Compounds and compositions as cereblon ligands and uses thereof

Abstract

Provided herein are compounds of Formulae I and II and their pharmaceutically acceptable salts, solvates, or stereoisomers thereof, as well as their uses (e.g., as cereblon-binding agents).

Description

Attorney Docket No. PRSC-092 / 001WO 343170-2289 COMPOUNDS AND COMPOSITIONS AS CEREBLON LIGANDS AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 508,558, filed June 16, 2023, 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 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 SUMMARY

[0005] In certain aspects, the present disclosure provides compounds or conjugates of Formula I or II:and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables in Formulae I and II is described, embodied, and exemplified herein.

[0006] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound or conjugate disclosed herein, and a pharmaceutically acceptable excipient.

[0007] In certain aspects, the present disclosure provides methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering a compound disclosed herein to the subject or contacting the biological sample with a compound disclosed herein.

[0008] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

[0009] In certain aspects, the present disclosure provides compounds disclosed herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

[0010] In certain aspects, the present disclosure provides methods of degrading a protein in a subject or biological sample comprising administering a conjugate disclosed herein to the subject or contacting the biological sample with a conjugate disclosed herein.

[0011] In certain aspects, the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for degrading a protein in a subject or biological sample.

[0012] In certain aspects, the present disclosure provides conjugates disclosed herein for use in degrading a protein in a subject or biological sample.

[0013] In certain aspects, the present disclosure provides methods of reducing a protein in a subject or biological sample comprising administering a conjugate disclosed herein to the subject or contacting the biological sample with a conjugate disclosed herein. 2 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0014] In certain aspects, the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for reducing a protein in a subject or biological sample.

[0015] In certain aspects, the present disclosure provides conjugates disclosed herein for use in reducing a protein in a subject or biological sample. DETAILED DESCRIPTION

[0016] The present disclosure relates to compounds that show potential cereblon-binding activity, pharmaceutical compositions comprising such compounds, as well as uses thereof. Compounds of the Present Disclosure Cereblon Ligands

[0017] In certain aspects, the present disclosure provides compound of Formula I:and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is 5- to 12-membered heterocycle; each RAis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; a is an integer selected from 0 to 8; B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -CN, -NO2, -OH, -NH2, C1-6alkyl, 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, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - 3 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD1is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; q is an integer from 0 to 2, each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and d is an integer selected from 0 to 5, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5- to 10-membered heteroaryl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- or 6-membered heteroaryl; each Rais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, - 4 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl; wherein each of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- or 6-membered heteroaryl.

[0018] In certain embodiments, the compound is not a compound selected from:

[0019] In certain embodiments, B1is CRB1. In certain embodiments, B1is N.

[0020] In certain embodiments, B2is CRB2. In certain embodiments, B2is N.

[0021] In certain embodiments, B3is CRB3. In certain embodiments, B3is N.

[0022] In certain embodiments, none of B1, B2, and B3is N.

[0023] In certain embodiments, one of B1, B2, and B3is N.

[0024] In certain embodiments, two of B1, B2, and B3are N.

[0025] In certain embodiments, each of B1, B2, and B3is N.

[0026] In certain embodiments, RB1, RB2, and RB3are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), oxo, -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n- butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, 5 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0027] In certain embodiments, RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0028] In certain embodiments, RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein 6 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0029] In certain embodiments, RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0030] In certain embodiments, RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0031] In certain embodiments, Ring A is 8-membered heterocycle.

[0032] In certain embodiments, Ring A is 8-membered heterocycle comprising at least one oxygen atom.

[0033] In certain embodiments, Ring A is 8-membered heterocycle comprising at least one double bond.

[0034] In certain embodiments, Ring A is 7-membered heterocycle comprising one nitrogen atom.

[0035] In certain embodiments, Ring A is 7-membered heterocycle comprising one nitrogen atom and one double bond.

[0037] In certain embodiments, the compound is a compound of Formula I-1, I-2, I-3, or I-4 7 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0038] In certain embodiments, the compound is a compound of Formula I-5, I-6, or I-7or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0039] In certain embodiments, each RAis independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (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, 8 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0040] In certain embodiments, each RAis independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0041] In certain embodiments, each RAis independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0042] In certain embodiments, each RAis 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- 9 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0043] In certain embodiments, each RAis independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0044] In certain embodiments, each RAis independently oxo or C1-6alkyl. In certain embodiments, at least one RAis oxo. In certain embodiments, at least one RAis C1-6 alkyl. In certain embodiments, at least one RAis methyl.

[0045] In certain embodiments, a is 0. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4. In certain embodiments, a is 5. In certain embodiments, a is 6. In certain embodiments, a is 7. In certain embodiments, a is 8.

[0046] In certain embodiments, a is 0, 1, or 2.

[0047] In certain aspects, the present disclosure provides compound of Formula II:and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; B4is CRB4or N; RC1is hydrogen, C1-6 alkyl, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; one of RB1and RB2, RB2and RB3, and RB3and RB4, together with the atoms to which they are bonded, forms Ring A’, wherein Ring A’ is optionally substituted C5-12 carbocycle or 5- to 12-membered heterocycle; the remaining of RB1, RB2, RB3, and RB4are independently hydrogen, halogen, oxo, -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, C6-10 aryl, 5- to 10-membered heteroaryl, - SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - 10 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD1is hydrogen, deuterium, C1-6haloalkyl, or C1-6alkyl; q is an integer from 0 to 2, each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and d is an integer selected from 0 to 5, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5- to 10-membered heteroaryl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- or 6-membered heteroaryl; each Rais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is 11 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 optionally substituted with one or more substituents selected from oxo, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl; wherein each of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz;

[0048] each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- or 6-membered heteroaryl.

[0049] In certain embodiments, RC1is hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-4 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- to 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 4-membered rings and 1-2 heteroatoms selected from N, O, and S), wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0050] In certain embodiments, RC1is hydrogen or C1-6 alkyl.

[0051] In certain embodiments, the compound of Formula II is a compound of Formula II-1 or II-2or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0052] In certain embodiments, one of RB1and RB2, RB2and RB3, and RB3and RB4, together with the atoms to which they are bonded, forms Ring A’, wherein Ring A’ is optionally substituted C5-12carbocycle (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) or 12 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 5- to 12-membered heterocycle (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0053] In certain embodiments, Ring A’ is C5-8carbocycle or 5- to 8-membered heterocycle.

[0054] In certain embodiments, Ring A’ is 5- to 8-membered heterocycle.

[0055] In certain embodiments, Ring A’ is 5-membered heterocycle comprising at least one oxygen.

[0057] In certain embodiments, the compound of Formula II is a compound of Formula II-1- i, II-1-ii, II-2-i, or II-2-iior a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0058] In certain embodiments, Ring A’ is optionally substituted with one or more Ru.

[0059] In certain embodiments, Ring A’ is optionally substituted with one or more RA’.

[0060] In certain embodiments, Ruis RA’.

[0061] In certain embodiments, each RA’is independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), 13 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (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), C2-6alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0062] In certain embodiments, each RA’is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, 14 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0063] In certain embodiments, each RA’is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0064] In certain embodiments, each RA’is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0065] In certain embodiments, each RA’is independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0066] In certain embodiments, at least one RA’is C1-6alkyl optionally substituted with one or more Ru. In certain embodiments, at least one RA’is C1-6alkyl optionally substituted oxo or - OH.

[0067] In certain embodiments, at least one RA’is -C(=O)CH3, -CH2OH, or methyl.

[0068] In certain embodiments, a’ is 0. In certain embodiments, a’ is 1. In certain embodiments, a’ is 2. In certain embodiments, a’ is 3. In certain embodiments, a’ is 4. In certain embodiments, a’ is 5. In certain embodiments, a’ is 6. In certain embodiments, a’ is 7. In certain embodiments, a’ is 8.

[0069] In certain embodiments, a’ is 0 or 1.

[0070] In certain embodiments, each RDis independently oxo, halogen (e.g., -F, -Cl, -Br, or - I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (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- 15 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0071] In certain embodiments, each RDis 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, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0072] In certain embodiments, each RDis independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0073] In certain embodiments, each RDis independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. 16 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0074] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4. In certain embodiments, d is 5.

[0075] In certain embodiments, RD1is hydrogen, deuterium, C1-6 haloalkyl (e.g., C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)) substituted by one or more halogens selected from -F, -Cl, -Br, and -I), or C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n- butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)).

[0076] In certain embodiments, RD1is hydrogen.

[0077] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0078] In certain embodiments, each Rais independently C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0079] In certain embodiments, each Rais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl.

[0080] In certain embodiments, each Rais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl. 17 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0081] In certain embodiments, each Rais independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0082] In certain embodiments, each Rbis independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0083] In certain embodiments, each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl.

[0084] In certain embodiments, each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

[0085] In certain embodiments, each Rbis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, or C2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0086] In certain embodiments, each Rcand each Rdis independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), 18 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0087] In certain embodiments, each Rcand each Rdis independently hydrogen, C1-6 alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more Ru.

[0088] In certain embodiments, Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more Ru.

[0089] In certain embodiments, Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz.

[0090] In certain embodiments, Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6- membered heterocyclyl.

[0091] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl- i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- 19 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6-membered heterocyclyl.

[0092] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6- membered heterocyclyl.

[0093] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6- membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally 20 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 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.

[0094] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6carbocyclyl, and 3- to 6-membered heterocyclyl.

[0095] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0096] In certain embodiments, the compound is selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[0097] In certain embodiments, the compound is selected from the compounds in Table 1. Table 1.21 304765419Attorney Docket No. PRSC-092 / 001WO 343170-228922 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289Bifunctional Degraders

[0098] 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).

[0099] In certain aspects, the present disclosure provides conjugates of Formula I:and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is 5- to 12-membered heterocycle; 23 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 each RAis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; a is an integer selected from 0 to 8; B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; RB1, RB2, and RB3are independently, hydrogen, halogen, oxo, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, wherein one RB1, RB2, and RB3isdenotes attachment to -L-T; RD1is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; q is an integer from 0 to 2, each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 5, L is a linker; and T is a ligand for a protein, wherein: 24 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, and 5- or 6-membered heteroaryl; or each Rais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, - NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, and 3- to 6- membered heterocyclyl; wherein each of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- or 6-membered heteroaryl, wherein each of the variables in Formula I is described herein.

[0100] In certain embodiments, the compound or conjugate is a conjugate of Formula I-1, I-2, I-3, or I-4 25 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0101] In certain embodiments, the compound is a compound of Formula I-1’, I-2’, I-3’, or I- 4’or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0102] In certain embodiments, the compound or conjugate is a conjugate of Formula I-5, I-6, or I-7 26 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0103] In certain embodiments, the compound is a compound of Formula I-5’, I-6’, or I-7’or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0104] L, a linker, is a divalent chemical moiety that connects the ligand of a protein with the cereblon ligand disclosed herein. L configures the ligand and the cereblon ligand such that the construct functions as a bifunctional degrader which binds the cereblon ligand and selectively degrades the target protein.

[0105] In certain embodiments, L is a linker comprising C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C3-12carbocyclylene, 3- to 12-membered heterocyclylene, C6-10arylene, 5- to 10- membered heteroarylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted by one or more Ru.

[0106] In certain embodiments, L is of Formula II 27 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289wherein: * denotes attachment to T and ** denotes attachment to C; each L’ is independently C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)- , -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru; each occurrence of RL’is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and l is an integer selected from 0 to 6.

[0107] In certain embodiments, each L’is independently C1-6 alkylene (e.g., methylene (-CH2- ), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-)), C2-6 alkenylene (e.g., ethenylene (C2), 1-propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2-butenylene (C4), butadienylene (C4), pentenylene (C5), pentadienylene (C5), or hexenylene (C6)), C2-6alkynylene (e.g., ethynylene (C2), 1-propynylene (C3), 2-propynylene (C3), 1-butynylene (C4), 2-butynylene (C4), pentynylene (C5), or hexynylene (C6)), C3-12 carbocyclylene (e.g., cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), cyclobutenylene (C4), cyclopentylene (C5), cyclopentenylene (C5), cyclohexylene (C6), cyclohexenylene (C6), cyclohexadienylene (C6), cycloheptylene (C7), cycloheptenylene (C7), cycloheptadienylene (C7), cycloheptatrienylene (C7), cyclooctylene (C8), cyclooctenylene (C8), bicyclo[2.2.1]heptanylene (C7), bicyclo[2.2.2]octanylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C10), cyclodecenylene (C10), octahydro-1H-indenylene (C9), decahydronaphthalenylene (C10), or spiro[4.5]decanylene (C10)), 3- to 12-membered heterocyclylene (e.g., heterocyclylene comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10arylene (e.g., phenylene or naphthylene), 5- to 10-membered heteroarylene (e.g., heteroarylene comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -C(=O)-, -C(=O)N(RL2)-, -C(=O)O-, -N(RL2)- 28 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 , -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0108] In certain embodiments, each L’ is independently C1-6alkylene, C3-12carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0109] In certain embodiments, each occurrence of RL’is independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1- butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0110] In certain embodiments, each occurrence of RL’is independently hydrogen, C1-6 alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0111] In certain embodiments, l is 0. In certain embodiments, l is 1. In certain embodiments, l is 2. In certain embodiments, l is 3. In certain embodiments, l is 4. In certain embodiments, l is 5. In certain embodiments, l is 6.

[0112] T, a ligand of a protein, is a chemical entity that competitively or non-competitively binds a protein. 29 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0113] 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.

[0114] 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), Ikaros Zinc Finger (IKZF)1, IKZF2, or IKZF3, 30 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 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).

[0115] In certain embodiments, T is a small molecule.

[0116] In certain embodiments, T is an antibody.

[0117] 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.

[0118] In certain embodiments, T is a ligand for an estrogen receptor. In certain embodiments, T is a ligand for SMARCA2 / 4 protein. In certain embodiments, T is a ligand for STAT3 protein. In certain embodiments, T is a ligand for CBP / p300 protein. In certain embodiments, T is a ligand for Ikaros Zinc Finger (IKZF)1, IKZF2, or IKZF3. In certain embodiments, T is ligand for an androgen receptor. In certain embodiments, T is a ligand for BRD9 protein.

[0119] In certain embodiments, T is an estrogen receptor inhibitor. In certain embodiments, T is a SMARCA2 / 4 protein inhibitor. In certain embodiments, T is a STAT3 protein inhibitor. In certain embodiments, T is a CBP / p300 protein inhibitor. In certain embodiments, T is a Ikaros Zinc Finger (IKZF)1, IKZF2, or IKZF3 degrader. In certain embodiments, T is an androgen receptor inhibitor. In certain embodiments, T is a BRD9 protein inhibitor.

[0120] Embodiments of the variables in any of the Formulae described herein, e.g., Formulae I, I-1, I-2, I-3, and II, as applicable, are described below. Any of the variables can be any moiety as described in the embodiments below. In addition, the combination of any moieties described for any of the variables, as applicable, with any moieties described for any of the remaining variables, is also contemplated.

[0121] Without wishing to be limited by this statement, while various options for variables are described herein, it is understood that the present disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options. 31 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0122] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0123] The compounds of the present disclosure may possess advantageous characteristics, as compared to known compounds, such as known cereblon-binding agents or known degraders comprising such cereblon-binding agents. For example, the compounds of the present disclosure may display more potent cereblon-binding activity or more potent degradation activity against certain proteins, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and / or AUC), and / or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction). These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein.

[0124] 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.

[0125] 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.

[0126] 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. 32 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Forms of Compounds Disclosed Herein Pharmaceutically acceptable salts

[0127] In certain embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0128] In certain embodiments, the compounds described herein possess acidic or basic groups and therefore may 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 acid form or free base form with a suitable acid or base, and isolating the salt thus formed.

[0129] 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.

[0130] 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 33 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0131] 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.

[0132] 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

[0133] 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 present disclosure.

[0134] 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 disclosure.

[0135] In certain embodiments, the compounds described herein exist as solvates. 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 34 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Isomers

[0136] 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.”

[0137] 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 disclosure.

[0138] 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 disclosure.

[0139] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In certain embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers

[0140] In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. 35 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0141] 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 present disclosure. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Pharmaceutical Compositions

[0142] 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 acceptable carrier (also referred to herein as a pharmaceutically acceptable excipient, physiologically acceptable excipient, or physiologically 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, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0143] 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.

[0144] 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.

[0145] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. Preparation and Characterization of the Compounds

[0146] 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 36 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The compounds of the present disclosure (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and / or synthesis described herein (e.g., Examples). General Synthetic Scheme

[0147] Exemplary compounds can be prepared by following the general synthetic procedures as outlined in the following scheme.Scheme 1

[0148] According to SCHEME 1, commercially available or synthetically accessible substituted phenyl aniline of formula (Ia, X = O or NH) is reacted with an alkylating agent, such as 1,2-di-Br-ethane, 1-chloro-2iodo ethane or the like; in the presence of an inorganic base such as potassium carbonate, sodium hydride and the like; in a suitable solvent such as DMF, DMSO, or the like; at temperatures ranging from 30 °C to 100 °C; to provide cyclized product of formula Ib. Cyclized product of formula Ib is then reduced by a palladium catalyst such as 5% Pd / C or Pd(OH)2, in the presence of a suitable solvent such as MeOH, ethyl acetate or the like; at temperatures ranging from 0 °C to 50 °C, preferably 25 °C; under hydrogen atmosphere of 10-55 psi, to provide a compound of formula (Ic). A compound of formula (Ic) is cyclized in the presence of a suitable imide such as CDI, tri phosgene or the like; in a suitable solvent such as dichloromethane (DCM), DMF or the like; at temperatures ranging from 25 °C 37 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 to 80 °C, preferably 40 °C; to afford a tricyclic compound of formula (Id). A compound of formula (Id) is coupled with commercially available bromo-glutarimide (Ie) with a suitable base such a K3PO4, Cs2CO3, KOAc, or the like; in a suitable solvent such as dioxane, DMF, THF, or the like; at temperatures ranging from 60 °C to about 120 °C; to provide tricyclic compound of formula (I).

[0149] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present dislosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

[0150] 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).

[0151] 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., 38 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022- 9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0- 471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645- X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0152] 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. Biological Assays

[0153] The biological activities of the compounds of the present disclosure can be assessed with methods and assays known in the art. 39 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0154] For example, the binding potency may be determined using HTRF assay technology. In a typical procedure, compounds are serially diluted in a certain solvent (e.g., DMSO) and certain volume (e.g., 0.2 µL) is transferred to white 384-well plate. The reaction is conducted in certain total volume (e.g., 20 µL) with addition of certain concentration (e.g., 2 nM) of His tagged CRBN+DDB-DLS7+CXU4 to compounds followed by addition of certain concentration (e.g., 60 nM) Fluorescent probe Cy5-labeled Thalidomide (Tenova Pharma, catalogue # T52461), and certain concentration (e.g., 0.4 nM) of MAb Anti-6HIS Tb cryptate Gold. After certain period of time (e.g., one hour incubation at room temperature, the HTRF signals are read on a reader (e.g., Envision reader from Perkin Elemer). Data is analyzed using XLfit using four parameters dose response curve to determine IC50s. Methods of Use

[0155] In certain aspects, the present disclosure provides methods of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample, comprising administering the compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein.

[0156] In certain aspects, the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

[0157] In certain aspects, the present disclosure provides compounds disclosed herein for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

[0158] “CRBN E3 ubiquitin ligase protein complex” is art recognized and refers to an association of proteins in which CRBN, a 442-amino acid protein, forms a Cullin-4-RING E3 ubiquitin ligase (CRL4) complex and interacts with the adaptor protein damaged DNA–binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). Within the CRL4 complex, CRBN acts as a substrate-specificity receptor.

[0159] In certain aspects, the present disclosure provides methods of degrading a protein in a subject or biological sample comprising administering a conjugate disclosed herein to the subject or contacting the biological sample with a conjugate disclosed herein.

[0160] In certain aspects, the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for degrading a protein in a subject or biological sample.

[0161] In certain aspects, the present disclosure provides conjugates disclosed herein for use in degrading a protein in a subject or biological sample. 40 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0162] In certain aspects, the present disclosure provides methods of reducing a protein in a subject or biological sample comprising administering a conjugate disclosed herein to the subject or contacting the biological sample with a conjugate disclosed herein.

[0163] In certain aspects, the present disclosure provides uses of a conjugate disclosed herein in the manufacture of a medicament for reducing a protein in a subject or biological sample.

[0164] In certain aspects, the present disclosure provides conjugates disclosed herein for use in reducing a protein in a subject or biological sample.

[0165] In certain embodiments, the subject is a mammal.

[0166] In certain embodiments, the subject is a human. Definitions

[0167] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions

[0168] 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, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0169] 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, 41 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 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).

[0170] The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0171] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0172] 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 disclosure. When describing the disclosure, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0173] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). 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 (“C1alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl 42 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-10alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), i-Pr (-CH(CH3)2), n- Pr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0174] “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 “alkylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (- CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0175] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2- 9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon- 43 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is substituted C2-10alkenyl.

[0176] “Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkenylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH- ) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., - C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)- CH=CH-,-C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0177] “Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain 44 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.

[0178] “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.

[0179] 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 (“C1-10 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“C1-9 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“C1-8heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“C1-7heteroalkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“C1-6 heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“C1-5heteroalkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms (“C1-4 45 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 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 (“C1-2heteroalkyl”). 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 (“C2-6heteroalkyl”). 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 C1-10heteroalkyl. In certain embodiments, the heteroalkyl group is a substituted C1-10heteroalkyl.

[0180] 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 (“C2-10heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C2-9heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C2-8heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“C2-7heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“C2-6 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C2-5 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and l or 2 heteroatoms (“C2-4 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“C2-3 heteroalkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C2-6heteroalkenyl”). 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 C2-1046 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 heteroalkenyl. In certain embodiments, the heteroalkenyl group is a substituted C2-10 heteroalkenyl.

[0181] 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 (“C2-10heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“C2-9 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 (“C2-7 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 (“C2-5heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“C2-4heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“C2-3heteroalkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C2-6heteroalkynyl”). 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 C2-10 heteroalkynyl. In certain embodiments, the heteroalkynyl group is a substituted C2-10heteroalkynyl.

[0182] 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. 47 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0183] “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 (“C6-14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as- indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14aryl. In certain embodiments, the aryl group is substituted C6-14aryl.

[0184] “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.

[0185] “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). 48 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0186] In certain embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In certain embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl.

[0187] 5-membered heteroaryl containing one heteroatom includes, 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, 49 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 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.

[0188] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.

[0189] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C3-12carbocyclyl”). 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 (“C3-8carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8 carbocyclyl”). 50 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Examples of C5-6 carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6carbocyclyl include the aforementioned C5-6carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-12carbocyclyl.

[0190] In certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-12carbocyclyl.

[0191] “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 carbocyclyl ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

[0192] “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 any of 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 any of the carbocyclyl rings in which the spiro structure is embeded.

[0193] “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 51 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 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.

[0194] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- 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.

[0195] 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 52 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 12-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10- membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0196] 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.

[0197] “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. 53 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289

[0198] “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.

[0199] “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than one atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embeded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embeded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the bridged rings.

[0200] “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, or 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.

[0201] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl, carbocyclyl, or heterocyclyl as defined herein. C1-6alkoxy refers to the group -OR, wherein each R is C1-6alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, as defined herein. Exemplary C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl is set forth above.

[0202] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R is independently alkyl, carbocyclyl, or heterocyclyl, as defined herein. C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl as defined herein. Exemplary C1-6alkyl, C3-6carbocyclyl, or 3- to 6- membered heterocyclyl is set forth above.

[0203] “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 54 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.

[0204] “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.

[0205] “Protecting group” as used herein is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.

[0206] 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)).

[0207] 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)).

[0208] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).

[0209] 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.

[0210] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents. 55 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Other Definitions

[0211] “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.

[0212] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure 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.

[0213] 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.

[0214] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect such treatment or prevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylatically effective amount” refers to the effective amount for prophylactic treatment.

[0215] “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).

[0216] The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure, the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0217] “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 56 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 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.

[0218] 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. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, or 5% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, or 3% of the stated number or numerical range.

[0219] 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.

[0220] 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.

[0221] 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 57 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0222] 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.

[0223] 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.

[0224] 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 58 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0225] 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. EXEMPLARY EMBODIMENTS EXEMPLARY EMBODIMENT 1. A compound of Formula I:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5- to 12-membered heterocycle; each RAis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5- to 10-membered heteroaryl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; a is an integer selected from 0 to 8; 59 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -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, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD1is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; q is an integer from 0 to 2, each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and d is an integer selected from 0 to 5, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5- to 10-membered heteroaryl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- or 6-membered heteroaryl; each Rais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; 60 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, - NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, and 3- to 6- membered heterocyclyl; wherein each of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- or 6-membered heteroaryl, wherein the compound is not a compound selected from:EXEMPLARY EMBODIMENT 2. A conjugate of Formula I:61 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5- to 12-membered heterocycle; each RAis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; a is an integer selected from 0 to 8; B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; RB1, RB2, and RB3are independently, hydrogen, halogen, oxo, -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, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and one RB1, RB2, and RB3isdenotes attachment to -L-T, RD1is hydrogen, deuterium, C1-6haloalkyl, or C1-6alkyl; q is an integer from 0 to 2, each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 5, L is a linker; and T is a ligand for a protein, 62 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- or 6-membered heteroaryl; each Rais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, - NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, and 3- to 6- membered heterocyclyl; wherein each of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- or 6-membered heteroaryl. EXEMPLARY EMBODIMENT 3. The compound or conjugate of any one of the preceding exemplary embodiments, wherein Ring A is 8-membered heterocycle. EXEMPLARY EMBODIMENT 4. The compound or conjugate of any one of the preceding exemplary embodiments, wherein Ring A is 8-membered heterocycle comprising at least one oxygen atom. 63 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 EXEMPLARY EMBODIMENT 5. The compound or conjugate of any one of the preceding exemplary embodiments, wherein Ring A is 8-membered heterocycle comprising at least one double bond. EXEMPLARY EMBODIMENT 6. The compound or conjugate of any one of the preceding exemplary embodiments, wherein Ring A is 7-membered heterocycle comprising one nitrogen atom. EXEMPLARY EMBODIMENT 7. The compound or conjugate of any one of the preceding exemplary embodiments, wherein Ring A is 7-membered heterocycle comprising one nitrogen atom and one double bond. EXEMPLARY EMBODIMENT 8. The compound or conjugate of any one of the preceding exemplary embodiments, wherein the compound or conjugate is a compound or conjugate of Formula I-1, I-2, I-3, or I-4or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. EXEMPLARY EMBODIMENT 9. The compound or conjugate of any one of the preceding exemplary embodiments, wherein each RAis independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. EXEMPLARY EMBODIMENT 10. The compound or conjugate of any one of the preceding exemplary embodiments, wherein RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, 64 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru. EXEMPLARY EMBODIMENT 11. The compound or conjugate of any one of the preceding exemplary embodiments, wherein the compound or conjugate is a compound or conjugate of Formula I-5, I-6, or I-7or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. EXEMPLARY EMBODIMENT 12. The compound or conjugate of any one of the preceding exemplary embodiments, wherein each RAis independently oxo or C1-6 alkyl. EXEMPLARY EMBODIMENT 13. The compound or conjugate of any one of the preceding exemplary embodiments, wherein a is 0, 1 or 2. EXEMPLARY EMBODIMENT 14. The compound or conjugate of any one of the preceding exemplary embodiments, wherein RB1, RB2, and RB3are independently hydrogen, halogen, C1-6alkoxy, C2-6alkynyl, or 3- to 12-membered heterocyclyl, wherein the alkoxy, alkynyl, or heterocyclyl is optionally substituted with one or more Ru. EXEMPLARY EMBODIMENT 15. The compound or conjugate of any one of the preceding exemplary embodiments, wherein each RDis independently oxo, halogen, -CN, -NO2, -OH, - NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru. EXEMPLARY EMBODIMENT 16. The compound or conjugate of any one of the preceding exemplary embodiments, wherein d is 0. EXEMPLARY EMBODIMENT 17. The compound or conjugate of any one of the preceding exemplary embodiments, wherein RD1is hydrogen. 65 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 EXEMPLARY EMBODIMENT 18. The compound or conjugate of any one of the preceding exemplary embodiments, wherein q is 1. EXEMPLARY EMBODIMENT 19. A compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. EXEMPLARY EMBODIMENT 20. A pharmaceutical composition comprising the compound of any one of the preceding exemplary embodiments, and a pharmaceutically acceptable excipient. EXEMPLARY EMBODIMENT 21. 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 22. 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 23. 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. EXEMPLARY EMBODIMENT 24. A method of degrading a protein in a subject or biological sample comprising administering the compound or conjugate of any one of the preceding exemplary embodiments to the subject or contacting the biological sample with the conjguate of any one of the preceding exemplary embodiments. EXEMPLARY EMBODIMENT 25. Use of the conjugate of any one of the preceding exemplary embodiments in the manufacture of a medicament for degrading a protein in a subject or biological sample. EXEMPLARY EMBODIMENT 26. A conjugate of any one of the preceding exemplary embodiments for use in degrading a protein in a subject or biological sample. EXEMPLARY EMBODIMENT 27. The method, use, or conjugate for use of any one of the preceding exemplary embodiments, wherein the protein is an estrogen receptor, a STAT3 protein, an androgen receptor, a SMARCA2 protein, a SMARCA4 protein, a BRD9 protein, or a CBP / p300 protein. EXAMPLES

[0226] 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 66 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. I. Synthesis and Characterization Example 1: 3-(2-oxo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-1(2H)- yl)piperidine-2,6-dioneStep A: 5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0227] To a solution of 2-amino-3-nitrophenol (5.0 g, 32.44 mmol, 1.0 eq) in DMF (80 mL) were added K2CO3(17.93 g, 129.76 mmol, 4.0 eq) and 1,2-dibromoethane (4.2 mL, 48.66 mmol, 1.5 eq) and the mixture was stirred at 100 ℃ for 18 h. The reaction was cooled to room temperature, diluted with water (200 mL), and extracted with EA (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 0% to 50%) to afford 5- nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.16 g, yield 20%) as a yellow solid. LC-MS (ESI): mass calcd. for C8H8N2O3, 180; m / z found, 181 [M+H]+. Step B: 3,4- dihydro-2H-1,4-benzoxazin-5-amine

[0228] To a solution of 5-nitro-3,4-dihydro-2H-1,4-benzoxazine (1.16 g, 6.44 mmol, 1.0 eq) in EtOH (10 mL) and water (2 mL) were added Fe powder (3.6 g, 64.4 mmol, 10.0 eq) and NH4Cl (1.03 g, 19.32 mmol, 3.0 eq) and the mixture was stirred at 80 ℃ for 3 h. The mixture was cooled to room temperature, diluted with EA (100 mL), and filtered. After the filtrate was concentrated under reduced pressure, the residue was dissolved in MeCN (20 mL) and NH4Cl was filtered. The organic layer was concentrated to afford 3,4- dihydro-2H-1,4-benzoxazin-5- amine (1.0 g, yield 98%) as a yellow solid. LC-MS (ESI): mass calcd. for C8H10N2O, 150; m / z found, 151 [M+H]+. Step C: 3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one

[0229] To a solution of 3,4-dihydro-2H-1,4-benzoxazin-5-amine (1.0 g, 6.66 mmol, 1.0 eq) in THF (30 mL) was added CDI (2.16 g, 13.32 mmol, 2.0 eq) and the mixture was stirred under N2at 60oC for 3 h. After cooled to room temperature, K2CO3(1.84 g, 13.32 mmol, 2.0 eq) 67 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 and H2O (30 mL) was added to above mixture. The mixture was stirred at room temperature for 30 min. After filtration, the filtrate was extracted with EA (50 mL x 3). The organic layer was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 1) to afford 3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one (670 mg, yield 58%) as a yellow solid. LC-MS (ESI): mass calcd. for C9H8N2O2, 176; m / z found, 177 [M+H]+. Step D: 3-(2-oxo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-1(2H)-yl)piperidine- 2,6-dione

[0230] To a solution of 3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one (600 mg, 3.41 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% suspend in oil) (586 mg, 17.03 mmol, 5.0 eq) in portions at 60 ℃ and the mixture was stirred for 1 h. Then 3- bromopiperidine-2,6- dione (654 mg, 3.41 mmol, 1.0 eq) was added to above mixture and the resulting mixture was stirred under N2 at 60 ℃ for 3 h. After cooled to room temperature, the reaction mixture was slowly poured into cooled saturated NH4Cl solution (15 mL) and extracted with EA (50 mL x 3). The organic layer was washed with brine (10 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was precipitated with EA (15 mL x 3) to afford the 3-(2-oxo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-1(2H)-yl)piperidine-2,6- dione (53 mg, yield 5%) as an off-white solid. LC-MS: 288 (M+H)+. Revised as the following: LC-MS (ESI): mass calcd. for C14H13N3O4, 287; m / z found, 288.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 6.88 (t, J = 8.2 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.35 - 5.30 (m, 1H), 4.41 - 4.38 (m, 2H), 3.99 - 3.92 (m, 2H), 2.98 - 2.85 (m, 1H), 2.74 - 2.58 (m, 2H), 2.07 - 1.99 (m, 1H). Example 2: 3-(2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dioneStep A: 1,2,3,4-tetrahydroquinolin-8-amine

[0231] To a solution of quinolin-8-amine (5.0 g, 34.68 mmol, 1.0 eq) in H2O (100 mL) was added Tetrahydroxydiboron (31.1 g, 346.8 mmol, 10.0 eq). The mixture was stirred at 80oC 68 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 for 1 h. The mixture was cooled to room temperature and exacted with EA (100 mL x 3). The organic layer was dried over anhyrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash colum chromatography on silica gel (EA / PE = 1 / 1) to afford 1,2,3,4-tetrahydroquinolin-8-amine (2.8 g, yield 54%) as a yellow solid. LC-MS (ESI): mass calcd. for C9H12N, 148; m / z found, 149 [M+H]+. Step B: 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

[0232] To a solution of 1,2,3,4-tetrahydroquinolin-8-amine (2.7 g, 18.21 mmol, 1.0 eq) in THF (50 mL) was added CDI (5.91 g, 36.42 mmol, 2.0 eq). The mixture was stirred under N2 at 60oC for 3 h. After evaporation, the residue was dissolved in EA (100 mL), washed with saturated aqueous NH4Cl solution (30 mL) and brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 1) to afford 5,6-dihydro-4H-imidazo[4,5,1- ij]quinolin-2(1H)-one (2.2 g, yield 69%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H10NO, 174; m / z found, 175 [M+H]+. Step C: 3-(2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)piperidine-2,6- dione

[0233] To a solution of 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (600 mg, 3.44 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% suspend in oil) (590 mg, 17.22 mmol, 5.0 eq) in portions at 60 ℃ and the mixture was stirred for 1 h. Then 3- bromopiperidine-2,6- dione (661 mg, 3.44 mmol, 1.0 eq) was added to above mixture and the reaction mixture was stirred under N2 at 60 ℃ for 3 h. After cooled to room temperature, the reaction mixture was slowly poured into cooled saturated NH4Cl solution (15 mL) and extracted with EA (50 mL x 3). The organic layer was washed with brine (10 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was precipitated with EA (15 mL x 3) to afford 3-(2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)piperidine-2,6-dione (289 mg, yield 29%) as na off-white solid. LC-MS (ESI): mass calcd. for C15H15N3O3, 285; m / z found, 286 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 6.91- 6.84 (m, 3H), 5.35 - 5.30 (m, 1H), 3.76 (t, J = 4.6 Hz, 2H), 2.98 - 2.85 (m, 1H), 2.81 (t, J = 4.6 Hz, 2H), 2.74 - 2.58 (m, 2H), 2.05 - 1.98 (m, 3H). 69 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Example 3: 3-(2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)- yl)piperidine-2,6-dioneStep A: 2-((2-methoxy-2-oxoethyl)amino)-3-nitrobenzoic acid

[0234] To a solution of 2-fluoro-3-nitrobenzoic acid (5.5 g, 29.71 mmol, 1.0 eq) and methyl glycinate hydrochloride (15.85 g, 126.28 mmol, 4.2 eq) in t-BuOH (50.0 mL) was added Na2CO3(22.61 g, 213.33 mmol, 7.2 eq) and the resulting mixture was stirred under N2at 90oC for 18 h. After evaporation, the mixture was diluted with H2O (100 mL) and extracted with EA (100 mL x 2). The organic layer was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-((2-methoxy-2- oxoethyl)amino)-3-nitrobenzoic acid (5.0 g, yield 66%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H10N2O6, 254; m / z found, 255 [M+H]+. Step B: methyl 2-(7-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate

[0235] To a solution of 2-[(2-methoxy-2-oxoethyl)amino]-3-nitrobenzoic acid (5.0 g, 19.67 mmol, 1.0 eq) and DIEPA (7.63 g, 59.01 mmol, 3.0 eq) in t-BuOH (30.0 mL) was added DPPA (6.5 g, 23.60 mmol, 1.2 eq) and the resulting mixture was stirred at 90oC for 1.5 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl solution (200 mL), and extracted with EtOAc (150 mL x 3). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 10) to give methyl 2-(7-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (3.3 g, yield 67%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H9N3O5, 251; m / z found, 252 [M+H]+. Step C: methyl 2-(7-amino-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate

[0236] To a solution of methyl 2-(7-nitro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetate (3.3 g, 13.14 mmol, 1.0 eq) in MeOH (25.0 mL) was added 10% Pd / C (350 mg). The resulting mixture was stirred under H2atmosphere (1 atm) at room temperature for 18 h. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2-(7-amino-2-oxo-2,3- dihydro-1H-1,3-benzodiazol-1-yl)acetate (2.7 g, yield 93%) as a yellow solid. LC-MS: 222 70 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 (M+H)+. Revised as the following: LC-MS (ESI): mass calcd. for C10H11N3O3, 221; m / z found, 222 [M+H]+. Step D: 4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione

[0237] To a solution of methyl 2-(7-amino-2-oxo-2,3- dihydro-1H-1,3-benzodiazol-1- yl)acetate (2.7 g, 12.21 mmol, 1.0 eq) in Ethyl acetate (80.0 mL) was added AcOH (5.5 mL, 94.24 mmol, 8.0 eq). The resulting mixture was stirred under N2at 80oC for 18 h. After evaporation, the residue was diluted with water (10 mL), adjusted to pH = 8 with saturated aqueous Na2CO3 solution, and extracted with EA (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / DCM = 1 / 3) to give 4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione (1.87 g, yield 81%) as a yellow solid. LC- MS (ESI): mass calcd. for C9H7N3O2, 189; m / z found, 190 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.72 (s, 1H), 6.84 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 4.46 (s, 2H). Step E: 5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-2(1H)-one

[0238] To a solution of 4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione (1.2 g, 6.34 mmol, 1.0 eq) in THF (100 mL) was added BH3-Me2S complex solution (1 N in THF) (19 mL, 19 mmol, 3.0 eq). The resulting mixture was stirred under N2 at 80oC for 2 h. After cooled to room temperature, the reaction mixture was slowly quenched with methanol (50 mL) and aqueous HCl solution (2 N) (10.0 mL), stirred for 1 h. After evaporation, the residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to give 5,6- dihydro-4H-imidazo[1,5,4-de]quinoxalin-2(1H)-one (900 mg, yield 81%) as a yellow solid. LC-MS (ESI): mass calcd. for C9H9N3O, 175; m / z found, 176 [M+H]+. Step F: tert-butyl 2-oxo-1,2,4,5-tetrahydro-6H-imidazo[1,5,4-de]quinoxaline-6- carboxylate

[0239] To a solution of 5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-2(1H)-one (900 mg, 5.14 mmol, 1.0 eq) and DMAP (63 mg, 0.51 mmol, 0.1 eq) in DCM (100 mL) were added DIPEA (2.5 mL, 15.41 mmol, 3.0 eq) and Boc2O (1.43 g, 6.16 mmol, 1.2 eq). The resulting mixture was stirred under N2at room temperature for 4 h. The mixture was diluted with H2O (10 mL) and extracted with EA (30 mL x 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / EA = 5 / 1) to give tert-butyl 2- oxo-1,2,4,5-tetrahydro-6H-imidazo[1,5,4-de]quinoxaline-6-carboxylate (870 mg, yield 62%) as a yellow solid. LC-MS (ESI): mass calcd. for C14H17N3O3, 275; m / z found, 276 [M+H]+.1H 71 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 3.95 (t, J = 5.0 Hz, 3H), 3.49 (t, J = 5.0 Hz, 2H), 1.67 (s, 9H). Step G: tert-butyl 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,4,5-tetrahydro-6H- imidazo[1,5,4-de]quinoxaline-6-carboxylate

[0240] To a solution of tert-butyl 2-oxo-1,2,4,5-tetrahydro-6H-imidazo[1,5,4-de]quinoxaline- 6-carboxylate (300 mg, 1.09 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% suspend in oil) (227 mg, 5.67 mmol, 5.0 eq) in portions at 60oC and the resulting mixture was stirred at 60oC under N2 for 1 h. Then a solution of 3-bromopiperidine-2,6- dione (272 mg, 1.42 mmol, 1.3 eq) in DMF (2 mL) was added to above mixture and the resulting mixture was stirred at 6 0oC under N2for 3 h. After cooled to room temperature, the reaction mixture was slowly poured into cooled saturated NH4Cl solution (15 mL) and extracted with EA (50 mL x 3). The organic layer was washed with brine (10 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 1) to give tert-butyl 1-(2,6-dioxopiperidin-3-yl)-2- oxo-1,2,4,5-tetrahydro-6H-imidazo[1,5,4-de]quinoxaline-6-carboxylate (110 mg, yield 28%) as a white solid. LC-MS (ESI): mass calcd. for C19H22N4O5, 386; m / z found, 387 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.33 (s, 1H), 6.96 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.37 - 5.32 (m, 1H), 3.95 (t, J = 5.0 Hz, 2H), 3.88 (t, J = 5.0 Hz, 2H), 2.93 - 2.88 (m, 1H), 2.78 - 2.58 (m, 2H), 2.04 - 2.00 (m, 1H), 1.51 (s, 9H). Step H: 3-(2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)piperidine- 2,6-dione

[0241] To a solution of tert-butyl 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,4,5-tetrahydro-6H- imidazo[1,5,4-de]quinoxaline-6-carboxylate (110 mg, 0.28 mmol, 1.0 eq) in MeCN (6.0 mL) was added HCl solution (4 N in 1,4-dioxane) (2.0 mL, 8.0 mmol, 28 eq). The resulting mixture was stirred at room temperature for 2 h. After evaporation, 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% HCOOH) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL / min to afford 3-(2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)piperidine- 2,6-dione (20.0 mg, yield 25%) as a white solid. LC-MS (ESI): mass calcd. for C22H28N4O6, 286; m / z found, 287 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 6.74 (t, J = 8.0 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 6.32 (d, J = 8.09 Hz, 1H), 6.00 (s, 1H), 5.28 - 5.23 (m, 1H), 3.80 (t, J = 5.0 Hz, 2H), 3.37 (t, J = 5.0 Hz, 2H), 2.95 - 2.85 (m, 1H), 2.68 - 2.54 (m, 2H), 2.03 - 1.98 (m, 1H). 72 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Example 4: 3-(2-oxo-7-(piperidin-4-yl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin- 1(2H)-yl)piperidine-2,6-dioneStep A: 5-bromo-1,2,3,4-tetrahydroquinolin-8-amine

[0242] To a solution of 5-bromoquinolin-8-amine (5.0 g, 22.4 mmol, 1.0 eq) in AcOH (50 mL) was added platinum dioxide (0.5 g, 2.2 mmol, 0.1 eq). The mixture solution was stirred under H2(1 atm) at room temperature for 12 h. After filtration, the filtrate was concentrated under reduced pressure to give crude 5-bromo-1,2,3,4-tetrahydroquinolin-8-amine (2.1 g, yield 41%) as a red solid. The crude product was directly used in the next step without further purification. LC-MS (ESI): mass calcd. for C9H11BrN2, 226.01; m / z found, 227.20 [M+H]+. Step B: 7-bromo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

[0243] To a solution of 5-bromo-1,2,3,4-tetrahydroquinolin-8-amine (2.0 g, 8.8 mmol, 1.0 eq) in THF (100 mL) was added CDI (2.9 g, 17.6 mmol, 2.0 eq). The mixture solution was stirred at 80 °C for 3 h. After evaporation, the residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 4) to afford 7-bromo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin- 2(1H)-one (1.6 g, yield 72%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H9BrN2O, 251.99; m / z found, 253.20 [M+H]+. Step C: tert-butyl 4-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7-yl)-3,6- dihydropyridine-1(2H)-carboxylate

[0244] To a solution of 7-bromo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (500 mg, 2.0 mmol, 1.0 eq) in dioxane (15 mL) and H2O (1 mL) were added tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (733 mg, 2.4 mmol, 1.2 eq), K3PO4(1.26 g, 5.9 mmol, 3.0 eq), and Pd(dtbpf)Cl2(127 mg, 0.2 mmol, 0.1 eq). The mixture solution was stirred under N2 at 100 °C for 4 h. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 4) to afford tert-butyl 4-(2-oxo-1,2,5,6-tetrahydro- 4H-imidazo[4,5,1-ij]quinolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (450 mg, yield 64%) as a yellow solid. LC-MS (ESI): mass calcd. for C20H25N3O3, 355.19; m / z found, 356.40 [M+H]+. 73 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Step D: tert-butyl 4-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7- yl)piperidine-1-carboxylate

[0245] To a solution of tert-butyl 4-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7- yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 1.1 mmol, 1.0 eq) in EtOH (10 mL) was added 10% Pd / C (40 mg). The mixture was stirred under H2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated under reduced pressure to afford tert- butyl 4-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7-yl)piperidine-1-carboxylate (245 mg, yield 61%) as a white solid. The crude product was directly used in the next step without further purification. LC-MS (ESI): mass calcd. for C20H27N3O3, 357.21; m / z found, 358.20 [M+H]+. Step E: tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H- imidazo[4,5,1-ij]quinolin-7-yl)piperidine-1-carboxylate

[0246] To a solution of tert-butyl 4-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7- yl)piperidine-1-carboxylate (200 mg, 0.56 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% suspend in oil) (112 mg, 2.8 mmol, 5.0 eq) in portions at 60oC and the mixture was stirred at 60 °C for 1 h. Then 3-bromopiperidine-2,6-dione (161 mg, 0.84 mmol, 1.5 eq) was added to above mixture and the mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature, slowly poured into cooled saturated NH4Cl solution (15 mL), and extracted with EA (50 mL x 3). The organic layer was washed with brine (10 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (THF / PE = 1 / 1) to afford tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2- oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7-yl)piperidine-1-carboxylate (120 mg, yield 46%) as a white solid. LC-MS (ESI): mass calcd. for C25H32N4O5, 468.24; m / z found, 469.30 [M+H]+. Step F: 3-(2-oxo-7-(piperidin-4-yl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dione

[0247] To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H- imidazo[4,5,1-ij]quinolin-7-yl)piperidine-1-carboxylate (100 mg, 0.21 mmol, 1.0 eq) in ACN (3 mL) was added HCl-dioxane (4 N) (1 mL, 4 mmol, 19 eq) and the mixture solution was stirred at room temperature for 1 h. After evaporation, the residue was purified by Prep-HPLC with YMC-TA C18 (5 um, 20 x 250 mm), and mobile phase of 5-95% MeCN (0.1% HCOOH) in water over 10 min, and then hold at 100% ACN for 2 min, at a flow rate of 25 mL / min to afford 3-(2-oxo-7-(piperidin-4-yl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dione formate (25 mg, yield 32%) as a white solid. LC-MS (ESI): mass calcd. 74 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 for C20H24N4O3, 368.18; m / z found, 369.30 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.34 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 5.33 - 5.28 (m, 1H), 3.73 (t, J = 5.8 Hz, 2H), 3.30 (d, J = 12.0 Hz, 2H), 2.97 - 2.95 (m, 4H), 2.83 (t, J = 5.8 Hz, 2H), 2.67 - 2.58(m, 2H), 2.09 - 1.95 (m, 3H), 1.78 (s, 4H). Example 5: 3-(2-oxo-7-(piperidin-4-yl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin- 1(2H)-yl)piperidine-2,6-dioneStep A: tert-butyl 4-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7- yl)piperazine-1-carboxylate

[0248] To a solution of 7-bromo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (500 mg, 2.0 mmol, 1.0 eq) in DMSO (5 mL) was added t-BuONa (379 mg, 4.0 mmol, 2.0 eq) and Pd(t-Bu3P)2 (511 mg, 4.6 mmol, 2.3 eq). The mixture solution was stirred under N2 at 100 °C for 2 h under microwave. After cooled to room temperature, the mixture solution was quenched with brine (10 mL) and extracted with EA (25 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 (EA / PE = 1 / 1) to afford tert-butyl 4-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7- yl)piperazine-1-carboxylate (230 mg, yield 32%) as a yellow solid. LC-MS (ESI): mass calcd. for C19H26N4O3, 358.20; m / z found, 359.30 [M+H]+. Step B: tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H- imidazo[4,5,1-ij]quinolin-7-yl)piperazine-1-carboxylate

[0249] To a solution of tert-butyl 4-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7- yl)piperazine-1-carboxylate (200 mg, 0.56 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% suspend in oil) (112 mg, 2.8 mmol, 5.0 eq) in portions at 60oC and the mixture was stirred at 60 °C for 1 h. Then 3-bromopiperidine-2,6-dione (214 mg, 1.1 mmol, 2.0 eq) was added to above mixture and the mixture solution was stirred at 60 °C for 2 h. the reaction mixture was slowly poured into cooled saturated NH4Cl solution (15 mL) and extracted with EA (50 mL x 3). The organic layer was washed with brine (10 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash 75 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 column chromatography on silica gel (THF / PE = 1 / 1) to afford tert-butyl 4-(1-(2,6- dioxopiperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7-yl)piperazine- 1-carboxylate (120 mg, yield 46%) as a yellow solid. LC-MS (ESI): mass calcd. for C24H31N5O5, 469.23; m / z found, 470.30 [M+H]+. Step C: 3-(2-oxo-7-(piperazin-1-yl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dione

[0250] To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H- imidazo[4,5,1-ij]quinolin-7-yl)piperazine-1-carboxylate (100 mg, 0.21 mmol, 1.0 eq) in ACN (3 mL) was added HCl-dioxane solution (4 N) (1 mL, 4 mmol, 19 eq). The mixture solution was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to afford 3-(2-oxo-7-(piperazin-1-yl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dione hydrochloride (28 mg, yield 36%) as a white solid. LC-MS (ESI): mass calcd. for C19H23N5O3, 369.18; m / z found, 370.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.51 (s, 2H), 6.90 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.34 - 5.29 (m, 1H), 3.81 - 3.66 (m, 2H), 3.23 (s, 4H), 3.11 (s, 4H), 2.97 - 2.85 (m, 1H), 2.77 (t, J = 5.2 Hz, 2H), 2.72 - 2.56 (m, 2H), 2.05 - 1.92 (m, 3H). Example 6: 3-(7-methoxy-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dioneStep A: methyl (5-methoxyquinolin-8-yl)carbamate

[0251] To a solution of 5-methoxyquinolin-8-amine (1.0 g, 5.74 mmol, 1.0 eq) and TEA (1.16 g, 11.48 mmol, 2.0 eq) in DCM (30.0 mL) was added methyl carbonochloridate (710.0 mg, 7.46 mmol, 1.3 eq) at 0oC. The resulting mixture was stirred under N2at room temperature for 18 h. The mixture was diluted with H2O (20.0 mL) and extracted with EA (50 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 (EA / PE = 1 / 3) to give methyl (5-methoxyquinolin-8- yl)carbamate (400 mg, yield 30%) as a yellow solid. LC-MS (ESI): mass calcd. for C12H12N2O3, 232; m / z found, 233 [M+H]+. 76 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Step B: methyl (5-methoxy-1,2,3,4-tetrahydroquinolin-8-yl)carbamate

[0252] To a solution of methyl N-(5-methoxyquinolin-8-yl)carbamate (400.0 mg, 1.72 mmol, 1eq) in AcOH (3.0 mL) and MeOH (20.0 mL) was added PtO2(180.0 mg, 0.79 mmol, 0.46 eq) and the resulting mixture was stirred under H2 (1 atm) at room temperature for 2 h. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 2) to give methyl (5-methoxy-1,2,3,4- tetrahydroquinolin-8-yl)carbamate (400 mg, yield 98%) as a yellow solid. LC-MS (ESI): mass calcd. for C12H16N2O3, 236; m / z found, 237 [M+H]+. Step C: 3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one

[0253] To a solution of methyl (5-methoxy-1,2,3,4-tetrahydroquinolin-8-yl)carbamate (400 mg, 1.69 mmol, 1.0 eq) in THF (30 mL) was added CDI (549 g, 3.38 mmol, 2.0 eq). The mixture was stirred under N2 at 70oC for 15 h. After evaporation, the residue was diluted with EA (50 mL), washed with saturated aqueous NH4Cl solution (30 mL) and brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 1) to afford 7-methoxy- 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (200 mg, yield 58%) as a yellow solid. LC-MS (ESI): mass calcd. for C11H12N2O2, 204; m / z found, 205 [M+H]+. Step D: 3-(7-methoxy-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dione

[0254] To a solution of 7-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (90 mg, 0.44 mmol, 1.0 eq) in DMF (15 mL) was added NaH (60% suspend in oil) (88 mg, 2.20 mmol, 5.0 eq) in portions at 60 ℃ and the mixture was stirred at 60oC for 1 h. Then 3- bromopiperidine-2,6-dione (127 mg, 0.66 mmol, 1.5 eq) was added to above mixture and the resulting mixture was stirred under N2 at 60 ℃ for 3 h. After cooled to room temperature, the reaction mixture was slowly poured into cooled saturated NH4Cl solution (15 mL) and extracted with EA (50 mL x 3). The organic layer was washed with brine (10 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was precipitated with EA (15 mL x 3) to afford 3-(7-methoxy-2-oxo-5,6-dihydro-4H- imidazo[4,5,1-ij]quinolin-1(2H)-yl)piperidine-2,6-dione (10 mg, yield 7%) as an off-white solid. LC-MS (ESI): mass calcd. for C16H17N3O4, 315; m / z found, 316 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.30 - 5.25 (m, 1H), 3.75 (s, 3H), 3.73 - 3.69 (m, 2H), 2.96 - 2.84 (m, 1H), 2.69 - 2.58 (m, 4H), 2.01 - 1.98 (m, 3H). 77 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Example 7: 3-(7-bromo-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dione

[0255] To a solution of 7-bromo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (297 mg, 1.2 mmol, 1.5 eq) in DMF (15 mL) was added NaH (60% suspend in oil) (94 mg, 3.9 mmol, 5.0 eq) in portions at 60oC and the mixture solution was stirred at 60 °C for 1 h. Then 3-bromopiperidine-2,6-dione (150 mg, 0.78 mmol, 1.0 eq) was added to above mixture and the resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature, slowly poured into cooled saturated NH4Cl solution (15 mL), and extracted with EA (50 mL x 3). The organic layer was washed with brine (10 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (THF / DCM = 1 / 2) to afford 3-(7-bromo-2-oxo-5,6- dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)piperidine-2,6-dione (8.1 mg, yield 3%) as a white solid. LC-MS (ESI): mass calcd. for C15H14BrN3O3, 363.02; m / z found, 365.90 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.37 - 5.31 (m, 1H), 3.75 (t, J = 5.8 Hz, 2H), 2.98 - 2.83 (m, 1H), 2.77 (t, J = 5.8 Hz, 2H), 2.73 - 2.56 (m, 2H), 2.11 - 1.99 (m, 3H). Example 8: 3-(7-(4-aminobut-1-yn-1-yl)-2-oxo-5,6-dihydro-4H-imidazo[4,5,1- ij]quinolin-1(2H)-yl)piperidine-2,6-dioneStep A: tert-butyl (4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H- imidazo[4,5,1-ij]quinolin-7-yl)but-3-yn-1-yl) carbamate

[0256] To a solution of 3-(7-bromo-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)- yl)piperidine-2,6-dione (500 mg, 1.4 mmol, 1.0 eq) in DMF (10 mL) were added tert-butyl but- 3-yn-1-ylcarbamate (929 mg, 5.5 mmol, 4.0 eq), Pd(PPh3)2Cl2(193 mg, 0.27 mmol, 0.2 eq), 78 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 CuI (105 mg, 0.55 mmol, 0.4 eq), and TEA (1 mL). The reaction mixture was stirred under N2 at 60 °C for 12 h. After cooled to room temperature, the resulting mixture was quenched with brine (15 mL) and extracted with EA (15 mL x 3). The organic phase was washed with brine (15 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 1) to afford tert-butyl (4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1- ij]quinolin-7-yl)but-3-yn-1-yl) carbamate (315 mg, yield 51%) as a white solid. LC-MS (ESI): mass calcd. for C24H28N4O5, 452.21; m / z found, 453.30 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 11.09 (s, 1H), 7.06 - 6.96 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 5.35 - 5.30 (m, 1H), 3.75 (t, J = 5.8 Hz, 2H), 3.15 (q, J = 5.8 Hz, 2H), 2.87 - 2.82 (m, 3H), 2.74 - 2.52 (m, 4H), 2.06 - 2.00 (m, 3H), 1.38 (s, 9H). Step B: 3-(7-(4-aminobut-1-yn-1-yl)-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin- 1(2H)-yl)piperidine-2,6-dione

[0257] To a solution of tert-butyl (4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro- 4H-imidazo[4,5,1-ij]quinolin-7-yl)but-3-yn-1-yl)carbamate (200 mg, 0.44 mmol, 1.0 eq) in DCM (5.00 mL) was added TFA (1.00 mL). The mixture was stirred at 25 °C for 1 h. After evaporation, the residue was purified by Prep-HPLC with Kromasil EternityXT C18 (21.2 x 250 mm, 10 um), and mobile phase of 5-95% ACN in water (with 0.1%FA) over 40 min and then hold at 95% ACN for 2 min, at a flow rate of 30 mL / min.) to afford 3-(7-(4-aminobut-1- yn-1-yl)-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)piperidine-2,6-dione formate (42.0 mg, yield 24%) as a white solid. LC-MS (ESI): mass calcd. for C19H20N4O3, 352.15; m / z found, 353.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 5.36 - 5.31 (m, 1H), 3.75 (t, J = 5.8 Hz, 2H), 3.01 - 2.77 (m, 5H), 2.75 - 2.52 (m, 4H), 2.15 - 1.93 (m, 3H). Example 9.1-(2,6-dioxopiperidin-3-yl)-6-methyl-1H-imidazo[1,5,4- de]quinoxaline-2,5(4H,6H) -dione  79 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Step A: N-(2-amino-3-nitrophenyl)-4-methylbenzenesulfonamide

[0258] To a solution of 3-nitrobenzene-1,2-diamine (4.0 g, 26.1 mmol, 1.0 eq) in pyridine (200 mL) was added TsCl (4.98 g, 26.1 mmol, 1.0 eq). The mixture was stirred at 125oC for 2 h. After cooled to room temperatrue, the reaction mixture was concentrated under reduced pressure to afford N-(2-amino-3-nitrophenyl)-4-methylbenzenesulfonamide (8.0 g, yield 100%) as a yellow solid. The crude product was directly used in next step without further purification. LC-MS (ESI): mass calcd. for C13H13N3O4S, 307.1; m / z found, 308.2 [M+H]+. Step B: 4-nitro-1-tosyl-1H-benzo[d]imidazol-2(3H)-one

[0259] To a solution of methyl N-(2-amino-3-nitrophenyl)-4-methylbenzenesulfonamide (8.0 g, 26.1 mmol, 1.0 eq) in ACN (400 mL) was added triphosgene (3.88 g, 13.0 mmol, 0.5 eq). The mixture was stirred at room temperature for 1 h. After filtration, the yellow solid was concentrated under reduced pressure to afford methyl 44-nitro-1-tosyl-1H-benzo[d]imidazol- 2(3H)-one (6.5 g, yield 75%) as a yellow solid. LC-MS (ESI): mass calcd. for C14H11N3O5S, 333.0; m / z found, 334.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, 1H), 2.40 (s, 3H). Step C: methyl 2-(7-nitro-2-oxo-3-tosyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ace tate

[0260] To a solution of 4-nitro-1-tosyl-1H-benzo[d]imidazol-2(3H)-one (2.5 g, 7.5 mmol, 1.0 eq) in DMF (250 mL) were added K2CO3(1.04 g, 7.5 mmol, 1.0 eq) and methyl 2-bromoacetate (1.15 g, 7.5 mmol, 1.0 eq). The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (150 mL) and the precipitate was formed. After filtration, the solid was dried to give methyl 2-(7-nitro-2-oxo-3-tosyl-2,3-dihydro-1H-benzo[d]imidazol- 1-yl)acetate (2.9 g, yield 95%) as a yellow solid. LC-MS (ESI): mass calcd. for C17H15N3O7S, 405.1; m / z found, 406.2 [M+H]+. Step D: 1-tosyl-1H-imidazo[1,5,4-de]quinoxaline-2,5(4H,6H)-dione

[0261] To a solution of methyl 2-(7-nitro-2-oxo-3-tosyl-2,3-dihydro-1H-benzo[d] imidazol-1- yl)acetate (2.5 g, 6.16 mmol, 1.0 eq) in EtOAc (30 mL) was added 10% Pd / C (250 mg). The mixture was stirred under H2(1 atm) at room temperature for 10 h. After filtration, HOAc (1 mL) was added to the filtrate and the resulting mixture was stirred at room temperature for 8 h. The mixture was concentrated under reduced pressure to afford 1-tosyl-1H-imidazo[1,5,4- de]quinoxaline-2,5(4H,6H)-dione (2.1 g, yield 89%) as a yellow solid. LC-MS (ESI): mass calcd. for C16H13N3O4S, 343.1; m / z found, 344.1 [M+H]+. 80 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Step E: 6-methyl-1H-imidazo[1,5,4-de]quinoxaline-2,5(4H,6H)-dione

[0262] To a solution of 1-tosyl-1H-imidazo[1,5,4-de]quinoxaline-2,5(4H,6H)-dione (2.1 g, 6.11 mmol, 1.0 eq) in DMF (100 mL) were added was added K2CO3(0.85 g, 6.11 mmol, 1.0 eq) and MeI (0.457 mL , 7.34 mmol, 1.2 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (150 mL) and filtered. The solid was washed with water (30 mL x 3) and dried under reduced pressure. The solid was dissolved in Con. H2SO4(2 mL) and the mixture was stirred 50oC for 1 h. After cooled to room temperature, the mixtrue was poured into ice-water (10 mL) and filtered. The cake was washed with water (10 mL x 3) and dried under reduced pressure to give 6-methyl-1H-imidazo[1,5,4- de]quinoxaline-2,5(4H,6H)-dione (458 mg, yield 37%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H9N3O2, 203.1; m / z found, 204.2 [M+H]+. Step F: 1-(2,6-dioxopiperidin-3-yl)-6-methyl-1H-imidazo[1,5,4-de]quinoxalin e- 2,5(4H,6H)-dione

[0263] To a solution of 6-methyl-1H-imidazo[1,5,4-de]quinoxaline-2,5(4H,6H)-dione (100 mg, 0.492 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% suspend in oil) (98.4 mg, 2.461 mmol, 5.0 eq) at 60oC. The mixture was stirred under N2at 60oC for 1 h. Then a solution of 3-bromopiperidine-2,6-dione (141.7 mg, 0.738 mmol, 1.5 eq) in DMF (1.0 mL) was added to above mixture and the resulting mixture was stirred at 60oC for 2 h. The mixture was cooled to room tempeature, quenched with saturated aqueous NH4Cl solution (15 mL) at 0oC, and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (50 mL x 4), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by Prep-TLC (THF / PE = 1 / 2) to give 1-(2,6-dioxopiperidin-3-yl)-6-methyl-1H- imidazo[1,5,4-de]quinoxaline-2,5(4H,6H)-dione (5.6 mg, yield 3.6%) as a white solid. LC- MS (ESI): mass calcd. for C15H14N4O4, 314.1; m / z found, 315.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 5.38 - 5.33 (m, 1H), 4.66 (d, J = 3.8 Hz, 2H), 3.29 (s, 3H), 3.01 - 2.84 (m, 1H), 2.70 - 2.60 (m, 2H), 2.07 - 2.01 (m, 1H). 81 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Example 10: 3-(5-methoxy-1-oxo-6,9-dihydro-2,9a-diazabenzo[cd]azulen-2(1H)- yl) piperidine -2,6-dioneStep A: 2-bromo-3-methoxy-6-nitroaniline

[0264] To a solution of 2-bromo-3-fluoro-6-nitroaniline (9.8 g, 41.7 mmol, 1.0 eq) in MeOH (150 mL) was added MeONa (2.25 g, 41.7 mmol, 1.0 eq) at 12oC and the mixture was stirred at 100oC for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (200 mL) and filtered. The cake was washed with cooled-water (50 mL x 2) and dried to give 2-brom-3-methoxy-6-nitroaniline (7.1 g, yield 69%) as a yellow solid. LC-MS (ESI): mass calcd. for C7H7BrN2O3, 245.96; m / z found, 247.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 9.6 Hz, 1H), 7.23 (s, 2H), 6.62 (d, J = 9.6 Hz, 1H), 3.96 (s, 3H). Step B: 2-allyl-3-methoxy-6-nitroaniline

[0265] To a solution of 2-bromo-3-methoxy-6-nitroaniline (6.8 g, 27.5 mmol, 1.0 eq) in dioxane (40 mL) and H2O (5.0 mL) were added 2-allyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (37.0 g, 220 mmol, 8.0 eq), Pd(dppf)Cl2(2.01 g, 2.75 mmol, 0.1 eq), and K2CO3(11.4 g, 82.6 mmol, 3.0 eq). The reaction mixture was stirred under N2 at 60oC for 18 h. After cooled to room temperature, the mixture was diluted with EA (250 mL), washed with water (100 mL x 3) and 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 (ethyl acetate in petroleum ether, from 0% to 10%) to give 2- allyl-3-methoxy-6-nitroaniline (900 mg, yield 16%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H12N2O3, 208.08; m / z found, 209.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.6 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 6.25 (s, 2H), 5.87 - 5.80 (m, 1H), 5.12 - 5.07 (m, 2H), 3.90 (s, 2H), 3.44 - 3.38 (m, 2H). Step C: methyl (2-allyl-3-methoxy-6-nitrophenyl)carbamate

[0266] A mixture of 2-allyl-3-methoxy-6-nitroaniline (880 mg, 4.23 mmol, 1.0 eq) in methyl chloroformate (10.0 mL) was stirred at 90oC for 18 h. The mixture was cooled to room 82 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 temperature and the precipitate is formed. The mixture was filtered and the cake was dried to give methyl (2-allyl-3-methoxy-6-nitrophenyl)carbamate (1.05 g, yield 93%) as a gray solid. LC-MS (ESI): mass calcd. for C12H14N2O5, 266.09; m / z found, 267.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 9.2 Hz, 1H), 7.19 (d, J = 9.2 Hz, 1H), 5.85 - 5.73 (m, 1H), 5.62 - 5.49 (m, 1H), 4.95 - 4.85 (m, 1H), 3.93 (s, 3H), 3.74 - 3.62 (m, 2H), 3.48 (s, 3H). Step D: methyl allyl(2-allyl-3-methoxy-6-nitrophenyl)carbamate

[0267] To a solution of methyl (2-allyl-3-methoxy-6-nitrophenyl)carbamate (1.23 g, 4.62 mmol, 1.0 eq) in DMF (15.0 mL) were added K2CO3 (1.92 g, 13.9 mmol, 3.0 eq) and allyl bromide (1.12 g, 0.8 mL, 9.24 mmol, 2.0 eq). The mixture was stirred under N2at 50oC for 18 h. After cooled to room temperature, the mixture was diluted with EA (100 mL), washed with water (30 mL x 3) and 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 in petroleum ether, from 0% to 15%) to afford methyl allyl(2-allyl-3-methoxy-6-nitrophenyl)carbamate (1.37 g, yield 96%) as a yellow oil. LC-MS (ESI): mass calcd. for C15H18N2O5, 306.12; m / z found, 307.1 [M+H]+. Step E: methyl 6-methoxy-9-nitro-2,5-dihydro-1H-benzo[b]azepine-1-carboxylate

[0268] To a solution of methyl allyl(2-allyl-3-methoxy-6-nitrophenyl)carbamate (430 mg, 1.4 mmol, 1.0 eq) in DCM (35 mL) was added Grubbs II (119 mg, 0.14 mmol, 0.1 eq). The reaction mixture was stirred under N2at 50oC for 18 h. After evaporation, the residue was purified by flash column chromatography on silice gel (ethyl acetate in petroleum ether, from 0% to 15%) to afford methyl 6-methoxy-9-nitro-2,5-dihydro-1H-benzo[b]azepine-1-carboxylate (370 mg, yield 95%) as a yellow oil. LC-MS (ESI): mass calcd. for C13H14N2O5, 278.09; m / z found, 279.1 [M+H]+. Step F: 5-methoxy-6,9-dihydro-2,9a-diazabenzo[cd]azulen-1(2H)-one

[0269] To a solution of methyl 6-methoxy-9-nitro-2,5-dihydro-1H-benzo[b]azepine-1- carboxylate (370 mg, 1.33 mmol, 1.0 eq) in AcOH (12.0 mL) was added Fe powder (743 mg, 13.3 mmol, 10.0 eq). The mixture was stirred at 50oC for 18 h. After cooled to room temperature, the mixture was diluted with EA (100 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50%) to give 5- methoxy-6,9-dihydro-2,9a-diazabenzo[cd]azulen-1(2H)-one (204 mg, yield 70%) as a yellow solid. LC-MS (ESI): mass calcd. for C12H12N2O2, 216.09; m / z found, 217.0 [M+H]+. 83 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Step G: 3-(5-methoxy-1-oxo-6,9-dihydro-2,9a-diazabenzo[cd]azulen-2(1H)- yl)piperidine-2,6-dione

[0270] To a solution of 5-methoxy-6,9-dihydro-2,9a-diazabenzo[cd]azulen-1(2H)-one (180 mg, 0.832 mmol, 1.0 eq) in dry DMF (6.0 mL) was added DIPEA (323 mg, 0.4 mL, 2.5 mmol, 3.0 eq) and the mixture was heated to 60oC. NaH (60% suspend in oil) (110 mg, 3.33 mmol, 4.0 eq) was added to above mixture and the mixture was stirred at 60oC for 1 h. Then a solution for 3-bromopiperidine-2,6-dione (160 mg, 0.832 mmol, 1.0 eq) in dry DMF (2.0 mL) was added slowly to above mixture and the resulting mixture was stirred at 60oC for 2 h. After cooled to room temperature, the mixture was diluted with EA (100 mL) and quenched with saturated aqueous NH4Cl solution (15 mL). The organic layer was washed with brine (15 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purifed by Prep-TLC (EA / PE / DCM = 1 / 1 / 1) to give 3-(5-methoxy-1-oxo-6,9- dihydro-2,9a-diazabenzo[cd]azulen-2(1H)-yl)piperidine-2,6-dione (25 mg, yield 9%) as a white solid. LC-MS (ESI): mass calcd. for C17H17N3O4, 327.12; m / z found, 328.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 11.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.14 - 6.09 (m, 1H), 5.36 - 5.32 (m, 1H), 4.00 - 3.84 (m, 2H), 3.78 (s, 3H), 2.96 - 2.83 (m, 1H), 2.77 - 2.56 (m, 4H), 2.06 - 1.97 (m, 1H). Example 11.3-(5-methoxy-1-oxo-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen- 2(1H)-yl)piperidine-2,6-dione

[0271] To a solution of 3-(5-methoxy-1-oxo-6,9-dihydro-2,9a-diazabenzo[cd]azulen-2(1H)- yl)piperidine-2,6-dione (14.0 mg, 42.8 umol, 1.0 eq) in EtOH (3.0 mL) was added 10% Pd / C (5.0 mg). The mixture was stirred under H2(1 atm) at room temperature for 30 min. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by Prep-TLC (EA / PE = 1 / 1) to affor 3-(5-methoxy-1-oxo-6,7,8,9-tetrahydro-2,9a- diazabenzo[cd]azulen-2(1H)-yl)piperidine-2,6-dione (11.0 mg, yield 78%) as a white solid. LC-MS (ESI): mass calcd. for C17H19N3O4, 329.14; m / z found, 330.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 5.33 - 5.28 84 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 (m, 1H), 3.84 - 3.82 (m, 2H), 3.75 (s, 3H), 2.96 - 2.83 (m, 3H), 2.75 - 2.57 (m, 2H), 2.01 - 1.88 (m, 5H). Example 12: (Z)-3-(5-bromo-1-oxo-7,10-dihydro-6-oxa-2,10a- diazacycloocta[cd]inden-2(1H)-yl)piperidine-2,6-dioneStep A: 2-amino-6-bromo-3-nitrophenol

[0272] To a solution of 2-bromo-5-nitrophenol (1.0 g, 4.6 mmol 1.0 eq) in DMSO (15.0 mL) was added amino(trimethyl)ammonium iodide (1.0 g, 5.05 mmol, 1.1 eq). The mixture was stirred at 25 °C for 1.5 h. Then sodium tert-pentoxide (2.5 g, 22.9 mmol, 5.0 eq) was added to above mixture and the resulting mixture was stirred at 25 °C for 18 h. The mixture was quenched with aqueous HCl solution (4 N) (7 mL) and water (10 mL) and stirred at 0 °C for 1 h. After filtration, the cake was washed with water (10 mL) and dried to afford 2-amino-6- bromo-3-nitrophenol (900 mg, yield 84%) as a yellow solid. LC-MS (ESI): mass calcd. for C6H5BrN2O3, 231.95; m / z found, 227.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.50 (d, J = 9.4 Hz, 1H), 7.17 (s, 2H), 6.77 (d, J = 9.4 Hz, 1H). Step B: 2-(allyloxy)-3-bromo-6-nitroaniline

[0273] To a solution of 2-amino-6-bromo-3-nitrophenol (500 mg, 2.15 mmol, 1.0 eq) in acetone (15.0 mL) were added K2CO3 (297 mg, 2.15 mmol, 1.0 eq) and allyl bromide (0.18 mL, 2.15 mmol, 1.0 eq). The solution was stirred at 50 °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 (EA / PE = 1 / 2) to afford 2-(allyloxy)-3-bromo-6-nitroaniline (459 mg, yield 78%) as a yellow solid. LC-MS (ESI): mass calcd. for C9H9BrN2O3, 271.98; m / z found, 272.90 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 9.4 Hz, 1H), 7.23 (s, 2H), 6.86 (d, J = 9.4 Hz, 1H), 6.22 - 6.15 (m, 1H), 5.47 - 5.36 (m, 1H), 5.34 - 5.23 (m, 1H), 4.50 (d, J = 6.0 Hz, 2H). Step C: methyl (2-(allyloxy)-3-bromo-6-nitrophenyl)carbamate

[0274] A solution of 2-(allyloxy)-3-bromo-6-nitroaniline (400 mg, 1.5 mmol, 1.0 eq) in methyl carbonochloridate (1.4 g, 14.6 mmol, 10.0 eq) was stirred under N2 at 90 °C for 12 h. After evaporation, the residue was purified by flash column chromatography on silica gel 85 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 (EA / PE = 1 / 5) to afford methyl (2-(allyloxy)-3-bromo-6-nitrophenyl)carbamate (300 mg, yield 62%) as a yellow solid. LC-MS (ESI): mass calcd. for C11H11BrN2O5, 329.99; m / z found, 331.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 6.09 - 5.99 (m, 1H), 5.38 (dd, J = 17.2, 1.4 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 4.49 (d, J = 5.8 Hz, 2H), 3.63 (s, 3H). Step D: methyl allyl(2-(allyloxy)-3-bromo-6-nitrophenyl)carbamate

[0275] To a solution of methyl (2-(allyloxy)-3-bromo-6-nitrophenyl)carbamate (300 mg, 0.9 mmol, 1.0 eq) in DMF (5.00 mL) were added K2CO3 (125 mg, 0.9 mmol, 1.0 eq) and 3- bromoprop-1-ene (164 mg, 1.4 mmol, 1.5 eq). The mixture was stirred at 50 °C for 12 h. After cooled to room temperature, the mixture was quenched with brine (15 mL) and extracted with EA (25 mL x 3). The combined organic layers were 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 (EA / PE = 1 / 1) to afford methyl allyl(2- (allyloxy)-3-bromo-6-nitrophenyl)carbamate (220 mg, yield 65%) as a yellow oil. LC-MS (ESI): mass calcd. for C14H15BrN2O5, 370.02; m / z found, 371.00 [M+H]+. Step E: methyl (Z)-10-bromo-7-nitro-2,5-dihydro-6H-benzo[b][1,4]oxazocine-6- carboxylate

[0276] To a solution of methyl allyl(2-(allyloxy)-3-bromo-6-nitrophenyl)carbamate (300 mg, 0.8 mmol, 1.0 eq) in DCM (25.0 mL) was added Grubbs II catalyst (69 mg, 0.08 mmol, 0.1 eq). The mixture solution was stirred at 50 °C for 16 h. After evaporation, the residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 5) to afford methyl (Z)-10- bromo-7-nitro-2,5-dihydro-6H-benzo[b][1,4]oxazocine-6-carboxylate (200 mg, yield 87%) as a yellow oil. LC-MS (ESI): mass calcd. for C12H11BrN2O5, 341.99; m / z found, 365.00 [M+Na]+.1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 6.04 - 5.98 (m, 1H), 5.93 - 5.85 (m, 1H), 4.98 - 4.66 (m, 4H), 3.54 (s, 3H). Step F: (Z)-5-bromo-7,10-dihydro-6-oxa-2,10a-diazacycloocta[cd]inden-1(2H)-one

[0277] To a solution of methyl (Z)-10-bromo-7-nitro-2,5-dihydro-6H- benzo[b][1,4]oxazocine-6-carboxylate (220 mg, 0.64 mmol, 1.0 eq) in AcOH (10.0 mL) was added Fe powder (716 mg, 13 mmol, 20 eq). The solution was stirred at 48 °C for 12 h. After evaporation, the residue was dissolved in DCM (50 mL) and filtrated. The filtrate was concentrated to afford (Z)-5-bromo-7,10-dihydro-6-oxa-2,10a-diazacycloocta[cd]inden- 1(2H)-one (110 mg, yield 61%) as a yellow solid. LC-MS (ESI): mass calcd. for C11H9BrN2O2, 279.98; m / z found, 281.00 [M+H]+. 86 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Step G: (Z)-3-(5-bromo-1-oxo-7,10-dihydro-6-oxa-2,10a-diazacycloocta[cd]inden- 2(1H)-yl)piperidine-2,6-dione

[0278] To a solution of (Z)-5-bromo-7,10-dihydro-6-oxa-2,10a-diazacycloocta[cd]inden- 1(2H)-one (105 mg, 0.37 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% suspend in oil) (90 mg, 2.24 mmol, 6.0 eq). The mixture solution was stirred at 60 °C for 1 hour. Then 3- bromopiperidine-2,6-dione (143 mg, 0.75 mmol, 2.0 eq) was added above mixture and the mixture was stirred at 60 °C for 2 h. After cooled to room temperature, the reaction mixture was slowly poured into cooled saturated NH4Cl solution (15 mL) and extracted with EA (20 mL x 3). The organic layer was washed with brine (10 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA / DCM = 1 / 1 / 1) to afford (Z)-3-(5-bromo-1-oxo-7,10-dihydro-6-oxa-2,10a- diazacycloocta[cd]inden-2(1H)-yl)piperidine-2,6-dione (30.0 mg, yield 18%) as a white solid. LC-MS (ESI): mass calcd. for C16H14BrN3O4, 391.02; m / z found, 392.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.97 - 5.92 (m, 1H), 5.83 - 5.79 (m, 1H), 5.39 - 5.34 (m, 1H), 4.85 (d, J = 2.2 Hz, 2H), 4.60 (d, J = 8.0 Hz, 2H), 2.95 - 2.80 (m, 1H), 2.75 - 2.58 (m, 2H), 2.11 - 1.97 (m, 1H). Example 13.3-(5-bromo-1-oxo-7,8,9,10-tetrahydro-6-oxa-2,10a- diazacycloocta[cd]inden-2(1H)-yl)piperidine-2,6-dione

[0279] To a solution of (Z)-3-(5-bromo-1-oxo-6-oxa-2,10a-diazacycloocta[cd]inden-2 (1H,7H,10H)-yl)piperidine-2,6-dione (40 mg, 0.102 mmol, 1.0 eq) in EtOAc (10 mL) was added 10% Pt / C (20.0 mg). The mixture was stirred under H2(1 atm) at 25oC for 10 min. After filtration, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by Prep-HPLC with YMC-Actus Triart 18C (5 μm, 20 x 250 mm), and mobile phase of 40-60% ACN in water (0.1% FA) over 10 min, at a flow rate of 20 mL / min to afford 3-(5-bromo-1-oxo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-2(1H)- yl)piperidine-2,6-dione (10.5 mg, yield 25%) as a white solid. LC-MS (ESI): mass calcd. For C16H16BrN3O4, 393.0; m / z found, 394.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 87 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 5.41 - 5.36 (m, 1H), 4.24 (t, J = 5.2 Hz, 2H), 4.11 (t, J = 6.0 Hz, 2H), 2.99 - 2.83 (m, 1H), 2.71 - 2.61 (m, 2H), 2.09 - 2.00 (m, 1H), 1.99 - 1.85 (m, 2H), 1.62 (s, 2H). Example 14. 3-(3-methyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-1(2H)- yl)piperidine -2,6-dione hydrochlorideStep A: 1-(isoindolin-2-yl)ethan-1-one

[0280] To a stirred solution of 2,3-dihydro-1H-isoindole (25 g, 160.637 mmol, 1.0 eq) in DCM (500 mL) was added TEA (33.5 mL, 240.96 mmol,1.5 eq) and Ac2O (16.6 mL, 176.70 mmol, 1.1 eq) at 0oC . The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to afford 1-(isoindolin-2-yl) ethan-1-one (23 g, yield 89%) as a pink solid. LC-MS (ESI): mass calcd. for C10H11NO, 161.08; m / z found, 162 [M+H]+. Step B: 2,2,2-trifluoro-1-(5-nitroisoindolin-2-yl)ethan-1-one

[0281] To a solution of 2,2,2-trifluoro-1-(isoindolin-2-yl)ethan-1-one (30 g, 139.4 mmol, 1.0 eq) in H2SO4(Con.) (200 mL) was slowly added HNO3(Con.) (18 mL， 2.0 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 10 min. The mixture was poured slowly into ice- water (1 L) and a white solid precipitated. After filtration, the cake was washed with water (100 mL x 2) and dried to afford 2,2,2-trifluoro-1-(5-nitroisoindolin-2-yl)ethan-1-one (30 g, yield, 83%) as a white solid. LC-MS (ESI): mass calced for C10H7F3N2O3260.1; m / z found, 259.1 [M-H]+. Step C: 2,2,2-trifluoro-N-(2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)acetamide

[0282] To a solution of 2,2,2-trifluoro-1-(5-nitroisoindolin-2-yl)ethan-1-one (30 g, 115.3 mmol, 1.0 eq) in MeOH (300 mL) was added 10% Pd / C (3 g) and the reaction mixture was stirred under H2atmosphere (1 atm) at room temperature for 16 h. After filtration, the filtrate was concentrated under reduced pressure and the residue was dissolved in DCM (200 mL). 88 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 TEA (29.0 mL, 210 mmol, 2.0 eq) was added to above solution and the resulting solution was stirred at room temperature for 0.5 h. TFAA (26.5 g, 128 mmol, 1.1 eq) was added dropwise to above solution at ice-bath and the reaction was stirred at room temperature overnight. After filtration, the cake was washed with H2O and dried to afford 2,2,2-trifluoro-N-(2-(2,2,2- trifluoroacetyl)isoindolin-5-yl)acetamide (32 g, yield 94%) as an off-white solid. LC-MS (ESI): mass calced for C12H8F6N2O2230.1; m / z found, 231.1 [M+H]+Step D: 2,2,2-trifluoro-N-(6-nitro-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)acetamide

[0283] To a solution of 2,2,2-trifluoro-N-(2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)acetamide (3 g, 9.2 mmol, 1.0 eq) in con. H2SO4(25 mL) was slowly added HNO3(w.t.67%) (3 mL) at -30 °C and the reaction mixture was stirred at -30 °C for 10 min. The mixture was poured slowly into ice-bath and extracted with EA (100 mL x 3). The organic layer was separated, washed with saturated NaHCO3 solution (100 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 10%) to afford 2,2,2- trifluoro-N-(6-nitro-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)acetamide (1.5 g, yield 44%) as a yellow solid. LC-MS (ESI): mass calced for C12H7F6N3O4371.1; m / z found, 370.1 [M-H]+.1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.17 (d, J = 11.6 Hz, 1H), 7.67 (d, J = 14.0 Hz, 1H), 5.13 (d, J = 10.2 Hz, 2H), 4.92 (d, J = 10.2 Hz, 2H). Step E: 6-nitroisoindolin-5-amine

[0284] To a solution of 2,2,2-trifluoro-N-(6-nitro-2-(2,2,2-trifluoroacetyl)isoindolin-5- yl)acetamide (1.2 g, 3.2 mmol, 1.0 eq) in THF-H2O (15 mL) was added NaOH (0.52 g, 12.8 mmol, 4.0 eq) and the reaction mixture was stirred at room temperature 16 h. After evaporation, the mixture was adjusted to pH 7-8 with glacial acetic acid, filtered, and dried to afford 6- nitroisoindolin-5-amine (500 mg, yield 86%) as a brown solid. LC-MS (ESI): mass calcd. for C8H9N3O2, 179.0; m / z found, 180.1 [M+H]+. Step F: benzyl 5-amino-6-nitroisoindoline-2-carboxylate

[0285] To a solution of 6-nitroisoindolin-5-amine (10 g, 55.8 mmol, 1.0 eq) in DCM (150 mL) were added Saturated aqueous NaHCO3 solution (50 mL) and benzyl chloroformate (12.38 g, 72.6 mmol, 1.3 eq) and the reaction mixture was stirred at room temperature for 1.5h. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was slurried with MTBE (20 mL), filtered, and dried to afford benzyl 5-amino-6-nitroisoindoline-2-carboxylate (13 g, yield 74%) as a yellow solid. LC-MS (ESI): mass calcd. for C16H15N3O4, 313.1; m / z found, 314.1 [M+H]+.1H NMR (400 89 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 MHz, DMSO-d6) δ 7.96 (d, J = 10.2 Hz, 1H), 7.52 - 7.19 (m, 7H), 6.93 (d, J = 9.4 Hz, 1H), 5.14 (s, 2H), 4.65 - 4.52 (m, 4H). Step G: benzyl 5,6-diaminoisoindoline-2-carboxylate

[0286] To a solution of benzyl 5-amino-6-nitroisoindoline-2-carboxylate (10 g, 31.9 mmol, 1.0 eq) in solution EtOH (120 mL) and H2O (25 mL) were added Fe powder (8.9 g, 159.59 mmol, 5.0 eq) and NH4Cl (8.5 g, 159.6 mmol, 5.0 eq) and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was filtered and the filtration was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The organic layer was collected, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM, from 0 to 8%) to afford benzyl 5,6-diaminoisoindoline-2-carboxylate (7.0 g, yield 77%) as a brown solid. LC-MS (ESI): mass calced for C16H17N3O2283.1; m / z found, 284.1 [M+H]+. Step H: benzyl 2-oxo-2,3,5,7-tetrahydroimidazo[4,5-f]isoindole-6(1H)-carboxylate

[0287] To a solution of benzyl 5,6-diaminoisoindoline-2-carboxylate (10 g, 35.3 mmol, 1.0 eq) in ACN (600 mL) was added CDI (11.5 g, 70.6 mmol, 2.0 eq) and the reaction mixture was stirred at 60 °C for 1 h. After cooled to room temperature, the reaction mixture was filtered and the cake was dried to afford benzyl 2-oxo-2,3,5,7-tetrahydroimidazo[4,5-f]isoindole-6(1H)- carboxylate (10 g, yield 92%) as a light brown solid. LC-MS (ESI): mass calced for C17H15N3O3309.1; m / z found, 310.1 [M+H]+. Step I: benzyl 1-methyl-2-oxo-2,3,5,7-tetrahydroimidazo[4,5-f]isoindole-6(1H)- carboxylate

[0288] To a solution of benzyl 2-oxo-2,3,5,7-tetrahydroimidazo[4,5-f]isoindole-6(1H)- carboxylate (10 g, 32.3 mmol, 1.0 eq) in DMF (250 mL) were added NaH (60% suspend in oil) (2.3 g, 96.9 mmol, 3.0 eq) and the reaction mixture was stirred at room temperature for 30 min. CH3I (1.4 mL, 22.6 mmol, 0.7 eq) was added to above mixture and the resulting mixture was stirred at room temperature for 30 min. The reaction was poured into saturated aqueous NaHCO3 solution (250 mL) and extracted with EA (200 mL x 3). The organic layer was separated, washed with brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM, from 0 to 4%) to afford benzyl 1-methyl-2-oxo- 2,3,5,7-tetrahydroimidazo[4,5-f]isoindole-6(1H)-carboxylate (2.5 g, yield 24%) as an off- white solid. LC-MS (ESI): mass calced for C18H17N3O3323.1; m / z found, 324.1 [M+H]+. 90 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Step J: benzyl 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3,5,7- tetrahydroimidazo[4,5-f]isoindole-6(1H)-carboxylate

[0289] To a solution of benzyl 1-methyl-2-oxo-2,3,5,7-tetrahydroimidazo[4,5-f]isoindole- 6(1H)-carboxylate (100 mg, 0.3 mmol, 1.0 eq) in DMF (30 mL) were added NaH (60% suspend in oil) (99.0 mg, 2.4 mmol, 8.0 eq) slowly at 60 °C and the reaction mixture was stirred at 60 °C for 1 h.3-bromopiperidine-2,6-dione (89.1 mg, 0.45 mmol, 1.5 eq) was added to above solution and the resulting mixture was stirred at 60 °C for 4 h. The reaction was quenched with aqueous NH4Cl saturated (50 mL) and extracted with EA (100 mL x 3). The organic layer was separated, washed with brine (50 mL x 4), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep- HPLC with YMC-Actus Triart C18 (20 x 250 mm, 5 um) and mobile phase of 15-60% ACN in water over 12 min and then hold at 95% ACN for 5 min, at a flow rate of15 mL / min to afford benzyl 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3,5,7-tetrahydroimidazo[4,5- f]isoindole-6(1H)-carboxylate (1.5 mg, yield 1.12%) as a white solid. LC-MS (ESI): mass calced for C23H22N4O5434.2; m / z found, 435.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.47 - 7.29 (m, 5H), 7.14 (t, J = 15.2 Hz, 2H), 5.41 - 5.31 (m, 1H), 5.16 (s, 2H), 4.72 - 4.64 (m, 4H), 3.43 (s, 3H), 2.94 - 2.86 (m, 1H), 2.73 - 2.62 (m, 2H), 2.04 - 1.97 (m, 1H). Step K: 3-(3-methyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-1(2H)- yl)piperidine-2,6-dione hydrochloride

[0290] To a solution of benzyl 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3,5,7- tetrahydroimidazo[4,5-f]isoindole-6(1H)-carboxylate (100 mg, 0.23 mmol, 1.0 eq) in DMF (5 mL) was added 10% Pd / C (24.5 mg) and the reaction mixture was stirred under H2atmosphere (1 atm) at room temperature overnight. After filtration, the filtrate was purified by Prep-HPLC with YMC-Actus Triart C18 (20 x 250 mm, 5 um), and mobile phase of 5-45% ACN in HO (0.1% FA) over 10 min at a flow rate of 15 mL / min to afford 3-(3- methyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-1(2H)-yl)piperidine-2,6-dione hydrochloride (6 mg, yield 8.7%) as a white solid. LC-MS (ESI): mass calced for C15H16N4O3 300.1; m / z found, 301.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.08 (s, 2H), 7.22 (s, 1H), 7.18 (s, 1H), 5.44 - 5.39 (m, 1H), 4.53 - 4.42 (m, 4H), 3.35 (s, 3H), 2.91 (d, J = 16.6 Hz, 1H), 2.79 - 2.58 (m, 2H), 2.07 - 1.97 (m, 1H). 91 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Example 15: 3-(3,6-dimethyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol- 1(2H)-yl)piperidine-2,6-dione

[0291] To a solution of 3-(3-methyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-1(2H)- yl)piperidine-2,6-dione hydrochloride (100 mg, 0.33 mmol, 1.0 eq) in DMF (5 mL) was added Formalin (37% in H2O) (0.1 mL, 0.66 mmol, 2.0 eq) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (210.71 mg, 1.0 mmol, 3.0 eq) was added to above mixture and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC with YMC-Actus Triart C18 (20 x 250 mm,5 um), and mobile phase of 5-45% ACN in H2O (0.1% FA) over 10 min at a flow rate of 15 mL / min to afford 3-(3,6- dimethyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-1(2H)-yl)piperidine-2,6-dione (5 mg, yield 4.8%) as an off-white solid. LC-MS (ESI): mass calced for C22H22N4O3314.1; m / z found, 315.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.18 (s, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 5.38 - 5.33 (m, 1H), 3.89 (d, J = 10.8 Hz, 4H), 3.32 (s, 3H), 2.95 - 2.85 (m, 1H), 2.76 - 2.59 (m, 2H), 2.53 (s, 3H), 2.05 - 1.94 (m, 1H). Example 16：3-(6-acetyl-3-methyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5- f]isoindol-1(2H)-yl) piperidine-2,6-dione  Step A: 1-(isoindolin-2-yl)ethan-1-one

[0292] To a stirred solution of 2,3-dihydro-1H-isoindole hydrochloride (25 g, 160.64 mmol, 1.0 eq) in DCM (500 mL) was added TEA (33.5 mL, 240.96 mmol, 1.5 eq) and Ac2O (16.6 mL, 176.70 mmol, 1.1 eq) at 0oC . The reaction mixture was stirred at room temperature 92 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 overnight. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure to afford 1-(isoindolin-2-yl)ethan-1-one (23 g, yield 89%) as a pink solid. LC-MS (ESI): mass calcd. for C10H11NO, 161.08; m / z found, 162.03 [M+H]+. Step B: 1-(5-nitroisoindolin-2-yl)ethan-1-one

[0293] To a stirred solution of 1-(isoindolin-2-yl)ethan-1-one (23 g, 142.68 mmol, 1.0 eq) in concentrated H2SO4 (200 mL) was added concentrated HNO3 (17.9 mL, 285.36 mmol, 2.0 eq) at 0oC. The reaction mixture was stirred at 0oC for 0.5 h. The reaction mixture was poured into ice-water (300 mL) and adjusted pH to 8~9 with aqueous NaOH solution (2 N), and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 1-(5-nitroisoindolin-2-yl)ethan-1-one (25 g, yield 85%) as a yellow solid. LC-MS (ESI): mass calcd. for C10H10N2O3, 206.07; m / z found, 207 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 9.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.65 - 7.60 (m, 1H), 4.93 (d, J = 7.6 Hz, 2H), 4.71 (s, 2H), 2.07 (s, 3H). Step C: N-(2-acetylisoindolin-5-yl)acetamide

[0294] To a stirred solution of 1-(5-nitroisoindolin-2-yl) ethan-1-one (24 g, 116.39 mmol, 1.0 eq) in MeOH (250 mL) was added 10% Pd / C (2.5 g) and Ac2O (21.9 mL, 232.78 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred under H2(1 atm) at room temperature overnight. After filtration, the filtrate was concentrated to afford N-(2-acetylisoindolin-5- yl)acetamide (14 g, yield 55%) as a white solid. LC-MS (ESI): mass calcd. for C12H14N2O2, 218.11; m / z found, 219 [M+H]+. Step D: N-(2-acetyl-6-nitroisoindolin-5-yl)acetamide

[0295] To a stirred solution of N-(2-acetylisoindolin-5-yl)acetamide (14 g, 64.14 mmol, 1.0 eq) in concentrated H2SO4(120 mL) was added potassium nitrate (12.97 g, 128.29 mmol, 2.0 eq) in portions at 0oC. The reaction mixture was stirred at 0oC for 0.5 h. The reaction mixture was poured into ice-water (200 mL), adjusted pH to 8~9 with aqueous NaOH solution (2 N), and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford N-(2-acetyl-6-nitroisoindolin-5-yl)acetamide (7.0 g, yield 41%) as a yellow solid. LC-MS (ESI): mass calcd. for C12H13N3O4, 263.09 m / z found, 264 [M+H]+. 93 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Step E: N-(2-acetyl-6-aminoisoindolin-5-yl) acetamide

[0296] To a stirred solution of N-(2-acetyl-6-nitroisoindolin-5-yl)acetamide (7 g, 26.59 mmol, 1.0 eq) in THF (100 mL) was added 10% Pd / C (1.2 g) at room temperature. The reaction mixture was stirred under H2 (1 atm) at room temperature overnight. After filtration, the filtrated was concentrated and the residue was purified by flash column chromatography on silica gel (methanol in dichloromethane, from 0% to 10%) to afford N-(2-acetyl-6- aminoisoindolin-5-yl)acetamide (3.8 g, yield 61%) as a yellow solid. LC-MS (ESI): mass calcd. for C12H15N3O2, 233.12; m / z found, 234 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.14 (s, 1H), 6.65 (d, J = 4.2 Hz, 1H), 4.90 (s, 2H), 4.66 (d, J = 12.8 Hz, 2H), 4.45 (d, J = 9.4 Hz, 2H), 2.03 (s, 6H). Step F: 1,1'-(2-oxo-2,3,5,7-tetrahydroimidazo[4,5-f]isoindole-1,6-diyl)bis(ethan-1- one)

[0297] To a stirred solution of N-(2-acetyl-6-amino-2,3-dihydro-1H-isoindol-5-yl)acetamide (4.5 g, 19.29 mmol, 1.0 eq) in THF (80 mL) was added CDI (6.26 g, 38.58 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 60oC overnight. The reaction mixture was cooled to room temperature and an orange yellow solid precipitated. The suspension was filtered and the cake was dried to give crude product 1,1'-(2-oxo-2,3,5,7- tetrahydroimidazo[4,5-f]isoindole-1,6-diyl)bis(ethan-1-one) (4.0 g, yield 80%) as an orange yellow solid, which was directly used in next step without further purification. LC-MS (ESI): mass calcd. for C13H13N3O3, 259.10; m / z found, 260 [M+H]+. Step G: 1,1'-(3-methyl-2-oxo-2,3,5,7-tetrahydroimidazo[4,5-f]isoindole-1,6- diyl)bis(ethan-1-one)

[0298] To a stirred solution of 1,1'-(2-oxo-2,3,5,7-tetrahydroimidazo[4,5-f]isoindole-1,6- diyl)bis(ethan-1-one) (2.5 g, 9.64 mmol, 1.0 eq) in DMF (40 mL) was added NaH (60% suspend in oil) (0.46 g, 11.57 mmol, 1.2 eq) in portions at 0oC under N2. The reaction mixture was stirred at 0oC for 0.5 h, and then CH3I (0.9 mL, 14.46 mmol, 1.5 eq) was added to above mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and a yellow solid was precipitated. The suspension was filtered and the cake was dried to give crude product 1,1'-(3-methyl-2-oxo-2,3,5,7- tetrahydroimidazo[4,5-f]isoindole-1,6-diyl)bis(ethan-1-one) (0.9 g, yield 34%) as a yellow solid. LC-MS (ESI): mass calcd. for C14H15N3O3,273.11; m / z found, 274 [M+H]+. Step H:6-acetyl-1-methyl-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-2(1H)-one

[0299] To a stirred solution of 1,1'-(3-methyl-2-oxo-2,3,5,7-tetrahydroimidazo[4,5- f]isoindole-1,6-diyl)bis(ethan-1-one) (0.9 g, 3.29 mmol, 1.0 eq) in MeOH (10 mL) and H2O (4 94 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 mL) was added NaOH (263 mg, 6.59 mmol, 2.0 eq) at room temperature . The reaction mixture was stirred at 70oC overnight. The reaction mixture was cooled to room temperature, diluted with water (5 mL), adjusted pH to 5~6 with aqueous HCl solution (2 N), and extracted with a mixed solvent of DCM and MeOH (10 / 1) (30 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methanol in dichloromethane, from 0% to 10%) to afford 6-acetyl-1-methyl-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-2(1H)-one (360 mg, yield 47%) as a yellow solid. LC-MS (ESI): mass calcd. for C12H13N3O2,231.10; m / z found, 232 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.85 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 12.2 Hz, 1H), 6.93 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 4.8 Hz, 2H), 4.60 (d, J = 6.2 Hz, 2H), 3.27 (d, J = 1.8 Hz, 3H), 2.06 (d, J = 2.8 Hz, 3H). Step I: 3-(6-acetyl-3-methyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-1(2H)- yl)piperidine-2,6-dione

[0300] To a solution of 6-acetyl-1-methyl-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-2(1H)- one (100 mg, 0.432 mmol, 1.0 eq) in dry DMF (3 mL) was added NaH (60% suspend in oil) (19.03 mg, 0.476 mmol, 1.1 eq) at 0oC, then the reaction mixture was stirred at 60oC for 30 min, 3-bromopiperidine-2,6-dione (83.03 mg, 0.432 mmol, 1.0 eq) was added to above mixture. The reaction mixture was stirred at 60oC overnight. The reaction was quenched with saturated NH4Cl (6 mL) and extracted with EtOAc (4 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with YMC-Actus Triart C18 (5 µm, 21.2 x 250 mm), and mobile phase 5-95% of 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-(6-acetyl-3- methyl-2-oxo-3,5,6,7-tetrahydroimidazo[4,5-f]isoindol-1(2H)-yl)piperidine-2,6-dione (1.7 mg, yield 1.1%) as a pink solid. LC-MS (ESI): mass calcd. for C17H18N4O4, 342.13; m / z found, 343.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.18 - 7.11 (m, 2H), 5.40 - 5.35 (m, 1H), 4.83 (d, J = 10.8 Hz, 2H), 4.61 (d, J = 10.8 Hz, 2H), 3.34 (d, J = 1.6 Hz, 3H), 2.94 - 2.87 (m, 1H), 2.77 - 2.60 (m, 2H), 2.06 (d, J = 4.8 Hz, 3H), 2.03 - 1.96 (m, 1H). 95 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Example 17.3-(6-(hydroxymethyl)-1,6-dimethyl-2-oxo-6,7-dihydro-1H- benzofuro[6,7-d]imidazol-3(2H)-yl)piperidine-2,6-dioneStep A: 2-(benzyloxy)-6-nitroaniline

[0301] To a mixture of 2-amino-3-nitrophenol (30.0 g, 195 mmol, 1.0 eq) and K2CO3 (53.8 g, 389 mmol, 2.0 eq) in DMF (300 mL) was added Benzyl bromide (39.9 g, 234 mmol, 1.2 eq) at -10 °C, then warmed to 15 °C and stirred for 16 h. The reaction mixture was diluted with water (700 mL) and extracted with EA (200 mL x 4). The combined organic layers were washed with brine (200 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc in petroleum ether, froom 0% to 10%) to afford 2-(benzyloxy)-6-nitroaniline (45.0 g, yield 95%) as a red solid. LC-MS (ESI): mass calcd. for C13H12N2O3, 244.1; m / z found, 245.1 [M+H]+. Step B: 2- (benzyloxy)-N-methyl-6-nitroaniline

[0302] To a mixture of 2-(benzyloxy)-6-nitroaniline (10.0 g, 40.9 mmol, 1.0 eq) in DMF (130 mL) was added NaH (60% suspend in oil) (2.1 g, 53.2 mmol, 1.3 eq) in portions at 0 °C and the reaction mixture stirred for 0.5 h. Then MeI (8.14 g, 57.3 mmol, 1.4 eq) was added to above mixture at 0 °C and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (500 mL) and extracted with EA (150 mL x 3). The combined organic layers were washed with brine (200 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2- (benzyloxy)- N-methyl-6-nitroaniline (10.0 g, yield 57 %) as a brown solid. The crude product was directly used in next step without further purification. LC-MS (ESI): mass calcd. for C14H14N2O3,258.1; m / z found, 259.2 [M+H]+. Step C: 6-(benzyloxy)-N1-methylbenzene-1,2-diamin

[0303] To a mixture of 2-(benzyloxy)-N-methyl-6-nitroaniline (5.00 g, 19.4 mmol, 1.0 eq) in EtOH (80.0 mL) was added Stannous chloride dihydrate (17.5 g, 77.4 mmol, 4.0 eq) in portions. The reaction mixture was exposed to ultrasonic radiation for 60 min at 25 °C. The reaction mixture was basified with aqueous NaOH solution (3 M) (200 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried 96 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM, from 0% to 4%) to afford 6-(benzyloxy)-N1-methylbenzene-1,2- diamine (3.00 g, yield 64%) as a yellow oil. LC- MS (ESI): mass calcd. for C23H25NO7, 228.1; m / z found, 229.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 7.2 Hz, 2H), 7.39 (dd, J = 8.0, 6.8 Hz, 2H), 7.35 - 7.29 (m, 1H), 6.63 (t, J = 8.0 Hz, 1H), 6.35 - 6.25 (m, 2H), 5.05 (s, 2H), 4.65 (s, 2H), 3.53 (s, 1H), 2.58 (s, 3H). Step D: 7-(benzyloxy)-1-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one

[0304] To a solution of 6-(benzyloxy)-N1-methylbenzene-1,2-diamine (6.50 g, 28.5 mmol, 1.0 eq) in MeCN (160 mL) was added CDI (4.62 g, 28.5 mmol, 1.0 eq) at 25 °C, then stirred at 25 °C for 16 h. After filtration, the cake was washed with MeCN (50 mL) and dried to afford 7- (benzyloxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (5.50 g, yield 76%) as a white solid. LC-MS (ESI): mass calcd. for C15H14N2O2, 254.1; m / z found, 255.2 [M+H]+. Step E: 4- (benzyloxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H- benzo[d]imidazol-2-one

[0305] To a mixture of 7-(benzyloxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (5.50 g, 21.6 mmol, 1.0 eq) in anhydrous DMF (50.0 mL) was added NaH (60% suspend in oil) (2.6 g, 64.9 mmol, 3.0 eq) in portions at 60 °C and the mixture was stirred at 60 °C for 0.5 h. SEMCl (6.13 g, 36.8 mmol, 1.7 eq) was added to above mixture and the resulting mixture was stirred at 60 °C for 3 h. After cooled to room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL) and extracted with EA (150 mL x 3). The combined organic layers were washed with brine (150 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 0% to 12%) to afford 4- (benzyloxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H- benzo[d]imidazol-2-one (6.50 g, yield 78%) as a yellow oil. LC-MS (ESI): mass calcd. for C21H28N2O3Si, 384.2; m / z found, 385.2 [M+H]+. Step F: 4-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H- benzo[d]imidazol-2-one

[0306] To a mixture of 4-(benzyloxy)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3- dihydro-2H-benzo[d]imidazol-2-one (6.20 g, 16.1 mmol, 1.0 eq) in MeOH (70.0 mL) was added 10% Pd / C (1.72 g) at room temperature. The mixture was stirred under H2 atmosphere (1 atm) at 20 °C for 3 h. After filtration, the filtrate was concentrated under reduced pressure to afford 4-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H- 97 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 benzo[d]imidazol-2-one (4.30 g, yield 90%) as a white solid. LC-MS (ESI): mass calcd. for C14H22N2O3Si, 294.1; m / z found, 295.1 [M+H]+. Step G: 5-bromo-4-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3- dihydro-2H- benzo[d]imidazol-2-one

[0307] To a solution of 4-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3- dihydro-2H-benzo[d]imidazol-2-one (4.50 g, 15.3 mmol, 1.0 eq) in THF (70.0 mL) was added NBS (2.69 g, 15.3 mmol, 1.0 eq) in portions at 0 °C. The mixture was warmed to 20 °C and stirred for 1 h. The reaction was diluted with DCM (160 mL) and washed with saturated aqueous NaHSO3solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 25%) to 5-bromo-4-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H- benzo[d]imidazol-2-one (4.80 g, yield 84%) as a yellow solid. LC-MS (ESI): mass calcd. for C14H21BrN2O3Si, 372.1; m / z found, 373.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.27 (s, 2H), 3.63 - 3.40 (m, 5H), 0.92 - 0.88 (m, 2H), 0.00 (s, 9H). Step H: 4-((2-((benzyloxy)methyl)allyl)oxy)-5-bromo-3-methyl-1-((2- (trimethylsilyl)ethoxy) methyl) -1,3-dihydro-2H-benzo[d]imidazol-2-one

[0308] To a mixture of 5-bromo-4-hydroxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1,3-dihydro-2H-benzo[d]imidazol-2- one (800 mg, 2.14 mmol, 1.0 eq) and potassium carbonate (888 mg, 6.43 mmol, 3.0 eq) in DMF (10.0 mL) was added (((2- (chloromethyl)allyl)oxy)methyl)benzene (548 mg, 2.79 mmol, 1.3 eq) at 20 °C. The resulting mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, diluted with water (40 mL), and extracted with EA (50 mL x 3). The organic layer was washed with brine (50 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 0% to 25%) to afford 4-((2-((benzyloxy)methyl)allyl)oxy)-5-bromo-3- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (900 mg, yield 79%) as a yellow oil. LC-MS (ESI): mass calcd. for C25H33BrN2O4Si,532.1; m / z found 533.1 [M+H]+. Step I: 6- ((benzyloxy)methyl)-1,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)- 1,3,6,7-tetrahydro-2H-benzofuro[6,7-d]imidazol- 2-one

[0309] To a mixture of 4-((2-((benzyloxy)methyl)allyl)oxy)-5-bromo-3-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (900 mg, 1.69 mmol, 98 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 1.0 eq) and AIBN (83.1 mg, 506 µmol, 0.3 eq) in Toluene (18.0 mL) was added tributylstannane (1.96 g, 6.75 mmol, 4.0 eq) at 20 °C. The mixture was stirred under N2 at 110 °C in a sealed tube for 10 h. After cooled to room temperature, the reaction mixture was quenched with saturated aqueous KF solution (50 mL), stirred for 2 h, and extracted with EA (50 mL x 3). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE = 1 / 4) to afford 6- ((benzyloxy)methyl)-1,6-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3,6,7-tetrahydro-2H-benzofuro[6,7-d]imidazol-2-one (550 mg, yield 72%) as a yellow oil. LC-MS (ESI): mass calcd. for C25H34N2O4Si, 454.2; m / z found, 454.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.48 - 7.26 (m, 5H), 6.96 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.24 (s, 2H), 4.68 (d, J = 8.8 Hz, 1H), 4.63 - 4.49 (m, 2H), 4.34 (d, J = 8.8 Hz, 1H), 3.62 - 3.56 (m, 2H), 3.52 (d, J = 2.0 Hz, 2H), 3.48 (s, 3H), 1.41 (s, 3H), 0.94 - 0.90 (m, 2H), 0.00 (s, 9H). Step J: 6-((benzyloxy)methyl)-1,6-dimethyl-1,3,6,7-tetrahydro-2H-benzofuro[6,7- d]imidazol-2-one

[0310] To a mixture 6-((benzyloxy)methyl)-1,6-dimethyl-3-((2- (trimethylsilyl)ethoxy)methyl)-1,3,6,7-tetrahydro-2H-benzofuro[6,7-d]imidazol-2-one (600 mg, 1.32 mmol, 1.0 eq) in TBAF (1.0 N in THF) (20.0 mL, 20.0 mmol, 15.0 eq) was added 1,2-Diaminoethane (635 mg, 10.6 mmol, 8.0 eq) at 20 °C. The mixture was stirred under N2at 70 °C for 16 h. After cooled to room temperature, the reaction mixture was diluted with EA (40 mL) and washed with water (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM, from 0% to 4%) to afford 6- ((benzyloxy)methyl)-1,6-dimethyl-1,3,6,7-tetrahydro-2H-benzofuro[6,7-d]imidazol-2-one (300 mg, yield 70%) as an off-white solid. LC-MS (ESI): mass calcd. for C19H20N2O3, 324.2; m / z found, 325.2 [M+H]+. Step K: 3-(6-((benzyloxy)methyl)- 1,6-dimethyl-2-oxo-1,2,6,8-tetrahydro-3H- isobenzofuro[4,5-d]imidazol-3-yl)piperidine-2,6-dione

[0311] To a mixture of 6-((benzyloxy)methyl)-1,6-dimethyl-1,3,6,8-tetrahydro-2H- isobenzofuro[4,5-d]imidazol-2-one (300 mg, 925 µmol, 1.0 eq) in anhydrous DMF (8.00 mL) was added sodium hydride (60% suspend in oil) (0.30 g, 7.40 mmol, 8.0 eq) in portions at 60 °C and the mixture was stirred at 60 °C for 0.5 h.3-bromopiperidine-2,6-dione (355 mg, 1.85 mmol, 2.0 eq) was added to above mixture and the resulting mixture was stirred at 60 °C for 3 h. After cooled to room temperature, the reaction mixture was quenched with ice-cooled 99 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 saturated aqueous NH4Cl solution (20 mL) and extracted with EA (30 mL x 3). The organic layers were washed with brine (30 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / DCM / PE = 1.5 / 1 / 1) to afford 3-(6-((benzyloxy)methyl)- 1,6-dimethyl-2-oxo-1,2,6,8-tetrahydro-3H- isobenzofuro[4,5-d]imidazol-3-yl)piperidine-2,6-dione (200 mg, yield 49%) as a white solid. LC-MS (ESI): mass calcd. for C24H25N3O5, 435.2; m / z found, 436.2 [M+H]+. Step L: 3-(6-(hydroxymethyl)-1,6-dimethyl-2-oxo-1,2,6,7- tetrahydro-3H- benzofuro[6,7-d]imidazol-3-yl)piperidine-2,6-dione

[0312] A mixture of 3-(6-((benzyloxy)methyl)-1,6-dimethyl-2-oxo-1,2,6,7-tetrahydro-3H- benzofuro[6,7-d]imidazol-3-yl)piperidine-2,6-dione (150 mg, 344 µmol, 1.0 eq) and 10% Pd / C (20.0 mg) in EA / THF (5.00 mL, 1 / 1) was stirred under H2 atmosphere (1 atm) at 20 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was slurried with EA (5 mL), filtered, and dried to afford 3-(6-(hydroxymethyl)-1,6-dimethyl-2- oxo-1,2,6,7-tetrahydro-3H-benzofuro[6,7-d]imidazol-3-yl)piperidine-2,6-dione (70.0 mg, yield 59%) as a white solid. LC-MS (ESI): mass calcd. for C17H19N3O5, 345.1; m / z found, 346.1 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ11.07 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 5.33 - 5.28 (m, 1H), 4.63 (d, J = 8.8 Hz, 1H), 4.20 (d, J = 8.8 Hz, 1H), 3.43 (s, 3H), 3.41 - 3.38 (m, 2H), 2.95 - 2.83 (m, 1H), 2.73 - 2.58 (m, 2H), 2.54 - 2.51 (m, 1H), 2.03 - 1.91 (m, 1H), 1.28 (s, 3H). II. Biological Assessment

[0313] 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. The results are summarized in Table E1 below. 100 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 Table E1. CRBN binding IC50A: IC50< 10 nM; B: 10 nM < IC50< 100 nM; C: 100 nM < IC50< 1000 nM; D: IC50> 1,000 nM 101 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 INCORPORATION BY REFERENCE

[0314] 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

[0315] 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.

[0316] 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. 102 304765419

Claims

Attorney Docket No. PRSC-092 / 001WO 343170-2289 CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula I:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5- to 12-membered heterocycle; each RAis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; a is an integer selected from 0 to 8; B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RD1is hydrogen, deuterium, C1-6haloalkyl, or C1-6alkyl; q is an integer from 0 to 2, each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, 103 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and d is an integer selected from 0 to 5, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, and 5- or 6-membered heteroaryl; each Rais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rbis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl; wherein each of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- or 6-membered heteroaryl, wherein the compound is not a compound selected from: 104 304765419Attorney Docket No. PRSC-092 / 001WO 343170-22892. A conjugate of Formula I:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5- to 12-membered heterocycle; each RAis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5- to 10-membered heteroaryl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; a is an integer selected from 0 to 8; B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; 105 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 RB1, RB2, and RB3are independently , hydrogen, halogen, oxo, -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, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and one RB1, RB2, and RB3isdenotes attachment to -L-T, RD1is hydrogen, deuterium, C1-6 haloalkyl, or C1-6 alkyl; q is an integer from 0 to 2, each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 5, L is a linker; and T is a ligand for a protein, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRbS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, and 5- or 6-membered heteroaryl; each Rais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; 106 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, - NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, and 3- to 6- membered heterocyclyl; wherein each of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- or 6-membered heteroaryl.

3. The compound or conjugate of claim 1 or 2, wherein Ring A is 8-membered heterocycle.

4. The compound or conjugate of claim 1 or 2, wherein Ring A is 8-membered heterocycle comprising at least one oxygen atom.

5. The compound or conjugate of claim 1 or 2, wherein Ring A is 8-membered heterocycle comprising at least one double bond.

6. The compound or conjugate of claim 1 or 2, wherein Ring A is 7-membered heterocycle comprising one nitrogen atom.

7. The compound or conjugate of claim 1 or 2, wherein Ring A is 7-membered heterocycle comprising one nitrogen atom and one double bond.

8. The compound or conjugate of claim 1 or 2, wherein the compound or conjugate is a compound or conjugate of Formula I-1, I-2, I-3, or I-4 107 304765419Attorney Docket No. PRSC-092 / 001WO 343170-22899. The compound or conjugate of claim 8, wherein each RAis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

10. The compound or conjugate of claim 8 or 9, wherein RB1, RB2, and RB3are independently hydrogen, halogen, oxo, -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, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

11. The compound or conjugate of claim 1 or 2, wherein the compound or conjugate is a compound or conjugate of Formula I-5, I-6, or I-7 108 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

12. The compound or conjugate of any one of claims 8-11, wherein each RAis independently oxo or C1-6 alkyl.

13. The compound or conjugate of any one of claims 8-12, wherein a is 0, 1 or 2.

14. The compound or conjugate of any one of claims 8-13, wherein RB1, RB2, and RB3are independently hydrogen, halogen, C1-6alkoxy, C2-6alkynyl, or 3- to 12-membered heterocyclyl, wherein the alkoxy, alkynyl, or heterocyclyl is optionally substituted with one or more Ru.

15. The compound or conjugate of any one of claims 1-14, wherein each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

16. The compound or conjugate of any one of claims 1-15, wherein d is 0.

17. The compound or conjugate of any one of claims 1-16, wherein RD1is hydrogen.

18. The compound or conjugate of any one of claims 1-17, wherein q is 1.

19. A compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. 109 304765419Attorney Docket No. PRSC-092 / 001WO 343170-2289 20. A pharmaceutical composition comprising the compound of any one of claims 1-19, and a pharmaceutically acceptable excipient.

21. A method of binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample comprising administering the compound of any one of claims 1-19 to the subject or contacting the biological sample with the compound of any one of claims 1-19.

22. Use of the compound of any one of claims 1-19 in the manufacture of a medicament for binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

23. A compound of any one of claims 1-19 for use in binding cereblon E3 ubiquitin ligase protein complex in a subject or biological sample.

24. A method of degrading a protein in a subject or biological sample comprising administering the compound or conjguate of any one of claims 1-18 to the subject or contacting the biological sample with the conjguate of any one of claims 1-18.

25. Use of the conjguate of any one of claims 1-18 in the manufacture of a medicament for degrading a protein in a subject or biological sample.

26. A conjguate of any one of claims 1-18 for use in degrading a protein in a subject or biological sample.

27. The method, use, or conjugate for use of any one of claims 24-26, wherein the protein is an estrogen receptor, a STAT3 protein, an androgen receptor, a SMARCA2 protein, a SMARCA4 protein, a BRD9 protein, or a CBP / p300 protein. 110 304765419

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