6 alkyl is optionally substituted with one or more R ^u . [00078] In certain embodiments, R ^H3 is hydrogen. [00079] In certain embodiments, R ^H4 is hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C ₃ ), i-propyl (C ₃ ), n-butyl (C ₄ ), i-butyl (C ₄ ), s-butyl (C ₄ ), t-butyl (C ₄ ), pentyl (C ₅ ), or hexyl (C6)), or a carboxylic acid-protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u . [00080] In certain embodiments, R ^H4 is hydrogen. [00081] In certain embodiments, each occurrence of G is independently -C(R ^G1 ) ₂ -, -O-, -NR ^G2 - , -C(=O)-, -S-, or -S(=O)2-. [00082] In certain embodiments, each occurrence of G is independently -C(R ^G1 ) ₂ -, -O-, -NR ^G2 - or -C(=O)-. [00083] In certain embodiments, each R ^G1 is independently hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, 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 . 19 275501297 v3 [00084] In certain embodiments, each R ^G1 is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C ₄ ), i-butyl (C ₄ ), s-butyl (C ₄ ), t-butyl (C ₄ ), pentyl (C ₅ ), or hexyl (C ₆ )), C _1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), or hexenyl (C ₆ )), C _2-6 alkynyl (e.g., ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (C ₈ ), cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), 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 ^c R ^d , -NR ^c S(=O)2R ^a , - NR ^c S(=O)R ^a , -NR ^c S(=O) ₂ OR ^b , -NR ^c S(=O) ₂ NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , - NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , -OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , - OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u . 20 275501297 v3 [00085] In certain embodiments, each R ^G1 is independently hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C _6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u . [00086] In certain embodiments, each R ^G1 is independently hydrogen, halogen, -CN, -NO ₂ , - OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 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 . [00087] In certain embodiments, each R ^G1 is independently hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00088] In certain embodiments, each R ^G1 is independently hydrogen, halogen, -CN, -NO2, - OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00089] In certain embodiments, each R ^G1 is independently hydrogen, halogen, or C _1-6 alkyl (e.g., methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), i-propyl (C ₃ ), n-butyl (C ₄ ), i-butyl (C ₄ ), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)) optionally substituted with one or more R ^u . [00090] In certain embodiments, R ^cp is -(CH ₂ ) _n OH, or -(CH ₂ ) _n NH ₂ , wherein n is an integer selected from 0 to 4. [00091] In certain embodiments, R ^cp is -CH2OH. [00092] In certain embodiments, each R ⁱ is independently oxo, halogen, -CN, -NO2, -OH, - NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5- to 10- membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . [00093] In certain embodiments, each R ⁱ is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C ₄ ), i-butyl (C ₄ ), s-butyl (C ₄ ), t-butyl (C ₄ ), pentyl (C ₅ ), or hexyl (C ₆ )), C _1-6 alkoxy (e.g., methoxy (C ₁ ), ethoxy (C ₂ ), n-propoxy (C ₃ ), i-propoxy (C ₃ ), n-butoxy (C ₄ ), i-butoxy (C ₄ ), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., 21 275501297 v3 dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C _2-6 alkenyl (e.g., ethenyl (C ₂ ), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), pentynyl (C ₅ ), or hexynyl (C ₆ )), 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 (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (C ₈ ), cyclononyl (C ₉ ), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C ₁₀ ), or spiro[4.5]decanyl (C ₁₀ )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ OR ^b , -S(=O) ₂ NR ^c R ^d , -NR ^c S(=O) ₂ R ^a , - NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , - NR ^b C(=O)OR ^b , -OS(=O)2R ^a , -OS(=O)2OR ^b , -OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , - OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u . [00094] In certain embodiments, each R ⁱ is independently oxo, halogen, -CN, -NO ₂ , -OH, - NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 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 . 22 275501297 v3 [00095] In certain embodiments, each R ⁱ is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C ₆ aryl, 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 . [00096] In certain embodiments, each R ⁱ is independently oxo, halogen, -CN, -NO ₂ , -OH, - NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _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 . [00097] In certain embodiments, each R ⁱ is independently oxo, halogen, -CN, -NO ₂ , -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more R ^u . [00098] In certain embodiments, each R ⁱ is independently oxo, -CN, -OH, -NH2, C1-6 alkyl, - NR ^c S(=O)2R ^a , or -NR ^b C(=O)R ^a , wherein the alkyl is optionally substituted with one or more R ^u . [00099] In certain embodiments, at least one R ⁱ is oxo. In certain embodiments, at least one R ⁱ is oxo. In certain embodiments, at least one R ⁱ is -CN. In certain embodiments, at least one R ⁱ is -OH. In certain embodiments, at least one R ⁱ is -NH ₂ . In certain embodiments, at least one R ⁱ is C _1-6 alkyl. In certain embodiments, at least one R ⁱ is -NR ^c S(=O) ₂ R ^a . In certain embodiments, at least one R ⁱ is -NR ^b C(=O)R ^a . [000100] 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. [000101] 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. [000102] In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is deuterium. In certain embodiments, R ⁴ is C1-6 haloalkyl. In certain embodiments, R ⁴ is C1-6 alkyl. 23 275501297 v3 [000103] 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. Bifunctional Degraders [000104] In certain aspects, the present disclosure provides conjugates comprising a compound disclosed herein being connected to a ligand for a protein (e.g., via a linker). [000105] In certain aspects, the present disclosure provides conjugates of Formula I: and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: R ¹ and R ² , or R ² and R ³ , together with the intervening carbon atoms, form Ring A’; Ring A’ is , wherein: R ^cp’ is , wherein: R ^v is -O-, -N(R ^G3 )-, -S-, or -C(=O)O-; R ^G3 is hydrogen or C _1-6 alkyl optionally substituted with one or more R ^u ; L is a linker; and T is a ligand for a protein, wherein all other variables are defined herein. [000106] In certain embodiments, Ring A’ is . [000107] In certain embodiments, R ^v is -O-, -N(R ^G3 )-, -S-, or -C(=O)O-. 24 275501297 v3 [000108] In certain embodiments, R ^v is -O- or -N(R ^G3 )-. [000109] In certain embodiments, R ^v is -O-. [000110] In certain embodiments, R ^G3 is hydrogen or C _1-6 alkyl (e.g., methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)) optionally substituted with one or more R ^u . [000111] In certain embodiments, -R ^V -[G] _p - is *-(CH ₂ ) _n O- or *-(CH ₂ ) _n NH-, wherein n is an integer selected from 0 to 4, and * denotes attachment to Ring A’. [000112] In certain embodiments, -R ^V -[G]p- is *-CH2O-. [000113] In certain embodiments, the conjugate of Formula I is a conjugate of Formula I-1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000114] In certain embodiments, the conjugate of Formula I is a conjugate of Formula I-2 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000115] In certain embodiments, the conjugate of Formula I-1 is a conjugate of Formula I’- 1-i’ or I’-1-ii’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000116] In certain embodiments, the conjugate of Formula I-1 is a conjugate of Formula I’- 1-i or I’-1-ii: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 25 275501297 v3 [000117] In certain embodiments, the conjugate of Formula I-2 is a conjugate of Formula I’- 2-i’ or I’-2-ii’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000118] In certain embodiments, the conjugate of Formula I-2 is a conjugate of Formula I’- 2-i or I’-2-ii: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000119] In certain embodiments, the conjugate of Formula I-1 is a conjugate of Formula I’- 1-iii’ or I’-1-iv’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000120] In certain embodiments, the conjugate of Formula I-1 is a conjugate of Formula I’- 1-iii or I’-1-iv: iv), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000121] In certain embodiments, the conjugate of Formla I-2 is a conjugate of Formula I’-2- iii’ or I’-2-iv’: 26 275501297 v3 (I’-2-iii’) or (I’-2-iv’), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000122] In certain embodiments, the conjugate of Formla I-2 is a conjugate of Formula I’-2- iii or I’-2-iv: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [000123] 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 degrades the target protein. [000124] 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. [000125] In certain embodiments, L is of formula , wherein: * denotes attachment to T and ** denotes attachment to C; each occurrence of -W’- is independently C1-3 alkylene, C2 alkenylene, C2 alkynylene, C3-12 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, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, 27 275501297 v3 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. [000126] T, a ligand of a protein, is a chemical entity that competitively or non-competitively a protein. [000127] In certain embodiments, the protein is B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo- oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5 -lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR), protein P- glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-l receptor, TNF-alphaR, ICAM1, Cat+ channels, VC AM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RaslRaflMEWERK pathway, interleukin- 1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-l (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, estrogen receptors, androgen receptors (AR), adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk- IIKDR, vitronectin receptor, integrin receptor, Her-2l neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channels. Still further target proteins include Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate- phosphate synthase. 28 275501297 v3 [000128] 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), or bromodomain-containing protein 4 (BRD4). [000129] In certain embodiments, T is a small molecule. [000130] 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. [000131] In certain embodiments, T is an antibody. [000132] 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. [000133] 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. [000134] In certain embodiments, the compound is selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof. [000135] In certain embodiments, the compound is selected from the compounds in Table 1. Table 1. 29 275501297 v3 30 275501297 v3 EXEMPLARY EMBODIMENTS Exemplary Embodiment 1. A compound of Formula I: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R ¹ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 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) ₂ R ^a , -S(=O) ₂ OR ^b , -S(=O) ₂ NR ^c R ^d , - NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , - NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O)2R ^a , -OS(=O)2OR ^b , -OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; or R ¹ and R ² , together with the intervening carbon atoms, form Ring A; 31 275501297 v3 Y” is N or CR ³ ; R ³ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 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 ^c R ^d , - NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , - NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , -OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; or R ² and R ³ , together with the intervening carbon atoms, form Ring A; provided that either R ¹ and R ² or R ² and R ³ form Ring A, Y’ is N or CR ^Y’ ; R ^Y’ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u ; denotes an optional covalent bond between Y and U; when the bond between Y and U is absent: r is 0 or 1; X is O or N; wherein when X is O, then U is absent; Y is N or CR ^Y ; R ^Y is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _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 ; and U is absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -S(=O)R ^a , -S(=O)2R ^a , - S(=O) ₂ OR ^b , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; when the bond between Y and U is present: r is 1; X is N; 32 275501297 v3 Y is C; and U is -CH2- or -C(=O)- R ⁴ is hydrogen, deuterium, C _1-6 haloalkyl, or C _1-6 alkyl; q is an integer from 0 to 2, Ring A is wherein: each R ⁱ independently is oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ OR ^b , - S(=O)2NR ^c R ^d , -NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , - NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O)2R ^a , -OS(=O)2OR ^b , - OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or - C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; s is an integer selected from 0 to 5; m is an integer selected from 0 to 2; R ^cp is , wherein: R ^end is -OR ^H1 , -N(R ^H2 ) ₂ , -SR ^H3 , or -C(=O)OR ^H4 ; R ^H1 is hydrogen, C _1-6 alkyl, -S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , or a hydroxyl- protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u ; R ^H2 is hydrogen, C _1-6 alkyl, -S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , or an amino- protecting group, wherein the C _1-6 alkyl is optionally substituted with one or more R ^u ; R ^H3 is hydrogen, C1-6 alkyl, -C(=O)R ^a , or a thiol-protecting group, wherein the C1-6 alkyl is optionally substituted with one or more R ^u ; R ^H4 is hydrogen, C _1-6 alkyl, or a carboxylic acid-protecting group, wherein the C _1-6 alkyl is optionally substituted with one or more R ^u ; each occurrence of G is independently -C(R ^G1 )2-, -O-, -NR ^G2 -, -C(=O)-, -S-, or -S(=O)2-; 33 275501297 v3 each R ^G1 is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u ; each R ^G2 is independently hydrogen or C _1-6 alkyl optionally substituted with one or more R ^u ; and p is an integer selected from 0 to 5, wherein: each R ^u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ OR ^b , - S(=O)2NR ^c R ^d , -NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , - NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O)2R ^a , -OS(=O)2OR ^b , - OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or - C(=O)NR ^c R ^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, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R ^u , together with the one or more intervening atoms, form C6-10 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, C6-10 aryl, or 5- to 10-membered heteroaryl; each R ^b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C _6-10 aryl, or 5- to 10-membered heteroaryl; and each R ^c and R ^d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or 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 34 275501297 v3 each R ^z is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl. Exemplary Embodiment 2. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is not Exemplary Embodiment 3. The compound of any one of the preceding Exemplary Embodiments, wherein R ^end is -OR ^H1 or -N(R ^H2 )2. Exemplary Embodiment 4. The compound of any one of the preceding Exemplary Embodiments, wherein each occurrence of G is independently -C(R ^G1 )2-, -O-, -NR ^G2 - or - C(=O)-, and each R ^G1 is independently hydrogen, halogen, or C1-6 alkyl. Exemplary Embodiment 5. The compound of any one of the preceding Exemplary Embodiments, wherein R ^cp is -(CH2)nOH, or -(CH2)nNH2, wherein n is an integer selected from 0 to 4. Exemplary Embodiment 6. A conjugate of Formula I: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R ¹ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, -SR ^b , -S(=O)R ^a , -S(=O)2R ^a , -S(=O)2OR ^b , -S(=O)2NR ^c R ^d , - NR ^c S(=O) ₂ R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O) ₂ OR ^b , -NR ^c S(=O) ₂ NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , - NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , -OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; R ¹ and R ² , together with the intervening carbon atoms, form Ring A’; Y” is N or CR ³ ; 35 275501297 v3 R ³ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ OR ^b , -S(=O) ₂ NR ^c R ^d , - NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , - NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O)2R ^a , -OS(=O)2OR ^b , -OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; or R ² and R ³ , together with the intervening carbon atoms, form Ring A’; provided that either R ¹ and R ² , or R ² and R ³ , form Ring A’; Y’ is N or CR ^Y’ ; R ^Y’ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 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; X is O or N; wherein when X is O, then U is absent; Y is N or CR ^Y ; R ^Y is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 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 ; and U is absent, hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -S(=O)R ^a , -S(=O)2R ^a , - S(=O)2OR ^b , -S(=O)2NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or -C(=O)NR ^c R ^d , wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; when the bond between Y and U is present: r is 1; X is N; Y is C; and 36 275501297 v3 U is -CH2- or -C(=O)-; R ⁴ is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; q is an integer from 0 to 2, Ring A’ is , wherein: each R ⁱ independently is oxo, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5- to 10-membered heteroaryl, C _3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SR ^b , -S(=O)R ^a , -S(=O)2R ^a , -S(=O)2OR ^b , - S(=O)2NR ^c R ^d , -NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , - NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , - OS(=O)2NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or - C(=O)NR ^c R ^d , wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ^u ; s is an integer selected from 0 to 5; m is an integer selected from 0 to 2; R ^cp’ is , wherein: R ^v is -O-, -N(R ^G3 )-, -S-, or -C(=O)O-; R ^G3 is hydrogen or C1-6 alkyl optionally substituted with one or more R ^u ; each occurrence of G is independently -C(R ^G1 ) ₂ -, -O-, -NR ^G2 -, -C(=O)-, -S-, or -S(=O) ₂ -; each R ^G1 is independently hydrogen, halogen, -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u ; each R ^G2 is independently hydrogen or C1-6 alkyl optionally substituted with one or more R ^u ; p is an integer selected from 0 to 5, L is a linker, and 37 275501297 v3 T is a ligand for a protein, wherein: each R ^u is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 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) ₂ R ^a , -S(=O) ₂ OR ^b , - S(=O)2NR ^c R ^d , -NR ^c S(=O)2R ^a , -NR ^c S(=O)R ^a , -NR ^c S(=O)2OR ^b , -NR ^c S(=O)2NR ^c R ^d , - NR ^b C(=O)NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , -OS(=O) ₂ R ^a , -OS(=O) ₂ OR ^b , - OS(=O) ₂ NR ^c R ^d , -OC(=O)R ^a , -OC(=O)OR ^b , -OC(=O)NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , or - C(=O)NR ^c R ^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, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two R ^u , together with the one or more intervening atoms, form C6-10 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, C6-10 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C _6-10 aryl, or 5- to 10-membered heteroaryl; 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, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, or 3- to 6-memberred heterocyclyl. Exemplary Embodiment 7. The conjugate of any one of the preceding Exemplary Embodiments, wherein R ^v is -O- or -N(R ^G3 )-. Exemplary Embodiment 8. The conjugate of any one of the preceding Exemplary Embodiments, wherein each occurrence of G is independently -C(R ^G1 ) ₂ -, -O-, -NR ^G2 - or - C(=O)-, and each R ^G1 is independently hydrogen, halogen, or C1-6 alkyl. 38 275501297 v3 Exemplary Embodiment 9. The conjugate of any one of the preceding Exemplary Embodiments, wherein -R ^V -[G]p- is *-(CH2)nO- or *-(CH2)nNH-, wherein n is an integer selected from 0 to 4, and * denotes attachment to Ring A’. Exemplary Embodiment 10. The conjugate of any one of the preceding Exemplary Embodiments, wherein -R ^V -[G]p- is *-CH2O-. Exemplary Embodiment 11. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein the compound or conjugate of Formula I is a compound or conjugate of Formula I-1 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Exemplary Embodiment 12. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein the compound or conjugate of Formula I is a compound or conjugate of Formula I-2 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Exemplary Embodiment 13. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein U is hydrogen or C _1-6 alkyl. Exemplary Embodiment 14. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein Y is CR ^Y , and R ^Y is hydrogen, halogen, -CN, -NO2, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _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 . Exemplary Embodiment 15. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein R ^Y is hydrogen. Exemplary Embodiment 16. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein R ¹ and R ² , together with the intervening carbon atoms, form Ring A or Ring A’. 39 275501297 v3 Exemplary Embodiment 17. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein the compound of Formula I-1 is a compound of Formula I-1-i’, I-1-ii’, I-1-iii’, or I-1-iv’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the conjugate of Formula I-1 is a conjugate of Formula I’-1-i’ or I’-1-ii’ or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Exemplary Embodiment 18. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein the compound of Formula I-2 is a compound of Formula I-2-i’, I-2-ii’, I-2-iii’, or I-2-iv’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the conjugate of Formula I-2 is a conjugate of Formula I’-2-i’ or I’-2-ii’ 40 275501297 v3 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Exemplary Embodiment 19. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein Y” is CR ³ , and R ³ is hydrogen, halogen, -CN, -NO ₂ , -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10- membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . Exemplary Embodiment 20. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein Y” is CR ³ , and R ³ is hydrogen. Exemplary Embodiment 21. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein R ² and R ³ , together with the intervening carbon atoms, form Ring A or Ring A’. Exemplary Embodiment 22. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein the compound of Formula I-1 is a compound of Formula I-1-v’, I-1-vi’, I-1-vii’, or I-1-viii’: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or wherein the conjugate of Formula I-1 is a conjugate of Formula I’-1-iii’ or I’-1-iv’ or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Exemplary Embodiment 23. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein the compound of Formula I-2 is a compound of Formula I-2-v’, I-2-vi’, I-2-vii’, or I-2-viii’: 41 275501297 v3 (I-2-v’), (I-2-vi’), (I-2-vii’), or (I-2-viii’), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the conjugate of Formula I-2 is a conjugate of Formula I’-2-iii’ or I’-2-iv’ or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Exemplary Embodiment 24. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein R ¹ is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . Exemplary Embodiment 25. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein R ¹ is hydrogen. Exemplary Embodiment 26. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein Y’ is CR ^Y’ , and R ^Y’ is hydrogen, halogen, -CN, -NO ₂ , - OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C _3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . Exemplary Embodiment 27. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein R ^Y’ is hydrogen. Exemplary Embodiment 28. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein each R ⁱ is independently oxo, halogen, -CN, -NO2, -OH, - 42 275501297 v3 NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10- membered heteroaryl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with one or more R ^u . Exemplary Embodiment 29. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein each R ⁱ is independently oxo, -CN, -OH, -NH ₂ , C _1-6 alkyl, -NR ^c S(=O) ₂ R ^a , or -NR ^b C(=O)R ^a , , wherein the alkyl is optionally substituted with one or more R ^u . Exemplary Embodiment 30. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein s is 0. Exemplary Embodiment 31. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein R ⁴ is hydrogen. Exemplary Embodiment 32. The compound or conjugate of any one of the preceding Exemplary Embodiments, wherein q is 1. Exemplary Embodiment 33. A compound selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof. Exemplary Embodiment 34. A pharmaceutical composition comprising the compound or conjugate of any one of the preceding Exemplary Embodiments, and a pharmaceutically acceptable excipient. Exemplary Embodiment 35. A method of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering the compound of any one of the preceding Exemplary Embodiments to the subject or contacting the biological sample with the compound of any one of the preceding Exemplary Embodiments. Exemplary Embodiment 36. Use of the compound of any one of the preceding Exemplary Embodiments in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. Exemplary Embodiment 37. A compound of any one of the preceding Exemplary Embodiments for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample. [000136] The compounds of the present disclosure possess advantageous characteristics, as compared to known compounds, such as known cereblon-binding agents or known degraders comprising cereblon-binding agents. For example, the compounds of the present disclosure display more potent cereblon-binding activity or more potent degradation activity against 43 275501297 v3 certain proteins, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and/or AUC), and/or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction). These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein. [000137] 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. [000138] 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. [000139] 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 [000140] 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. 44 275501297 v3 In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [000141] 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. [000142] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, 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. [000143] 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- 45 275501297 v3 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. [000144] In certain embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (C1-4 alkyl)4, and the like. [000145] 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 [000146] 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. [000147] 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. [000148] 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. [000149] 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 46 275501297 v3 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 [000150] 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.” [000151] 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. [000152] 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. [000153] 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 47 275501297 v3 solubility. In certain embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers [000154] In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. [000155] 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 [000156] 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)). [000157] 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. [000158] 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. [000159] 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 48 275501297 v3 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. [000160] 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 [000161] 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). 49 275501297 v3 General Synthetic Scheme Scheme 1 [000162] According to Scheme 1, commercially available or synthetically accessible lactone of formula II is brominated in the presence of a brominating agent such as Br ₂ , NBS and the like; in the presence of an acid such as acetic acid, pTSA and the like; in an alcoholic solvent such as MeOH, EtOH and the like; at temperatures ranging from 0 °C to about 50 °C, preferably 25 °C; to afford a compound of formula (III). Bromo lactone of formula III is reacted with a compound of formula (IV) commercially available or synthetically accessible (where X = OH) under Mitsunobu condition, in the presence of a coupling agent such DIAD, DEAD, and the like; with a coupling co-agent such as Ph ₃ P, Bu ₃ P and the like; in a solvent such as diethyl ether, THF and the like; at temperatures ranging from -20 °C to about 50 °C, preferably 0 °C; to afford an ether compound of formula (V); Alternatively, bromo lactone of formula III is reacted with a compound of formula (IV) commercially available or synthetically accessible (where X = halogen) under coupling condition, in the presence of a base such K ₂ CO ₃ , NaH, Na ₂ CO ₃ , and 50 275501297 v3 the like; in a solvent such as THF, DMF, DMSO and the like; at temperatures ranging from 0 °C to about 100 °C, preferably 40 °C; to afford an ether compound of formula (V); a compound of formula (V) is cyclized under radical cyclization condition with a radical initiator such as BPO, AIBN and the like; in the presence of a suitable reductant such as Bu3SnH, (TMS)3SiH and the like; in a solvent such as benzene, toluene and the like; at temperatures ranging from 80 °C to about 120 °C, preferably 100 °C; to afford a compound of formula (VI). A lactone compound of formula (VI) is reacted with a suitable base such as LiOH, NaOH, and the like; in a suitable solvent such as THF, MeOH, and the like; in a co-solvent such as water; at temperatures ranging from 25 °C to 80 °C, preferably at 50 °C; to provide an acid compound of formula (VII). An acid compound of formula (VII) is oxidized in the presence of an oxidant such as MnO2, Dess-Martin periodinane, and the like; in a suitable solvent such as DCM, acetonitrile, and the like; at temperatures ranging from 0 °C to 50 °C, preferably at 25 °C; to provide a compound of formula (VIII). An aldehyde compound of formula (VIII) is reacted with a commercially available or synthetically accessible amine of formula (IX), in the presence of a suitable reductant such as NaBH(OAc)3, NaCNBH3 and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford a compound of formula (X). A compound of formula (X) is cyclized with a coupling agent such as HTAU, EDCI and the like; in the presence of a suitable base such as TEA, DIPEA and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from 0 °C to about 60 °C, preferably 25 °C; to afford an cyclized compound of formula (I-1-iii); Alternatively, a compound of formula (X) is cyclized in the presence of a suitable acid such as AcOH, TFA, pTSA and the like; in a suitable solvent such as DMF, THF, dioxane and the like; at temperatures ranging from 0 °C to about 80 °C, preferably 25 °C; to afford an cyclized compound of formula (I-1-iii). [000163] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present dislosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, 51 275501297 v3 "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). [000164] 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). [000165] 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, 52 275501297 v3 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. [000166] 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 [000167] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC/MS) were collected using a SHIMADZU LCMS-2020EV or Agilent 1260-6125B LCMS. Purity and low resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C182.7 μm 4.6 X 100 mm; Flow rate 0.8 mL/min; Solvent A (100/0.1 water/formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C181.7 µm 2.1 X 50 mm; Flow rate 0.5 mL/min; Solvent A (0.1%formic acid water), 53 275501297 v3 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 [000168] The biological activities of the compounds of the present application can be assessed with methods and assays known in the art. [000169] The binding potency may be determined using HTRF assay technology (e.g., Perkin Elmer). In a typical assay, in a HTRF assay, compounds are diluted in DMSO and react with His tagged CRBN+DDB-DLS7+CXU4 followed by addition of Fluorescent probe Cy5-labeled Thalidomide, and MAb Anti-6HIS Tb cryptate Gold. After a certain period of incubation at room temperature, the HTRF signals are read on Envision reader (e.g., Perkin Elemer). Data is analyzed using XLfit using four parameters dose response curve to determine IC50s. Methods of Use [000170] 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 (e.g., in a therapeutically effective amount). [000171] 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. [000172] 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. [000173] 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 conjugate described herein (e.g., in a therapeutically effective amount). [000174] 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. [000175] In certain aspects, provided herein are conjugates described herein for use in degrading a protein in a subject or biological sample. [000176] 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, 54 275501297 v3 Subfamily A, Member 2/4 (SMARCA2/4), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS G12D), Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), or bromodomain-containing protein 4 (BRD4). [000177] 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 (e.g., in a therapeutically effective amount). [000178] 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. [000179] 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. [000180] In certain embodiments, the disease or disorder is an androgen receptor (AR)- mediated disease or disorder, an estrogen receptor (ER)-mediated disease or disorder, signal transducer and activator of transcription 3 (STAT3)-mediated disease or disorder, signal transducer and activator of transcription 5 (STAT5)-mediated disease or disorder, CREB- binding protein/EP300(E1A) binding protein (CBP/p300)-mediated disease or disorder, SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2/4 (SMARCA2/4)-mediated disease or disorder, Kirsten rat sarcoma viral oncogene homolog G12D (KRAS G12D)-mediated disease or disorder, Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2)-mediated disease or disorder, or bromodomain-containing protein 4 (BRD4)-mediated disease or disorder. [000181] In certain embodiments, the subject is a mammal. [000182] In certain embodiments, the subject is a human. Definitions [000183] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions [000184] 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; 55 275501297 v3 Smith and March, March’s Advanced Organic Chemistry, 5 ^th Edition, John Wiley &amp; 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. [000185] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). [000186] The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [000187] 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, C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [000188] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. 56 275501297 v3 [000189] “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 (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“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 (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1-6 alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ) 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., -CH ₃ ). 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 (-CH ₂ CH ₂ CH ₃ ), n-Bu (-CH ₂ CH ₂ CH ₂ CH ₃ ), or i-Bu (-CH ₂ CH(CH ₃ ) ₂ ). [000190] “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 (- CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (- CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH ₃ )-, (-C(CH ₃ ) ₂ -), substituted ethylene (-CH(CH ₃ )CH ₂ -,-CH ₂ CH(CH ₃ )-, -C(CH ₃ ) ₂ CH ₂ -,-CH ₂ C(CH ₃ ) ₂ -), substituted 57 275501297 v3 propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like. [000191] “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 (“C2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C _2-9 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 (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C _2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C _2-4 alkenyl groups include ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C _2-4 alkenyl groups as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl. [000192] “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=CHCH ₂ -, -CH ₂ -CH=CH-). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not 58 275501297 v3 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(CH ₃ ) ₂ -CH=CH-, -CH ₂ -C(CH ₃ )=CH-, -CH ₂ -CH=C(CH ₃ )-), and the like. [000193] “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) (“C _2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C _2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C _2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2- ₆ alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C _2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C ₂ alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), and the like. Examples of C _2-6 alkenyl groups include the aforementioned C _2-4 alkynyl groups as well as pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C _2-10 alkynyl. [000194] “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. 59 275501297 v3 [000195] 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 (“C _1-10 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“C _1-9 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“C1-8 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“C1-7 heteroalkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“C _1-6 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“C1-5 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and/or 2 heteroatoms (“C _1-4 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“C1-3 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“C _1-2 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C1 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“C _2-6 heteroalkyl”). 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 C1-10 heteroalkyl. In certain embodiments, the heteroalkyl group is a substituted C _1-10 heteroalkyl. [000196] 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 (“C _2-10 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double 60 275501297 v3 bond, and 1, 2, 3, or 4 heteroatoms (“C2-9 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C _2-8 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C2-7 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“C _2-6 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C _2-5 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and l or 2 heteroatoms (“C _2-4 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“C _2- 3 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C2-6 heteroalkenyl”). 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 C2-10 heteroalkenyl. In certain embodiments, the heteroalkenyl group is a substituted C _2-10 heteroalkenyl. [000197] 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 are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C2-10 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C _2-9 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C2-8 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C _2-7 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“C2-6 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C _2-5 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“C2-4 heteroalkynyl”). In certain embodiments, a heteroalkynyl group 61 275501297 v3 has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“C2-3 heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C _2-6 heteroalkynyl”). 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 C _2-10 heteroalkynyl. In certain embodiments, the heteroalkynyl group is a substituted C _2-10 heteroalkynyl. [000198] 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. [000199] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C ₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C ₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C ₁₄ aryl”; e.g., anthracyl). [000200] 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. 62 275501297 v3 [000201] “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. [000202] “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. [000203] “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). [000204] 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. 63 275501297 v3 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. [000205] 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. [000206] “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. [000207] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3- ₁₀ carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C _3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C _5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C _5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon 64 275501297 v3 atoms (“C5-6 carbocyclyl”). Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (C ₈ ), and the like. Exemplary C _3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro[4.5]decanyl (C ₁₀ ), and the like. [000208] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C _3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C _5-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C _5-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C _5-6 carbocyclyl”). Examples of C _5-6 carbocyclyl include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of C _3-6 carbocyclyl include the aforementioned C _5-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (C ₈ ). 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. [000209] 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 65 275501297 v3 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 C3-12 carbocyclyl. [000210] “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. [000211] “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. [000212] “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. [000213] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, 66 275501297 v3 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. [000214] 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 67 275501297 v3 nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [000215] 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. [000216] “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. [000217] “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. [000218] “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 68 275501297 v3 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. [000219] “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. [000220] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl as defined herein. C1-6 alkoxy refers to the group -OR, wherein each R is C1-6 alkyl, as defined herein. Exemplary C _1-6 alkyl is set forth above. [000221] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R is independently alkyl, as defined herein. C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C _1-6 alkyl, as defined herein. Exemplary C _1-6 alkyl is set forth above. [000222] “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. [000223] “Azido” refers to the radical -N3. [000224] “Amino” refers to the radical -NH2. [000225] “Hydroxy” refers to the radical -OH. [000226] “Thioketo” refers to the group =S. [000227] “Carboxy” refers to the radical -C(=O)OH. [000228] “Cyano” refers to the radical -CN. [000229] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. [000230] “Nitro” refers to the radical -NO ₂ . [000231] “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, 69 275501297 v3 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. [000232] 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)). [000233] 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)). [000234] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)). [000235] 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. [000236] 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 [000237] “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. 70 275501297 v3 [000238] “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. [000239] The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci.66 (1):1-79 (January 77). [000240] “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. [000241] “Pharmaceutically acceptable metabolically cleavable group” refers to a group which is cleaved in vivo to yield the parent molecule of the structural formula indicated herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONR2 and -CH2OR radicals, where R is selected independently at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy or 71 275501297 v3 alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups. [000242] “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. [000243] 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. [000244] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylatically effective amount” refers to the effective amount for prophylactic treatment. [000245] “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). [000246] 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 72 275501297 v3 chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high. [000247] “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. [000248] “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. [000249] 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.” [000250] 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”. [000251] “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 its 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 73 275501297 v3 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. [000252] 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. [000253] 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. [000254] 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. [000255] 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 74 275501297 v3 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. [000256] 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. [000257] 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. [000258] 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. [000259] 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. [000260] 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 75 275501297 v3 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. [000261] 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. [000262] 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. [000263] 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 76 275501297 v3 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. [000264] 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 [000265] 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 ^ Synthesis and Characterization Compound 1:  3-(3-(hydroxymethyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7H-fu ro[2,3- e]isoindol-7-yl)piperidine-2,6-dione   [000266] To a solution of NaH (60% suspend in oil) (1.44 g, 60.0 mmol, 1.0 eq) in THF (10 mL) were added benzyl alcohol (4.56 g, 40.00 mmol, 1.0 eq) and DMF (40 mL) at 0 °C. The mixture was stirred at room temperature for 45 min, and then warmed to reflux and stirred for 1 h. The mixture was allowed to cool to room temperature and then transferred into a dropping funnel. The resulting solution was added dropwise to a solution of 3-chloro-2- (chloromethyl)prop-1-ene (4.63 mL, 40.00 mmol, 1.0 eq) in THF (100 mL) over 1 h. The 77 275501297 v3 mixture was stirred at room temperature overnight. The mixture was quenched with ice water (200 mL) and exacted with EA (300 mL x 3). The organic layer was washed with brine (150 mL x 4), and dried over anhydrous Na ₂ SO ₄ , 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 10%) to give the (((2-(chloromethyl)allyl)oxy)methyl)benzene (3.5 g, yield 44%) as a light yellow solid. LC-MS (ESI): mass calcd. for C ₁₁ H ₁₃ ClO, 196.07; m/z found, 197.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.35 - 7.28 (m, 5H), 5.32 (d, J = 1.2 Hz, 1H), 5.27 (d, J = 1.2 Hz, 1H), 4.52 (s, 2H), 4.12 (d, J = 1.2 Hz, 4H). Step B: 4-((2-((benzyloxy)methyl)allyl)oxy)-5-bromoisobenzofuran-1(3 H)-one [000267] To a solution of 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (5 g, 21.83 mmol, 1.0 eq) in DMF (50 mL) were added (((2-(chloromethyl)allyl)oxy)methyl)benzene (5.58 g, 28.38 mmol, 1.25 eq) and K2CO3 (5.43 g, 39.29 mmol, 1.8 eq). The mixture was stirred at 80 ^o C for 5 h. After cooled to room temperature, the mixture was diluted with H ₂ O (150 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with brine (100 mL x 4), 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 30% to 70%) to give 4-((2-((benzyloxy)methyl)allyl)oxy)-5-bromoisobenzofuran- 1(3H)-one (4.3 g, yield 50%) as a light yellow oil. LC-MS (ESI): mass calcd. for C19H17BrO4, 388.03; m/z found, 389.3 [M+H] ⁺ . Step C: 3-((benzyloxy)methyl)-3-methyl-2,3-dihydrobenzo[2,1-b:3,4-c' ]difuran-6(8H)-one [000268] To a solution of 4-((2-((benzyloxy)methyl)allyl)oxy)-5-bromoisobenzofuran-1(3 H)- one (4.3 g, 11.05 mmol, 1.0 eq) in Toluene (40 mL) were added tributylstannane (14.89 mL, 55.23 mmol, 4.5 eq) and AIBN (0.36 g, 2.21 mmol, 0.2 eq). The mixture was stirred at 110 ^o C in a sealed tube overnight. After cooled to room temperature, the mixture was diluted with aqueous KF solution (2 N) (100 mL) and stirred for 1 h. After separation, the aqueous layer was extracted with ethyl acetate (40 mL x 3). The combined extracts were washed with water (40 mL x 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 50%) to give 3-((benzyloxy)methyl)-3-methyl-2,3- dihydrobenzo[2,1-b:3,4-c']difuran-6(8H)-one (3.2 g, yield 93%) as a light yellow solid. LC- MS (ESI): mass calcd. for C19H18O4, 310.12; m/z found, 311.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.46 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.34 - 7.24 (m, 5H), 5.35 (s, 2H), 4.66 (d, J = 9.0 Hz, 1H), 4.48 (d, J = 5.0 Hz, 2H), 4.36 (d, J = 9.0 Hz, 1H), 3.54 - 3.51 (m, 2H), 1.37 (s, 3H). 78 275501297 v3 Step D: 3-((benzyloxy)methyl)-7-(hydroxymethyl)-3-methyl-2,3-dihydro benzofuran-6- carboxylic acid [000269] To a solution of 3-((benzyloxy)methyl)-3-methyl-2,3-dihydrobenzo[2,1-b:3,4- c']difuran-6(8H)-one (3.2 g, 10.31 mmol, 1.0 eq) in THF (20 mL) and MeOH (5 mL), was added a solution of sodium hydroxide (0.82 g, 20.62 mmol, 2.0 eq) and water (5 mL). The mixture was stirred at 40 ^o C for 3 h. After evaporation, the residue was diluted with water (100 mL), adjusted to pH 5 with aqueous HCl solution (2 N), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 3-((benzyloxy)methyl)-7-(hydroxymethyl)-3-methyl-2,3- dihydrobenzofuran-6-carboxylic acid (2.8 g, yield 82%) as a light yellow oil. The crude product was directly used in the next step without further purification. LC-MS (ESI): mass calcd. for C19H20O5, 328.132; m/z found, 329.2 [M+H] ⁺ . [000270] ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 7.34 - 7.25 (m, 6H), 6.96 (d, J = 8.0 Hz, 1H), 4.48 (s, 2H), 4.44 (d, J = 8.8 Hz, 1H), 4.39 (s, 2H), 4.10 (d, J = 8.8 Hz, 1H), 3.44 - 3.39 (m, 2H), 1.30 (s, 3H). Step E: 3-((benzyloxy)methyl)-7-formyl-3-methyl-2,3-dihydrobenzofura n-6-carboxylic acid [000271] To a solution of 3-((benzyloxy)methyl)-7-(hydroxymethyl)-3-methyl-2,3- dihydrobenzofuran-6-carboxylic acid (2.8 g, 8.53 mmol, 1.0 eq) in DCM (50 mL) was added Dess-Martin Periodinane (7.24 g, 17.06 mmol, 2.0 eq). The mixture was stirred at room temperature overnight. After evaporation, the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 40% to 80%) to give 3- ((benzyloxy)methyl)-7-formyl-3-methyl-2,3-dihydrobenzofuran- 6-carboxylic acid (1.3 g, yield 46%) as a light yellow solid. LC-MS (ESI): mass calcd. for C ₁₉ H ₁₈ O ₅ , 326.12; m/z found, 327.3 [M+H] ⁺ . Step F: 3-(3-((benzyloxy)methyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7 H-furo[2,3-e]isoindol- 7-yl)piperidine-2,6-dione [000272] To a solution of 3-[(benzyloxy)methyl]-7-formyl-3-methyl-2,3-dihydro-1- benzofuran-6-carboxylic acid (1.3 g, 3.98 mmol, 1.0 eq) in DMF (30 mL) and AcOH (10 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (0.56 g, 4.38 mmol, 1.5 eq) and NaBH(OAc) ₃ (1.68 g, 7.97 mmol, 2.0 eq). The mixture was stirred at room temperature overnight. The mixture was quenched with aqueous NH4Cl solution (50 mL) and diluted with ethyl acetate (100 mL x 3). The organic layer was washed with brine (50 mL x 3), dried over anhydrous Na ₂ SO ₄ , 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 79 275501297 v3 50%) to give 3-(3-((benzyloxy)methyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7 H-furo[2,3- e]isoindol-7-yl)piperidine-2,6-dione (1 g, yield 74%) as a light yellow solid. LC-MS (ESI): mass calcd. for C ₂₄ H ₂₄ N ₂ O ₅ , 420.17; m/z found, 421.2 [M+H] ⁺ . Step G: 3-(3-(hydroxymethyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7H-fu ro[2,3-e]isoindol-7- yl)piperidine-2,6-dione [000273] To a solution of 3-{3-[(benzyloxy)methyl]-3-methyl-6-oxo-2H,3H,6H,7H,8H- furo[2,3-e]isoindol-7-yl}piperidine-2,6-dione (1 g, 2.38 mmol, 1.0 eq) in Ethyl acetate (10 mL) was added 10% Pd/C (200 mg). The mixture was stirred under hydrogen (1 atm) at room temperature for 5 h. After filtration, the filtrate was concentrated to give 3-(3-(hydroxymethyl)- 3-methyl-6-oxo-2,3,6,8-tetrahydro-7H-furo[2,3-e]isoindol-7-y l)piperidine-2,6-dione (680 mg, yield 86%) as an off-white solid. LC-MS (ESI): mass calcd. for C17H18N2O5, 330; m/z found, 331.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 5.11 - 5.04 (m, 2H), 4.64 - 4.62 (md, 1H), 4.37 (d, J = 16.4 Hz, 1H), 4.25 - 4.18 (m, 2H), 3.55 - 3.39 (m, 2H), 2.97 - 2.80 (m, 1H), 2.65 - 2.58 (m, 1H), 2.49 - 2.42 (m, 1H), 1.99 - 1.96 (m, 1H), 1.319 (d, J = 3.2 Hz, 3H). Compound 2: 3-(3-(2-hydroxyethyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7H-f uro[2,3- e]isoindol-7-yl)piperidine-2,6-dione   Step A: methyl 4-bromo-2-formyl-3-hydroxybenzoate [000274] A solution of methyl 4-bromo-3-hydroxybenzoate (5 g, 21.64 mmol, 1.0 eq) and Hexamethylenetetramine (11.53 g, 82.24 mmol, 3.8 eq) in TFA (50 mL) was stirred at 90 ^o C for 18 h. After cooled to room temperature, the mixture was diluted with water (200 mL), stirred for 1 h, and filtered. The cake was slurried with methanol (50 mL), filtered, and dried to obtain methyl 4-bromo-2-formyl-3-hydroxybenzoate (3 g, yield 54%) as a white solid. LC- MS (ESI): mass calcd. for C9H7BrO4, 259.06; m/z found, 260.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.06 (s, 1H), 10.39 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 3.88 (s, 3H). Step B: 5-bromo-4-hydroxyisobenzofuran-1(3H)-one [000275] To a solution of methyl 4-bromo-2-formyl-3-hydroxybenzoate (3 g, 11.58 mmol, 1.0 eq) in MeOH (30 mL) was added NaBH4 (1.17 g, 34.74 mmol, 3.0 eq) in portions at 0 ^o C. Then 80 275501297 v3 the mixture was stirred at 65 ^o C for 16 h. After cooled to room temperature and the mixture was filtered. The filtration was concentrated under reduced pressure. The residue was diluted with water (60 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was slurried with MTBE (50 mL), filtered and dried to obtain 5- bromo-4-hydroxy-1,3-dihydro-2-benzofuran-1-one (2 g, yield 75%) as a white solid. LC-MS (ESI): mass calcd. for C ₈ H ₅ BrO ₃ , 229.03; m/z found, 230.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.34 (s, 2H). Step C: 4-(benzyloxy)-2-methylenebutanal [000276] To a solution of oxalic dichloride (2.859 mL, 33.287 mmol, 1.5 eq) in anhydrous DCM (160 mL) was added dropwise DMSO (4.73 mL, 66.57 mmol, 3.0 eq) under N2 at - 78 ^o C. After stirring for 20 min, a solution of 5-(benzyloxy)pentan-1-ol (4.0 g, 22.19 mmol, 1.0 eq) in DCM (30 mL) was added dropwise to above solution over 20 min and the resulting mixture was stirred at -78 ^o C for 1 h. TEA (15.42 mL, 110.95 mmol, 5.0 eq) was added to above mixture at -78 ^o C and the resulting mixture was stirred at 0 ^o C for 30 min. CH2NMe2Cl (4.13 g, 44.383 mmol, 2.0 eq) and DBU (3.31 mL, 22.19 mmol, 1.0 eq) were added to above mixture and the mixture was stirred 25 ^o C for 22 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL) and extracted with DCM (300 mL x 2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , 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 9%) to provide 4-(benzyloxy)-2-methylidenebutanal (1.7 g, yield 40%) as a colorless oil. LC-MS (ESI): mass calcd. for C ₁₂ H ₁₄ O ₂ , 190.2; m/z found, 191.3 [M+H] ⁺ . Step D: 4-(benzyloxy)-2-methylenebutan-1-ol [000277] To a solution of 2-[(benzyloxy)methyl]prop-2-enal (1.7 g, 9.64 mmol, 1.0 eq) in THF (50 mL) was added LiAlH ₄ (0.55 g, 14.47 mmol, 1.5 eq) in small portions over 5 min at 0 ^o C and the mixture was stirred at 0 ^o C for 30 min. The reaction mixture was cautiously quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (200 mL x 2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate (EA) in petroleum ether, from 20% to 30%) to provide 2- [(benzyloxy)methyl]prop-2-en-1-ol (1.5 g, yield 87%) as a colorless oil. LC-MS (ESI): mass calcd. for C ₁₂ H ₁₆ O ₂ , 192.2; m/z found, 193.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.38 - 7.27 (m, 5H), 4.99 (d, J = 2.0 Hz, 1H), 4.83 - 4.75 (m, 2H), 4.46 (s, 2H), 3.87 (d, J = 5.6 Hz, 81 275501297 v3 2H), 3.53 (t, J = 6.8 Hz, 2H), 2.27 (t, J = 6.8 Hz, 2H). Step E: 4-(4-(benzyloxy)-2-methylenebutoxy)-5-bromoisobenzofuran-1(3 H)-one [000278] A solution of 5-bromo-4-hydroxy-1,3-dihydro-2-benzofuran-1-one (1.8 g, 7.80 mmol, 1.0 eq), 4-(benzyloxy)-2-methylidenebutan-1-ol (1.5 g, 7.80 mmol, 1.0 eq), and PPh3 (3.0 g, 11.70 mmol, 1.5 equiv) in dry THF (20 mL) was stirred under N2 atmosphere at 0 ^o C for 10 min. Then DIAD (2.32 mL, 11.70 mmol, 1.5 equiv) was added dropwise to above mixture and the resulting solution was stirred at room temperature for 2 h. After evaporation, the residue was purified by flash column chromatography on silica gel (ethl acetate in petroleum ether, from 9% to 50%) to afford 4-(4-(benzyloxy)-2-methylenebutoxy)-5- bromoisobenzofuran-1(3H)-one (1.9 g, yield 61%) as a light-yellow oil. LC-MS (ESI): mass calcd. for C20H19BrO4, 402.05; m/z found, 231.2 [M+H] ⁺ . Step F: 3-(2-(benzyloxy)ethyl)-3-methyl-2,3-dihydrobenzo[2,1-b:3,4-c ']difuran-6(8H)-one and 3-(2-(benzyloxy)ethyl)-3,4-dihydro-2H-furo[3,4-h]chromen-7(9 H)-one [000279] To a solution of 4-(4-(benzyloxy)-2-methylenebutoxy)-5-bromoisobenzofuran- 1(3H)-one (7.7 g, 19.09 mmol, 1.0 eq) in toluene (100 mL) were added AIBN (627.3 mg, 3.82 mmol, 0.2 eq) and tributyltin hydride (15.4 mL, 57.28 mmol, 3.0 eq). The mixture was stirred under N ₂ at 110 ^o C in a sealed tube overnight. After cooled to room temperature, the mixture was quenched with saturated aqueous potassium fluoride solution (150 mL) and stirred for 2 h. Then the mixture was extracted with EA (150 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethl acetate in petroleum ether, from 9% to 50%) to give 3-(2-(benzyloxy)ethyl)-3-methyl-2,3- dihydrobenzo[2,1-b:3,4-c']difuran-6(8H)-one (1.7 g, yield 27%) as a white solid and 3-(2- (benzyloxy)ethyl)-3,4-dihydro-2H-furo[3,4-h]chromen-7(9H)-on e (2.1 g, yield 34%) as a white solid. [000280] 3-(2-(benzyloxy)ethyl)-3-methyl-2,3-dihydrobenzo[2,1-b:3,4-c ']difuran-6(8H)-one: LC-MS (ESI): mass calcd. for C20H20O4, 324.14; m/z found, 325.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.36 - 7.28 (m, 5H), 5.37 (s, 2H), 4.68 (d, J = 9.0 Hz, 1H), 4.44 (s, 2H), 4.37 (d, J = 9.0 Hz, 1H), 3.57 - 3.47 (m, 2H), 2.07 - 2.01 (m, 2H), 1.37 (s, 3H). [000281] 3-(2-(benzyloxy)ethyl)-3,4-dihydro-2H-furo[3,4-h]chromen-7(9 H)-one: LC-MS (ESI): mass calcd. for C ₂₀ H ₂₀ O ₄ , 324.14; m/z found, 325.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.37 - 7.28 (m, 7H), 5.30 (s, 2H), 4.52 (s, 2H), 4.39 - 4.31 (m, 1H), 3.90 (t, J = 9.2 Hz, 1H), 3.63 - 3.54 (m, 2H), 3.02 - 2.90 (m, 1H), 2.65 - 2.58 (m, 1H), 2.24 - 2.10 (m, 1H), 82 275501297 v3 1.72 – 1.52 (m, 2H). Step G: 3-(2-(benzyloxy)ethyl)-7-(hydroxymethyl)-3-methyl-2,3-dihydr obenzofuran-6- carboxylic acid [000282] To a solution of 3-(2-(benzyloxy)ethyl)-3-methyl-2,3-dihydrobenzo[2,1-b:3,4- c']difuran-6(8H)-one (100 mg, 0.307 mmol, 1.0 eq) in THF/MeOH/H2O (3/3/1, 7 mL) was added NaOH (49 mg, 1.233 mmol, 4.0 eq) and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with water (4 mL), acidified to pH 5-6 with diluted aqueous HCl solution (2 N), and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-(2-(benzyloxy)ethyl)-7-(hydroxymethyl)-3-methyl-2,3- dihydrobenzofuran-6-carboxylic acid (274.4 mg, yield 100%) as a brown oil. The crude product was directly used in the next step without further purification. LC-MS (ESI): mass calcd. for C ₂₀ H ₂₂ O ₅ , 342.15; m/z found, 341.2 [M-H]-. Step H: 3-(2-(benzyloxy)ethyl)-7-formyl-3-methyl-2,3-dihydrobenzofur an-6-carboxylic acid [000283] To a solution of 3-(2-(benzyloxy)ethyl)-7-(hydroxymethyl)-3-methyl-2,3- dihydrobenzofuran-6-carboxylic acid (274.44 mg, 0.802 mmol, 1.0 eq) in DCM (10 mL) was added Dess-Martin periodinane (680 mg, 1.603 mmol, 2.0 eq) in portions at 0 ^o C and the mixture was stirred for 1 h, After evaporation, the residue was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether, from 0% to 30%) to give 3-(2- (benzyloxy)ethyl)-7-(hydroxymethyl)-3-methyl-2,3-dihydrobenz ofuran-6-carboxylic acid (210 mg, yield 77%) as a colorless oil. LC-MS (ESI): mass calcd. for C20H20O5, 340.13; m/z found, 341.2 [M+H] ⁺ . Step I: 3-(2-(benzyloxy)ethyl)-7-(((2,6-dioxopiperidin-3-yl)amino)me thyl)-3-methyl-2,3- dihydrobenzofuran-6-carboxylic acid [000284] To a mixture of 3-(2-(benzyloxy)ethyl)-7-(hydroxymethyl)-3-methyl-2,3- dihydrobenzofuran-6-carboxylic acid (210 mg, 0.617 mmol, 1.0 eq) in methanol (5 mL) and DCM (5 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (158.10 mg, 1.23 mmol, 2.0 eq), sodium acetate (202.44 mg, 2.468 mmol, 4.0 eq), and AcOH (0.354 mL, 6.170 mmol, 10.0 eq). The mixture was stirred at 20 ^o C for 30 min. Then sodium cyanoborohydride (116.31 mg, 1.851 mmol, 3.0 eq) was added to above mixture and the mixture was further stirred for 30 min. The reaction mixture was quenched with water (3 mL) and concentrated under reduced pressure to give a crude product. The crude product was purified by Prep-TLC (DCM/MeOH = 10/1) to give 3-(2-(benzyloxy)ethyl)-7-(((2,6-dioxopiperidin-3-yl)amino)me thyl)-3-methyl- 2,3-dihydrobenzofuran-6-carboxylic acid (150 mg, yield 54%) as a blue solid. LC-MS (ESI): 83 275501297 v3 mass calcd. for C25H28N2O6, 452.19; m/z found, 453.2 [M+H] ⁺ . Step J: 3-(3-(2-(benzyloxy)ethyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro- 7H-furo[2,3-e]isoindol- 7-yl)piperidine-2,6-dione [000285] To a solution of 3-(2-(benzyloxy)ethyl)-7-(((2,6-dioxopiperidin-3-yl)amino)me thyl)- 3-methyl-2,3-dihydrobenzofuran-6-carboxylic acid (150 mg, 0.331 mmol, 1.0 eq) in DMF (3 mL) were added HATU (189.06 mg, 0.497 mmol, 1.5 eq) and N,N-Diisopropylethylamine (0.274 mL, 1.657 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 10 min. The reaction was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by Prep-TLC (100% EA) to give 3-{3-[2-(benzyloxy)ethyl]- 3-methyl-6-oxo-2H,3H,6H,7H,8H-furo[2,3-e]isoindol-7-yl}piper idine-2,6-dione (100 mg, yield 69%) as a white solid. LC-MS (ESI): mass calcd. for C25H26N2O5, 434.18; m/z found, 435.4 [M+H] ⁺ . Step K: 3-(3-(2-hydroxyethyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7H-f uro[2,3-e]isoindol-7- yl)piperidine-2,6-dione [000286] A mixture of 3-{3-[2-(benzyloxy)ethyl]-3-methyl-6-oxo-2H,3H,6H,7H,8H-furo [2,3- e]isoindol-7-yl}piperidine-2,6-dione (100 mg, 0.230 mmol, 1 equiv) and 10% Pd/C (25 mg) in 2,2,2-trifluoroethanol (20 mL) was stirred under H ₂ (1 atm) at room temperature for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Pprep-HPLC with YMC-Actus Triart C18 (5 µm, 21.2 x 250 mm), and mobile phase of 5-95% ACN in water (0.1% FA) over 23 min and then hold at 95% ACN for 3 min, at a flow rate of 20 mL/min to give 3-[3-(2-hydroxyethyl)-3-methyl-6-oxo-2H,3H,6H,7H,8H-furo[2,3 - e]isoindol-7-yl]piperidine-2,6-dione (79.2 mg, yield 100%) as a white solid. LC-MS (ESI): mass calcd. for C ₁₈ H ₂₀ N ₂ O ₅ , 344.13; m/z found, 345.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6) δ 10.97 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.59 (d, J = 8.8 Hz, 1H), 4.48 (t, J = 5.0 Hz, 1H), 4.39 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 4.21 (d, J = 17.2 Hz, 1H), 3.56 - 3.45 (m, 1H), 3.42 - 3.36 (m, 1H), 2.97 - 2.84 (m, 1H), 2.63 - 2.60 (m, 1H), 2.44 - 2.39 (m, 1H), 1.99 - 1.93 (m, 1H), 1.88 - 1.80 (m, 2H), 1.51 - 1.41 (m, 1H), 1.33 (s, 3H). Compound 3: 3-(3-(3-hydroxypropyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7H- furo[2,3- e]isoindol-7-yl)piperidine-2,6-dione 84 275501297 v3   Step A: 5-(benzyloxy)-2-methylenepentanal [000287] To a solution of Oxalyl Chloride (6.6 mL, 77.2 mmol, 1.5 eq) in anhydrous DCM (300 mL) was slowly added DMSO (10.9 mL, 154.4 mmol, 3.0 eq) at -78 ^o C and the mixture was stirred for 20 min. A solution of 5-(Benzyloxy)pentan-1-ol (10 g, 51.4 mmol, 1.0 eq) in anhydrous DCM (70 mL) was added dropwise to above mixture and the resulting mixture was stirred at -78 ^o C for 1 h. TEA (35.7 mL, 257.3 mmol, 5.0 eq) was added dropwise to above mixture at -78 ^o C and the mixture was heated to 0 ^o C. After 30 min, ESCHENMOSER'S SALT (9.63 g, 102.9 mmol, 2.0 eq) and DBU (7.84 g, 7.7 mL, 51.4 mmol, 1.0 eq) was added to above mixture and the mixture was stirred for 30 min. The reaction mixture was quenched with saturated aqueous NH ₄ Cl solution (120 mL) and extracted with DCM (120 mL x 3). The organic layer was washed with brine (300 mL), dried over anhydrous Na2SO4, 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 5%) to give 5- (benzyloxy)-2-methylenepentanal  (4.3 g, yield 40%) as a yellow oil. LC-MS (ESI): mass calcd. for C ₁₃ H ₁₆ O ₂ , 204.27; m/z found, 205.27 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.53 (s, 1H), 7.38 - 7.30 (m, 5H), 6.25 (s, 1H), 5.99 (s, 1H), 4.49 (s, 2H), 3.49 - 3.46 (m, 2H), 2.37 - 2.32 (m, 2H), 1.81 - 1.74 (m, 2H). Step B: 5-(benzyloxy)-2-methylenepentan-1-ol [000288] To a solution of 5-(benzyloxy)-2-methylenepentanal (4.3 g, 21.0 mmol, 1.0 eq) in THF (50 mL) was added LiAlH4 (0.4 g, 10.5 mmol, 0.5 eq) at 0 ^o C and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with Na ₂ SO ₄ ^. 10H ₂ O and filtered. The filtrate was concentrated under reduced pressure to give crude 5-(benzyloxy)-2-methylenepentan-1-ol (3.5 g, yield 80%) as a colorless oil. LC-MS (ESI): mass calcd. for C ₁₃ H ₁₈ O ₂ , 206.29; m/z found, 207.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 - 7.27 (m, 5H), 5.05 - 5.00 (m, 1H), 4.87 (d, J = 1.2 Hz, 1H), 4.50 (s, 2H), 4.06 (s, 2H), 3.50 (t, J = 6.4 Hz, 2H), 2.18 - 2.13 (m, 2H), 1.81 - 1.77 (m, 2H). Step C: 4-((5-(benzyloxy)-2-methylenepentyl)oxy)-5-bromoisobenzofura n-1(3H)-one [000289] To a solution of 5-bromo-4-hydroxy-1,3-dihydro-2-benzofuran-1-one (3.87 g, 16.9 mmol, 1.0 eq) and 5-(benzyloxy)-2-methylidenepentan-1-ol (3.49 g, 16.9 mmol, 1.0 eq), and PPh ₃ (5.32 g, 20.3 mmol, 1.2 eq) in dry THF (40 mL) was added dropwise DIAD (4.10 g, 85 275501297 v3 20.3 mmol, 1.2 eq) and the reaction mixture was stirred under N2 at room temperature for 16 h. The reaction mixture was quenched with water (50 ml) and extracted with EA (50 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroluem ether, from 0% to 11%) to give 4-((5- (benzyloxy)-2-methylenepentyl)oxy)-5-bromoisobenzofuran-1(3H )-one (6.8 g, yield 96%) as a colorless oil. LC-MS (ESI): mass calcd. for C H BrO , 417.3; m/z found, 418 ⁺ 21 21 4 .3 [M+H]. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35 - 7.27 (m, 5H), 5.05 - 5.00 (m, 1H), 5.68 (s, 2H), 5.25 (s, 1H), 5.02 (s, 1H), 4.71 (s, 2H), 4.46 (s, 2H), 4.06 (s, 2H), 3.48 (t, J = 6.4 Hz, 2H), 2.29 - 2.21 (m, 2H), 1.80 - 1.73 (m, 2H). Step D: 3-(3-(benzyloxy)propyl)-3-methyl-2,3-dihydrobenzo[2,1-b:3,4- c']difuran-6(8H)-one [000290] To a solution of 4-((5-(benzyloxy)-2-methylenepentyl)oxy)-5-bromoisobenzofura n- 1(3H)-one (1.0 g, 2.4 mmol, 1.0 eq) in toluene (25 mL) were added Bu3SnH (2.38 g, 9.6 mmol, 4.0 eq) and AIBN (80 mg, 479 µmol, 0.2 eq). The mixture was stirred at 100 ^o C in a sealed tube for 16 h. After cooled to room temperature, the reaction mixture was quenched with aqueous KF solution (20 mL), stirred for 2 h, and extracted with EA (20 mL x 3). The organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography with C18 spherical (20-35 µm, 100A), and mobile phase of 5%-70% ACN in H ₂ O (0.1% FA) over 16 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min to give 3-(3- (benzyloxy)propyl)-3-methyl-2,3-dihydrobenzo[2,1-b:3,4-c']di furan-6(8H)-one (370 mg, yield 45%) as a white solid. LC-MS (ESI): mass calcd. for C ₂₁ H ₂₂ O ₄ , 338.4; m/z found, 339.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.41 (q, J = 7.6 Hz, 2H), 7.35 - 7.26 (m, 5H), 5.35 (s, 2H), 4.55 (d, J = 9.0 Hz, 1H), 4.40 (s, 2H), 4.32 (d, J = 9.0 Hz, 1H), 3.37 (t, J = 6.4 Hz, 2H), 1.70 - 1.60 (m, 2H), 1.59 - 1.53 (m, 1H), 1.35 (s, 3H), 1.32 - 1.23 (m, 1H). Step E: 3-(3-(benzyloxy)propyl)-7-(hydroxymethyl)-3-methyl-2,3-dihyd robenzofuran-6- carboxylic acid [000291] To a solution of 3-(3-(benzyloxy)propyl)-3-methyl-2,3-dihydrobenzo[2,1-b:3,4- c']difuran-6(8H)-one (370 mg, 1.1 mmol, 1.0 eq) in THF (3 mL) and water (1.5 mL) were added NaOH (174.9 mg, 4.4 mmol, 4.0 eq). The mixture was stirred at 40 °C for 2 h. The mixture was cooled to room temperature, adjusted to pH 6 with aqueous HCl solution (1 N), and extracted with EA (30 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude 3-(3- 86 275501297 v3 (benzyloxy)propyl)-7-(hydroxymethyl)-3-methyl-2,3-dihydroben zofuran-6-carboxylic acid (400 mg, yield 102%) as a yellow oil. LC-MS (ESI): mass calcd. for C21H24O5, 356.42; m/z found, 355.4 [M-H]-. Step F: 3-(3-(benzyloxy)propyl)-7-formyl-3-methyl-2,3-dihydrobenzofu ran-6-carboxylic acid [000292] To a solution of 3-(3-(benzyloxy)propyl)-7-(hydroxymethyl)-3-methyl-2,3- dihydrobenzofuran-6-carboxylic acid (210 mg, 589 µmol, 1.0 eq) in DCM (10 mL) were added MnO ₂ (1.02 g, 11.7 mmol, 20.0 eq). The mixture was stirred at room temperature for 1 h. After filtered to remove MnO2, the filtrate was collected and concentrated under reduced pressure to give crude 3-(3-(benzyloxy)propyl)-7-formyl-3-methyl-2,3-dihydrobenzofu ran-6-carboxylic acid (160 mg, yield 76%) as a yellow oil. LC-MS (ESI): mass calcd. for C ₂₁ H ₂₂ O ₅ , 354.4; m/z found, 353.4 [M-H]-. Step G: 3-(3-(3-(benzyloxy)propyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro -7H-furo[2,3- e]isoindol-7-yl)piperidine-2,6-dione [000293] To a solution of 3-(3-(benzyloxy)propyl)-7-formyl-3-methyl-2,3- dihydrobenzofuran-6-carboxylic acid (250 mg, 705 µmol, 1.0 eq) in DMF (2.5 mL) and AcOH (0.2 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (135.5 mg, 1.06 mmol, 1.5 eq) and the mixture was stirred at 30 ^o C for 30 min. Sodium triacetoxyborohydride (446.4 mg, 2.1 mmol, 3.0 eq) was added to above mixture and the resulting mixture was stirred at 30 ^o C for 16 h. The reaction mixture was quenched with aqueous NH ₄ Cl solution (10 mL) and extracted with EA (5 mL x 4). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4, 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 70%) to give 3-(3-(3-(benzyloxy)propyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro -7H- furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (240 mg, yield 75%) as a blue solid. LC-MS (ESI): mass calcd. for C26H28N2O5, 448.52; m/z found, 449.5 [M+H] ⁺ . Step H: 3-(3-(3-hydroxypropyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7H- furo[2,3-e]isoindol-7- yl)piperidine-2,6-dione [000294] To a solution of 3-(3-(3-(benzyloxy)propyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro -7H- furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (40 mg, 89 µmol, 1.0 eq) in 2,2,2- trifluoroethanol (2 mL) was added 10% Pd/C (630 mg). The mixture was stirred in H ₂ atmosphere (1 atm) at 40 °C for 2 h. After evaporation, the filtrate was collected and concentrated under reduced pressure. The crude product was purified by Prep-TLC (DCM/MeOH = 10/1) to give 3-(3-(3-hydroxypropyl)-3-methyl-6-oxo-2,3,6,8-tetrahydro-7H- furo[2,3-e]isoindol-7-yl)piperidine-2,6-dione (24.2 g, yield 75%) as a white solid. LC-MS 87 275501297 v3 (ESI): mass calcd. for C19H22N2O5, 358.39; m/z found, 359.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 5.10 - 5.06 (m, 1H), 4.51 - 4.47 (m, 1H), 4.41 - 4.18 (m, 4H), 3.34 (s, 2H), 2.97 - 2.83 (m, 1H), 2.61 - 2.56 (m, 1H), 2.44 - 2.39 (m, 1H), 2.00 - 1.96 (m, 1H), 1.66 - 1.61 (m, 2H), 1.48 - 1.39 (m, 1H), 1.34 (d, J = 3.4 Hz, 3H), 1.18 - 1.172 (m, 1H). Compound 4: 3-(4-(2-hydroxyethyl)-8-oxo-2,3,4,5,8,10-hexahydro-9H-oxepin o[2,3- e]isoindol-9-yl)piperidine-2,6-dione Step A: (((5-bromo-3-methylenepentyl)oxy)methyl)benzene [000295] To a solution of 5-(benzyloxy)-3-methylidenepentan-1-ol (1 g, 4.8 mmol, 1.0 eq) and PPh3 (1.4 g, 5.3 mmol, 1.1 eq) in DCM (10 mL) was added CBr4 (1.8 g, 5.3 mmol, 1.1 eq) at 0 ^o C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EA = 20/1) to give (((5-bromo-3-methylenepentyl)oxy)methyl)benzene (1.0 g, yield 77%) as a yellow oil. LC-MS (ESI): mass calced for: C13H17BrO 268.0; m/z found, 269.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 7.28 - 7.15 (m, 5H), 4.84 (s, 1H), 4.80 (s, 1H), 4.45 (s, 2H), 3.50 (t, J = 6.8 Hz, 2H), 3.38 (t, J = 7.4 Hz, 2H), 2.52 (t, J = 7.4 Hz, 2H), 2.27 (t, J = 6.8 Hz, 2H). Step B: 4-((5-(benzyloxy)-3-methylenepentyl)oxy)-5-bromoisobenzofura n-1(3H)-one [000296] To a mixture of 5-bromo-4-hydroxy-1,3-dihydro-2-benzofuran-1-one (200 mg, 0.9 mmol, 1.0 eq) in DMF (5 mL) was added (((5-bromo-3-methylenepentyl)oxy)methyl)benzene (234.99 mg, 0.9 mmol, 1.0 eq) and K ₂ CO ₃ (362 mg, 2.6 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 80 ^o C overnight. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine (30 mL x 4), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50%) to give 4-((5- (benzyloxy)-3-methylenepentyl)oxy)-5-bromoisobenzofuran-1(3H )-one (200 mg, yield 55%) as a yellow oil. LC-MS (ESI): mass calced for: C21H21BrO4416.06; m/z found, 417.3 [M+H] ⁺ . ¹ H 88 275501297 v3 NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.26 - 7.19 (m, 5H), 5.23 (s, 2H), 4.88 (d, J = 5.2 Hz, 2H), 4.44 (s, 2H), 4.14 (t, J = 6.8 Hz, 2H), 3.55 (t, J = 6.8 Hz, 2H), 2.51 (t, J = 6.8 Hz, 2H), 2.36 (t, J = 6.8 Hz, 2H). Step C: 4-(2-(benzyloxy)ethyl)-2,3,4,5-tetrahydrooxepino[2,3-e]isobe nzofuran-8(10H)-one [000297] To a mixture of 4-{[5-(benzyloxy)-3-methylidenepentyl]oxy}-5-bromo-1,3-dihyd ro- 2-benzofuran-1-one (2.2 g, 5.272 mmol, 1.0 eq) and AIBN (1.73 g, 10.544 mmol, 2.0 eq) in Toluene (30 mL) was added Bu ₃ SnH (5.37 mL, 10.544 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred under N2 at 100 ^o C in a sealed tube overnight. The reaction mixture was cooled to room temperature, quenched with aqueous KF solution (50 mL), stirred for 2 h, and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), 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 50%) to afford 4-(2-(benzyloxy)ethyl)-2,3,4,5-tetrahydrooxepino[2,3- e]isobenzofuran-8(10H)-one (1.5 g, yield 84%) as a yellow oil. LC-MS (ESI): mass calced for: C21H22O4338.15; m/z found, 339.2 [M+H] ⁺ . ¹ HNMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 1H), 7.30 - 7.20 (m, 5H), 7.14 (d, J = 8.0 Hz, 1H), 5.18 (s, 2H), 4.45 (s, 2H), 4.27 - 4.44 (m, 1H), 3.84 - 3.78 (m, 1H), 3.51 - 3.47 (m, 2H), 2.79 - 2.75 (m, 2H), 1.98 - 1.90 (m, 2H), 1.75 - 1.59 (m, 2H), 1.32 - 1.28 (m, 1H). Step D: 4-(2-(benzyloxy)ethyl)-9-(hydroxymethyl)-2,3,4,5-tetrahydrob enzo[b]oxepine-8- carboxylic acid [000298] To a solution of 4-(2-(benzyloxy)ethyl)-2,3,4,5-tetrahydrooxepino[2,3- e]isobenzofuran-8(10H)-one (1.5 g, 4.433 mmol, 1.0 eq) in THF (20 mL) and MeOH (20 mL) was added dropwise aqueous NaOH solution (886.5 mg, 22.163 mmol, 5.0 eq) in water (10 mL) and the resulting mixture was stirred at 40 ℃ for 2 h. After evaporation, the residue was diluted with water (30 mL), acidified to pH 5-6 with diluted HCl solution (1 N), and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4-[2- (benzyloxy)ethyl]-9-(hydroxymethyl)-2,3,4,5-tetrahydro-1-ben zoxepine-8-carboxylic acid (1.5 g, yield 93%) as a yellow solid. The crude product was directly used in the next step without further purification. LC-MS (ESI): mass calced for: C ₂₁ H ₂₄ O ₅ 356.16; m/z found, 357.0 [M+H] ⁺ . Step E: 4-(2-(benzyloxy)ethyl)-9-formyl-2,3,4,5-tetrahydrobenzo[b]ox epine-8-carboxylic acid [000299] To a solution of 4-[2-(benzyloxy)ethyl]-9-(hydroxymethyl)-2,3,4,5-tetrahydro- 1- 89 275501297 v3 benzoxepine-8-carboxylic acid (1.5 g, 4.489 mmol，1.0 eq) in DCM (50 mL) was added active manganese dioxide (7.8 g, 89.782 mmol, 20.0 eq) in one portion at room temperature. The reaction mixture was stirred at room temperature for 1 h. After filtration, the filtrate was concentrated under reduced pressure to give 4-[2-(benzyloxy)ethyl]-9-formyl-2,3,4,5- tetrahydro-1-benzoxepine-8-carboxylic acid (1.3 g, yield 82%) as a yellow solid. The crude product was directly used in next step without further purification. LC-MS (ESI): mass calced for: C21H22O5354.15; m/z found, 355.0 [M+H] ⁺ . Step F: 3-(4-(2-(benzyloxy)ethyl)-8-oxo-2,3,4,5,8,10-hexahydro-9H-ox epino[2,3-e]isoindol-9- yl)piperidine-2,6-dione [000300] To a solution of 4-[2-(benzyloxy)ethyl]-9-formyl-2,3,4,5-tetrahydro-1-benzoxe pine- 8-carboxylic acid (1.3 g, 3.668 mmol, 1.0 eq) and 3-aminopiperidine-2,6-dione hydrochloride (0.71 g, 5.502 mmol, 1.5 eq) in DMF (20 mL) was added AcOH (2.11 mL, 37 mmol, 10.0 eq). The mixture was stirred at room temperature for 1 h. Then NaBH(OAc)3 (2.33 g, 11.00 mmol, 3.0 eq) was added to above mixture and the resulting reaction mixture was stirred at 40 ^o C overnight. After cooled to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (50 mL x 3). The organic layer was washed with brine (30 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 10/1) to give 3-(4- (2-(benzyloxy)ethyl)-8-oxo-2,3,4,5,8,10-hexahydro-9H-oxepino [2,3-e]isoindol-9- yl)piperidine-2,6-dione (780 mg, yield 55%) as a yellow solid. LC-MS (ESI): mass calced for: C ₂₆ H ₂₈ N ₂ O ₅ 448.20; m/z found, 449.2 [M+H] ⁺ . Step G: 3-(4-(2-hydroxyethyl)-8-oxo-2,3,4,5,8,10-hexahydro-9H-oxepin o[2,3-e]isoindol-9- yl)piperidine-2,6-dione [000301] To a solution of 3-(4-(2-(benzyloxy)ethyl)-8-oxo-2,3,4,5,8,10-hexahydro-9H- oxepino[2,3-e]isoindol-9-yl)piperidine-2,6-dione (610 mg, 1.360 mmol, 1.0 eq) in 2,2,2- trifluoroethanol (20 mL) was added 10% Pd/C (100 mg) at room temperature. The mixture was stirred under H2 (1 atm) at room temperature for 3 h. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with YMC-Actus Triart C18 (5 um, 20 x 250 mm), and mobile phase of 5-95% ACN in water (0.1% HCOOH) over 20 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min to give 3-(4-(2-hydroxyethyl)-8-oxo-2,3,4,5,8,10-hexahydro-9H-oxepin o[2,3-e]isoindol-9- yl)piperidine-2,6-dione (390 mg, yield 80%) as a white solid. LC-MS (ESI): mass calced for: C19H22N2O5358.15; m/z found, 359.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 90 275501297 v3 1H), 7.42 - 7.24 (m, 2H), 5.11 - 5.06 (m, 1H), 4.40 - 4.18 (m, 4H), 3.92 - 3.77 (m, 1H), 3.49 (t, J = 5.4 Hz, 2H), 2.97 - 2.82 (m, 2H), 2.83 - 2.69 (m, 1H), 2.67 - 2.56 (m, 1H), 2.45 - 2.42 (m, 1H), 2.00 - 1.95 (m, 2H), 1.84 - 1.81 (m, 1H), 1.77 - 1.67 (m, 1H), 1.49 - 1.42 (m, 2H). Compound 5: 3-(3-(2-hydroxyethyl)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]i soindol- 8(2H)-yl)piperidine-2,6-dione   Step A: 3-(2-(benzyloxy)ethyl)-8-(hydroxymethyl)chromane-7-carboxyli c acid [000302] To a solution of 3-(2-(benzyloxy)ethyl)-3,4-dihydro-2H-furo[3,4-h]chromen-7(9 H)- one (320 mg, 0.986 mmol, 1.0 eq) in THF/MeOH/H2O (3/3/1, 7 mL) was added NaOH (158 mg, 3.946 mmol, 4.0 eq) and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with water (4 mL), acidified to pH 5-6 with diluted aqueous HCl solution (2 N), and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 3-(2-(benzyloxy)ethyl)-8-(hydroxymethyl)chromane-7-carboxyli c acid (337.8 mg, yield 100%) as a brown oil. The crude product was directly used in the next step without further purification. LC-MS (ESI): mass calcd. for C20H22O5, 342.15; m/z found, 341.2 [M-H]-. Step B: 3-(2-(benzyloxy)ethyl)-8-formylchromane-7-carboxylic acid [000303] To a solution of 3-(2-(benzyloxy)ethyl)-8-(hydroxymethyl)chromane-7-carboxyli c acid (338 mg, 0.987 mmol, 1.0 eq) in DCM (10 mL) was added Dess-Martin periodinane (837 mg, 1.974 mmol, 2.0 eq) in portions at 0 ^o C and the mixture was stirred for 1 h, After evapoation, the residue was purified by flash silica gel column chromatography (ethyl acetate in petroleum ether, from 0% to 30%) to give 3-(2-(benzyloxy)ethyl)-8-formylchromane-7- carboxylic acid (180 mg, yield 54%) as a colorless oil. LC-MS (ESI): mass calcd. for C20H20O5, 340.13; m/z found, 341.2 [M+H] ⁺ . Step C: 3-(2-(benzyloxy)ethyl)-8-(((2,6-dioxopiperidin-3-yl)amino)me thyl)chromane-7- carboxylic acid [000304] To a mixture of 3-(2-(benzyloxy)ethyl)-8-formylchromane-7-carboxylic acid (180 mg, 0.529 mmol, 1.0 eq) in methanol (5 mL) and DCM (5 mL) were added 3-aminopiperidine- 2,6-dione hydrochloride (135.5 mg, 1.06 mmol, 2.0 eq), sodium acetate (100 mg, 1.586 mmol, 4.0 eq), and AcOH (0.303 mL, 5.288 mmol, 10.0 eq). The mixture was stirred at 20 ^o C for 30 91 275501297 v3 min. Then sodium cyanoborohydride (173.58 mg, 1.586 mmol, 3.0 eq) was added to above mixture and the mixture was further stirred for 30 min. The reaction mixture was quenched with water (3 mL) and concentrated under reduced pressure to give a crude product. The crude product was purified by Prep-TLC (DCM/MeOH = 10/1) to give 3-(2-(benzyloxy)ethyl)-8- (((2,6-dioxopiperidin-3-yl)amino)methyl)chromane-7-carboxyli c acid (150 mg, yield 63%) as a blue solid. LC-MS (ESI): mass calcd. for C ₂₅ H ₂₈ N ₂ O ₆ , 452.19; m/z found, 453.2 [M+H] ⁺ . Step D: 3-(3-(2-(benzyloxy)ethyl)-7-oxo-3,4,7,9-tetrahydropyrano[2,3 -e]isoindol-8(2H)- yl)piperidine-2,6-dione [000305] To a solution of 3-(2-(benzyloxy)ethyl)-8-(((2,6-dioxopiperidin-3- yl)amino)methyl)chromane-7-carboxylic acid (750 mg, 1.657 mmol, 1.0 eq) in DMF (2 mL) were added HATU (945.3 mg, 2.486 mmol, 1.5 eq) and N,N-Diisopropylethylamine (1.370 mL, 8.287 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 10 min. The reaction was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by prep-TLC (100% EA) to give 3-(3-(2-(benzyloxy)ethyl)-7-oxo-3,4,7,9- tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)piperidine-2,6-dion e (600 mg, yield 83%) as a white solid. LC-MS (ESI): mass calcd. for C ₂₅ H ₂₆ N ₂ O ₅ , 434.18; m/z found, 435.4 [M+H] ⁺ . Step E: 3-(3-(2-hydroxyethyl)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]i soindol-8(2H)- yl)piperidine-2,6-dione [000306] A mixture of 3-(3-(2-(benzyloxy)ethyl)-7-oxo-3,4,7,9-tetrahydropyrano[2,3 - e]isoindol-8(2H)-yl)piperidine-2,6-dione (30 mg, 0.069 mmol, 1 equiv) and 10% Pd/C (10 mg) in 2,2,2-trifluoroethanol (10 mL) was stirred under H2 (1 atm) at room temperature for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with YMC-Actus Triart C18 (5 µm, 21.2 x 250 mm), and mobile phase of 5- 95% ACN in water (0.1% FA) over 23 min and then hold at 95% ACN for 3 min, at a flow rate of 20 mL/min to give 3-(3-(2-hydroxyethyl)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]i soindol- 8(2H)-yl)piperidine-2,6-dione (23 mg, yield 99%) as a white solid. LC-MS (ESI): mass calcd. for C18H20N2O5, 344.13; m/z found, 345.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.24 - 7.16 (m, 2H), 5.32 (t, J = 4.8 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.36 - 4.10 (m, 3H), 3.92 - 3.79 (m, 1H), 3.55 (t, J = 5.4 Hz, 2H), 2.99 - 2.86 (m, 2H), 2.62 - 2.57 (m, 1H), 2.45 - 2.37 (m, 1H), 2.20 - 2.10 (m, 1H), 2.02 - 1.95 (m, 1H), 1.53 - 1.42 (m, 2H), 1.36 - 1.30 (m, 1H). Compound 8: 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-2,3,8,9-tetrahydrop yrano[2,3- e]isoindole-4,7-dione 92 275501297 v3 [000307] To a solution of 3-(2,2-dimethyl-7-oxo-2,3,7,9-tetrahydro-8H-spiro[pyrano[2,3 - e]isoindole-4,2'-[1,3]dioxolan]-8-yl)piperidine-2,6-dione (2.6 g, 6.7 mmol, 1.0 eq) in acetone (15 mL) was added aqueous HCl solution (4 N) (5 mL, 20.0 mmol, 3.0 eq) and the reaction mixture was stirred at room temperature for 3 h. The reaction was diluted with EA (60 mL), washed with saturated NaHCO ₃ solution (10 mL x 3) and brine (10 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-2,3,8,9-tetrahydrop yrano[2,3-e]isoindole-4,7-dione (1.9 g, yield 82%) as an off-white solid. LC-MS (ESI): mass calcd. for C18H18N2O5, 342.12; m/z found, 343.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.01 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 5.16 - 5.11 (m, 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 17.2 Hz, 1H), 2.97 - 2.85 (m, 3H), 2.68 - 2.54 (m, 1H), 2.45 - 2.40 (m, 1H), 1.98 - 1.93 (m, 1H), 1.44 (d, J = 2.0 Hz, 6H). Compound 9: 3-(4-hydroxy-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3 -e]isoindol- 8(2H)-yl)piperidine-2,6-dione [000308] To a solution of 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-2,3,8,9- tetrahydropyrano[2,3-e]isoindole-4,7-dione (40 mg, 0.12 mmol, 1.0 eq) in THF (5 mL) was added NaBH4 (14 mg, 0.36 mmol, 3.0 eq) in portions. The reaction mixture was stirred at 40 ℃ for 3 h. After cooled to room temperature, the reaction mixture was diluted with EA (30 mL) and quenched with water (10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified with Prep-HPLC with YMC-Actus Triart C18 (5 µm, 21.2 x 250 mm), and mobile phase of 5-95% ACN in water (0.1% FA) over 23 min and then hold at 95% ACN for 3 min, at a flow rate of 20 mL/min to afford 3-(4-hydroxy-2,2-dimethyl-7-oxo-3,4,7,9- tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)piperidine-2,6-dion e (17.4 mg, yield 43%) as an off- 93 275501297 v3 white solid. LC-MS (ESI): mass calcd. for C18H20N2O5, 344.14; m/z found, 345.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.57 (d, J = 6.2 Hz, 1H), 5.10 - 5.06 (m, 1H), 4.81 - 4.67 (m, 1H), 4.29 (d, J = 17.23 Hz, 1H), 4.13 (d, J = 17.2 Hz, 1H), 2.99 - 2.82 (m, 1H), 2.60 - 2.54 (m, 1H), 2.47 - 2.38 (m, 1H), 2.21 - 2.11 (m, 1H), 1.99 - 1.97 (m, 1H), 1.85 - 1.72 (m, 1H), 1.41 (s, 3H), 1.29 (s, 3H). Compound 10: 3-(4-amino-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e ]isoindol- 8(2H)-yl)piperidine-2,6-dione Step A: (E)-3-(4-(hydroxyimino)-2,2-dimethyl-7-oxo-3,4,7,9-tetra hydropyrano[2,3-e]isoindol- 8(2H)-yl)piperidine-2,6-dione [000309] To a solution of 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-2,3,8,9- tetrahydropyrano[2,3-e]isoindole-4,7-dione (350 mg, 1.0 mmol, 1.0 eq) in EtOH (10 mL) were added pyridine (0.25 mL, 3.1 mmol, 3.1 eq) and hydroxylamine hydrochloride (0.25 mL, 3.1 mmol, 3.1 eq). The reaction mixture was stirred under N2 at 70 ℃ for 3 h. After cooled to room temperature, the reaction mixture was evaporated and the residue was diluted with EA (100 mL). The organic layer was washed with saturated NH4Cl solution (20 mL x 3) and brine(20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA/PE = 2/1) to afford (E)-3-(4-(hydroxyimino)-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydr opyrano[2,3-e]isoindol-8(2H)- yl)piperidine-2,6-dione (342 mg, yield 94%) as an off-white solid. LC-MS (ESI): mass calcd. for C ₁₈ H ₁₉ N ₃ O ₅ , 357.13; m/z found, 358.2 [M+H] ⁺ . Step B: 3-(4-amino-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e ]isoindol-8(2H)- yl)piperidine-2,6-dione [000310] To a solution of (E)-3-(4-(hydroxyimino)-2,2-dimethyl-7-oxo-3,4,7,9- tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)piperidine-2,6-dion e (342 mg, 0.96 mmol, 1.0 eq) in AcOH (10 mL) was added Zn powder (936 mg, 14.4 mmol, 15.0 eq). The reaction mixture was stirred at 120 ℃ for 1.5 h. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EA (100 mL), washed with saturated aqueous NaHCO3 solution (20 mL x 3) and brine (20 mL), dried 94 275501297 v3 over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/EtOH = 10/1) to afford 3- (4-amino-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]i soindol-8(2H)-yl)piperidine- 2,6-dione (150 mg, yield 45%) as an off-white solid. LC-MS (ESI): mass calcd. for C18H21N3O4, 343.15; m/z found, 344.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.29 (d, J = 17.2 Hz, 1H), 4.21 - 4.10 (m, 2H), 2.96 - 2.85 (m, 1H), 2.61 - 2.55 (m, 1H), 2.49 - 2.37 (m, 1H), 2.22 - 2.12 (m, 1H), 2.01 - 1.93 (m, 1H), 1.76 - 1.61 (m, 1H), 1.42 (s, 3H), 1.26 (s, 3H). Compound 11: N-(8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-2,3,4,7,8, 9-hexahydro pyrano[2,3-e]isoindol-4-yl)acetamide   [000311] To a solution of 3-(4-amino-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3- e]isoindol-8(2H)-yl)piperidine-2,6-dione (50 mg, 146 ummol, 1.0 eq) in DCM (5 mL) were added DIPEA (0.072 mL, 437 umol, 3.0 eq) and Ac2O (0.021 mL, 218 umol, 1.5 eq). The reaction was stirred at room temperature for 1.5 h. The mixture was diluted with DCM (20 mL), washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeCN = 1/1) to give N-(8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-2,3,4,7,8, 9- hexahydropyrano[2,3-e]isoindol-4-yl)acetamide (39.5 mg, yield 70%) as an off-white solid. LC-MS (ESI): mass calcd. for C20H23N3O5, 385.16; m/z found, 386.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.96 (d, J = 4.4 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.16 - 5.07 (m, 2H), 4.30 (d, J = 17.4 Hz, 1H), 4.20 - 4.14 (m, 1H), 2.99 - 2.81 (m, 1H), 2.62 - 2.54 (m, 1H), 2.44 - 2.35 (m, 1H), 2.13 - 2.05 (m, 1H), 2.02 - 1.95 (m, 1H), 1.94 (s, 3H), 1.83 - 1.72 (m, 1H), 1.42 (s, 3H), 1.30 (s, 3H). Compound 12: N-(8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-2,3,4,7,8, 9-hexahydro pyrano[2,3-e]isoindol-4-yl)methanesulfonamide 95 275501297 v3 [000312] To a solution of 3-(4-amino-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3- e]isoindol-8(2H)-yl)piperidine-2,6-dione (50 mg, 146 ^mmol, 1.0 eq) in DCM (5 mL) were added DIPEA (0.028 mL, 218 ^mol, 1.5 eq) and Ms ₂ O (0.021 mL, 218 ^mol, 1.5 eq). The reaction was stirred at room temperature for 1.5 h. The mixture was diluted with DCM (20 mL), washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeCN = 1/2) to give N-(8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-2,3,4,7,8, 9- hexahydropyrano[2,3-e]isoindol-4-yl)methanesulfonamide (7.0 mg, yield 11%) as an off-white solid. LC-MS (ESI): mass calcd. for C19H23N3O6S, 421.13; m/z found, 422.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 7.71 - 7.67 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.12 - 5.07 (m, 1H), 4.71 - 4.55 (m, 1H), 4.30 (d, J = 17.4 Hz, 1H), 4.22 - 4.10 (m, 1H), 3.13 (s, 3H), 2.99 - 2.83 (m, 1H), 2.61 - 2.55 (m, 1H), 2.47 - 2.41 (m, 1H), 2.35 - 2.29 (m, 1H), 2.00 - 1.95 (m, 1H), 1.91 - 1.81 (m, 1H), 1.43 (s, 3H), 1.31 (s, 3H). Compound 13: 3-(4-(aminomethyl)-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydropyra no[2,3- e]isoindol-8(2H)-yl)piperidine-2,6-dione Step A:  8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-4-((trimethyl silyl)oxy)-2,3,4,7,8,9- hexahydropyrano[2,3-e]isoindole-4-carbonitrile [000313] To a solution of 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-2,3,8,9- tetrahydropyrano[2,3-e]isoindole-4,7-dione (750 mg, 2.19 mmol, 1.0 eq) in anhydrous DCM (15.0 mL) were added anhydrous ZnI2 (210 mg, 657 µmol, 0.3 eq) and TMSCN (2.17 g, 2.87 mL, 21.9 mmol, 10.0 eq). The reaction mixture was stirred under N2 at room temperature for 36 h. The reaction mixture was diluted with EA (150 mL), washed with saturated aqueous NaHCO ₃ solution (15 mL x 2) and brine (15 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column 96 275501297 v3 chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50%) to afford 8- (2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-4-((trimethylsi lyl)oxy)-2,3,4,7,8,9- hexahydropyrano[2,3-e]isoindole-4-carbonitrile (950 mg, yield 98%) as a yellow solid. LC- MS (ESI): mass calcd. for C22H27N3O5Si, 441.17; m/z found, 442.2 [M+H] ⁺ . Step B: 3-(4-(aminomethyl)-2,2-dimethyl-7-oxo-3,4,7,9-tetrahydropyra no[2,3-e]isoindol- 8(2H)-yl)piperidine-2,6-dione [000314] To a solution of 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-4- ((trimethylsilyl)oxy)-2,3,4,7,8,9-hexahydropyrano[2,3-e]isoi ndole-4-carbonitrile (50.0 mg, 113 µmol, 1.0 eq) in EtOH (4.00 mL) were added con. HCl (1.00 mL, 12.0 mmol, 106 Eq) and 10% Pd/C (12.1 mg, 113 µmol, 1.0 eq). The reaction mixture was stirred under H ₂ atmosphere (1 atm) at 12 °C for 18 h. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (EtOH in DCM, from 0% to 20%) to afford a crude product (30 mg). The crude product was further purified by Prep-HPLC with YMC-Actus Triart C18 (5 µm, 21.2 x 250 mm), and mobile phase of 5-95% ACN in water (0.1% FA) over 23 min and then hold at 95% ACN for 3 min, at a flow rate of 20 mL/min to afford 3-(4-(aminomethyl)-2,2-dimethyl-7-oxo-3,4,7,9- tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)piperidine-2,6-dion e formate (1.70 mg, yield 4.2%) as a white solid. LC-MS (ESI): mass calcd. for C19H23N3O4, 357.17; m/z found, 358.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 8.31 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.28 (d, J = 17.2 Hz, 1H), 4.12 (d, J = 17.3 Hz, 1H), 3.06 - 3.01 (m, 1H), 2.93 - 2.84 (m, 2H), 2.63 - 2.54 (m, 1H), 2.48 - 2.38 (m, 2H), 2.11 - 2.03 (m, 1H), 2.02 - 1.93 (m, 1H), 1.74 - 1.62 (m, 1H), 1.43 (s, 3H), 1.22 (s, 3H). Compound 14: 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-2,7,8,9- tetrahydropyrano[2,3-e]isoindole-4-carbonitrile [000315] To a solution of 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo-4- ((trimethylsilyl)oxy)-2,3,4,7,8,9-hexahydropyrano[2,3-e]isoi ndole-4-carbonitrile (30.0 mg, 67.9 µmol, 1.0 eq) in Toluene (4.00 mL) was added p-toluenesulfonic acid (2.34 mg, 13.6 µmol, 0.2 eq). The reaction mixture was stirred under N2 at 100 °C for 18 h. After evaporation, 97 275501297 v3 the residue was purified by Prep-HPLC with YMC-Actus Triart 18C (5 µm, 20 x 250 mm), and mobile phase of 5-99% ACN in water (0.1% FA) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min to afford 8-(2,6-dioxopiperidin-3-yl)-2,2-dimethyl-7-oxo- 2,7,8,9-tetrahydropyrano[2,3-e]isoindole-4-carbonitrile (8.00 mg, yield 33%) as a white solid. LC-MS (ESI): mass calcd. for C19H17N3O4, 351.12; m/z found, 352.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.99 (s, 1H), 7.41 (s, 2H), 7.06 (s, 1H), 5.13 - 5.08 (m, 1H), 4.40 (d, J = 17.4 Hz, 1H), 4.23 (d, J = 17.4 Hz, 1H), 2.97 - 2.83 (m, 1H), 2.64 - 2.54 (m, 1H), 2.47 - 2.36 (m, 1H), 2.04 - 1.94 (m, 1H), 1.49 (s, 6H). Compound 15: 3-(7- (hydroxymethyl)-7-methyl-3-oxo-1,3,7,8-tetrahydro-2H-furo[3, 2- e]isoindol-2-yl)piperidine-2,6-dione Step A: 5-((2- methylallyl)oxy)isobenzofuran-1(3H)-one [000316] To a solution of 5-hydroxyisobenzofuran-1(3H)-one (5.00 g, 33.3 mmol, 1.0 eq) in DMF (30.0 mL) were added cesium carbonate (32.6 g, 99.9 mmol, 3.0 eq) and 3-bromo-2- methylprop-1-ene (4.37 mL, 43.3 mmol, 1.3 eq) at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EA (80 mL) and filtered. The filtrate was washed with brine (60 mL x 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 20%) to afford 5- ((2- methylallyl)oxy)isobenzofuran-1(3H)-one (6 g, yield 88%) as a white solid. LC-MS (ESI): mass calcd. for C12H12O3, 204.1; m/z found, 205.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.75 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.4, 2.0 Hz, 1H), 5.33 (s, 2H), 5.07 (s, 1H), 4.99 (s, 1H), 4.61 (s, 2H), 1.78 (s, 3H). Step B: 5-hydroxy-4-(2- methylallyl)isobenzofuran-1(3H)-one [000317] A solution of 5-((2-methylallyl)oxy)isobenzofuran-1(3H)-one (220 mg, 1.08 mmol, 1.0 eq) in 1-methylpyrrolidin-2-one (6.00 mL) was stirred under microwave at 150 oC for 1 h. After cooled to room temperature, the reaction mixture was diluted with EA (30 mL), washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate 98 275501297 v3 in petroleum ether, from 0% to 20%) to afford 5-hydroxy-4-(2- methylallyl)isobenzofuran- 1(3H)-one (100 mg, yield 50%) as a white solid. LC-MS (ESI): mass calcd. for C12H12O3, 204.1; m/z found, 205.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.22 (s, 2H), 4.73 (s, 1H), 4.54 (s, 1H), 3.30 (s, 2H), 1.68 (s, 3H) Step C: 5-hydroxy-4-((2-methyloxiran-2-yl)methyl)isobenzofuran-1(3H) -one [000318] To a solution of 5-hydroxy-4-(2-methylallyl)isobenzofuran-1(3H)-one (670 mg, 3.28 mmol, 1.0 eq) in DCM (15.0 mL) was added m-CPBA (85%) (906 mg, 5.25 mmol, 1.6 eq). The reaction was stirred at 40 ^o C for 1 h. After cooled to room temperature, the reaction was diluted with EA (40 mL), washed with saturated aqueous NaHCO ₃ solution (20 mL x 2) and brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get 5-hydroxy-4-((2-methyloxiran-2-yl)methyl)isobenzofuran-1(3H) -one (700 mg, yield 98%) as a yellow solid. The crude product was directly used in next step without further purification. LC-MS (ESI): mass calcd. for C12H12O4, 220.2; m/z found, 221.1 [M+H] ⁺ . Step D: (7-methyl-3-oxo-1,3,7,8-tetrahydrobenzo[1,2-b:3,4-c']difuran -7-yl)methyl formate [000319] A solution of 5-hydroxy-4-((2-methyloxiran-2-yl)methyl)isobenzofuran-1(3H) -one (700 mg, 3.18 mmol, 1 eq) in HCOOH (8.00 mL) was stirred at 90 ^o C for 30 min. After evaporation, the residue was diluted with EA (40 mL), washed with saturated aqueous NaHCO3 solution (20 mL x 2) and brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30%) to afford (7- methyl-3-oxo-1,3,7,8-tetrahydrobenzo[1,2-b:3,4-c']difuran-7- yl)methyl formate (370 mg, yield 46%) as a colorless oil. LC-MS (ESI): mass calcd. for C ₁₃ H ₁₂ O ₅ , 248.2; m/z found, 249.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.32 (s, 2H), 4.31 (s, 2H), 3.24 (d, J = 16.4 Hz, 1H), 3.05 (d, J = 16.4 Hz, 1H), 1.49 (s, 3H). Step E: 2,4-bis(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5- carboxylic acid [000320] To a solution of (7-methyl-3-oxo-1,3,7,8-tetrahydrobenzo[1,2-b:3,4-c']difuran -7- yl)methyl formate (680 mg, 2.74 mmol, 1.0 eq) and NaOH (0.55 g, 13.7 mmol, 5.0 eq) in THF/MeOH/H ₂ O (7.0 mL 3 mL/3 mL/1 mL) and the reaction mixture was stirred at 50 ^o C for 1 h. After cooled to room temperature, the reaction mixture was diluted with EA (50 mL), adjusted to pH 4-5 with diluted aqueous HCl solution (3 M), and extracted with EA (40 mL x 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2,4-bis(hydroxymethyl)-2-methyl- 99 275501297 v3 2,3-dihydrobenzofuran-5-carboxylic acid (600 mg, yield 92%) as a colorless oil. The crude product was directly used in next step without further purification. LC-MS (ESI): mass calcd. for C ₁₂ H ₁₄ O ₅ , 238.2; m/z found, 237.1 [M-H]-. Step F: 1-hydroxy-7-(hydroxymethyl)-7-methyl-7,8-dihydrobenzo[1,2-b: 3,4-c']difuran-3(1H)- one [000321] To a solution of 2,4-bis(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5- carboxylic acid (600 mg, 2.52 mmol, 1.0 eq) in DMF (20.0 mL) was added MnO ₂ (4.38 g, 13.7 mmol, 20.0 eq). The mixture was stirred at room temperature for 12 h. After filtration, the filtrate was collected and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methanol in dichloromethane, from 0% to 10%) to afford 1-hydroxy-7-(hydroxymethyl)-7-methyl-7,8-dihydrobenzo[1,2-b: 3,4-c']difuran-3(1H)- one (310 mg, yield 52%) as a white solid. LC-MS (ESI): mass calcd. for C12H12O5, 236.2; m/z found, 235.0 [M-H]-. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.57 (s, 1H), 5.17 (t, J = 5.6 Hz, 1H), 3.52 - 3.44 (m, 2H), 3.28 (d, J = 16.4 Hz, 1H), 2.90 (d, J = 16.4 Hz, 1H), 1.38 (s, 3H). Step G: 3-(7- (hydroxymethyl)-7-methyl-3-oxo-1,3,7,8-tetrahydro-2H-furo[3, 2-e]isoindol-2- yl)piperidine-2,6-dione [000322] To a solution of 3-aminopiperidine-2,6-dione hydrochloride (418 mg, 2.54 mmol, 1.5 eq) in DMF (10.0 mL) was added TEA (257 mg, 2.54 mmol, 0.35 mL, 2.0 eq) and the reaction mixture was stirred at 40 ^o C for 10 min. Then 1-hydroxy-7-(hydroxymethyl)-7-methyl-7,8- dihydrobenzo[1,2-b:3,4-c']difuran-3(1H)-one (300 mg, 1.27 mmol, 1.0 eq) and acetic acid (0.52 g, 8.7 mmol, 0.50 mL, 6.8 eq) were added to above mixture and the resulting mixture was stirred at 40 ^o C for 2 h. Then Sodium triacetoxyborohydride (565 mg, 2.67 mmol, 3.0 eq) was added to above mixture and the resulting mixture was stirred at 40 ^o C for 16 h. After cooled to room temperature, the mixture was diluted with EA (50 mL), washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methanol in dichloromethane, from 0% to 10%) to afford 3-(7- (hydroxymethyl)-7-methyl-3-oxo-1,3,7,8- tetrahydro-2H-furo[3,2-e]isoindol-2-yl)piperidine-2,6-dione (340.0 mg, yield 81%) as a gray solid. LC-MS (ESI): mass calcd. for C ₁₇ H ₁₈ N ₂ O ₅ , 330.3; m/z found, 331.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.12 - 5.06 (m, 2H), 4.34 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.2 Hz, 1H), 3.50 - 3.45 (m, 2H), 3.21 (d, J = 16.0 Hz, 1H), 2.97 - 2.85 (m, 2H), 2.61 - 2.56 (m, 1H), 2.44 - 2.30 (m, 1H), 2.01 - 1.92 (m, 1H), 1.38 (s, 3H). 100 275501297 v3 Compound 16: 3-(4-(2-aminoethyl)-4-methyl-6-oxo-3,4,6,8-tetrahydropyrano[ 2,3- f]isoindol-7(2H)-yl)piperidine-2,6-dione [000323] To a solution of freshly distilled TMEDA (13.9 g, 120 mmol, 2.0 eq) in THF (30 mL) was added dropwise n-BuLi (2.5 M in hexane) (75 mL, 120 mmol) at 0 °C and the mixture was stirred for 15 min. A solution of 3-methylbut-3-en-1-ol (6.1 mL, 60 mmol, 1.0 eq) in THF (20 mL) was added dropwise to above mixture over 15 min and the reaction mixture allowed to warm to temperature over 30 min. The reaction mixture was then vigorously stirred for 15 h at room temperature to give a pale yellow suspension, diluted with freshly distilled THF (30 mL), and cooled to –78 °C before addition of dry paraformaldehyde (1.9 g, 63.0 mmol, 1.05 eq) in one portion. The reaction mixture was then allowed to warm to room temperature over 1 h and stirred vigorously overnight. The reaction mixture was quenched with saturated aqueous NH4Cl solution (50 mL) and the aqueous layer was extracted with CHCl3/i-PrOH (8/2, 100 mL x 5). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue purified by flash column chromatography on silica gel (100% EA) to give 3-methylidenepentane-1,5-diol (1.7 g, yield 24%) as a light yellow oil. LC- MS (ESI): C6H12O2 mass calcd. for 116.1; m/z found, 117.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.97 (s, 2H), 3.75 (t, J = 6.2 Hz, 4H), 2.32 (t, J = 6.2 Hz, 4H). Step B: 5-(benzyloxy)-3-methylenepentan-1-ol [000324] To a solution of 3-methylidenepentane-1,5-diol (1.7 g, 15 mmol, 1.0 eq) in DCM (30 mL) were added Silver(I) Oxide (6.8 g, 30 mmol, 2.0 eq) and Benzyl bromide (2.7 g, 15 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (100% EA) to give 5-(benzyloxy)-3-methylidenepentan-1-ol (2.1 g, yield 70%) as a yellow oil. LC-MS (ESI): C13H18O2 mass calcd. for 206.1; m/z found, 207.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 - 7.18 (m, 5H), 4.88 - 4.81 (m, 2H), 4.44 (s, 2H), 3.63 (t, J = 6.2 Hz, 2H), 3.53 (t, J = 6.8 Hz, 2H), 2.31 - 2.22 (m, 4H). 101 275501297 v3 Step C: methyl 5-((5-(benzyloxy)-3-methylenepentyl)oxy)-4-bromo-2-methylben zoate [000325] To a solution of methyl 4-bromo-5-hydroxy-2-methylbenzoate (4.2 g, 17.1 mmol, 1.0 eq)，5-(benzyloxy)-3-methylidenepentan-1-ol (4.24 g, 20.6 mmol, 1.2 eq), and PPh ₃ (5.39 g, 20.6 mmol, 1.2 eq) in THF (45 mL) was added dropwise DIAD (4.16 g, 20.6 mmol, 1.2 eq). The mixture was stirred under N2 at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL x 3). The organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from )5 to 6%) to give methyl 5-((5-(benzyloxy)-3- methylenepentyl)oxy)-4-bromo-2-methylbenzoate (6.6 g, yield 88%) as a colorless oil. LC-MS (ESI): mass calcd. for C ₂₂ H ₂₅ BrO ₄ , 433.34; m/z found, 434.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.59 (s, 1H), 7.44 (s, 1H), 7.34 - 7.25 (m, 5H), 4.91 (d, J = 13.8 Hz, 2H), 4.47 (s, 2H), 4.16 (t, J = 6.6 Hz, 2H), 3.83 (s, 3H), 3.58 (t, J = 6.8 Hz, 2H), 2.49 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H), 2.39 (t, J = 6.8 Hz, 2H). Step D: methyl 4-(2-(benzyloxy)ethyl)-4,6-dimethylchromane-7-carboxylate [000326] To a solution of methyl 5-((5-(benzyloxy)-3-methylenepentyl)oxy)-4-bromo-2- methylbenzoate (6.6 g, 15.2 mmol, 1.0 eq) in DMF (66 mL) were added NaOAc (3.37 g, 41.1 mmol, 2.7 eq), sodium formate (1.35 g, 19.8 mmol, 1.3 eq), Tetraethylammonium chloride monohydrate (3.64 g, 19.8 mmol, 1.3 eq), and Pd(OAc) ₂ (340 mg, 1.5 mmol, 0.1 eq). The mixture was stirred under N2 at 90 ^o C for 3 h. After cooled to room temperature, the reaction mixture was quenched with water (120 mL) and extracted with EA (90 mL x 3). The organic layer was washed with brine (100 mL x 4), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroluem ether, from 0% to 5%) to give methyl 4-(2-(benzyloxy)ethyl)-4,6-dimethylchromane-7-carboxylate (3.5 g, yield 64%) as a colorless oily. LC-MS (ESI): mass calcd. for C22H26O4, 354.45; m/z found, 355.45 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d6) δ 7.38 - 7.30 (m, 6H), 7.22 (s, 1H), 4.46 (s, 2H), 4.24 - 4.20 (m, 1H), 4.16 - 4.10 (m, 1H), 3.85 (s, 3H), 3.54 - 3.44 (m, 2H), 2.46 (s, 3H), 2.10 - 1.97 (m, 3H), 2.07 - 2.00 (m, 1H), 1.36 (s, 3H). Step E: methyl 4-(2-hydroxyethyl)-4,6-dimethylchromane-7-carboxylate [000327] To a solution of methyl 4-(2-(benzyloxy)ethyl)-4,6-dimethylchroman-7-carboxylate (3.0 g, 8.5 mmol, 1.0 eq) in MeOH (30 mL) was added 10% Pd/C (300 mg). The mixture was stirred under H2 (1 atm) at room temperature for 10 h. After filtration, the filtrate was 102 275501297 v3 concentrated under reduced pressure to afford methyl 4-(2-hydroxyethyl)-4,6- dimethylchroman-7-carboxylate (2.0 g, yield 89%) as a colorless oil. The crude product was directly used in next step without further purification. LC-MS (ESI): mass calcd. for C ₁₅ H ₂₀ O ₄ , 264.1; m/z found, 265.1 [M+H] ⁺ . Step F: methyl 4-(2-bromoethyl)-4,6-dimethylchroman-7-carboxylate [000328] To a solution of methyl 4-(2-hydroxyethyl)-4,6-dimethylchroman-7-carboxylate (1.5 g, 5.67 mmol, 1.0 eq) and PPh ₃ (1.94 g, 7.38 mmol, 1.3 eq) in DCM (30 mL) was added CBr ₄ (2.26 g, 6.81 mmol, 1.2 eq) at 0 ^o C. The mixture was stirred under N2 at 25 ^o C overnight. After evaporation, the residue was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous MgSO ₄ , 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 10%) to give methyl 4-(2-bromoethyl)-4,6-dimethylchroman-7-carboxylate (1.6 g, yield 86%) as a colorless oil. LC-MS (ESI): mass calcd. for C ⁺ 15H19BrO3, 326.05; m/z found, 327.3 [M+H]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (s, 1H), 7.01 (s, 1H), 4.34 - 4.02 (m, 2H), 3.86 (s, 3H), 3.33 - 3.27 (m, 1H), 3.20 - 3.15 (m, 1H), 2.52 (s, 3H), 2.44 - 2.14 (m, 2H), 2.11 - 1.93 (m, 1H), 1.74 - 1.68 (m, 1H), 1.37 (s, 3H). Step G: methyl 4-(2-azidoethyl)-4,6-dimethylchroman-7-carboxylate [000329] To a solution of methyl 4-(2-bromoethyl)-4,6-dimethylchroman-7-carboxylate (1.5 g, 4.60 mmol, 1.0 eq) in DMF (30 mL) was added NaN3 (598 mg, 9.2 mmol, 2.0 eq). The mixture was stirred at 60 ^o C for 12 h. The reaction mixture was cooled to room temperature, quenched with water (60 mL), and extracted with EtOAc (60 mL x 3). The organic layer was washed with brine (40 mL x 4), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure to afford methyl 4-(2-azidoethyl)-4,6-dimethylchroman- 7-carboxylate (1.1 g, yield 83%) as a colorless oil. The crude product was directly used in next step without further purification. LC-MS (ESI): mass calcd. for C15H19N3O3, 289.1; m/z found, 290.2 [M+H] ⁺ . Step H: methyl 4-(2-aminoethyl)-4,6-dimethylchroman-7-carboxylate [000330] To a solution of methyl 4-(2-azidoethyl)-4,6-dimethylchroman-7-carboxylate (1.1 g, 3.8 mmol, 1.0 eq) in MeOH (15 mL) was added 10% Pd/C (110 mg). The mixture was stirred under H ₂ (1 atm) at room temperature for 10 h. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 4-(2-aminoethyl)-4,6-dimethylchroman-7-carboxylate (940 mg, yield 94%) as a colorless oil. The crude product was directly used in next step without 103 275501297 v3 further purification. LC-MS (ESI): mass calcd. for C15H21NO3, 263.2; m/z found, 264.2 [M+H] ⁺ . Step I: methyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)-4,6-dimethylchroman- 7-carboxylate [000331] To a solution of methyl 4-(2-aminoethyl)-4,6-dimethylchroman-7-carboxylate (940 mg, 3.56 mmol, 1.0 eq) in DCM (25 mL) were added Boc2O (1.1 g, 5.34 mmol, 1.5 eq), DMAP (43 mg, 0.356 mmol, 0.1 eq), and TEA (719 mg, 7.12 mmol, 2.0 eq). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (40 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous MgSO ₄ , 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 20%) to methyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)-4,6-dimethylchroman- 7- carboxylate (1.1 g, yield 83%) as a colorless oil. LC-MS (ESI): mass calcd. for C20H29NO5, 363.2; m/z found, 364.2 [M+H] ⁺ .   [000332] ¹ H NMR (400 MHz, DMSO-d6) δ 7.19 (s, 1H), 7.15 (s, 1H), 6.73 (d, J = 5.0 Hz, 1H), 4.25 - 4.01 (m, 2H), 3.78 (s, 3H), 3.00 - 2.69 (m, 2H), 2.45 (s, 3H), 1.98 - 1.87 (m, 1H), 1.82 - 1.60 (m, 3H), 1.35 (s, 9H), 1.27 (s, 3H). Step J: methyl 6-(bromomethyl)-4-(2-((tert-butoxycarbonyl)amino)ethyl)-4-me thyl chroman- 7-carboxylate [000333] To a solution of methyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)-4,6-dimethylchr oman-7-carboxylate (500 mg, 1.38 mmol, 1.0 eq) in CCl ₄ (15 mL) were added NBS (269 mg, 1.51 mmol, 1.1 eq) and BPO (100 mg, 0.413 mmol, 0.3 eq). The mixture was stirred at 80 ^o C for 4 h. After evaporation, the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroluem ether, from 0% to 10%) to afford methyl 6-(bromomethyl)-4- (2-((tert-butoxycarbonyl)amino)ethyl)-4-methylchroman-7-carb oxylate (410 mg, yield 67%) as a yellow solid. LC-MS (ESI): mass calcd. for C20H28BrNO5, 441.2; m/z found, 464.3 [M+23] ⁺ . Step K: tert-butyl(2-(7-(2,6-dioxopiperidin-3-yl)-4-methyl-8-oxo-2,3 ,4,6,7,8-hexahy dropyrano[2,3-f]isoindol-4-yl)ethyl)carbamate [000334] To a solution of methyl 6-(bromomethyl)-4-(2-((tert-butoxycarbonyl)amino)ethyl)- 4-methylchroman-7-carboxylate (280 mg, 0.633 mmol, 1.0 eq) in ACN (50 mL) was added DIEA (245 mg, 1.9 mmol, 3.0 eq) and 3-aminopiperidine-2,6-dione hydrochloride (104 mg, 0.633 mmol, 1.0 eq). The mixture was stirred at 80 ^o C for 12 h. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum 104 275501297 v3 ether, from 0% to 80%)  to afford  tert-butyl(2-(7-(2,6-dioxopiperidin-3-yl)-4-methyl-8-oxo- 2,3,4,6,7,8-hexahydro pyrano[2,3-f]isoindol-4-yl)ethyl)carbamate (200 mg, yield 69%) as a white solid. LC-MS (ESI): mass calcd. for C ₂₄ H ₃₁ N ₃ O ₆ , 457.2; m/z found, 402.2 [M+H-56] ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 10.98 (s, 1H), 7.52 (s, 1H), 7.01 (s, 1H), 6.75 (s, 1H), 5.11 - 5.06 (m, 1H), 4.35 (dd, J = 16.6, 2.0 Hz, 1H), 4.27 - 4.09 (m, 3H), 3.00 - 2.76 (m, 3H), 2.65 - 2.54 (m, 1H) , 2.46 - 2.34 (m, 1H), 2.00 - 1.95 (m, 2H), 1.85 - 1.67 (m, 3H), 1.36 (d, J = 2.8 Hz, 9H), 1.32 (d, J = 4.8 Hz, 3H). Step L: 3-(4-(2-aminoethyl)-4-methyl-8-oxo-3,4-dihydropyrano[2,3-f]i soindol-7(2H,6H,8H)- yl)piperidine-2,6-dione hydrochloride [000335] To a solution of tert-butyl (2-(7-(2,6-dioxopiperidin-3-yl)-4-methyl-8-oxo - 2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-4-yl)ethyl)carbam ate (200 mg, 0.437 mmol, 1.0 eq) in 1,4-dioxane (5 mL) was added HCl-dioxane (4 M) (5 mL, 20 mmol, 45 eq). The mixture was stirred at room temperature for 1 h. After filtration, the filter cake was washed with ACN (10 mL x 3) and dried to afford 3-(4-(2-aminoethyl)-4- methyl-8-oxo-3,4-dihydropyrano[2,3- f]isoindol-7(2H,6H,8H)-yl)piperidine-2,6-dione hydrochloride (125 mg, yield 69%) as a light blue solid. LC-MS (ESI): mass calcd. for C ₁₉ H ₂₃ N ₃ O ₄ , 357.2; m/z found, 358.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.11 (s, 3H), 7.54 (d, J = 6.0 Hz, 1H), 7.03 (s, 1H), 5.11 - 5.06 (m, 1H), 4.47 - 4.08 (m, 4H), 2.99 - 2.72 (m, 2H), 2.61 - 2.57 (m, 2H), 2.41 - 2.36 (m, 1H), 2.09 - 2.06 (m, 1H), 2.02 - 1.94 (m, 3H) , 1.77 - 1.66 (m, 1H), 1.34 (d, J = 4.6 Hz, 3H). ^ Biological Actvity of Cereblon Ligands Cereblon Binding Assay [000336] In vitro Assay: IC50 Measurements for binding to CRBN/DDB1 (Table E1) [000337] The binding potency was determined using HTRF assay technology (Perkin Elmer). Compounds were serially diluted in DMSO and 0.2 µL volume was transferred to white 384- well plate. The reaction was conducted in total volume of 20 µL with addition of 2 nM His tagged CRBN+DDB-DLS7+CXU4 (Wuxi, catalogue # RP210521GA) to compounds followed by addition of 60 nM Fluorescent probe Cy5-labeled Thalidomide (Tenova Pharma, catalogue # T52461), and 0.4 nM of MAb Anti-6HIS Tb cryptate Gold (Cisbio, catalogue # 61HI2TLA in the assay buffer (50 mM HEPES pH 7.5, 1 mM TCEP, 0.01% Brij-35, 50 mM NaCl, and 0.1% BSA). After one hour incubation at room temperature, the HTRF signals were read on Envision reader (Perkin Elemer). Data was analyzed using XLfit using four parameters dose response curve to determine IC50s. 105 275501297 v3 Table E1. Note: A: IC50 < 0.01 ^M; B: 0.01 ^M < IC50 < 0.1 ^M; C: 0.1 ^M < IC50 < 1 ^M 106 275501297 v3 INCORPORATION BY REFERENCE [000338] 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 [000339] 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. [000340] 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. 107 275501297 v3