Molecular glues targeting a transcriptional regulator of aberrant metabolic states

Abstract

Composition and methods of use to treat ZBTB11 associated disorders such as cancer comprising compounds as described herein that effect ZBTB11 degradation.

Description

PATENT APPLICATIONFORMOLECULAR GLUES TARGETING A TRANSCRIPTIONAL REGULATOR OF ABERRANT METABOLIC STATESCROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 515,472 filed July 25, 2023, which application is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present invention relates to transcriptional regulation for therapeutic applications.BACKGROUND

[0003] Most existing oxidative phosphorylation (OxPhos) inhibitors have properties limiting their clinical use, including insufficient potency and poor selectivity. Others, such as IACS- 010759 — which inhibits an unidentified subunit of complex I, the first component of the mitochondrial electron transport chain — have achieved success in preclinical models of GBM. Although this validates the pathway, IACS-010759 has not advanced to GBM clinical trials but has been pursued as a treatment for other cancer types. Unfortunately, in those trials, doselimiting peripheral neuropathy was observed. To tackle cancer drug resistance in GBM, validation of mechanistically orthogonal novel therapeutic targets to exploit adaptive metabolic vulnerabilities in the OxPhos pathway is necessary.SUMMARY OF THE INVENTION

[0004] Over 95% of pancreatic ductal adenocarcinomas (PDAC) are driven by mutant K-Ras. Upon treatment with K-Ras inhibitors, PDAC cancer cells undergo metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. However, direct inhibition of Complex I is poorly tolerated in patients due to on-target induction of peripheral neuropathy. In this work, the inventors have developed molecular glue degraders against ZBTB11, a C2H2 zinc finger transcription factor that regulates the nuclear transcription of components of the mitoribosome and electron transport chain. ZBTB11 degraders leverage the differences inmitochondrial biogenesis demand between human neurons and rapidly-dividing pancreatic cancer cells to selectively target the K-Ras inhibitor resistant state in PDAC. Combination treatment of both K-Ras inhibitor-resistant cell lines and multidrug resistant patient-derived organoids resulted in superior anti-cancer activity compared to single agent treatment, while sparing hiPSC-derived neurons. Proteomic and stable isotope tracing studies revealed mitoribosome depletion and impairment of the TCA-cycle as key events that mediate this response. Thus, the instant disclosure validates ZBTB11 as a vulnerability in K-Ras inhibitorresistant PDAC and provides a suite of molecular glue degrader tool compounds with which to investigate its function.

[0005] Highly aggressive pancreatic ductal adenocarcinomas (PDAC) make up >90% of all pancreatic cancers and are the third leading cause of cancer deaths in the US.1Innovations in surgical management and adjuvant therapy have led to improved outcomes for patients that present with resectable (Stage 0-IIB) PDAC, who have a 5-year overall survival rate of 21%.2Unfortunately, as early stage PDAC has few symptoms, the majority (>85%) of PDAC patients present with unresectable Stage III and Stage IV disease, where the 5-year overall survival remains below 1% due to an absence of efficacious anticancer drugs.2Over 95% of PDAC patients harbor tumors driven by activating mutations in K-Ras,3and inhibitors that target oncogenic K-Ras were anticipated to herald paradigm-shifting improvements in patient outcomes. Unfortunately, these benefits have yet to be realized, due to the rapid onset of K-Ras inhibitor drug resistance.4

[0006] Over 98% of the oncogenic K-Ras mutants found in PDAC are now targetable by at least one clinical-stage inhibitor, and development of both reversible and covalent mutant K-Ras inhibitors is now a highly productive field of research.5'9Currently approved K-Ras inhibitors include sotorasib and adagrasib, which were FDA approved for treatment of K-RasG12Cmutant NSCLC in 2021 and 2022 respectively.10 11Although encouraging responses to sotorasib in PDAC have been reported, resistance swiftly arises.4In a Ph I / II study of patients with K- RasG12Cpancreatic cancer who had received at least one previous systemic therapy, an encouraging 21% objective overall response rate and an 84% disease control rate were reported, but this led to a meager 4 month progression-free survival benefit and 5.7 month median duration of response.4 12In both clinical and laboratory studies of K-Ras inhibitor resistance, acquiredsecondary mutations in K-Ras itself are relatively rare, occurring -3-4% of the time.13,14Resistance to K-Ras inhibition is more commonly mediated by the accumulation of mutations and activation events in other pathways, posing a challenge for the development of second-line K-Ras inhibitors, vertical pathway targeting, or combination therapies once resistance has developed.15,16These data highlight the urgent need to identify and validate new targets that can combat acquired resistance to K-Ras inhibition in PDAC.

[0007] Adaptive K-Ras inhibitor resistance is accompanied by significant metabolic reprogramming of cancer cells, including hyperactivation of the PI3K / AKT pathway17,18, elevated TCA cycle flux19, Myc amplification20, and upregulation of mitochondrial biogenesis21, culminating in heightened reliance on oxidative phosphorylation (OXPHOS).21,22As K-Ras pathway inhibition impairs glycolysis, forcing cancer cells to rely on OXPHOS for their energetic demands, this mechanism of clinical resistance is expected to impact the entire pharmacological class and is already being reported in laboratory studies of other K-Ras mutant targeting drug candidates.14,15For example, K-RasG12Dis the most common K-Ras mutation in PDAC3and inhibitors that selectively target K-RasG12Dare currently the subject of Ph I clinical trials in PDAC patients (NCT05737706). It was recently demonstrated that acquired resistance to the K-RasG12Dinhibitor MRTX1133 develops in human PDAC cells and is associated with feedback activation of ERBB / AKT signaling and enhanced OXPHOS (Fig. 3).14Resistance to the mechanistically orthogonal pan K-Ras(ON) inhibitor RM-7977 has been recently reported in murine models of PDAC, and is associated with Myc amplification20. Whilst metabolic profiling was not performed in this study, Myc overexpression has been shown to result in increased mitochondrial biogenesis23, and over 200 OXPHOS genes are regulated by Myc. These K-Ras inhibitor resistance studies concur with genetic studies in inducible K-RasG12D / p53+ / ’ PDAC murine models, which reported a subpopulation of cancer cells were able to overcome genetic ablation of K-RasG12Dto re-seed tumors, and that this subpopulation was highly dependent on OXPHOS.21Pairing oncogenic K-Ras inhibition with OXPHOS inhibition is therefore an attractive therapeutic strategy in PDAC and other Ras addicted malignancies.

[0008] Unfortunately, most existing OXPHOS inhibitors have properties limiting their clinical use, including insufficient potency24and poor selectivity23,26. Others, such as the mitochondrial complex I inhibitor IACS-010759, display dose-limiting on-target toxicity in the clinic due totheir action on actively respiring mitochondria in peripheral neurons.27To identify mechanistically orthogonal approaches to combating OXPHOS-mediated adaptive K-Ras inhibitor resistance, public datasets were evaluated to find targets that met the following four criteria: 1) Upregulated at the protein level during the development K-Ras inhibitor resistance in PDAC cells at at least one time point.222) Essential for cell survival in glycolysis suppression media (low glucose, plus galactose), which forces dependency on OXPHOS.283) Not a component of complex I, to identify mechanistically orthogonal targets, with the goal of limiting effects on peripheral neurons and other high-OXPHOS healthy cells.274) Chemically tractable via inhibition or targeted protein degradation.29-30This approach identified Zinc Finger and BTB Domain Containing 11 (ZBTB11) as an attractive anti-OXPHOS target for molecular glue degrader development.

[0009] ZBTB11 is a zinc finger transcription factor that co-operates with NRF2 to regulate nuclear expression of components of complex I and the mitoribosome, thereby maintaining functional homeostasis in mitochondria.31'33ZBTB11 is transiently upregulated in PDAC cells during the development of K-Ras inhibitor resistance, potentially to help sustain their increased demands on mitochondrial biogenesis.22Although ZBTB11 is a pan-essential gene34'36, it was hypothesized that partial loss of ZBTB11 would impair K-Ras inhibitor resistant PDAC fitness, but have minimal effects on post-mitotic neurons due to differences in the mitochondrial biogenesis demand between these cell types.37ZBTB1 1 is a C2H2 zinc finger protein that contains a CXXCG sequence motif in its beta-hairpin loop, making it potentially chemically targetable via molecular glue degrader-mediated recruitment to the E3 -ligase CRL4CRBN.38In the instant disclosure, ZBTB11 is validated as a mechanistically orthogonal target for addressing OXPHOS-dependent drug resistant states in PDAC, using both genetic and pharmacological approaches.

[0010] Now, therefore, according to one aspect of the instant disclosure is a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound which inhibits or degrades Zinc Finger and BTB Domain Containing 11 (ZBTB11). In embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In embodiments, the cancer is characterized by a K-Ras mutation. In embodiments, the cancer is a K-Ras inhibitor-resistant cancer. In embodiments, the cancer is resistant or refractory to treatment with an additionaltherapeutic intervention in the absence of the compound. In embodiments, the method further comprises administering the additional therapeutic intervention. In embodiments, the additional therapeutic intervention comprises chemotherapy, targeted therapy, immunotherapy, a kinase inhibitor, Ras pathway inhibitors, DNA damaging agents, and / or a PARP inhibitor. In embodiments, the cancer relies on elevated oxidative phosphorylation for survival.

[0011] In one aspect herein is a method of treating a ZBTB11 -related disease or disorder in a subject in need thereof, comprising administering to the subject a compound which inhibits or degrades Zinc Finger and BTB Domain Containing 11 (ZBTB11). In embodiments, ZBTB11- related disease or disorder is characterized by elevated oxidative phosphorylation.

[0012] Further provided herein is a method of treating a disease or disorder associated with elevated oxidative phosphorylation in a subject in need thereof, comprising administering to the subject a compound which inhibits or degrades Zinc Finger and BTB Domain Containing 11 (ZBTB11). Also provided herein is a method of inhibiting oxidative phosphorylation in a subject, comprising administering to the subject a compound which inhibits or degrades Zinc Finger and BTB Domain Containing 11 (ZBTB11).

[0013] In embodiments, the compound used in a method provided herein is a degrader of ZBTB11. In embodiments, the compound binds the E3-ligase CRL4-CRBN and promotes interaction with ZBTB11 by binding at the interface of ZBTB11 and CRBN, leading to ZBTB11 ubiquiti nation and degradation.

[0014] In embodiments, the compound is a compound of Formula (I)Formula (I); wherein:each X1is independently O or S;X2is a bond, optionally substituted alkylene or heteroalkylene, optionally substituted cycloalkylene or heterocycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, — O — , — N(RA) — , — S — , — C(=O) — , — C(=O)O — , — C(=O)NRA— , — NRAC(=O)— , — NRAC(=O)RA— , — C(=O)RA— , — NRAC(=O)O— , — NRAC(=O)N(RA)—, — OC(=O)— , — OC(=O)O— , — OC(=O)N(RA)— , — S(O)2NRA— , or — NRAS(O)2— ;X3is a bond, optionally substituted alkylene or heteroalkylene, optionally substituted cycloalkylene or heterocycloalkylene, optionally substituted arylene or heteroarylene, — O— , — N(RB)— , — S— , — C(=O)— , — C(=O)O— , — C(=O)NRB— , — NRBC(=O)— , — NRBC(=O)RB— , — C(=O)RB— , — NRBC(=O)O— , — NRBC(=O)N(RA)— , — OC(=O)— , — OC(=O)O— , — OC(=O)N(RB)— , — S(O)2NRB— , or — NRBS(O)2— ;A1is optionally substituted aryl or heteroaryl;A2is optionally substituted aryl or heteroaryl;R1is H, optionally substituted alkyl, halogen, a bond with A1, or optionally substituted alkylene forming a bond with A1; each R2and R3is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, optionally substituted alkylene forming a bond with an RB, or R2and R3are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl; each R4and R5, when present, is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, or two R4or two R?are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl;1 is 0 or 1; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; each RA, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; andRB, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl; or a bond with an optionally substituted alkylene of R2or R3; or a pharmaceutically acceptable salt thereof.

[0015] In embodiments, each X1is O. In embodiments, X2is -NH-. In embodiments, X3is -NH- or - N(RB)-, wherein RBis a bond with an optionally substituted alkylene of R2or R3. In embodiments, A1is optionally substituted phenyl or pyridyl. In embodiments, A1has the structure In embodiments, A2is optionally substituted phenyl. In embodiments,A2is substituted by one substituent R6and further optionally substituted by one or more R7, wherein R6is -CF3 or halogen; andeach R7is independently halogen, — CN, — ORC, —S(=O)2RC, — N(RC)2, — S(=O)2N(RC)2, — C(=O)RC, — OC(=O)RC, — C(=O)ORC, — OC(=O)ORc, — C(=O)N(RC)2, — OC(=O)N(RC)2, — NRCC(=O)N(RC)2, — NRcC(=O)Rc, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; and wherein each Rcis independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl. In embodiments, R6is -CF3 or chloro. In embodiments, 1 or 2 R7are present andembodiments, R1is H. In embodiments, 1 is 1. In embodiments, each R2and R3is independently H, methyl, or ethyl, or wherein R2and R3are taken together with the carbon atom to which they are attached to form a cyclobutyl. In embodiments, R2is C2 alkylene forming a bond with an RBand R3is H. In embodiments, n is 0, 1, or 2. In embodiments, each R4is H. In embodiments, m is 1 or 2. In embodiments, each R5is H. In embodiments, the compound is one provided in Table 1, or a pharmaceutically acceptable salt thereof.

[0016] In one aspect herein is a compound having a structure according to Formula (la)Formula (la) wherein: each X1is independently O or S;A2is phenyl substituted by one substituent R6and further optionally substituted by one or more R7, wherein:R6is -CF3; and eacoptionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; and wherein each Rcis independently optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl;R1is H, optionally substituted alkyl, halogen, or optionally substituted alkylene forming a bond with A1; each R2and R3is independently optionally substituted alkyl, optionally substituted alkylene forming a bond with an RB, or R2and R3are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl; each R4and R5, when present, is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, or two R4or two R?are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkylR8is H, optionally substituted alkyl or heteroalkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, -CN, or halogen; m is 1, 2, or 3; n is 0, 1, 2, or 3; andRBis H or a bond with an optionally substituted alkylene of R2or R3; or a pharmaceutically acceptable salt thereof, and

[0017] In embodiments, each X1is O. In embodiments, A2is substituted 0, 1 or 2 R7. In embodiments, each R7is independently chloro or -CF3. In embodiments, R1is H. In embodiments, R2and R3are each independently methyl, ethyl, propyl, or taken together with thecarbon to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl. In embodiments, RBis H. In embodiments, n is 0. In embodiments, m is 2. In embodiments, each R5is H. In embodiments, R8is H.

[0018] In embodiments, the compound according to Formula (I) has a structure according to Formula (laa) or Formula (lab), or a pharmaceutically acceptable salt thereof: wherein,R8is H or Ci-6 alkyl; p is 1, 2 or 3; and R1Ais H or C1-6 alkyl.

[0019] In embodiments, R8is H or methyl. In embodiments, R8is H. In embodiments, R1Ais H or methyl. In embodiments, R1Ais H. In embodiments, A2is optionally substituted phenyl. In embodiments, A2is substituted by one substituent R6and further optionally substituted by one or more R7, wherein R6is -CF3 or halogen; and each R7is independently halogen, — CN, — ORC, — S(=O)2RC, — N(RC)2, — S(=O)2N(RC)2, — C(=O)Rc, — OC(=O)Rc, — C(=O)ORc, — OC(=O)ORc, — C(=O)N(RC)2, — OC(=O)N(RC)2, — NRCC(=O)N(RC)2, — NRCC(=O)RC, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; and wherein each Rcis independently optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl. In embodiments, R6is -CF3 or chloro. In embodiments, 1 or 2 R7are present and each R7isp is 1.

[0020] In an aspect herein is a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0021] In an aspect herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutical composition described herein. In embodiments, the compound degrades ZincFinger and BTB Domain Containing 11 (ZBTB11). In embodiments, the disease or disorder is characterized by elevated oxidative phosphorylation. In embodiments, the disease or disorder is cancer. In embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In embodiments, the cancer is characterized by a K-Ras mutation. In embodiments, the cancer is a K-Ras inhibitor-resistant cancer. In embodiments, the cancer relies on elevated oxidative phosphorylation for survival. In embodiments, the compound binds the E3-ligase CRL4-CRBN and promotes interaction with ZBTB11 by binding at the interface of ZBTB11 and CRBN, leading to ZBTB11 ubiquitination and degradation. In embodiments, the disease or disorder resistant or refractory to treatment with an additional therapeutic intervention in the absence ofthe compound. In embodiments, the method further comprises administering an additional therapeutic intervention. In embodiments, the additional therapeutic intervention comprises chemotherapy, targeted therapy, immunotherapy, a kinase inhibitor, Ras pathway inhibitors, DNA damaging agents, and / or a PARP inhibitor.BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawing (also “figure” and “Fig.” herein), of which:

[0023] Figure 1 | OXPHOS is upregulated in K-Ras inhibitor resistant PDAC cells, and countered by ZBTB11 knockdown. Panel A. Sotorasib / AMG-510-resistant MIA PaCa-2 cells are 100-fold less sensitive to sotorasib / AMG-510 than parental MIA PaCa-2 cells. Cells were treated with the indicated dose of sotorasib for 72 hrs, and viability was evaluated by CellTiterGlo®. Data is depicted as the average + / - standard deviation (S.D.) of n = 3 biological replicates and is normalized to DMSO vehicle treatment controls. See also Fig. 2 Panel A. Panel B. Sotorasib-resistant MIA PaCa-2 cells perform higher basal and maximal levels of OXPHOS than parental MIA PaCa-2 cells. Panel C. Sotorasib-resistant MIA PaCa-2 cells are more energetic than parental MIA PaCa-2 cells. Panel D. Expression of genes regulated by ZBTB11 decreases following CRISPRi-mediated knockdown. Cells were treated with 500 ng / ml of doxycycline for 72 hrs to induce Cas9 expression, and mRNA levels were quantified by RT- qPCR. Data is depicted as the average + / - S.D. of n = 3 biological replicates and is normalized to H2O vehicle treatment controls. For each gene, data is shown from left to right for the following groups: Dox; sfNS; sgZBTBl l #1; sgZBTBl l #2See also Fig. 3. Panel E. ZBTB11 knockdown reduces rates of OXPHOS. Cells were treated with 500 ng / ml of doxycycline for 72 hrs to induce Cas9 expression. Both Dox and sgNS groups showed similar results (top lines in plot) and the two sgZBTBl l groups showed similar results (bottom lines in plot). Panel F. ZBTB11 knockdown reduces ATP production by OXPHOS. Panels B-C, E-F. Cellular respiration rates were evaluated in a mitochondrial stress test using a Seahorse analyzer. Oxygen ConsumptionRates (OCR) and Extracellular Acidification Rates (ECAR) from the mitochondrial stress test were used to calculate ATP production rates. Data is depicted as the average + / - S.D. of n = 2 biological replicates with n = 3 technical replicates each.

[0024] Figure 2 | Metabolomic profiling of parental and K-Ras G12C inhibitor resistant PDAC cell lines. Panel A. Sotorasib / AMG-510-resistant MIA PaCa-2 cells are 100-fold less sensitive to sotorasib / AMG-510 than parental MIA PaCa-2 cells. Cells were treated with the indicated dose of sotorasib for 72 hrs, and viability was evaluated by CellTiterGlo®. Data is depicted as the average + / - standard deviation (S.D.) of n = 3 biological replicates and is normalized to DMSO vehicle treatment controls. Panel B. MSEA identifies amino acid metabolic pathways as major metabolic shifts between parental and sotorasib-resistant MIA PaCa-2 cells. Parental and sotorasib-resistant MIA PaCa-2 cells were labeled with13C-labeled glucose or glutamine for 24 hrs followed by global metabolomics analysis, n = 3 biological replicates per condition. Metabolite abundance changes were analyzed by the global t-test (P < 0.05). Metabolites were then evaluated using metabolite set enrichment analysis (MSEA) using KEGG pathways and fdtered for pathways containing a minimum of four hits. Full datasets in Dataset 1.

[0025] Figure 3 | Metabolic profiling of parental and K-Ras G12D inhibitor resistant PDAC cell lines. Panel A. MRTX1 133 -resistant SUIT-2 cells are 100-fold less sensitive to MRTX1133 than parental SUIT-2 cells. Cells were treated with the indicated dose of MRTX1133 for 72 hrs, and viability was evaluated by CellTiterGlo®. Data is depicted as the average + / - standard deviation (S.D.) of n = 3 biological replicates and is normalized to DMSO vehicle treatment controls. Panel B. MRTX1133-resistant SUIT-2 cells perform higher basal and maximal levels of OXPHOS than parental SUIT-2 cells. Panel C. MRTX1133-resistant SUIT-2 cells are more energetic than parental SUIT-2 cells. Panels B-C. Cellular respiration rates were evaluated in a mitochondrial stress test with the indicated drugs using a Seahorse analyzer. Oxygen Consumption Rates (OCR) and Extracellular Acidification Rates (ECAR) from the mitochondrial stress test were used to calculate ATP production rates. Data is depicted as the average + / - S.D. of n = 2 biological replicates with n = 3 technical replicates each. Panel D. MSEA identifies oxidative stress and metabolism-related pathways as major metabolic shifts between parental and MRTX1133-resistant SUIT-2 cells. Parental and MRTX1133-resistantSUIT-2 cells were labeled with13C-labeled glucose or glutamine for 24 hrs followed by global metabolomics analysis, n = 3 biological replicates per condition. Metabolite abundance changes were analyzed by the global test (P < 0.05). Metabolites were then evaluated for pathway enrichment using KEGG pathway analysis and filtered for pathways containing a minimum of four hits. Full datasets in Dataset 1.

[0026] Figure 4 | CRISPRi ZBTB11 knockdown impacts OXPHOS-related genes. Panel A. ZBTB 11 -targeting sgRNAs facilitate CRISPRi-mediated knockdown of ZBTB11. Cells were treated with 500 ng / ml of doxycycline for 72 hrs to induce Cas9 expression, and protein levels were quantified by WB. Depicted blots are representative of n = 2 independent experiments. Uncropped blots found in Source Data. Panels B-E. CRISPRi-mediated knockdown induces downregulation of ZBTB 11 and ZBTB 11 -regulated genes. Cells were treated with 500 ng / ml of doxycycline for 24 or 72 hrs to induce Cas9 expression, and mRNA levels were quantified by RT-qPCR. Data is depicted as the average + / - S.D. of n = 3 biological replicates and is normalized to H2O vehicle treatment controls. For Panels B-E, for each gene, data is shown form left to right for the following experimental groups: Dox; sfNS; sgZBTBl 1 #1; sgZBTBl 1 #2.

[0027] Figure 5 | Development of a ZBTB11 molecular glue degrader. Panel A. Depiction of ZBTB11 domains and the ZBTBl l-HiBiT assay. Panel B. Screening of glutarimide-containing analogues in the ZBTBl l-HiBiT assay identifies candidate ZBTB11 degraders. MOLT-4 ZBTBl l-HiBiT knock-in cells were treated with 10 LIM compound for 8 hrs. Data is depicted as the average of n = 3 technical replicates and is normalized to DMSO vehicle treatment control. Panel C. Chemical structure of screening hits and optimized ZBTB 11 degrader and negative controls. Panel D. JWJ-01-306, but not negative controls, degrades ZBTBl l-HiBiT in MIA PaCa-2 knock-in cells. Cells were treated for 5 hrs with the indicated compound. Panel E. Mechanism-based controls rescue ZBTBl l-HiBiT degradation in MIA PaCa-2 knock-in cells. Cells were pre-treated with carfdzomib, MLN4924, or lenalidomide for 1 hr prior to treatment with the indicated compound for 5 hrs. Protein levels were quantified by western blot. Depicted blots are representative of n = 3 independent experiments. Uncropped blots found in Source Data. Panel F. JWJ-01-306, but not negative controls, induces CRBN:degrader:ZBTBl 1 complex in NanoBRET™ ternary complex assay. A MOLT-4 cell line with stable expression of the indicated constructs was generated. Cells were pre-treated with carfdzomib and theHaloTag® NanoBRET™ 618 Ligand for 1 hr prior to treatment with the indicated compound for 5 hrs. Panel G. Computational model generated using RosettaDock of the CRBN:JWJ-01- 3O6:ZBTB11 ZF10 complex reveals binding mode and key residues for complex stabilization. Top ten scoring structure clusters found in Source Data. Panel H. Global proteomics analysis of MIA PaCa-2 cells treated with 10 pM JWJ-01-306 for 5 hrs. Samples were prepared as n = 3 biological replicates. Full datasets in Dataset 2. Panel I. ZBTB11 K866T ablates ternary complex formation. MOLT-4 cell lines with stable expression of the indicated constructs were generated and used in the NanoBRET™ ternary complex assay. Panel J. ZBTB11 K866T rescues JWJ-01- 306-mediated degradation. MIA PaCa-2 cell lines with stable expression of the indicated constructs were generated. Cells were treated with JWJ-01-306 for 5 hrs. Panel K. K866 is necessary but not sufficient for ZBTB11 degradation. MOLT-4 cell lines with stable expression of the indicated constructs were generated. Cells were treated with 1 pM screening hit compound ALV-05-184 for 5 hrs. Panels D, F, LK. Data is depicted as the average + / - S.D. of n = 3 biological replicates and is normalized to DMSO vehicle treatment control.

[0028] Figure 6 | Characterization of the ZBTB11 degrader pharmacology. Panel A Cellular CRBN engagement. HEK293 cells were transiently transfected with NanoLuc-CRBN and treated with the NanoBRET™ Tracer Reagent and indicated compound for 2 hrs. Panel B. Time-course ZBTBl l-HiBiT degradation. Cells were treated with 10 pM JWJ-01-306 for indicated amount of time, and protein levels were quantified by western blot. Depicted blots are representative of n = 2 independent experiments. Uncropped blots found in Source Data. Panel C. Construct design for ZBTB11 ZF fingerprinting experiments. Panels D-E. ZBTB11 ZF fingerprinting reveals ZF10 as the primary CRBN target degron. MOLT-4 cell lines with stable expression of the indicated constructs were generated. Cells were treated with 1 pM screening hit compound ALV-05-184 for 5 hrs. Panel F. IKZFl-HiBiT degradation in Jurkat knock-in cells. Cells were treated for 8 hrs with the indicated compound. Panel G. GSPTl-HiBiT degradation in Jurkat knock-in cells. Cells were treated for 8 hrs with the indicated compound. Panels A, D-G. Data is depicted as the average + / - S.D. of n = 3 biological replicates and is normalized to DMSO vehicle treatment control.

[0029] Figure 7 | Further characterization of ZBTB11 degrader compound and controls. Panel A. Global proteomics analysis of MIA PaCa-2 cells treated with 10 pM JWJ-01-368 for 5hrs. Samples were prepared as n = 3 biological replicates. Full datasets in Dataset 2. Panel B. ZBTBl l-HiBiT degradation by JWJ-01-306 achieves optimal kinetics by 2 hrs. MIA PaCa-2 knock-in cells were treated for the indicated time. Panel C. ZBTBl l-HiBiT protein levels decrease following JWJ-01-306 washout. MIA PaCa-2 knock-in cells were treated for 2 hrs with 10 pM JWJ-01-306, followed by three media washes to remove drug. ZBTB11 levels were evaluated by ZBTBl l-HiBiT luminescence assay. Panel D. Pharmacokinetics of JWJ-01-306 in C57BL / 6 mice dosed intraperitoneal with 10 mg / kg JWJ-01-306-HC1. Full datasets in Dataset 3. Panels B-C. Data is depicted as the average + / - S.D. of n = 3 biological replicates and is normalized to DMSO vehicle treatment control.

[0030] Figure 8 | JWJ-01-306 combination treatment overcomes acquired resistance to K- Ras inhibitors in PDAC via metabolic pathway reprogramming. Panel A. JWJ-01-306 synergizes with sotorasib to inhibit proliferation of sotorasib-resistant MIA PaCa-2 cells. Cells were treated with the indicated compounds and cell numbers were measured using trypan blue exclusion. Data is depicted as the average + / - S.D. of n = 3 biological replicates. Panel B. JWJ- 01-306 effectively inhibits proliferation of SUIT-2 cells. Cells were treated with the indicated compounds and cell confluence was measured using a Cellcyte X live cell analyzer. Data is depicted as the average + / - S.D. of n = 3 biological replicates with n = 4 technical replicates each. Panel C. Sotorasib-resistant MIA PaCa-2 cells were treated with DMSO, 1 pM sotorasib, 10 pM JWJ-01-306, or 1 pM sotorasib + 10 pM JWJ-01-306 (combo) for 72 hrs followed by global proteomics analysis, n = 3 biological replicates per condition. Protein abundance changes were analyzed by one-way ANOVA test (FDR < 0.05) and clustered using K-nearest neighbors clustering. Each line within the clusters is color-coded according to its distance from the cluster center, ranging from purple (close) to light blue (far). Proteins in each cluster were then evaluated for pathway enrichment using GO and KEGG pathway analysis. Representative pathways are shown and pathways associated with ZBTB11 function are highlighted in blue text. Full datasets in Dataset 4.

[0031] Figure 9 | Cellular processes targeted by K-Rasi+ZBTBll degrader combinations in K-Rasi resistant PDAC at 5d. Sotorasib-resistant MIA PaCa-2 cells were treated with DMSO, 1 pM sotorasib, 10 pM JWJ-01-306, or 1 pM sotorasib + 10 pM JWJ-01-306 (combo) for 120 hrs followed by global proteomics analysis, n = 3 biological replicates per condition. Proteinabundance changes were analyzed by one-way ANOVA test (FDR < 0.05) and clustered using K-nearest neighbors clustering. Each line within the clusters is color-coded according to its distance from the cluster center, ranging from purple (close) to light blue (far). Proteins in each cluster were then evaluated for pathway enrichment using GO and KEGG pathway analysis. Representative pathways are shown and pathways associated with ZBTB11 function are highlighted in text. Full datasets in Dataset 4.

[0032] Figure 10 | JWJ-01-306 leads to reduction in ZBTB11 downstream mitochondrial proteins. Panel A. Comparison between MitoCarta 3.0 database and significantly regulated protein hits identified in proteomics reveals enrichment of mitochondria-related proteins. Panel B. Protein abundances of ZBTB11 -regulated targets decrease with treatment of 10 pM JWJ-01- 306. Each boxplot represents the median value, with the bounds indicating the 25thand 75thpercentiles. Significance level is marked with asterisks (two-tailed moderated t-test, * p-value < 0.05, ** p-value < 0.01, *** p-value < 0.001).

[0033] Figure 11 | Metabolic reprogramming of K-Ras inhibitor resistant PDAC cells by ZBTB11 degradation. Panel A. ZBTB11 degradation reduces rates of OXPHOS in sotorasib- resistant MIA PaCa-2 cells. Cells were treated with 10 pM of the indicated compound for 24 hrs. Panel B. ZBTB11 degradation reduces ATP production by OXPHOS in sotorasib-resistant MIA PaCa-2 cells. Panel C. ZBTB1 1 degradation reduces rates of OXPHOS in MRTX1133-resistant SUIT-2 cells. Cells were treated with 10 pM of the indicated compound for 24 hrs. Panel D. ZBTB11 degradation reduces ATP production by OXPHOS in MRTX1133-resistant SUIT -2 cells. Panel E. Overexpression of ZBTB 1 1WTor ZBTB11K866Trescues JWJ-01-306-mediated reduction of OXPHOS. Sotorasib-resistant MIA PaCa-2 cell lines with stable expression of NanoLuc-ZBTB 11WTor NanoLuc-ZBTB l 1K866Twere generated. Cells were treated with 10 pM JWJ-01-306 for 24 hrs. Panel F. Overexpression of ZBTB 1 1WTor ZBTB11K866Trescues JWJ- 01-306-mediated reduction of ATP production by OXPHOS. Panel G. ZBTB11 degradation induces downregulation of ZBTB11 -regulated genes. Sotorasib-resistant MIA PaCa-2 cells were treated with 10 pM of the indicated compound for 24 hrs. For each gene, data is shown for DMSO, JWJ-01-306, JWJ-01-368, and JWJ-01-334 from left to right. Panel H. Overexpression of ZBTB1 1WTor ZBTB11K866Trescues JWJ-01-306-mediated downregulation of ZBTB11- regulated genes. Cells were treated with 10 pM JWJ-01-306 for 24 hrs. For each gene, data isshown for the following experimental groups from left to right: OE ZBTB11K866TDMSO; OE ZBTB11K866TJWJ-01-306; OE ZBTB11 DMSO; OE ZBTB11 JWJ-01-306. Panel I. MSEA identifies the TCA cycle as the major metabolic pathway disrupted by ZBTB11 degradation. Sotorasib-resistant MIA PaCa-2 cells were treated with DMSO or 10 pM JWJ-01-306 for 24 hrs. Cells were then labeled with13C-labeled glucose or glutamine for an additional 24 hrs followed by global metabolomics analysis, n = 3 biological replicates per condition. Metabolite abundance changes were analyzed by the global test (P < 0.05). Metabolites were then evaluated for pathway enrichment using KEGG pathway analysis and filtered for pathways containing a minimum of four hits. Full datasets in Dataset 5. Panel J. Representative metabolite abundances from MSEA. Data is depicted as the median of n = 3 biological replicates. Panels A-F. Cellular respiration rates were evaluated in a mitochondrial stress test with the indicated drugs using a Seahorse analyzer. Oxygen Consumption Rates (OCR) and Extracellular Acidification Rates (ECAR) from the mitochondrial stress test were used to calculate ATP production rates. A-D. Data is depicted as the average + / - S.D. of n = 2 biological replicates with n = 3 technical replicates each. E-F. Data is depicted as the average + / - S.D. of n = 5 biological replicates with n = 3 technical replicates each. G-H. mRNA levels were quantified by RT-qPCR. Data is depicted as the average + / - S.D. of n = 3 biological replicates and is normalized to DMSO vehicle treatment controls.

[0034] Figure 12 | Metabolic reprogramming of parental and K-Ras inhibitor resistant PDAC cells by ZBTB11 degradation. Panel A. ZBTB11 degradation reduces rates of OXPHOS in parental MIA PaCa-2 cells. Cells were treated with 10 pM of the indicated compound for 24 hrs. Panel B. ZBTB11 degradation reduces ATP production by OXPHOS in parental MIA PaCa- 2 cells. Panel C. ZBTB11 degradation induces compensatory genetic upregulation of ZBTB11 and downregulation of ZBTB11 -regulated genes. Parental MIA PaCa-2 cells were treated with 10 pM of the indicated compound for 24 hrs. Panel D. ZBTB11 degradation reduces rates of OXPHOS in parental SUIT -2 cells. Cells were treated with 10 pM of the indicated compound for 24 hrs. Panel E. ZBTB11 degradation reduces ATP production by OXPHOS in parental SUIT-2 cells. Panel F. ZBTB11 degradation induces compensatory genetic upregulation of ZBTB11 and downregulation of ZBTB11 -regulated genes. Parental SUIT-2 cells were treated with 10 pM of the indicated compound for 24 hrs. Panel G. ZBTB1 1 degradation induces compensatory genetic upregulation of ZBTB11 and downregulation of ZBTB11 -regulated genes. MRTX1133-resistantSUIT-2 cells were treated with 10 pM of the indicated compound for 24 hrs. Panel H. ZBTB11 degradation induces compensatory genetic upregulation of ZBTB11. Sotorasib-resistant MIA PaCa-2 cells were treated with 10 pM of the indicated compound for 24 hrs. Panesl A-B, D-E. Cellular respiration rates were evaluated in a mitochondrial stress test with the indicated drugs using a Seahorse analyzer. Oxygen Consumption Rates (OCR) and Extracellular Acidification Rates (ECAR) from the mitochondrial stress test were used to calculate ATP production rates. Panels C, F-H. mRNA levels were quantified by RT-qPCR. Data is depicted as the average + / - S.D. of n = 3 biological replicates and is normalized to DMSO vehicle treatment controls.

[0035] Figure 13 | ZBTB11 degradation spares neurons and deepens the response of PDAC patient-derived organoids to K-Ras inhibitors. Panel A. Mitochondrial activity and oxidative stress assays show differential pharmacology of Complex I and ZBTB11 perturbation. hiPSC- derived neurons were treated for 24 h with DMSO, 1 pM IACS 010759, 1 pM JWJ-01-306 or 1 pM JWJ-01-368. Panel B. Neurotoxicity assays show differential pharmacology of Complex I and ZBTB11 perturbation. hiPSC-derived neurons were treated for 72 h with DMSO, 1 pM IACS 010759, 1 pM JWJ-01-306 or 1 pM JWJ-01-368. Panel C. Proliferation assays show ZBTB11 + K-Ras inhibitor combination has superior antiproliferative effects in PDAC patient- derived organoids. Cells were treated with DMSO vehicle, 1 pM JWJ-01-306, 200 nM MRTX1133 or 1 pM JWJ-01-306 + 200 nM MRTX1133 (COMBO) and cellular confluence observed using brightfield imaging at the indicated timepoints. Panels A, C. Data plotted as mean + / - S.D. of n = 3 biological replicates.DETAILED DESCRIPTION

[0036] The present invention provides in embodiments therapeutic compounds as described herein, pharmaceutical compositions comprising the compounds, and methods of use for treatment of various diseases and disorders in which inhibition and / or degradation of ZBTB11 can be an effective treatment, such as cancer. The compounds can induce targeted protein degradation of a transcriptional regulator of mitochondrial biogenesis, such as ZBTB 11.

[0037] Mitochondrial biogenesis, and downstream OxPhos metabolism, is adaptively upregulated by drug-resistant cancers, including KRAS G12C inhibitors in pancreatic cancer, and BRAF inhibitors in melanoma. Beyond this, numerous cancers have demonstrated thisphenomena, including KRAS inhibitor resistant lung cancers, and TMZ resistant glioblastomas. The instant ZBTB11 molecular glues combat this effect, sensitizing the cancers to chemotherapy or targeted therapy to overcome their drug resistance.

[0038] In on aspect the invention provides that the compounds are small molecule molecular glue degraders that works via a molecular glue mechanism whereby the molecules bind the E3- ligase CRL4-CRBN and promotes interaction with ZBTB11 by binding at the interface of ZBTB 11 and CRBN, leading to ZBTB 11 ubiquitination and degradation.

[0039] The invention provides that the compounds, and pharmaceutical compositions containing the compounds, can be used to treat cancer for tumors that rely on elevated OxPhos for survival, and for drug-resistant tumors that evade chemotherapy via up regulation of mitochondrial biogenesis.

[0040] In embodiments, the invention provides methods of treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of a composition as described herein. In embodiments the method further comprises co-administering a chemotherapeutic agent with the compounds described herein.

[0041] Further compounds and methods of manufacture in other embodiments of the invention can be found in the Examples herein. The invention further contemplates precursors and derivatives of the compounds disclosed herein.Certain Definitions

[0042] The term “derivative” refers to a chemical substance related structurally to another substance, or a chemical substance that can be made from another substance (i.e., the substance it is derived from), e.g., through chemical or enzymatic modification.

[0043] The term “attached” or “conjugated” refers to interactions and / or states in which material or compounds are connected or otherwise joined with one another. These interactions and / or states are typically produced by, e.g., covalent bonding, ionic bonding, chemisorption, physisorption, and combinations thereof.

[0044] Various further aspects and embodiments of the disclosure are provided by the following description. Before further describing various embodiments of the presently disclosed inventive concepts in more detail by way of exemplary description, examples, and results, it is to be understood that the presently disclosed inventive concepts are not limited in application to the details of methods and compositions as set forth in the following description. The presently disclosed inventive concepts are capable of other embodiments or of being practiced or carried out in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments are meant to be exemplary, not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting unless otherwise indicated as so. Moreover, in the following detailed description, numerous specific details are set forth in order to provide a more thorough understanding of the disclosure. However, it will be apparent to a person having ordinary skill in the art that the presently disclosed inventive concepts may be practiced without these specific details. In other instances, features which are well known to persons of ordinary skill in the art have not been described in detail to avoid unnecessary complication of the description. All of the compositions and methods of production and application and use thereof disclosed herein can be made and executed without undue experimentation in light of the present disclosure.

[0045] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0046] Unless defined otherwise, all technical and scientific terms and any acronyms used herein have the same meanings as commonly understood by one of ordinary skill in the art in the field of the invention. Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the exemplary methods, devices, and materials are described herein.

[0047] The practice of the present invention may employ conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in theliterature, such as Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al, 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (MJ. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J .E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993- 1998) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D .M. Weir and CC. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); Current Protocols in Molecular Biology (F .M. Ausubel et al , eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al, eds., 1994); Current Protocols in Immunology (J.E. Coligan et al, eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the exemplary methods, devices, and materials are described herein. For the purposes of the present disclosure, the following terms are defined below. Additional definitions are set forth throughout this disclosure.

[0048] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by,” or any other variation thereof, are intended to encompass a non-exclusive inclusion, subject to any limitation explicitly indicated otherwise, of the recited components. For example, a composition, and / or a method that “comprises” a list of elements (e.g., components, features, or steps) is not necessarily limited to only those elements (or components or steps), but may include other elements (or components or steps) not expressly listed or inherent to the composition and / or method.

[0049] Reference throughout this specification to “one embodiment,” “an embodiment,” “a particular embodiment,” “a related embodiment,” “a certain embodiment,” “an additional embodiment,” or “a further embodiment” or combinations thereof means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the sameembodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0050] As used herein, the transitional phrases “consists of’ and “consisting of’ exclude any element, step, or component not specified. For example, “consists of’ or “consisting of’ used in a claim would limit the claim to the components, materials or steps specifically recited in the claim except for impurities ordinarily associated therewith (i.e., impurities within a given component). When the phrase “consists of’ or “consisting of’ appears in a clause of the body of a claim, rather than immediately following the preamble, the phrase “consists of’ or “consisting of’ limits only the elements (or components or steps) set forth in that clause; other elements (or components) are not excluded from the claim as a whole.

[0051] As used herein, the transitional phrases “consists essentially of’ and “consisting essentially of’ are used to define a fusion protein, pharmaceutical composition, and / or method that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of’ occupies a middle ground between “comprising” and “consisting of’. It is understood that aspects and embodiments of the invention described herein include “consisting” and / or “consisting essentially of’ aspects and embodiments.

[0052] When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0053] The term “and / or” when used in a list of two or more items, means that any one of the listed items can be employed by itself or in combination with any one or more of the listed items. For example, the expression “A and / or B” is intended to mean either or both of A and B, i.e. A alone, B alone or A and B in combination. The expression “A, B and / or C” is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination.

[0054] It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Values or ranges may be also be expressed herein as “about,” from “about” one particular value, and / or to “about” another particular value. When such values or ranges are expressed, other embodiments disclosed include the specific value recited, from the one particular value, and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that there are a number of values disclosed therein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. In embodiments, “about” can be used to mean, for example, within 10% of the recited value, within 5% of the recited value, or within 2% of the recited value.

[0055] It will be further understood that there are a number of values disclosed therein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. In embodiments, “about” can be used to mean, for example, a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In various embodiments, the term “about” or “approximately” refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0056] As used herein any reference to "one embodiment" or "an embodiment" means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. The appearances of the phrase "in oneembodiment" in various places in the specification are not necessarily all referring to the same embodiment.

[0057] In an aspect, the disclosure provides a pharmaceutical composition comprising the compounds of the disclosure and one or more pharmaceutically acceptable excipients or diluents.

[0058] As used herein the term “pharmaceutical composition” refers to pharmaceutically acceptable compositions, wherein the composition comprises a pharmaceutically active agent, and in some embodiments further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may be a combination of pharmaceutically active agents and carriers.

[0059] As used herein the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia, other generally recognized pharmacopoeia in addition to other formulations that are safe for use in animals, and more particularly in humans and / or non-human mammals.

[0060] As used herein the term “pharmaceutically acceptable diluent or excipient” or “pharmaceutically acceptable carrier” refers to an excipient, diluent, preservative, solubilizer, emulsifier, adjuvant, and / or vehicle with which the compounds of the disclosure, is administered. Such carriers may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be a carrier. Methods for producing compositions in combination with carriers are known to those of skill in the art. In some embodiments, the language “pharmaceutically acceptable diluent or excipient” is intended to include any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. See, e.g, Remington, The Science and Practice of Pharmacy, 20th ed., (Lippincott, Williams & Wilkins 2003). Exceptinsofar as any conventional media or agent is incompatible with the active compound, such use in the compositions is contemplated.

[0061] Formulations of a pharmaceutical composition suitable for administration typically generally comprise the active ingredient combined with a pharmaceutically acceptable diluents or excipients, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multi-dose containers containing a preservative. Formulations for administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and the like. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. Formulations may also include aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents or sterile, pyrogen-free, water. Exemplary administration forms may include solutions or suspensions in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0062] The pharmaceutical compositions of the disclosure may be administered in a number of ways depending upon whether local or systemic treatment is desired. The pharmaceutical compositions are typically suitable for parenteral administration, wherein administration includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrastemal, intravenous, intranasal, intratracheal, intraarterial, intrathecal, intradermal, intrasynovial injection or infusions. In some embodiments, the pharmaceutical compositions of the present disclosure comprise intravenous administration.

[0063] The term “combination” refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where one or more active compounds and a combination partner (e.g., another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals. In some circumstances, the combination partners show a cooperative, e.g., synergistic effect. The terms “co-admini strati on” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e g., the administration of three or more active ingredients.

[0064] In an aspect, the disclosure provides a method of treating a subject in need thereof, comprising administering to the subject an effective amount of the compounds of the disclosure or the pharmaceutical composition of the disclosure.

[0065] The terms “subject,” “patient” and “individual” are used interchangeably herein to refer to an animal. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed. A “subject,” “patient” or “individual” as used herein, includes any animal that can be treated with the vectors, compositions, and methods contemplated herein. Suitable subjects (e.g., patients) include laboratory animals (such as mouse, rat, rabbit, or guinea pig), farm animals, and domestic animals or pets (such as a cat or dog). In some embodiments, administering comprises administering a therapeutically effective amount to a human subject.

[0066] As used herein, the term “amount” refers to “an amount effective” or “an effective amount” of a cell to achieve a beneficial or desired prophylactic or therapeutic result, including clinical results. As used herein, “therapeutically effective amount” refers to an amount of a pharmaceutically active compound(s) that is sufficient to treat or ameliorate, or in some manner reduce the symptoms associated with diseases and medical conditions. When used with reference to a method, the method is sufficiently effective to treat or ameliorate, or in some manner reduce the symptoms associated with diseases or conditions. For example, an effective amount in reference to diseases is that amount which is sufficient to block or prevent onset; or if disease pathology has begun, to palliate, ameliorate, stabilize, reverse or slow progression of the disease, or otherwise reduce pathological consequences of the disease. In any case, an effective amount may be given in single or divided doses.

[0067] As used herein, the terms “treat,” “treatment,” or “treating” embraces at least an amelioration of the symptoms associated with diseases in the patient, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. a symptom associated with the disease or condition being treated. As such, “treatment” also includes situations where the disease, disorder, or pathological condition, or at least symptoms associated therewith, are completely inhibited (e.g. prevented from happening) or stopped (e.g. terminated) such that the patient no longer suffers from the condition, or at least the symptoms that characterize the condition.

[0068] As used herein, and unless otherwise specified, the terms "prevent," "preventing" and "prevention" refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. In certain embodiments, the terms refer to the treatment with or administration of a compound or dosage form provided herein, with or without one or more other additional active agent(s), prior to the onset of symptoms, particularly to subjects at risk of disease or disorders provided herein. The terms encompass the inhibition or reduction of a symptom of the particular disease. In certain embodiments, subjects with familial history of a disease are potential candidates for preventive regimens. In certain embodiments, subjects who have a history of recurring symptoms are also potential candidates for prevention. In this regard, the term "prevention" is encompassed by “treatment” and may be interchangeably used with the term "prophylactic treatment."

[0069] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with one or more other agent(s), which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0070] The term “alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a Ci-Cio alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, Ci-Cio alkyl, C1-C9 alkyl, Ci-Cs alkyl, C1-C7 alkyl, Ci- C6alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-Cs alkyl, C3-C8alkyl and C4- C alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, -propyl, 1 - methyl ethyl, -butyl, -pentyl, 1,1 -dimethyl ethyl, 3-methylhexyl, 2- methylhexyl, 1 -ethylpropyl, and the like. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, the alkyl is -CH(CH3)2 or -C(CH3)3. Unless otherwise specified, “alkyl” can comprise saturated or unsaturated alkyl groups (i.e., groups containing one or more carbon-carbon double or triple bonds). Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted. “Alkylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, and likewise can be saturated or unsatured. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CIUCIUCIU-. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted. "Heteroalkyl" refers to an alkyl group wherein one or more of the carbons of the alkyl group is replaced with a heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms, preferably N, O and S. Note that valency of heteroatoms may not be identical to that of a carbon atom, so, for example, a methylene (CH2) of an alkyl may be replaced with an NH group, S group, O group, or the like in a heteroalkyl. "Heteroalkylene" refers to an alkylene group wherein one or more of the carbons of the alkylenegroup is replaced with a heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms, preferably N, O and S.

[0071] The term “aryl” refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.

[0072] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4- dihydronaphthalenyl-l(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[l.l.l]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

[0073] The term “heteocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

[0074] The term “heteroaryl” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, 0-1 P atoms, and 0- 1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). A heteroaryl radical can be a monocyclic or polycyclic (e g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.

[0075] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). In preferred embodiments, each additional group is individually and independently selected from D, halogen, -CN, -NH2, - NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CHi), - N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), - C(=O)NH2, -C(=O)NH(Ci -C4alkyl), -C(=O)N(Ci- C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(CI- C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-Cecycloalkyl, Ci-C4fluoroalkyl, Ci- C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi- C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci- C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, - NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and - OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).Compounds

[0076] In certain embodiments herein are compounds which are capable of inhibiting or degrading ZBTB11. In embodiments, the compounds provided herein are capable of degrading ZBTB11. In embodiments, the compounds act as a molecular glue with an E3-ligase. In embodiments, the E3 ligase comprises cereblon (CRBN). In embodiments, the compounds herein bind the E3 -ligase CRL4-CRBN. In embodiments, the compounds herein promote interaction between ZBTB11 and the E3-ligase CRL4-CRBN. In embodiments, the compounds bind at the interface of ZBTB11 and CRBN. In embodiments, the compounds are effective to induce ubiquitination and degradation of ZBTB11. In embodiments, the compounds described herein are effective in the methods of treatment described herein.

[0077] In embodiments, a compound according to the instant disclosure is a compound of Formula (I):Formula (I) wherein: each X1is independently O or S;X2is a bond, optionally substituted alkylene, optionally substituted cycloalkylene or heterocycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heteroalkylene, — O — , — N(RA) — , — S — , — C(=O)— , — C(=O)O— , — C(=O)NRA— , — NRAC(=O)— , — NRAC(=O)RA— , — C(=O)RA— , — NRAC(=O)O— , — NRAC(=O)N(RA)— , — OC(=O)— , — OC(=O)O— , — OC(=O)N(RA)— , — S(O)2NRA— or — NRAS(O)2— ;X3is a bond, optionally substituted alkylene, optionally substituted cycloalkylene or heterocycloalkylene, optionally substituted arylene or heteroarylene, e, — O — , — N(RB)— , — S— , — C(=O)— , — C(=O)O— , — C(=O)NRB— , — NRBC(=O)— , — NRBC(=O)RB— , — C(=O)RB— — NRBC(=O)O— , — NRBC(=O)N(RA)— , — OC(=O)— , — OC(=O)O— , — OC(=O)N(RB)—, — S(O)2NRB— , or — NRBS(0)2— ;A1is optionally substituted aryl or heteroaryl;A2is optionally substituted aryl or heteroaryl;R1is H, optionally substituted alkyl, halogen, a bond with A1, or optionally substituted alkylene forming a bond with A1; each R2and R3is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, optionally substituted alkylene forming a bond with an RB, or R2and R3are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl; each R4and R5, when present, is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, or two R4or two R5are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl;1 is 0 or 1; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3;RA, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; andRB, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl; or a bond with an optionally substituted alkylene of R2or R3; or a pharmaceutically acceptable salt thereof.

[0078] In embodiments, each X1is independently O or S. In embodiments, each X1is O.

[0079] In embodiments, X2is a bond, optionally substituted alkylene or heteroalkylene, optionally substituted cycloalkylene or heterocycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted heteroalkylene, — O — , — N(RA) — , — S— , — C(=O)— , — C(=O)O— , — C(=O)NRA— , — NRAC(=O)— , — NRAC(=O)RA— , — C(=O)RA— , — NRAC(=O)O— , — NRAC(=O)N(RA)— , — OC(=O)— , — OC(=O)O— , — OC(=O)N(RA) — , — S(O)2NRA— , or — NRAS(O)2 — . In embodiments, X2is optionally substituted alkylene or heteroalkylene, — O — , — N(RA) — , — S — , — C(=O)NRA— , — NRAC(=O) , NRAC(=O)RA, NRAC(=O)O , NRAC(=O)N(RA) ,OC(=O)N(RA) — , or — S(O)2NRA— . In embodiments, X2is — O — , — N(RA) — , — S — , —C(=O)NRA— , — NRAC(=O)— , — NRAC(=O)RA— ,— NRAC(=O)O— , — NRAC(=O)N(RA)— , — OC(=O)N(RA) — , or — S(O)2NRA— . In embodiments, X2is — N(RA) — , — C(=O)NRA— , — NRAC(=O)— , — NRAC(=O)N(RA)— , or — S(O)2NRA— . In embodiments, X2is — N(RA)— , — C(=O)NRA— , or — NRAC(=O) — . In embodiments, X2is — N(RA) — . In embodiments, X2is -NH- or -N(CH3)-. In embodiments, X2is -NH-.

[0080] In embodiments, each RA, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl. In embodiments, each RA, if present, is H, optionally substituted alkyl, or optionally substituted cycloalkyl. In embodiments, each RA, if present, is H or optionally substituted alkyl. In embodiments, each RA, if present, is H or C1-C3 alkyl. In embodiments, each RA, if present, is H or -CH3. In embodiments, each RA, if present, is H.

[0081] In embodiments, X3is a bond, optionally substituted alkylene or heteroalkylene, optionally substituted cycloalkylene or heterocycloalkylene, optionally substituted arylene or heteroarylene, — O— , — N(RB)— , — S— , — C(=O)— , — C(=O)O— , — C(=O)NRB— , — NRBC(=O)— , — NRBC(=O)RB— , — C(=O)RB— , — NRBC(=O)O— , — NRBC(=O)N(RA)— , — OC(=O)— , — OC(=O)O— , — OC(=O)N(RB)— , — S(O)2NRB— , or — NRBS(O)2— . In embodiments, X3is optionally substituted alkylene or heteroalkylene, optionally substituted cycloalkylene or heterocycloalkylene, — O — , — N(RI!) — , — S — , — C(=O) — , — C(=O)O — , — C(=O)NRB— , — NRBC(=O)— , — NRBC(=O)RB— , — C(=O)RB— , — NRBC(=O)O— , —NRBC(=O)N(RA)— — 0C(=0)— — 0C(=0)0— — OC(=O)N(RB)— — S(O)2NRB— , or — NRBS(O)2— . In embodiments, X3is optionally substituted alkylene or heteroalkylene, optionally substituted cycloalkylene or heterocycloalkylene, — O — , — N(RB) — , — S — , — C(=O) — , — C(=O)O— , — C(=O)NRB— , — NRBC(=O)— , — NRBC(=O)RB— , — C(=O)RB— , — NRBC(=O)O— , — NRBC(=O)N(RA)— , — OC(=O)— , — OC(=O)O— , — OC(=O)N(RB)— , — S(O)2NRB— , or — NRBS(O)2— . In embodiments, X3is optionally substituted cycloalkylene or heterocycloalkylene, — O — , — N(RB) — , — S — , — C(=O)NRB— , — NRBC(=O) — , — NRBC(=O)N(RA)— , — OC(=O)N(RB)— , — S(O)2NRB— , or — NRBS(O)2— . In embodiments, X3is optionally substituted heterocycloalkylene. In embodiments, X3is — N(RB) — , C(=O)NRB— , or — NRBC(=O) — . In embodiments, X3is — N(RB) — . In embodiments, X3is - NH- or -N(CH3)-. In embodiments, X3is -N(RB), wherein RBis a bond with an optionally substituted alkylene of R2or R3.

[0082] In embodiments, RB, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl; or a bond with an optionally substituted alkylene of R2or R3. In embodiments, RB, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl, or a bond with an optionally substituted alkylene of R2or R3. In embodiments, RB, if present, is H or optionally substituted alkyl. In embodiments, RB, if present, is H or C1-C3 alkyl. In embodiments, RB, if present, is H or -CH3. In embodiments, RB, if present, is H. In embodiments, RB, if present, is a bond with an optionally substituted alkylene of R2or R3.

[0083] In embodiments, A1is optionally substituted aryl or heteroaryl. In embodiments, A1is optionally substituted 6-membered aryl or heteroaryl. In embodiments, A1is optionally substituted phenyl or pyridyl. In embodiments, A1is optionally substituted phenyl. In embodiments, A1has the structure of optionally substitutedIn embodiments, A1has the structure of

[0084] In embodiments, the aryl or heteroaryl of A1is optionally substituted with R8, wherein R8is H, optionally substituted alkyl or heteroalkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, -CN, or halogen. In embodiments, R8is H, optionally substituted alkyl, -CN, or halogen. In embodiments, R8is H or C1-C3 alkyl.

[0085] In embodiments, A2is optionally substituted aryl or heteroaryl. In embodiments, A2is optionally substituted 6-membered aryl or heteroaryl. In embodiments, A2is optionally substituted phenyl or pyridyl. In embodiments, A2is optionally substituted phenyl.

[0086] In embodiments, A2is substituted by one substituent R6and further optionally substituted by one or more R7, wherein R6is -CF3 or halogen; and each R7is independently halogen, — CN, — ORC, — S(=O)2RC, — N(RC)2, — S(=O)2N(RC)2, — C(=O)Rc, — OC(=O)Rc, — C(=O)ORc, — OC(=O)ORc, — C(=O)N(RC)2, — OC(=O)N(RC)2, — NRCC(=O)N(RC)2, — NRCC(=O)RC, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; and each Rcis independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl. In embodiments, the R6is -CF3 or chloro. In embodiments, the R6is -CF3. In embodiments, each Rc, if present, is H or optionally substituted alkyl. In embodiments, each Rc, if present, is H.

[0088] In embodiments, 1 or 2 R7are present. In embodiments, 1 or 2 R7are present and each R7is independently -CN, halogen, or optionally substituted alkyl. In embodiments, each R7is independently -CN, halogen, or fluoroalkyl. In embodiments, each R7is independently -CN, halogen, or -CF3. In embodiments, each R7is independently -CF3 or halogen. In embodiments,each R7is independently -CF3 or chloro. In embodiments, one R7is present. In embodiments, no R7are present.

[0090] In embodiments, R1is H, optionally substituted alkyl, halogen, a bond with A1, or optionally substituted alkylene forming a bond with A1. In embodiments, R1is H or optionally substituted alkyl. In embodiments, R1is H.

[0091] In embodiments, 1 is 0 or 1. In embodiments, 1 is 1.

[0092] In embodiments, each R2and R3is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, optionally substituted alkylene forming a bond with an RB, or R2and R3are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl. In embodiments, R2and R3are each independently H, optionally substituted alkyl, or optionally substituted cycloalkyl. In embodiments, R2and R3are each independently H, C1-C3 alkyl, or C3-C6 cycloalkyl. In embodiments, each R2and R3is independently H, methyl, or ethyl, or wherein R2and R3are taken together with the carbon atom to which they are attached to form a cyclobutyl. In embodiments, each R2and R3are independently H, methyl, or ethyl. In embodiments, R2and R3are taken together with the carbon atom to which they are attached to form a cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In embodiments, R2and R3are each independently methyl, ethyl, propyl, or taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl

[0093] In embodiments, R2is alkylene forming a bond with an RBand R3is H. In embodiments, R2is C1-C4 alkylene forming a bond with an RBand R3is H. In embodiments, R2is C2 alkylene forming a bond with an RBand R3is H.

[0094] In embodiments, m is 0, 1, 2, or 3. In embodiments, m is 1 or 2. In embodiments, m is 2. In embodiments, each R5, when present, is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, or two R5are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl. In embodiments, each R5, when present, is independently H or optionally substituted alkyl. In embodiments, each R5, when present, is independently H or C1-C3 alkyl. In embodiments, each R\ when present, is H.

[0095] In embodiments, n is 0, 1, 2, or 3. In embodiments, n is 0, 1 or 2. In embodiments, n is 0. In embodiments, n is 1 or 2. In embodiments, n is 2. In embodiments, each R4, when present, is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, or two R4are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl. In embodiments, each R4, when present, is independently H or optionally substituted alkyl. In embodiments, each R4, when present, is independently H or C1-C3 alkyl. In embodiments, each R4, when present, is H.

[0096] In certain embodiments, the compound having a structure according to Formula (I) conforms to the substructure of Formula (la):Formula (la); wherein: each X1is independently O or S;A2is phenyl substituted by one substituent R6and further optionally substituted by one or more R7, wherein:R6is -CF3; and each R7is independently halogen, — CN, — ORC, — S(=O)2RC, — N(RC)2, — )ORc, —optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; andwherein each Rcis independently optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl;R1is H, optionally substituted alkyl, halogen, or optionally substituted alkylene forming a bond with A1; each R2and R3is independently optionally substituted alkyl, optionally substituted alkylene forming a bond with an RB, or R2and R3are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl; each R4and R5, when present, is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, or two R4or two R5are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkylR8is H, optionally substituted alkyl or heteroalkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, -CN, or halogen; m is 1, 2, or 3; n is 0, 1, 2, or 3; andRBis H or a bond with an optionally substituted alkylene of R2or R3; or a pharmaceutically acceptable salt thereof, and. In embodiments, the compound of Formula (la) is not a compound provided in US Patent Application Publication No. US2023 / 0192644.

[0097] In embodiments, any one of the variables set forth in Formula (la) may be the same as those defined in relation to Formula (I).

[0098] In embodiments, a compound according to the instant disclosure useful in the inhibition and / or degradation of ZBTB11 is one selected from Table 1 below. Table 1 - Exemplary Compounds of the Disclosure

[0099] In embodiments, the instant disclosure provides additional compound analogs to those specifically exemplified herein, such as those in Table 2 below. It is predicted that the compounds in Table 2 below may also exhibit ZBTB11 degradation activity.Table 2 - Additional Potential ZBTB11 DegradersIn Table 2 above, in each instance n is preferably an integer from 1 to 3.Pharmaceutical Compositions

[0100] In another aspect of the instant disclosure is a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the relevant compound. The therapeutically effective amount of a disclosed compound will depend on the route of administration, the species of subject and the physical characteristics of the subject being treated. Specific factors that can be taken into account include disease severityand stage, weight, diet and concurrent medications. The relationship of these factors to determining a therapeutically effective amount of the disclosed compounds is understood by those of skill in the art. The pharmaceutical composition can also further comprise an additional therapeutic agent (e.g., any of those described herein in reference to combination therapies).

[0101] harmaceutical compositions for administration to a subject can include at least one further pharmaceutically acceptable additive such as carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.

[0102] Pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like. The pharmaceutically acceptable carriers useful for these formulations are conventional. Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describes compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed.

[0103] In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (for example, powder, pill, tablet, or capsule forms), conventional nontoxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

[0104] Pharmaceutical compositions disclosed herein include those formed from pharmaceutically acceptable salts and / or solvates of the disclosed compounds.

[0105] To formulate the pharmaceutical compositions, the compound can be combined with various pharmaceutically acceptable additives, as well as a base or vehicle for dispersion of the compound. Desired additives include, but are not limited to, pH control agents, such asarginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, and the like. In addition, local anesthetics (for example, benzyl alcohol), isotonizing agents (for example, sodium chloride, mannitol, sorbitol), adsorption inhibitors, solubility enhancing agents (for example, cyclodextrins and derivatives thereof), stabilizers (for example, serum albumin), and reducing agents (for example, glutathione) can be included.

[0106] The compositions of the disclosure can alternatively contain as pharmaceutically acceptable vehicles substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate. For solid compositions, conventional nontoxic pharmaceutically acceptable vehicles can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.

[0107] The pharmaceutical compositions of the disclosure typically are sterile and stable under conditions of manufacture, storage and use. Sterile solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by fdtered sterilization. Generally, dispersions are prepared by incorporating the compound and / or other biologically active agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile powders, methods of preparation include vacuum drying and freeze-drying which yields a powder of the compound plus any additional desired ingredient from a previously sterile-fdtered solution thereof. The prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0108] In accordance with the various treatment methods of the disclosure, the compound can be delivered to a subject in a manner consistent with conventional methodologies associated with management of the disorder for which treatment or prevention is sought. In accordance with the disclosure herein, a prophylactically or therapeutically effective amount of the compound and / or other biologically active agent is administered to a subject in need of such treatment for atime and under conditions sufficient to prevent, inhibit, and / or ameliorate a selected disease or condition or one or more symptom(s) thereof.

[0109] For prophylactic and therapeutic purposes, the compound can be administered to the subject by the oral route or in a single bolus delivery, via continuous delivery (for example, continuous transdermal, mucosal or intravenous delivery) over an extended time period, or in a repeated administration protocol (for example, by an hourly, daily or weekly, repeated administration protocol). The therapeutically effective dosage of the compound can be provided as repeated doses within a prolonged prophylaxis or treatment regimen that will yield clinically significant results to alleviate one or more symptoms or detectable conditions associated with a targeted disease or condition as set forth herein. Determination of effective dosages in this context is typically based on animal model studies followed up by human clinical trials and is guided by administration protocols that significantly reduce the occurrence or severity of targeted disease symptoms or conditions in the subject. Suitable models in this regard include, for example, murine, rat, avian, dog, sheep, porcine, feline, non-human primate, and other accepted animal model subjects known in the art. Alternatively, effective dosages can be determined using in vitro models.

[0110] Using such models, only ordinary calculations and adjustments are required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the compound (for example, amounts that are effective to alleviate one or more symptoms of a targeted disease). In alternative embodiments, an effective amount or effective dose of the compound may simply inhibit or enhance one or more selected biological activities correlated with a disease or condition, as set forth herein, for either therapeutic or diagnostic purposes.

[0111] The instant disclosure also includes kits, packages and multi-container units containing the herein described pharmaceutical compositions, active ingredients, and / or means for administering the same for use in the prevention and treatment of diseases and other conditions in mammalian subjects. Kits for diagnostic use are also provided. In certain embodiments, these kits include a container or formulation that contains one or more of the compounds described herein.

[0112] In one example, this component is formulated in a pharmaceutical preparation for delivery to a subject. The compound is optionally contained in a bulk dispensing container or unit or multi-unit dosage form. Optional dispensing means can be provided, for example a pulmonary or intranasal spray applicator. Packaging materials optionally include a label or instruction indicating for what treatment purposes and / or in what manner the pharmaceutical agent packaged therewith can be used.Methods

[0113] Also provided herein are methods of treating disease and disorders by administering a compound which inhibits ZBTB11 activity, such as by directly inhibiting the function of the protein or by lowering the amount of ZBTB11 present in a subject or cell (e.g., by degrading ZBTB11). In embodiments described herein is a method of treating a ZBTB11 -related disease or disorder in a subject in need thereof, comprising administering to the subject a compound which inhibits or degrades ZBTB11. In embodiments herein is a method of treating a disease or disorder characterized by elevated oxidative phosphorylation in the subject, the method comprising administering to the subject a compound which inhibits or degrades ZBTB11. IN preferred embodiments, the compound is delivered in a therapeutically effective amount.

[0114] In embodiments, a disease or disorder associated with ZBTB11 includes those in which ZBTB11 acts to modulate oxidative phosphorylation in the subject. In embodiments, ZBTB11 acts in diseased tissue to regulate oxidative phosphorylation. In embodiments, the disease or disorder is characterized by elevated oxidative phosphorylation. In embodiments, the disease or disorder is one in which diseased tissue (e.g., cancer cells) rely on elevated oxidative phosphorylation for survival.

[0115] In embodiments, the disease or disorder to be treated by a ZBTB11 inhibitor or degrader e.g., a compound as described herein) is one which has become dependent on elevated oxidative phosphorylation for survival due to a mutation, inhibition, or modulation of one or more pathways within the disease tissue. In embodiments, the disease or disorder develops the elevated oxidative phosphorylation state in response to a mutation. In embodiments, the diseaseor disorder develops the elevated oxidative phosphorylation state due to treatment with a therapeutic intervention (e.g., treatment of cancer with a K-Ras inhibitor).

[0116] In embodiments, the disease or disorder to be treated by targeting ZBTB11 is one which is resistant or refractory to treatment with another therapeutic intervention. In embodiments, the disease or disorder is resistant or refractory to treatment with the other therapeutic intervention in the absence of a ZBTB11 inhibitor or degrader. In embodiments, the disease or disorder is refractory due at least partially to enhanced reliance on oxidative phosphorylation upon treatment with the other therapeutic intervention.

[0117] In embodiments, the disease or disorder treated with a ZBTB11 inhibitor or degrader is further treated with an additional therapeutic intervention. In embodiments, the method of treatment comprises administering an additional therapeutic intervention. In embodiments, the additional therapeutic intervention comprises chemotherapy, targeted therapy, immunotherapy, a kinase inhibitor, a Ras pathway inhibitor, DNA damaging agents, and / or a PARP inhibitor. In embodiments, the additional therapeutic intervention is a K-Ras inhibitor (e.g., sotorasib and / or adagrasib). In embodiments, the additional therapeutic intervention is an anti-angiogenic therapy. In embodiments, the additional therapeutic intervention is a BCL2 inhibitor, tyrosine kinase inhibitor, or BRAF inhibitor. In embodiments, the additional therapeutic intervention is one which results in elevated oxidative phosphorylation in the subject. In embodiments, the additional therapeutic intervention is one to which resistance can be developed due to enhanced oxidative phosphorylation in the relevant tissue.

[0118] In embodiments, the disease or disorder to be treated with a ZBTB11 inhibitor or degrader (e.g., a compound as described herein) is cancer. In embodiments, the cancer is a drugresistant cancer. In embodiments, the cancer is one which exhibits elevated oxidative phosphorylation. In embodiments, the cancer relies on elevated oxidative phosphorylation for survival. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is a K-Ras mutant cancer. In embodiments, the cancer is pancreatic dual adenocarcinoma.EXAMPLES

[0119] Example 1 - Identification of ZBTB11 as an Orthogonal Therapeutic Target

[0120] To validate that K-Ras inhibitor resistance reliably generates a high-OXPHOS state, and to develop in-house PDAC models, 3 independent K-RasG12C MIA PaCa-2 lines were cultured with escalating sublethal concentrations of sotorasib (AMG-510) to generate sotorasib-resistant cell lines Rl, R2 and R3 (Fig. 1 Panel A, Fig. 2 Panel A). The cellular metabolic state was characterized using Seahorse bioenergetic analysis, where a mitochondrial stress test revealed increased basal and maximal oxidative phosphorylation in the resistant cells compared to parental cell controls, as well as increased extracellular acidification rate (ECAR) resulting in overall higher concentrations of ATP produced per minute per cell (Fig. 1 Panels B- C). Seahorse bioenergetic analysis was performed on previously reported K-RasG12D MTXR SUIT2 lines which are resistant to MRTX1133, and compared them to parental SUIT2 cells (Fig. 3 Panels A-C). Increased basal and maximal oxidative phosphorylation was also observed, and overall higher concentrations of ATP produced per minute per cell in MTXR cells. Finally, mass-spectrometry based metabolomics was performed following 13C glucose or 13C glutamine labeling to identify differences between parental and resistant MiaPaCa-2 cells (Fig. 2 Panel B, Dataset 1) and parental and resistant SUIT2 cells (Fig. 3 Panel D, Dataset 1). Metabolite set enrichment analysis identified changes in diverse metabolic pathways including branched chain amino acid biosynthesis / degradation, glycolysis / gluconeogenesis, and the TCA cycle. These data highlight the breadth of metabolites and pathways altered during the development of resistance, that culminate in the observed increases in OXPHO S.

[0121] ZBTB 11 regulates nuclear transcription of components of the mitoribosome and complex I in murine ES cells and HEK293 cells33to modulate OXPHOS, but its functions in PDAC have not been characterized. To evaluate if human ZBTB 11 regulates these genes, inducible ZBTB 11 CRISPRi cell lines were developed to evaluate effects of ZBTB 11 depletion genetically, confirming knockdown by immunoblot and qPCR (Fig. 4 Panels A-B, D). 4 mitoribosome genes (MRPL48, MRPL44, MRPL1, MRPL30) and 4 complex I genes (NDUF37, NDUFA12, NDUFC2, NDUFAF1) reported to be regulated by murine ZBTB 1133were selected, and qPCR was performed to quantify their mRNA levels 1 and 3 days after hZBTBl 1 CRISPRi knockdown. Reduction of the mitoribosome mRNA set was observed 24 hrs after dCas9-KRAB induction, and reduction of the complex I mRNA set after 3 days (Fig. 1 Panel D, Fig. 4 Panels C, E). To test if ZBTB11 depletion leads to reduced OXPHOS, Seahorse bioenergetic analysis was performed and observed the expected reduction in oxygen consumption rate (OCR), with nochange to the ECAR 24 hrs following cas9 induction (Fig. 1 Panels E-F). ZBTB11 is thus concluded to be a transcriptional regulator of mitochondrial genes and OXPHOS in K-Ras mutant PDAC, consistent with its reported role in other organisms and cell types.

[0122] Example 2 - Identification of ZBTB 11 Molecular Glue Degraders

[0123] Although ZBTB 11 harbors the CXXCG beta-hairpin motif found in many CRBN molecular glue targets, no CRBN-recruiting degraders of ZBTB 11 have been reported.38To enable high-throughput quantification of ZBTB11 protein levels in 384 well plates, CRISPR / cas9 was used to knock in a HiBiT tag at the c-termini of the endogenous ZBTB 11 locus and used this assay to profile a diverse in-house library of CRBN-binding molecular glue candidates (Fig. 5 Panel A). Several multi -targeted hits able to deplete ZBTB 11 by greater than 30% were identified, from the same chemical series (Fig. 5 Panels B-C). Medicinal chemistry optimization (to be reported elsewhere), culminated in the identification of JWJ-01-306 (Fig. 5 Panel C) which degrades ZBTB11 up to a Dmax of 60% by HiBiT quantification, and up to a Dmax of 90% by immunoblot at the 16 hr time point (Fig. 5 Panel D, Fig. 6 Panel B). Rescue of JWJ- 01-306 mediated ZBTB 11 degradation was confirmed upon pre-treatment with proteasomal inhibitor carfilzomib, NAE inhibitor MLN4924, and by competition with CRBN binder lenalidomide (Fig. 5 Panel E).39

[0124] Molecular glue degraders depend on formation of ternary complexes for their cellular activity. To measure intracellular ternary complex between molecules, ZBTB 11 and CRBN, a nanoBRET assay was developed and used it to confirm that JWJ-01-306 promotes a ZBTB 11 :molecular glue:CRBN ternary complex (Fig. 5 Panel F). To enable structure-based design of improved ZBTB 11 degraders and controls, ternary complex molecular modeling protocols was established (Fig. 5 Panel G). ZBTB 11 contains 12 C2H2 zinc finger domains, 7 of which harbor a CXXCG motif (ZF1, ZF3, ZF4, ZF6, ZF9, ZF10, and ZF11). NLuc tagged ZF constructs were generated, and quantified the change in individual ZF-nLuc fusion protein levels upon treatment with ZBTB 11 degrader molecules was quantified, to elucidate that zinc finger 10 (ZF10) contains the primary JWJ / CRBN degron (Fig. 6 Panels C-E). Next, an AlphaFold240model of ZBTB 11 ZF10 was generated and this structure was used to perform Rosetta proteincomplex docking to JWJ-01-306 bound CRBN.41Manual inspection of the clusters revealed abinding mode consistent with previously reported cryo-EM structures of CRBN-binding molecular glue degraders.42The glutarimide binds in the tri -tryptophan pocket where it makes two H-bonds to His378 and one H-bond to the backbone amide of Ser379 in CRBN (Fig. 5 Panel G). The aniline ring makes an edge-to-face TL interaction with His353 in CRBN, and 3- substitution orients the benzylic cyclobutane ring towards the interface of ZBTB11 ZF10 and CRBN, making hydrophobic contact with CRBN Pro352. Finally, ZBTB11 residue Lys866 and CRBN residue Glu377 form a cation-7r-anion stacking interaction with the 4-C1, 3-CFa substituted phenyl ring in JWJ degraders, that bridges the ternary complex.43These interactions agree with trends in the ZBTB11 degrader structure activity relationships.

[0125] Example 3 - Selectivity Confirmation

[0126] To aid interpretation of phenotypic data and confirm observed effects are on- target, two negative control compounds were developed: JWJ-01-334 and JWJ-01-368. To rescue all CRBN-dependent pharmacology, JWJ-01-334, which contains an N-Methyl glutarimide that prevents binding to CRBN in cellular CRBN target engagement assays44, and rescues ZBTB11 ternary complex formation and degradation (Fig. 5 Panels D, F, Fig. 6 Panel A) was synthesized. To rescue ZBTB11 -dependent pharmacology, JWJ-01-368, which lacks the aromatic CF3 substituent crucial for achieving the cation-7t-anion interaction that promotes ZBTB1 1 :JWJ:CRBN ternary complex formation, was synthesized. In live cells JWJ-01 -368 efficiently binds CRBN (Fig. 6 Panel A) but fails to promote both ZBTB11 ternary complex formation (Fig. 5 Panel F) and ZBTB11 degradation (Fig. 5 Panel D).

[0127] Next, as common CRBN-recruiting molecular glue degrader off-target IKZF1 is not expressed in PDAC, follow-up screening was performed in a Jurkat IKZF l-HiBiT cell line. Here, JWJ-01-306 and JWJ-01-368 showed potent activity, indicating they would not be selective in certain lymphoid or myeloid cell lines and should be used with caution in that context (Fig. 6 Panel F). Finally, to confirm selectivity against GSPT1, follow-up screening was performed in a Jurkat GSPTl-HiBiT cell line, where all 3 compounds were inactive (Fig. 6 Panel G).

[0128] The selectivity of JWJ-01-306 and JWJ-01-368 was evaluated in Mia PaCa-2 cells by global proteomics analysis, following a 5 hr treatment with 10 pM compound (Fig. 5Panel H and Fig. 7 Panel A, Dataset 2). In JWJ-01-306 treated cells, potent ZBTB11 downregulation was observed, and off-target degradation of three related C2H2 ZF transcription factors; ZFP91, ZBTB21 and WIZ. In JWJ-01-368 treated cells, ZBTB11 degradation was not observed, indicating JWJ-01-368 is a suitable control compound for rescue of ZBTB11 -specific pharmacology (Fig. 7 Panel A, Dataset 2).

[0129] To account for pharmacology that may be mediated by off-target activities of JWJ-01-306, the structural model was used to design a degradation-resistant mutant for use as a genetic control in rescue experiments. Here, ZBTB11 ZF3, which has a CXXCG motif but a threonine (T659) in the equivalent position to K866, which was not degraded as an NLuc fusion by the instant molecules (Fig. 5 Panel K) was identified. Site-directed mutagenesis was performed to generate ZBTB11K866T, which ablated both ternary complex formation and degradation of full length ZBTB11 by JWJ-01-306 (Fig. 5 Panels I- J). To examine if a lysine in the K866 position alone can promote degradation by JWJ-01-306, ZF3 T659 to lysine was mutated to generate ZF3T659K. This construct remained recalcitrant to degradation, indicating that K866 is necessary but not sufficient for degradation by the instant compounds, and highlighting the importance of the additional contacts made between ZBTB11 ZF10 and CRBN in the ternary complex that drive the specificity of the instant degrader proteome-wide (Fig. 5 Panels H, K).

[0130] Example 4 - Further Characterization of JWJ-01 -306

[0131] To evaluate the kinetics of JWJ-01-306 mediated degradation, time-course studies were performed which indicated that the majority of observed degradation occurs within 2 hrs (Fig. 7 Panel B). Next, the rebound rate of ZBTB11 levels following compound washout was evaluated. Here, observed no rebound in ZBTB 11 levels over a 24 hr time period, although insufficient washout as a confounding factor cannot be completely ruled out(Fig. 7 Panel C). Finally, pharmacokinetic analysis in C57BL / 6 mice dosed via intraperitoneal (IP) injection with 10 mg / kg JWJ-01-306*HCl was performed. Here, a half-life of 91 minutes and a Cmax of 1.67 pM (Fig. 7 Panel D, Dataset 3) was observed. Plasma protein binding analysis revealed that JWJ-01-306 is over 99% protein bound (Dataset 3). Taken together, these data indicate that the free drug levels of JWJ-01-306 in vivo are unlikely to be sufficient to support ZBTB11 degradation at reasonable dosing regimes, and that further chemistry optimization is needed toimprove the stability and physicochemical properties of JWJ-01-306. Therefore, JWJ-01-306 is recommended as a cell-based tool compound for target validation and mechanistic studies.

[0132] To determine the effectiveness of the instant ZBTB11 degraders for targeting K- Ras inhibitor-resistant PDAC, cell proliferation assays were performed via cell counting over time (Mia PaCa-2, 14d) and live cell brightfield-imaging (SUIT2, 6d) (Fig. 8 Panels A-B). As expected, proliferation of parental MIA PaCa-2 cells was completely impaired by high- concentrations of sotorasib. In these cells, which are highly glycolytic,45single agent JWJ-01- 306 treatment had only mild effects on proliferation over a 2-week time period, comparable to negative control JWJ-01-368 (Fig. 8 Panel A). K-Ras inhibitor-resistant MIA PaCa-2 cells showed significantly impaired proliferation only in the presence of sotorasib+JWJ-01-306 (Fig. 8 Panel A), but not sotorasib+JWJ-01-368. In SUIT2, proliferation of parental cells was completely impaired by high-concentration (500 nM) of MRTX1133 and by JWJ-01-306 as a single agent within 5 days (10 pM, Fig. 8 Panel B). Gratifyingly, cell growth in MRTX1133- resistant SUIT2 lines was blocked by JWJ-01-306 single agent treatment and MRTX1133 + JWJ-01-306, but not MRTX1133 alone or MRTX1133 + JWJ-01-368 (Fig. 8 Panel B). These data demonstrate that JWJ-01-306 can counter K-Ras inhibitor resistance in multiple types of mutant K-Ras-driven PDAC and may also have single agent antiproliferative activity in some PDAC contexts.

[0133] It was next sought to mechanistically interrogate the metabolic, transcriptomic and proteomic changes induced by JWJ-01-306 in the context of K-Ras inhibitor resistant PDAC. To identify how both K-Ras inhibitors and ZBTB11 degraders affect the cellular state at phenotypically relevant time points, global proteomics analysis of Sotorasib-resistant MiaPaCa-2 cells treated with DMSO, 1 pM Sotorasib (resistant cell media), 10 pM JWJ-01-306 and 1 pM Sotorasib + 10 pM JWJ-01-306 for 3 and 5 days was performed(Fig. 8 Panel C, Fig. 9, Fig. 10, Dataset 4). A 4-way ANOVA test was usedto compare the proteomic changes between treatment groups and supervised K-nearest neighbor clustering analysis to identify protein groups with the same changes in protein abundance in response to each treatment condition (Fig. 8 Panel C, Fig. 9, Dataset 4). Next, gene ontology analysis was performed to identify the biological pathways enriched within each protein cluster. Proteins downregulated by JWJ-01-306 treatment correspond to mitochondrial, oxidative phosphorylation, mitoribosome, and differentiationpathways (Fig. 8 Panel C cluster 3, 7 and 9, Fig. 9 cluster 4). Protein sets primarily responsive to Sotorasib include upregulation of mitochondrial ATP synthesis, and changes to glycine, serine and threonine metabolism pathway proteins, consistent with the observed metabolic and metabolomic differences observed between WT and Sotorasib resistant cell lines (Fig. 8 Panel C cluster 8, Fig. 9 cluster 5). Finally, clusters representing proteins that change only in response to the combination treatment are enriched for nucleoside metabolism, ER membrane, and gene expression (upre, DNA replication (downregulated, Fig. 8 Panel C cluster 4). To further elucidate the effects of ZBTB11 on mitochondrial proteins, proteins downregulated in JWJ-01- 306 treatment conditions were evaluated and compared to the mitocarta 3.0 database of mitochondrial proteins (Fig. 10 Panel A). Significant overlap was observed (592 proteins day 5, 554 proteins day 3), in each condition with mitochondrial proteins. ZBTB11 was confirmed to be downregulated in JWJ-01-306 treated samples (Fig 10 Panel B) alongside a subset of ZBTB11 downstream proteins (NDUFS7, NDUFA12, NDUFC2, NDUFAF1, MRPL48, MRPL44, MRPL1, MRPL30, Fig 10 Panel B). K-Ras levels were also reduced in the 5 d samples in response to JWJ-01-306 but not Sotorasib (Fig. 10 Panel B).[00134J To evaluate the impact of ZBTB11 degradation and consequent downstream proteome changes alter OXPHOS levels, parental and Sotorasib -resistant MiaPaCa-2 cells were treated with 10 pM JWJ-01-306, JWJ-01-334 or JWJ-01-368 and performed a mitochondrial stress test at the 24 hr time point (Fig. 11 Panel A, Fig. 12 Panel A). Statistically significant reductions in basal and maximal oxidative phosphorylation were observed (one-way ANOVA P < 0.005) in cells treated with JWJ-01-306 but not JWJ-01-334 or JWJ-01-368. Changes in the metabolic index (OCRZECAR ratio) were also observed in cells treated with JWJ-01-306 but not JWJ-01-334 or JWJ-01-368, reflecting the greater reduction in OXPHOS (Fig. 11 Panel B, Fig. 12 Panel B). Finally, these experiments were repeated in parent and resistant MRTX1133- resistant SUIT2 cells, and also observed JWJ-01-306-dependent reductions in basal, maximal and mitoATP / glycoATP ratios, that were rescued by the control compounds (Fig. 11 Panels C-D, Fig. 12 Panels D-E). To confirm these effects are specific to ZBTB11 degradation, full length ZBTB 11WT(control) or ZBTB11K866Twas stable expressed in Sotorasib-resistant MiaPaCa-2 cells, followed by treatment with 10 pM JWJ-01-306, and performed a mitochondrial stress test after 24 hrs of drug treatment (Fig. 11 Panel E). Complete rescue of oxidative phosphorylationand restoration of the OCR / ECAR ratio by the ZBTB11K866Tmutant relative to WT control was observed (Fig. 11 Panels E-F).

[0135] To identify how mitoribosome and Complex I genes downstream of ZBTB11 are directly altered by ZBTB11 degraders to effect the observed proteomic and metabolic changes, qPCR was performed in parent and Sotorasib-resistant MiaPaCa-2 cells treated with 10 pM JWJ- 01-306, JWJ-01-334 or JWJ-01-368 for 24 hrs. Here, downregulation of transcripts was observed by JWJ-01-306 but not negative controls JWJ-01-334 or JWJ-01-368 (Fig. 11 Panel G, Fig. 12 Panel C). These results were confirmed in matched experiments in parent and MRTX1133 resistant SUIT2 cells (Fig. 12 Panels F-G). To confirm these effects are specific to ZBTB11 degradation, Sotorasib-resistant MiaPaCa-2 cells that stably expressed ZBTB 1 1WT(control) or ZBTB11K866Twere treated with 10 pM JWJ-01-306 for 24 hrs and assessed levels of relevant downstream transcripts by qPCR. Here, complete rescue of transcript loss by the degradationresistant ZBTB11K866Tmutant for 7 / 8 downstream genes, and partial rescue of MRPL1 (Fig. 11 Panel H) was observed. Finally, effects of ZBTB11 degraders on ZBTB11 and K-Ras transcript levels were examined, where compensatory upregulation of ZBTB11 was observed in the presence of JWJ-01-306 but not negative controls JWJ-01-334 and JWJ-01-368 in parent and resistant Mia PaCa-2 cells and SUIT2 cells (Fig. 12 Panels C, F, G, H). Varied effects on K-Ras transcript levels were observed, indicating that K-Ras transcription is not endogenously regulated by ZBTB11 (Fig. 12 Panels C, F, G, H).

[0136] To identify the metabolic pathway alterations that mediate the effects of ZBTB11 degradation on cellular respiration, metabolomics on Sotorasib-resistant MiaPaCa-2 cells labeled with13C Glc or13C Gin and treated with 10 pM JWJ-01-306 for 24 hrs (Fig. 11 Panels I- J, Dataset 5) was performed. Metabolite set enrichment analysis revealed significant JWJ-01-306 induced changes consistent with reduced OXPHOS, including in the TCA cycle and pyruvate metabolism (Fig. 11 Panel I). Manual examination of key metabolites associated with these pathways confirmed the expected JWJ-01-306-dependent decreases in citric acid, glutamic acid and pyruvic acid and increased malic acid (Fig. 11 Panel J).

[0137] Having established the mechanism-of-action of JWJ-01-306, it was next sought to compare ZBTB11 degradation to Complex I inhibition in human models of neuronal health. Theprimary safety liability of OXPHOS-targeting drugs are toxic effects on neurons, which rely heavily on mitochondrial metabolism to sustain their bioenergetic needs.27These effects often go unnoticed in murine studies, due to species differences between the human and murine nervous system, and challenges with accurately measuring neuropathy in mice.46Furthermore, molecular glue degraders often have different target profdes in murine and human systems due to sequence differences in both CRBN and the targets that alter the induced protein-protein interaction interface47'49. To overcome these limitations, and provide an early readout of the disclosed ZBTB11 degraders propensity to cause drug-induced neuropathy, the neurotoxicity of ZBTB11 degraders was profiled using a suite of assays developed in human induced pluripotent stem cell (hiPSC)-derived neurons?0'53Neuronal viability, morphology, and mitochondrial function was monitored, demonstrating that iPSC-derived neurons exposed to 1 pM IACS-010759 for 24 hrs exhibit significantly decreased mitochondrial membrane potential (MMP) and increased reactive oxygen species (ROS), consistent with inhibition of mitochondrial complex I and reported adverse events in clinical trials (Fig. 13 Panel A). Following a 72 hr 1 pM IACS-010759 treatment, neurite length and neuronal survival were also decreased (Fig. 13 Panel B). In contrast, 1 pM JWJ-01-306, showed minimal effects on all phenotypes assayed (Fig. 13 Panels A-B). Together these results show the instant panel accurately identifies neurotoxic compounds targeting mitochondrial function and demonstrate ZBTB11 degradation has reduced acute neuronal toxicity in vitro relative to complex I inhibition.

[0138] In the instant disclosure, molecular glue degraders of the transcription factor ZBTB11 are disclosed. By generating a comprehensive set of chemical and genetic tools, ZBTB11 -governed metabolic networks were identified in human PDAC. In contrast to existing OXPHOS inhibitors, most of which are thought to target Complex I-V enzymatic activity, JWJ- 01-306 directly targets the transcriptional upregulation of OXPHOS genes associated with cancer drug resistance. It was demonstrated that pharmacological degradation of ZBTB11 counters this metabolic reprogramming associated with acquired resistance to K-Ras inhibitor in multiple ex vivo models of PDAC, identifying ZBTB11 as a druggable therapeutic vulnerability in PDAC.

[0139] A major limitation for targeting aberrant OXPHOS are the neurotoxic side effects of Complex I inhibition, observed as on-target adverse events in clinical trials and later in focused murine studies.27Using human iPSC-derived neuronal models, it was demonstrated thatZBTB11 degradation had minimal effects on neuronal viability and function at phenotypically relevant time points (3d), in contrast to Complex I inhibitor IACS-010759. While comprehensive studies in in vivo mammalian models at extended time points will be critical for establishing the preclinical therapeutic window of ZBTB11 degradation in PDAC, this disclosure marks a critical milestone by identifying a mechanistically orthogonal therapeutic strategy for targeting high OXPHO S cancer states.

[0140] The instant patient-derived organoid study demonstrated that concurrent K-Ras and ZBTB11 blockade deepens responses to K-RasG12Dinhibition in patient-derived PDAC organoids that had not been previously treated with MRTX1133, including in the multi-drug resistant PDAC line hMlE. ZBTB11 degradation may therefore have applications in other cancers that upregulate OXPHOS to drive resistance to therapeutic interventions, including chemotherapies55'57, anti -angiogenic therapies58, and targeted therapies such as inhibition of BCL259, tyrosine kinases60, and BRAF61. It is anticipated that the instant suite of chemical and genetic tools will accelerate efforts to map ZBTB11 sensitive cancer cell states and identify additional tumor types where ZBTB11 depletion can address cancer drug resistance.

[0141] Example 5 - ZBTBl l-HiBiT Degradation in MOLTA Cell Characterization of Additional Compounds

[0142] Compounds provided herein were assessed for their ability to degrade HiBiT- tagged ZBTB11 endogenously expressed by modified MOLT-4 cells according to the methods described herein. Results from these assays are shown in the table below. In the table below, DCso refers to the half-maximal degradation concentration; Dmax refers to the maximum fraction of ZBTB11 degradation; and DCmaxrefers to the concentration at which maximum degradation was observed.

[0143] Example 6 - Materials and Methods

[0144] The protocols below were used to generate the data and figures described herein in the previous examples.

[0145] Cell culture. MIA PaCa-2 and HEK293 cells were cultured in DMEM (Corning&10-017-CM) supplemented with 10% fetal bovine serum (FBS; Gibco #A5256701) and 1% penicillin / streptomycin (P / S; Corning &30-002-CI) in a 37 °C incubator with 5% CO2. Wildtype and Crbn- / - MOLT-4, Jurkat, and SUIT-2 cells were cultured in RPMI1640 (Corning #10-040-CM) supplemented with 10% FBS and 1% penicillin / streptomycin in a 37 °C incubator with 5% CO2. All cell lines were tested for mycoplasma contamination using the MycoAlert PLUS Mycoplasma Detection Kit (Lonza #LT07-710). IKZFl-HiBiT and GSPTl-HiBiT Jurkat knock- in cell lines were a generous gift from Dr. Nathanael Gray (Stanford University).

[0146] Organoid culture. Patient-derived organoids were maintained in complete human feeding medium in a 37 °C incubator with 5% CO2. The protocol to propagate and sustain organoid cultures was described previously.1’2

[0147] Generation of ZBTBll-HiBiT cell lines. The HiBiT tag3(VSGWRLFKKIS) was introduced into the C-terminus of ZBTB11 in its endogenous gene locus in MOLT-4 and MIA PaCa-2 cells via CRISPR / Cas9 editing. Alt-R™ CRISPR RNA (crRNA) and transactivating CRISPR RNA (tracrRNA) (Integrated DNA Technologies; IDT) were resuspended in nuclease-free duplex buffer (IDT #11-05-01-12) at a final concentration of 100 pM. Equal volumes of crRNA and tracrRNA were mixed and heated for 5 min at 95°C. After heating, the complex was cooled to room temperature and then incubated for 20 min with Alt-R™ S.p. HiFi Cas9 Nuclease V3 (IDT # 1081060) to form the ribonucleoprotein (RNP) complex. Subsequently, the double-stranded DNA HDR template to append the HiBiT tag, the RNP complex, and Alt-R™ Cas9 Electroporation Enhancer (IDT #1075916) were electroporated into cells using a Neon™ Transfection System (Thermo Scientific #MPK5000). Cells were seeded into media containing Alt-R™ HDR Enhancer V2 (IDT #10007910). Single cells were then isolated via FACS sorting, and HiBiT expression from individual clones was measured using the Nano-Gio® HiBiT Lytic Detection System (Promega #N3040) on a ClarioSTAR Plus microplate reader (BMG LabTech) with NanoLuc® module (470 nm with 80 nm bandpass). Correct insertion of the HiBiT tag into the genome of the knocked-in cells was confirmed by sequencing. DNA HDR template and guide RNA sequences are detailed in Supplementary Table 1.

[0148] Generation of K-Rasi-resistant PDAC cell lines. MIA PaCa-2 ZBTB11 -HiBiT cells were cultured in stepwise increasing concentrations (5 nM to 10 pM) of sotorasib (MedChemExpress #HY-114277) to afford the MIA PaCa-2 AMG510R cell lines. SUIT-2 MRTXR cell lines resistant to MRTX1133 (MedChemExpress #HY-134813) were generatedpreviously4. MIA PaCa-2 AMG510R and SUIT-2 MRTXR cell lines were maintained in appropriate media supplemented with 10 pM of sotorasib or MRTX1133.

[0149] Cell viability. MIA PaCa-2 and SUIT-2 cells were resuspended to 1 x 103cells in 50 pl of complete growth medium and plated in solid white 384-well tissue culture plates (Corning #3570). Adherent cells were incubated for 24 h to allow for cell adhesion and recovery. Compounds were dispensed in dose response as indicated using a D300e Digital Dispenser (Tecan #30100152). Cells were incubated for 3 days, and endpoint viability was measured with CellTiterGlo® Luminescent Cell Viability Assay (Promega #G7572) on a ClarioSTAR Plus microplate reader with NanoLuc® module.

[0150] ZBTBll-HiBiT degradation assay. Cells with endogenously HiBiT-tagged ZBTB11 were resuspended to 1 * 104cells in 50 pl of complete growth medium and plated in solid white 384-well tissue culture plates. Adherent cells were incubated for 24 h to allow for cell adhesion and recovery. Compounds were dispensed in dose response as indicated using a D300e Digital Dispenser. Cells were incubated for the indicated amount of time, and endpoint HiBiT luminescence was measured with the Nano-Gio® HiBiT Lytic Detection System on a ClarioSTAR Plus microplate reader with NanoLuc® module.

[0151] CRBN engagement assay. The NanoBRET™ TE Intracellular E3 Ligase Assay Kit for CRBN (Promega #N2910) was used to measure CRBN engagement by compounds. Briefly, HEK293 cells were transfected with NanoLuc-CRBN and DDB1 expression vectors using OptiMEM™ I Reduced Serum Medium with no phenol red (Gibco #11058021) and TransIT-2020 Transfection Reagent (Minis Bio #5400). After incubating for 24 h, transfected cells were resuspended to 6.8 x 103cells in 34 pl of OptiMEM™ I Reduced Serum Medium with no phenol red and plated in solid white 384-well tissue culture plates. NanoBRET™ Tracer Reagent and compounds were dispensed in dose response as indicated using a D300e Digital Dispenser. Cells were incubated for 2 h prior to addition of 17 pl of Complete Substrate Plus Inhibitor Solution and subsequent readout on a ClarioSTAR Plus microplate reader with NanoBRET™ module (donor: 460 nm with 80 nm bandpass, acceptor: >610 nm longpass).

[0152] Ternary complex formation assay. A quadruple-zinc finger construct containing human ZBTB11 zinc fingers 9-12 was cloned into the pNLFl-N NanoLuc® ProteinFusion Vector (Promega #N1351). Additionally, full length human CRBN was cloned into the pHTC HaloTag® CMV-neo Vector (Promega #G7711). Crbn-. - MOLT-4 cells were transfected with both plasmid vectors using a Neon™ Transfection System. Following a two-day recovery period, transfected cells were subjected to dual hygromycin B (Gibco #10687010) and G418 (Gibco #10131035) selection for seven days to yield a stable NanoBRET™ expression cell line. NanoBRET™ MOLT-4 cells were resuspended to 1x104cells in 50 pl of OptiMEM™ I Reduced Serum Medium with no phenol red and plated in solid white 384-well tissue culture plates. Carfdzomib (MedChemExpress #HY-10455) and the HaloTag® NanoBRET™ 618 Ligand were dispensed to a final concentration of 100 nM using a D300e Digital Dispenser. After a 1 h pre-incubation, compounds were dispensed in dose response as indicated using a D300e Digital Dispenser. Cells were incubated for 5 h, and endpoint signals were measured with the NanoBRET™ Nano-Gio® Detection System (Promega #N1662) on a ClarioSTAR Plus microplate reader with NanoBRET™ module.

[0153] ZBTB11 ZF fingerprinting and mutagenesis. Full length human ZBTB11, or select portions of its tandem zinc finger domains, were cloned into the pNLFl-N NanoLuc® Protein Fusion Vector. QuikChange Site-Directed Mutagenesis Kit (Agilent #200519) was used to introduce ZBTB11 K866T and T659K mutations. MOLT-4 and MIA PaCa-2 cells were transfected with NLuc-ZBTBl l fusion protein vectors using a Neon™ Transfection System. Following a two-day recovery period, transfected cells were subjected to hygromycin B selection for seven days to yield stable NLuc-ZBTBl l expression cell lines. Cells were resuspended to 1 x 104cells in 50 pl of complete growth medium and plated in solid white 384-well tissue culture plates. Adherent cells were incubated for 24 h to allow for cell adhesion and recovery. Compounds were dispensed to a final concentration of 1 pM for ZF fingerprinting or in dose response as indicated for full length ZBTB11 studies using a D300e Digital Dispenser. Cells were incubated for 5 h, and endpoint NLuc luminescence was measured with the Nano-Gio® Luciferase Assay System (Promega #N1120) on a ClarioSTAR Plus microplate reader with NanoLuc® module. Plasmids encoding NanoLuc-ZBTBl 1WTand NanoLuc-ZBTBl 1K866Thave been deposited in Addgene.

[0154] Cell growth over time. MIA PaCa-2 cells were resuspended to 5 x 104cells in 1 ml of complete growth medium and plated in clear 12-well tissue culture plates (Corning #3506).Cells were then treated with DMSO, sotorasib (1 pM), JWJ-01-306 (10 pM), or sotorasib + JWJ- 01-306. Viable cells were passaged and quantified by trypan blue exclusion (Invitrogen T10282) twice weekly using a Countess 3 Automated Cell Counter (Invitrogen #AMQAX2000).

[0155] Patient-derived organoids (PDOs) and SUIT-2 cells were resuspended to 5 x 103cells in 400 pl of complete growth medium and plated in clear 48-well tissue culture plates (Corning #3548). Cells were then treated with DMSO, MRTX1133 (0.5 pM), JWJ-01-306 (10 pM), or MRTX1133 + JWJ-01-306 using a D300e Digital Dispenser and placed into a Cellcyte X live cell analyzer (Cytena) within a 37 °C incubator with 5% CO2. Four phase contrast images of each well were collected at 6-hour intervals with a 10X objective lens. The percentage of cell confluence within each well was determined at all time points using Cellcyte X analysis software according to the manufacturer’s instructions.

[0156] Generation of inducible CRISPRi cell lines. MIA PaCa-2 ZBTB11-HiBiT cells were transduced with lentiviruses to introduce Tet-On 3G-Neo, TRE-dCas9-KRAB-mCherry, and sgRNA-BFP-Puro (nontargeting or against ZBTB11; see Supplemental Table 1). Following transduction, cells were sorted for mCherryhlgh / BFPhl8hexpression and selected with 500 pg / ml G418 and 5 pg / ml puromycin. CRISPRi cells were then maintained in complete growth media supplemented with 200 pg / ml G418 and 2 pg / ml puromycin. CRISPRi-mediated knockdown was induced by treatment with 500 ng / ml doxycycline as indicated.

[0157] Western blot. Cells were lysed in M-PER buffer (Thermo Scientific #78501) containing cOmplete™ Mini protease inhibitor (Roche #04693124001) and PhosSTOP phosphatase inhibitor (Roche #04906837001). After assessing protein concentration by the Pierce BCA assay (Thermo Scientific #23225), equal amounts of protein for each sample were loaded onto NuPage 4-12% Bis-Tris gels (Invitrogen #NP0323BOX), transferred to nitrocellulose membranes (Bio-Rad #1620112), and immunoblotted with antibodies against ZBTB11 (Bethyl Labs #A303-239A) or actin (CST #3700S). ZBTB11-HiBiT signal was detected using the Nano-Gio® HiBiT Blotting System (Promega #N2410). Membranes were detected on an Odyssey CLXdetection system (LI-COR Biosciences) after incubation with IRDye®800-labeled goat anti-rabbit IgG (LI-COR # 926-32211) and IRDye®680-labeled goat anti-mouse IgG (LI-COR #926-68070) secondary antibodies.

[0158] Quantitative PCR. Total RNA was extracted from cells using the Uzc'#-RNA MiniPrep kit (Zymo Research #R1055), and cDNA was generated using the SuperScript IV Reverse Transcriptase kit (Invitrogen #18090050). Quantitative PCR was performed on a 7900HT Fast Real-Time PCR System (Applied Biosystems #4329001) using Power SYBR Green PCR Master Mix (Applied Biosystems #4368706), and transcript levels were normalized to RPL13A. Primer sequences are detailed in Supplemental Table 1.

[0159] Seahorse assay. MIA PaCa-2 and SUIT-2 cells were resuspended to 5 x io4cells in 100 pl of complete growth medium supplemented with 10 pM of sotorasib or MRTX1133 for K-Rasz-resistant cells and plated in Seahorse XF24 V7 PS Cell Culture Microplates (Agilent #100777-004). Adherent cells were incubated for 24 h to allow for cell adhesion and recovery. Cells were incubated with compounds for 24 h prior to wash and replacement with Seahorse XF DMEM medium, pH 7.4 (Agilent #103575-100) supplemented with 10 mM Seahorse XF glucose, 1 mM Seahorse XF pyruvate, and 2 mM Seahorse XF glutamine (Agilent #103577-100, #103578-100, #103579-100). Mitochondrial stress tests were performed on a Seahorse XFe24 analyzer (Agilent) according to the manufacturer’s instructions. Oxygen consumption and extracellular acidification rates were measured under basal conditions and in response to sequential treatment with oligomycin (16 pM), BAM15 (22.5 pM), and rotenone / antimycin A (10 pM each).

[0160] Metabolomics. Cells were resuspended to 5 x io5cells in 1 ml of complete growth medium supplemented with 10 pM sotorasib or MRTX1133 (as appropriate for K-Rasz- resistant cells) and plated in clear 6-well tissue culture plates (Corning #3506). Adherent cells were incubated for 24 h to allow for cell adhesion and recovery. Cells were treated with compounds for 24 h prior to labeling with13C-labeled glucose or glutamine for an additional 24 h in the presence of K-Rasz and compound treatment. For13C-glutamine labeling: MEM containing 1 g / 1 glucose and no glutamine (Coming #15-010-CV) was supplemented with 1 g / 1 unlabeled glucose (Gibco #A24940-01), 1 mM unlabeled glutamine (Gibco #25030-149), 1 mM13C5-glutamine (Sigma-Aldrich #605166), 1% MEM non-essential amino acids (NEAA), 10% FBS, and 1% P / S. For13C-glucose labeling: MEM containing 1 g / 1 glucose and no glutamine was supplemented with 1 g / 113C6-glucose (Sigma-Aldrich #389374), 2 mM unlabeled glutamine, 1% NEAA, 10% FBS, and 1% P / S. After treatment, cells were washed three times with cold PBSand extracted with ice-cold 50% methanol / HzO containing 20 pM L-norvaline, and subsequent addition of chloroform, mixing by vortex, and centrifugation at 21,000 g for 5 min at 4 °C. The upper polar phase was transferred to a separate tube and dried in a Speedvac, derivatized with isobutylhydroxylamine (20 mg / ml solution in pyridine), and mixed with N-tert- Butyldimethylsilyl-N-methyltri fluoroacetamide.

[0161] Samples and standards were analyzed by GC-MS using an TG-SQC column (15 m x 0.25 mm x 0.25 pm, Thermo Scientific) installed in a Thermo Scientific TSQ 9610 GC- MS / MS. The GC was programmed with an injection temperature of 300°C and a 0.5 pl splitless injection. The GC oven temperature was initially 130°C for 4 min, rising to 250°C at 6°C / min, and to 310°C (280°C for serum) at 60°C / min with a hold at the final temperature for 2 min. GC flow rate with helium carrier gas was 50 cm / s. The GC-MS interface temperature was 300°C and (electron impact) ion source temperature was 200°C, with 70 eV ionization voltage. Standards were run in parallel with samples. Metabolites in samples and standards were detected by MS / MS using precursor and product ion masses, and collision energies. Sample metabolites were quantified using calibration curves made from the standards in Chromeleon software (Thermo Scientific), and further data processing to adjust for the relative quantities of metabolites in the standards, and for recovery of the internal standard, were done in MS Excel. Normalized metabolite abundances were then used as inputs into Metab o Analyst5with default settings and KEGG pathways to perform Metabolite Set Enrichment Analysis (MSEA).

[0162] Selectivity profiling proteomics. MIA PaCa-2 cells were resuspended to 1 x 106cells in 1 ml of complete growth medium and plated in clear 6-well tissue culture plates. Adherent cells were incubated for 24 h to allow for cell adhesion and recovery. Cells were treated with compounds for 5 h prior to harvest and lysis in M-PER buffer containing cOmplete™ Mini protease inhibitor by sonication. Equal volumes of cell lysate and SDS protein solubilization buffer (10% SDS, 100 mM triethylammonium bicarbonate (TEAB), pH 7.55) were mixed and reduced by incubation with 5 mM tris-(2-carboxyethyl)-phosphine (TCEP) for 30 min at room temperature (RT). Subsequent alkylation was performed by adding 15 mM chloroacetamide (CAA) and incubating for 30 min at RT. Phosphoric acid was added to a final concentration of 1.2%, followed by six volumes of binding buffer (90% methanol; 100 mM TEAB, pH 7.1). After gentle mixing, the colloidal protein solution was loaded onto a S-Trapmicro column (Protifi #C02-micro-10) and centrifuged 1500 g for 2 min. The columns were washed with binding / wash buffer (100 mM TEAB in 90% MeOH) four times and sequencinggrade trypsin (Protnega #V5l 1 1) in digestion buffer (100 mM TEAB) was added in 1 :10 (w / w) ratio. Proteins were digested on-column for 3 h at 47 °C. Peptides were eluted by a step-wise elution method using 50 mM TEAB, pH 8.5, followed by 0.2% formic acid (FA) in HrO, and finally 50% acetonitrile (ACN) / 0 2% FA in H2O. Eluted peptides were then vacuum dried before further processing

[0163] Prior to LC-MS / MS analysis, dried peptides were reconstituted in 2% ACN / 0.1% FA in H2O and concentration was determined using a NanoDrop™ spectrophotometer (Thermo Scientific). Samples were then analyzed by LC-MS / MS using a Proxeon EASY-nanoLC system (Thermo Scientific) coupled to a Orbitrap Fusion Lumos Tribid mass spectrometer (Thermo Scientific) equipped with FAIMS. Peptides were separated using an analytical C18 Aurora column (75pm x 250 mm, 1.6 pm particles; lonOpticks) at a flow rate of 300 nL / min (60°C) using a 120-min gradient: 0% to 6% B in 1 min, 6% to 23% B in 78 min, 23% to 34% B in 30 min, and 34% to 50% B in 1 min (A= 0.1% FA in H2O; B= 0.1% FA / 80% ACN in H2O).

[0164] The mass spectrometer was operated in positive data-independent acquisition mode with the following settings: 120,000 resolution, 350-2000 m / z scan range, injection time set at auto, FAIMS CV at -40 and AGC target of 4 * 105for MSI scan. MS2 scans were acquired at a resolution of 30,000 using the following settings: precursor range of 400-100 m / z, isolation window at 8 m / z with Im / z overlap, giving 75 windows. Fragmentation was done using HCD collision energy of 30% and AGC target at 800% and maximum injection time at 54 ms.

[0165] Time-course proteomics. The protein extraction followed a previously established protocol6. Briefly, cells were harvested and washed with cold PBS three times. Then, cell pellets were homogenized in lysis buffer (8 M urea, 50 mM Tris, pH 7.4) supplemented with protease inhibitor. The homogenate underwent sonication using a probe sonicator, and protein concentration was determined using a BCA Protein Assay Kit (Thermo Pierce, Rockford, IL) according to the manufacturer's instructions. Subsequently, samples were reduced with 10 mM DTT for 30 minutes, at 56°, and alkylated with 40 mM IAA for 30 minutes in darkness at room temperature. Lysates were diluted four-fold, and proteins were digested with trypsin at 37°C for16 hours using a 50:1 (protein: enzyme) ratio, followed by quenching by lowering the pH to <3 with 10% TFA. Peptides were purified using SepPak Cl 8 solid-phase extraction (SPE) cartridges (Waters, Milford, MA) and dry-down, then stored at -80° before run on LC-MS / MS. All the samples were analyzed on a timsTOF Pro 2 (Bruker) coupled to a EvosepOne LC system (Evosep) using the dia-PASEF method as previously described7.

[0166] Proteomics data analysis and statistics. Protein identifications and quantifications were performed using DIA-NN 1.8.1sagainst the Uniprot Homo sapiens reviewed database (November 2023). “FASTA digest for the library-free search” and “Deep learning-based spectra, RTs, and IMs predication” were enabled. Oxidation of methionine residues (+0x(M)), carbamidomethylation of cysteine residues (C carbamidomethylation), and N-terminal acetylation (Ac(N-term)) were set as modifications. Search results underwent filtering to achieve a 1% FDR at both peptide and protein levels, with a mass tolerance of lO p.p.m. for the most confident centroid. The Protein. Group column in DIA-NN’s report was used for quantification. In brief, the protein intensities were normalized by sum and transformed to log2. Missing intensity was filtered. Two-sample moderated t-test with a two-tailed distribution for binary comparison and one-way ANOVA analysis was conducted for multiple group comparisons using the Umma package in R. Bioinformatics analyses including hierarchical clustering, box plots, volcano plots, and gene function annotation were performed using R packages.

[0167] Pharmacokinetics. A single dose of JWJ-01-306 formulation (5% DMSO / 20% Solutol® HS 15 / 0.9% NaCl) was administered intravenously at 2 mg / kg or intraperitoneally at 10 mg / kg into male C57BL / 6J mice (n = 3 for each method). Plasma was extracted from each mouse after indicated time and JWJ-01-306 in plasma was quantified by LC-MS / MS analysis.

[0168] Plasma protein binding. A Rapid Equilibrium Dialysis (RED) device (Thermo Scientific #90006) was used to perform the plasma protein binding assay. Briefly, phosphate- buffered saline (PBS) and plasma were loaded into buffer and plasma wells; respectively. JWJ- 01-306 was added to the plasma to final concentrations of 0.1 pM and 1 pM, and the RED device was incubated on an orbital shaker for 4.5 h at 37 °C. Standards for reference compound warfarin and for JWJ-01-306 were prepared in a separate clear 96-well plate by mixing equalvolumes of PBS and plasma, followed by serial 10-fold dilution of 10 pM compound. Following incubation of the RED device, standards and RED device samples were transferred into a separate clear 96-well plate for extraction with ACN / H2O solution containing indomethacin. The extraction plate was mixed thoroughly for 10 min and centrifuged 4000 RPM for 10 min at 4 °C. Supernatant was collected and analyzed by LC-MS / MS.

[0169] Neurotoxicity screening. For mitochondrial and morphology assays, hiPSC derived neurons (Fuji Film Cellular Dynamics International (FFCDI)) were plated at 3000 cells / well in 384-well imaging plate. Compounds were tested for effects on mitochondrial membrane potential and reactive oxygen species (ROS) generation in a multiplexed, live cell assay based on the potentiometric dye TMRE (Thermo Fisher), the ROS sensor CellRox (Thermo Fisher), the mitochondrial dye Mitotracker Green (Thermo Fisher), and the nuclear stain Hoechst , as a readout for detecting blockers of the electron transport chain. Cells were exposed to compounds for 24 h in a 7-point dose response in triplicate followed by Hoechst stain and imaging. Menadione, which decreases TMRE and increases CellRox, but has minimal effects on MitoTracker, was included as a control on every plate. Compounds were also tested in 7-point dose response in triplicate for effects on neurite growth and cell viability after a chronic 3-day exposure and staining with the neuronal marker TuJl and the nuclear stain Hoechst. The control compounds staurosporine, which induces neurite growth at low concentrations and is toxic at high concentrations, and BIO, which induces neurite retraction, were included as controls on every plate. For both mitochondrial and morphology assays, 9 fields (typically -1000 cells) were acquired per well at 20X magnification on the Phenix High Content Screening System (Perkin Elmer). Images were transferred to the Columbus Database (Perkin Elmer) and analyzed using optimized algorithms based on Acapella software (Perkin Elmer). For the mitochondrial assay, intensity of TMRE, CellRox, and Mitotracker stains were quantified; for the neurite morphology assay, primary neurite number, length and branching were determined. For both assays, cell viability was assessed based on nuclear number, intensity of Hoechst stain (as a measure of chromosome condensation), and nuclear size and shape. All measures were expressed as average values / well.

[0170] Ternary complex modeling. A homology modeling approach was taken to generate a model of the CRBN:JWJ-O1-3O6:ZBTB11 ZF 10 ternary complex. TheCRBN:pomalidomide:IKZFl ZF2 complex was extracted from RCSB PDB entry 6H0F9. In the absence of any experimentally determined structure of ZBTB11 (at the time of writing), ZBTB11 ZF10 was extracted from the ZBTB11 structure predicted by AlphaFold210(AFDB accession AF-O95625-F1). Using PyMOL command line, ZBTB11 ZF10 and JWJ-01-306 were structurally aligned with IKZF1 ZF2 and pomalidomide; respectively. Following alignment, IKZF1 ZF2 and pomalidomide were removed, and the initial pose was prepacked using the docking prepack application within the Rosetta modeling suite (release 2021.16.61629). Ligand conformers for JWJ-01-306 were generated using RDKit (release 2024.03.01) and were converted to params files using the convert_mol_to_params python script provided within Rosetta. The prepacked initial pose and the ligand params files were then used as inputs to the Rosetta relax application for conservative conformational searching, sidechain rotamer optimization, and overall energy minimization. 1000 structures were generated and clustered by Rosetta energy based clustering. Batch scripts for prepacking, relaxing, and clustering structures, as well as top ten scoring structure clusters, can be found in Source Data.References for Materials and Methods1 Tiriac, H. et al. Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8, 1112-1129, doi: 10.1158 / 2159-8290. CD-18-0349 (2018).2 Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324-338, doi:10.1016 / j.cell.2014.12.021 (2015).3 Schwinn, M. K. et al. CRISPR-Mediated Tagging of Endogenous Proteins with a Luminescent Peptide. ACS Chem Biol 13, 467-474, doi:10.1021 / acschembio.7b00549 (2018).4 Gulay, K. C. M. et al. Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma. Cancer Res 83, 3001-3012, doi: 10.1158 / 0008- 5472.CAN-23-1313 (2023).5 Ewald, J. D. et al. Web-based multi-omics integration using the Analyst software suite. Nat Protoc, doi :10.1038 / s41596-023-00950-4 (2024).6 Ma, M. et al. Proteome-wide Profiling of Asymmetric Dimethylated Arginine in Human Breast Tumors. J Am Soc Mass Spectrom 34, 1692-1700, doi:10.1021 / jasms.3c00154 (2023).7 Tao, A. J. et al. A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ. Nat Commun 14, 8016, doi:10.1038 / s41467-023-43507-5 (2023).8 Demichev, V., Messner, C. B., Vernardis, S. I., Lilley, K. S. & Raiser, M. DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat Methods 17, 41-44, doi:10.1038 / s41592-019-0638-x (2020).9 Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, doi:10.1126 / science.aat0572 (2018).10 Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583-589, doi:10.1038 / s41586-021-03819-2 (2021).

[0171] Example 7- Compound Synthesis

[0172] Unless otherwise noted, reagents and solvents were obtained from commercial suppliers and were used without further purification. 'H and13C NMR spectra were recorded on 500 MHz JEOL ECA spectrometer or 400 MHz Varian Mercury Plus spectrometer and chemical shifts are reported in parts per million (ppm, 6) downfield from tetramethylsilane (TMS). Coupling constants (J) are reported in Hz. Spin multiplicities are described as s (singlet), br (broad singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Mass spectra were obtained on a Waters Acquity UPLC / MS. Preparative HPLC was performed on a Waters Sunfire C18 column (19 mm x 50 mm, 5 pM) using a gradient of 15-95% methanol in water containing 0.05% trifluoroacetic acid (TFA) over 22 min (28 min run time) at a flow rate of 20 mL / min. Assayed compounds were isolated and tested as TFA salts. Purities of assayed compounds were in all cases greater than 95%, as determined by reverse-phase HPLC analysis.3 -(3 -Bromo-2, 5 -dioxo-2, 5 -dihydro- I / / -pyrrol - 1 -yl)piperidine-2, 6-dione

[0173] A solution of glycinamide hydrochloride (1.7 g, 15.3 mmol, 1.5 eq.), maleic anhydride (1.0 g, 10.2 mmol, 1.0 eq.) and KOAc (1.5 g, 15.3 mmol, 1.5 eq.) in acetic acid (20 mL) was stirred for 4 h at reflux temperature (110 °C). After the reaction mixture was cooled to rt, chilled NaHCCh solution was added, and the product was extracted with DCM twice. The result organic phase was washed with brine. After drying over anhydrous MgSO4, the organic solvent was removed on vacuum and the residue was purified by silica gel column chromatography, which provided the title compound as a beige solid (1.3 g, 72% yield).!H NMR (500 MHz, DMSO-r / c,) δ 11.12 (s, 1H), 7.58 (s, 1H), 5.04 (dd, J= 13.1, 5.4 Hz, 1H), 2.83 (ddd, J= 17.3, 13.9, 5.5 Hz, 1H), 2.57 (dt, J= 3.5 Hz, 1H), 2.40 (qd, J= 13.3, 4.5 Hz, 1H), 2.01 (dtd, J= 13.1, 5.5, 2.8 Hz, 1H).3 -(3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-l-yl)-l-methylpiperidine-2, 6-dione

[0174] The maleimide intermediate (25 mg, 0.087 mmol), triphenylphosphine (27 mg, 0.11 mmol) and MeOH (7.1 pL, 0.17 mmol) were dissolved in dry THF (2 mL) in 8 mL scintillation vial. DIAD (20 pL, 0.11 mmol) was added to the reaction mixture dropwise at rt. The resulting yellow solution was further stirred for Ih before being quenched with EtOAc (25 mL) and DI water (25 mL). The aqueous layer was further extracted with EtOAc (25 mL) once. The combined organic layer was washed with brine and dried over anhydrous MgSO4. The organic solvent was removed on vacuum and the residue was subjected to column chromatography to obtain the A-methyl-maleimide compound (13 mg, 50%).rH NMR (400 MHz, DMSO-d6) 8 7.60 (d, J= 3.3 Hz, IH), 5.10 (dddd, J= 13.3, 5.2, 3.2, 1.7 Hz, IH), 2.99 (d,2.8 Hz, 3H), 2.90 (dddd, J= 16.8, 13.9, 5.5, 2.7 Hz, IH), 2.78-2.70 (m, IH), 2.42 (dtd, J = 17.6, 8.5, 7.6, 5.2 Hz, IH), 2.02 (dtd, J= 13.3, 5.4, 2.9 Hz, IH)1 -(3 -bromophenyl )cy clobutane- 1 -carbonitrile

[0175] A solution of 2-(3-bromophenyl)acetonitrile (1.0 g, 5.1 mmol) and 1, 3- dibromopropane (1.0 g, 5.1 mmol) in DMSO (10 mL) was added dropwise to a suspension of KOH (1.1 g, 20.4 mmol) in DMSO (10 mL). After stirring at room temperature for 5 h, the reaction mixture was quenched by adding DI water (50 mL). The resulting suspension was further extracted with EtOAc (50 mL) three times. The combined organic layer was dried over anhydrous MgSO4. The organic solvent was removed on vacuum and the residue was subjected to the next step without further purifications. l-(3-bromophenyl)cyclobutane-l-carboxylic acid

[0176] The nitrile intermediate (1.2 g, 5.0 mmol) and KOH (4.0 g, 74 mmol) was suspended in ethylene glycol (30 mL). The suspension was heated turned to 165 °C, which results in a dark orange solution. Upon complete consumption of nitrile monitored by LCMS, the solution was acidified with IM HC1 solution and extracted with EtOAc three times. The combineorganic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure, which provided the title carboxylic acid intermediates without further purification. MS (ESI ) m / z 252.9, 254.9 (M-H)'.1 -(3 -Bromophenyl)cyclopentane-1 -carboxamide

[0177] The acid intermediate (1.1 g, 4.5 mmol) and thionyl chloride (10 mL) was charged to a 40 mL scintillation vial. The mixture was heated to reflux for 1 h. The excess thionyl chloride were then removed under reduce pressure. The residue was re-dissolved in anhydrous DCM and added dropwise to the ice-chilled ammonium hydroxide (2 mL). Upon completion of amidation monitored by LCMS, the solution was neutralized with IM HC1 solution and extracted with EtOAc three times. The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified via flash column chromatography to generate the amide intermediate (902 mg, 76% with 2 steps).!H NMR (500 MHz, Methanol-d4) 6 7.53 (t, J = 1.9 Hz, 1H), 7.37 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 7.34 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 2.82-2.72 (m, 2H), 2.48-2.39 (m, 2H), 1.98-1.91 (m, 1H), 1.82 (dtt, J = 11.3, 8.9, 5.8 Hz, 1H). MS (ESI+) m / z 253.9, 256.0 (M+H)+.1 -(3-bromophenyl)cyclobutan- 1 -amine

[0178] To a solution of amide (902 mg, 3.6 mmol) in MeCN (6 mL) was added [bis(trifluoroacetoxy)iodo]benzene (1.7 g, 3.9 mmol) and water (6 mL) . The mixture was stirred at rt for 18 h. The aqueous phase was basified with 1 M NaOH solution. After diluting with water, the aqueous layer was further extracted with EtOAc twice. The combined organic layer was washed with brine, dried M SO4, concentrated under reduced pressure, which provided the title amine intermediate without further purification (430 mg, 54%). MS (ESI+) m / z 224.0, 226.0 (M+H)+. tert-butyl (1 -(3-bromophenyl)cyclobutyl)carbamate

[0179] To a solution of amine (430 mg, 1.9 mmol) in DCM, BOC2O (498 mg, 2.3 mmol) and TEA (0.4 mL, 2.9 mmol) were added and stirred overnight. Upon complete consumption of amine monitored by LCMS, saturated aqueous NH4Q and DCM were added. The phases were separated, and the aqueous phase was extracted with DCM twice. The combined organic layer was dried over anhydrous MgSCh and concentrated under reduced pressure. The residue was purified via flash column chromatography, which provided the title compound as colorless oil (548 mg, 88%). 'H NMR (500 MHz, Methanol-d4) δ 7.54 (d, J= 2.0 Hz, 1H), 7.39 (dd, J= 7.7, 1.6 Hz, 1H), 7.34 (d, J= 7.8 Hz, 1H), 7.22 (t, J= 7.9 Hz, 1H), 2.44 (ddd, J= 19.5, 14.5, 9.1 Hz, 4H), 2.07 (s, 1H), 1.86 (s, 1H), 1.29 (d, J = 82.8 Hz, 9H). MS (ESI+) m 'z 326.1, 327.9 (M+H)+. tert-butyl (l-(3-aminophenyl)cyclobutyl)carbamate

[0180] To a two-necked round bottom flask equipped with a nitrogen balloon and a septum, the Boc protected intermediate (274 mg, 0.85 mmol), BINAP (105 mg, 0.17 mmol), Pd2(dba)3 (77 mg, 0.084 mmol), CS2CO3 (822 mg, 2.5 mmol), and benzophenone imine (0.16 mb, 0.17 mmol) were charged. Anhydrous 1,4-dixoane (6 mL) was then added and the system was flushed with nitrogen three times. The mixture was heated to 100 °C and stirred overnight. Upon complete consumption of the starting material monitored by LCMS, 50 mL EtOAc was added and filtered through a pad of Celite. The filtrate was saved and washed with brine twice. The organic layer was dried over anhydrous MgSCL, concentrated under reduced pressure, and purified via flash column chromatography, which provided the imine intermediate as lightyellow oil. The imine intermediate was re-dissolved in THF (4 mL) and 1 M HC1 solution (2 mL) was added. After 0.5 h, the mixture was neutralized with saturated NaHCCh solution and extracted with EtOAc twice. The combined organic layer was combined, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified via flash column chromatography, which yielded the title compound as pale-yellow solid (136 mg, 62%).!H NMR (500 MHz, Methanol-t / A 5 7.03 (t, J = 7.8 Hz, 1H), 6.81 (t, J = 2.0 Hz, 1H), 6.76 (dt, J =7.8, 1.3 Hz, 1H), 6.60-6.54 (m, 1H), 2.47-2.30 (m, 4H), 2.01 (d, J = 13.4 Hz, 1H), 1.83 (h, J = 7.8 Hz, 1H), 1.48-1.10 (m, 9H). MS (ESI+) m / z 263.1 (M+H)+.3 -( 1 -aminocy clobutyl)aniline

[0181] The aniline intermediate was dissolved in 2 mL DCM and 0.5 mL TFA, and stirred at rt for 2 h. Upon complete consumption of starting material monitored by LCMS, 20 mL DCM and 20 mL IM NaOH solution were added. The organic solution was dried over anhydrous MgSCh and concentrated under reduced pressure, which provided the title amine compound as light-yellow oil. MS (ESI+) m / z 146.1 (M-NH2+H)+.3-(l-((4-chloro-3-(trifluoromethyl)phenethyl)amino)cyclobutyl)aniline(trifluoromethyl)phenyl)acetaldehyde (0.5 equiv, freshly prepared from the corresponding nitrile and D1BAL-H) were added to a 20 mL scintillation vial. After the addition of 3 mL DCM, the solution was stirred for 0.5 h. NaBH(OAc)? (1.5 equiv) was added and the resulting mixture was further stirred for 1 h. EtOAc and DI water were added. The phases were separated, and the aqueous phase was further extracted with EtOAc once. The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified via flash column chromatography, which provided the title compound as light-yellow oil.3-(3-((3-(l-((4-chloro-3-(trifluoromethyl)phenethyl)amino)cyclobutyl)phenyl)amino)-2,5-dioxo- 2, 5-dihydro-1H -pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-306)

[0183] The reductive amination intermediate (25 mg, 0.068 mmol), 3-(3-bromo-2,5- di oxo-2, 5-dihydro-1H-pyrrol-l-yl)piperidine-2, 6-dione (14 mg, 0.047 mmol), TEA (14 uL) werecharged to a 8 mL scintillation vial. Upon the addition of 1,4-di oxane (1 mL), the mixture was stirred at 65 °C for 12 h. 6 mL EtOAc was added, and the mixture was fdtered through a pad of Celite. The filtrate was collected and concentrated under reduced pressure. The residue was sequentially purified by preparative HPLC, which yielded the title compound as a yellow solid (1.3 mg, 3%) with 99% purity.rH NMR (400 MHz, DMSO-d6) δ 1 1.08 (s, 1H), 9.89 (s, 1H), 9.41 (t, J = 5.8 Hz, 2H), 7.65 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 3.4 Hz, 4H), 7.33 (dt, J = 6.8, 3.8 Hz, 1H), 5.86 (s, 1H), 4.97 (dd, J = 13.0, 5.4 Hz, 1H), 2.93-2.80 (m, 5H), 2.74-2.67 (m, 2H), 2.62 (tt, J= 7.8, 4.3 Hz, 3H), 2.44 (dd, J= 13.2, 4.5 Hz, 1H), 2.08-1.94 (m, 2H), 1.72 (dq, J= 10.9, 8.5 Hz, 1H).13C NMR (100 MHz, DMSO-t / e) δ 173.4, 172.0, 170.7, 167.6, 144.4, 141.5, 139.5, 134.9, 131.7, 129.4, 128.4, 128.3, 126.8, 126.5, 124.9, 122.3, 122.1, 118.2, 118.1, 88.7, 62.9, 49.1, 44.2, 35.5, 33.6, 31.5, 22.9, 15.0. HRMS (m / z): [M+H]+calcd. for C28H27CIF3N4O4, 575.1667; found, 575.16653 -(3 -((3 -( 1 -((3 -chi orophenethyl)amino)cy cl obutyl)phenyl)amino)-2, 5 -dioxo-2,5 -dihy dro- 1H- pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01-368)

[0184] By employment of the similar procedure to JWJ-01-304, from the corresponding reductive amination intermediate (22 mg, 0.072 mmol), the title compound was prepared as a yellow solid (13.3 mg, 30%) with 99% purity.JH NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.91 (s, 1H), 9.55-9.32 (m, 2H), 7.54-7.51 (m, 1H), 7.51-7.47 (m, 2H), 7.35 (dt, J= 5.1, 3.7 Hz, 1H), 7.31-7.26 (m, 3H), 7.11 (dt, J = 6.7, 1.9 Hz, 1H), 5.90 (s, 1H), 4.98 (dd, J = 13.0, 5.4 Hz, 1H), 2.84-2.79 (m, 3H), 2.73 (dt, J= 12.7, 9.1 Hz, 4H), 2.64-2.58 (m, 2H), 2.56 (d, J= 4.3 Hz, 1H), 2.45 (dd, J= 13.3, 4.5 Hz, 1H), 2.11-1.96 (m, 2H), 1.72 (tdd, J= 17.2, 8.7, 2.0 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 173.4, 172.1, 170.7, 167.7, 158.7, 143.9, 140.4, 139.9, 139.0, 133.7, 130.9, 130.3, 129.1, 127.9, 127.4, 123.7, 121.1, 118.7, 90.2, 63.7, 49.2, 43.2, 40.9, 31.8, 31.5, 22.9, 14.1. HRMS (m / z): [M+H]+calcd. for C27H28CIN4O4, 507.1794; found, 507.1790.3-(3-((3-(l-((3-chloro-4-(trifluoromethyl)phenethyl)amino)cyclobutyl)phenyl)amino)-2,5-dioxo- 2, 5 -dihy dro- 17 / -py rrol - 1 -yl)- 1 -methylpiperidine-2, 6-dione (JWJ-01-334)

[0185] By employment of the similar procedure to JWJ-01-304, from the corresponding reductive amination intermediate (15 mg, 0.029 mmol), the title compound was prepared as a yellow solid (7.9 mg, 18%) with 96% purity.JH NMR (500 MHz, DMSO-d6) 5 9.92 (s, 1H),9.30 (s, 2H), 7.68 (s, 1H), 7.63 (d, J= 8.1 Hz, 1H), 7.49 (d, J= 4.4 Hz, 4H), 7.33 (s, 1H), 5.89 (s, 1H), 5.05 (dd, J = 13.2, 5.3 Hz, 1H), 3.00 (s, 3H), 2.89 (t, J = 4.6 Hz, 3H), 2.82 (s, 2H), 2.79- 2.67 (m, 4H), 2.66-2.60 (m, 2H), 2.03 (t, J = 13.2 Hz, 2H), 1.72 (q, J = 10.0, 9.3 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 172.3, 172.1, 170.5, 167.7, 143.8, 140.4, 139.0, 137.6, 135.1, 132.2, 130.3, 129.7, 127.2, 126.9, 124.7, 123.7, 122.0, 121.1, 118.6, 90.2, 63.7, 49.8, 42.9, 40.9,31.7, 31.3, 27.1, 22.0, 14.0. HRMS (m / z): [M+H]+calcd. for C29H29CIF3N4O4, 589.1824; found, 589.1821.

[0186] Additional compounds were synthesized as described in more detail below using the below described overall synthetic schemes depicted below (or substantially analogous schemes).3-(3-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-l-yl)piperidine-2, 6-dione

[0187] A solution of glycinamide hydrochloride (1.7 g, 15.3 mmol, 1.5 eq ), maleic anhydride (1.0 g, 10.2 mmol, 1.0 eq.) and potassium acetate (1.5 g, 15.3 mmol, 1.5 eq.) in acetic acid (20 mL) was stirred for 4 h at reflux temperature (110 °C). After the reaction mixture was cooled to rt, chilled NaHCO3 solution was added, and the product was extracted with di chloromethane (DCM) twice. The result organic phase was washed with brine. After drying over anhydrous MgSO4, the organic solvent was removed on vacuum and the residue was purified by silica gel column chromatography, which provided the title compound as a beige solid (1.3g, 72% yield). 1H NMR (500 MHz, DMSO-d6) 5 11.12 (s, 1H), 7.58 (s, 1H), 5.04 (dd,J= 13.1, 5.4 Hz, 1H), 2.83 (ddd, .7 = 17.3, 13.9, 5.5 Hz, 1H), 2.57 (dt, .7= 17.3, 3.5 Hz, 1H), 2.40 (qd, J= 13.3, 4.5 Hz, 1H), 2.01 (dtd, J= 13.1, 5.5, 2.8 Hz, 1H).General procedure of Grignard reaction[00188J To a solution of alkylmagnesium bromide solution (1.5 equiv) at 0 °C was added a solution of l-(3- bromophenyl)ethan-l-one (1 equiv) in anhydrous THF dropwise. After complete addition, the solution was warmed to rt gradually. Upon complete consumption of ketone indicated by LCMS, saturated NH4CI and ethyl acetate were added. The phases were separated, and the aqueous phase was further extracted with ethyl acetate. The combined organic solution was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was concentrated under reduced pressure, which provided the crude title compound without further purification.2-(3 -Bromophenyl)propan-2-ol

[0189] 1H NMR (500 MHz, CDCh) δ 7.65 (t, .7= 1.9 Hz, 1H), 7.38 (dddd, .7 = 13.4, 7.9,1.9, 1.0 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 1.72 (s, 1H), 1.56 (s, 6H). MS (ESI) m / z 197.1 (M - OH)+.2-(3-Bromophenyl)butan-2-ol

[0190] 1H NMR (500 MHz, CDCh) 8 7.59 (t, , / = 1.9 Hz, 1H), 7.34 (ddt, .7 = 14.5, 7.9, 1.2 Hz, 2H), 7.19 (t, J= 7.9 Hz, 1H), 1.89 (s, 1H), 1.80 (p, J= 6.8 Hz, 2H), 1.51 (s, 3H), 0.78 (t, J= 7.4 Hz, 3H). MS (ESI) m / z 197.1 (M - OH)+.3 -(3 -Bromopheny l)pentan-3 -ol

[0191] 1H NMR (500 MHz, Methanol-d4) 8 7.57 (t, J = 1.9 Hz, 1H), 7.34-7.27 (m, 2H), 7.20 (t, J= 7.8 Hz, 1H), 1.78 (qd, J= 7.2, 3.5 Hz, 4H), 0.71 (t, J= 7.4 Hz, 6H).General procedure of azide reaction

[0192] To a solution of alcohol (1 equiv) and NaNs (2.2 equiv) in CHC13 was added TFA(5 equiv) at 0 °C. The reaction mixture was stirred at rt until complete consumption of alcohol monitored by LCMS. Saturated aqueous NH4C1 was added, followed by slow addition of IM NaOH solution to adjust the pH of the aqueous phase to 7-8. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic solution was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified via flash column chromatography, which provided the title azide compound as colorless oil.General procedure of lithium aluminum hydride (LAH) reduction

[0193] To a solution of resulting azide (1 equiv) in anhydrous THF at 0 °C, LAH solution (IM in THF, 2 equiv) was added dropwise. Upon complete consumption of azide monitored by LCMS, saturated aqueous NH4C1 was added slowly to quench the remaining LAH. Then IM HC1 solution was added to acidify the mixture, which was extracted with methyl / e / V-butyl ether (MTBE) to remove the nonpolar faction. The resulting aqueous layer was then basified with IM NaOH solution, which was extracted with ethyl acetate (EtOAc) twice. The combined organic solution was dried over anhydrous MgSCU and concentrated under reduced pressure, which provided the title amine compound as colorless oil without further purification.General procedure of cyclization

[0194] A solution of 2-(3-bromophenyl)acetonitrile (1 equiv) and 1,3 -dibromopropane or 1,4-dibromobutane (1 equiv) in DMSO was added dropwise to a suspension of KOH (4 equiv) in DMSO. The mixture was stirred at rt for 5 h and quenched with DI water, which was extract with EtOAc three times. The combine organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure, which provided the title cyclic intermediates without further purification.General procedure of hydrolysis

[0195] The cyclic intermediate (1 equiv) and KOH (14 equiv) was charged to a 20 mL scintillation vial, followed by the addition of ethylene glycol. The mixture was heated to 165 °C to generate a clear solution. Upon complete consumption of nitrile monitored by LCMS, the solution was acidified with IM HC1 and extracted with EtOAc three times. The combine organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure, which provided the title acid intermediates without further purification.General procedure of amidation

[0196] The acid intermediate (1 equiv) and thionyl chloride (2 equiv) was charged to a 20 mL scintillation vial, followed by the addition of THF. The mixture was heated to reflux for 1 h. The solvent and excess thienyl chloride were then removed under reduce pressure. The residue was re-dissolved in anhydrous DCM and added dropwise to the ice-chilled ammonium hydroxide (3 equiv). Upon completion of amidation monitored by LCMS, the solution was neutralized with IM HC1 and extracted with EtOAc three times. The combine organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure, which was purified via flash column chromatography1 -(3-Bromophenyl)cyclobutane- 1 -carboxamide

[0197] 1H NMR (500 MHz, Mcthanol-d4) δ 7.53 (t, J = 1.9 Hz, 1H), 7.37 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 7.34 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 2.82-2.72 (m, 2H), 2.48-2.39 (m, 2H), 1.98-1.91 (m, 1H), 1.82 (dtt, J= 11.3, 8.9, 5.8 Hz, 1H).1 -(3 -Bromophenyl)cyclopentane-1 -carboxamide

[0198] 1H NMR (500 MHz, Methanol-d4) 8 7.54 (t, J= 1.9 Hz, 1H), 7.38-7.34 (m, 2H), 7.22 (t, J= 7.9 Hz, 1H), 2.49 (ddt, J = 12.8, 6.1, 3.3 Hz, 2H), 1.94-1.85 (m, 2H), 1.72 (pd, J = 4.5, 2.5 Hz, 4H).General procedure of amination

[0199] To a solution of amide (1 equiv) in MeCN was added [bis(trifluoroacetoxy)iodo]benzene (BTI, 1 equiv) and water . The mixture was stirred at rt for 18 h. The aqueous phase was basified with 1 M NaOH solution. After diluting with water, the aqueous layer was extracted with EtOAc twice. The combined organic extracts were washed with brine, dried MgSO4, concentrated under reduced pressure, which provided the title amine intermediate without further purification.General procedure of Boc protection

[0200] To a solution of amine (1 equiv) in DCM, Boc2O and DIPEA were added and stirred overnight. Upon complete consumption of amine monitored by LCMS, saturated aqueous NH4C1 and DCM were added. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic solution was dried over anhydrous MgSCh and concentrated under reduced pressure. The residue was purified via flash column chromatography, which provided the title compound as colorless oil. tert-Butyl (2-(3-bromophenyl)propan-2-yl)carbamate

[0201] 1H NMR (500 MHz, CDCh) 5 7.52 (t, J= 2.0 Hz, 1H), 7.36-7.29 (m, 2H), 7.17 (t, J= 7.9 Hz, 1H), 4.94 (s, 1H), 1.58 (s, 6H), 1.46-1.21 (m, 9H). tert-Butyl (2-(3 -bromophenyl)butan-2-yl)carbamate

[0202] 1H NMR (500 MHz, Methanol-d4) 8 7.48 (d, J= 2.0 Hz, 1H), 7.29 (tt, J = 15.1, 7.4 Hz, 2H), 7.19 (t, J= 7.8 Hz, 1H), 6.95-6.35 (m, 1H), 1.99-1.85 (m, 1H), 1.75 (tq, J= 14.3, 7.4 Hz, 1H), 1.53 (s, 3H), 1.24 (d, J= 135.9 Hz, 9H), 0.78 (t, J= 7.4 Hz, 3H). tert- Butyl (3-(3-bromophenyl)pentan-3-yl)carbamate

[0203] 1H NMR (500 MHz, Methanol-d4) 8 7.47 (s, 1H), 7.31 (dd, J = 17.0, 8.1 Hz, 2H), 7.20 (t, J = 7.9 Hz, 1H), 2.01 (d, J= 8.3 Hz, 2H), 1.82 (dq, J= 14.4, 7.3 Hz, 2H), 1.23 (d, J = 146.2 Hz, 9H), 0.72 (t, J= 7.5 Hz, 6H). tert-Butyl (l-(3-bromophenyl)cyclobutyl)carbamateChemic

[0204] 1H NMR (500 MHz, Methanol 74) 8 7.54 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 1.7 , 1.6 Hz, 1H), 7.34 (d, J= 7.8 Hz, 1H), 7.22 (t, J= 7.9 Hz, 1H), 2.44 (ddd, J= 19.5, 14.5, 9.1 Hz, 4H), 2.07 (s, 1H), 1.86 (s, 1H), 1.29 (d, J= 82.8 Hz, 10H). tert-Butyl (l-(3-bromophenyl)cyclopentyl)carbamateChemi

[0205] 1H NMR (500 MHz, Methanol-d4) 8 7.52 (t, , / = 2.0 Hz, 1H), 7.37-7.28 (m, 2H), 7.18 (t, J = 7.9 Hz, 1H), 2.22 (s, 2H), 1.93 (s, 2H), 1.87-1.71 (m, 4H), 1.26 (d, J = 115.0 Hz, 9H).General procedure of Buchwald Hartwig cross coupling

[0206] To a two-necked round bottom flask equipped with a nitrogen balloon and a septum, the resulting Boc protected intermediate (1 equiv), Xantphos (0.2 equiv), Pd2(dba)3 (0.1 equiv), Cs2CO3 (3 equiv), and benzophenone imine (1.1 equiv) were charged. 1,4-dixoane was then added and the system was flushed with nitrogen three times. The mixture was heated to 100 °C and stirred overnight. Upon complete consumption of Boc starting material monitored by LCMS, 50 mb EtOAc was added and filtered through a pad of Celite. The filtrate was saved and washed with brine twice. The organic solution was dried over anhydrous MgSCh and concentrated under reduced pressure, and purified via flash column chromatography, which provided the title compound as brown oil. tert-Butyl (2-(3-((diphenylmethylene)amino)phenyl)propan-2-yl)carbamate

[0207] 1H NMR (500 MHz, Methanol-d4) 8 7.67-7.63 (m, 2H), 7.51-7.47 (m, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.26 (d, J = 6.6 Hz, 3H), 7.11-7.04 (m, 3H), 6.95 (d, J = 7.8 Hz, 1H), 6.75 (d, J= 30.3 Hz, 2H), 6.56 (s, 1H), 1.37 (s, 15H).Zc / 'Z- Butyl (2-(3-((diphenylmethylene)amino)phenyl)butan-2-yl)carbamate

[0208] 1H NMR (500 MHz, Methanol-r / 4) 6 7.78-7.74 (m, 1H), 7.67-7.63 (m, 2H), 7.52-7.49 (m, 2H), 7.45-7.39 (m, 3H), 7.26-7.24 (m, 2H), 7.08 (dd, J = 6.5, 2.5 Hz, 2H), 6.91 (dd, J= 7.7, 1.6 Hz, 1H), 6.63 (d, J= 30.4 Hz, 2H), 1.72 (s, 1H), 1.53 (s, 1H), 1.41 (s, 3H), 1.37 (s, 9H), 0.53 (s, 3H). tert- Butyl (3-(3-((diphenylmethylene)amino)phenyl)pentan-3-yl)carbamate

[0209] 1H NMR (500 MHz, MethanolW4) 5 7.67-7.62 (m, 2H), 7.50-7.46 (m, 1H), 7.41 (dd, J= 8.4, 6.9 Hz, 2H), 7.24 (dd, J= 5.2, 2.0 Hz, 3H), 7.09 (dt, J= 7.8, 3.9 Hz, 3H), 6.91 (d, J = 7.9 Hz, 1H), 6.62 (s, 2H), 6.39 (s, 1H), 1.86 (s, 2H), 1.66 (s, 2H), 1.37 (s, 9H), 0.52 (t, J = 7.4Hz, 6H).General procedure of diphenylmethane removal

[0210] The resulting Buchwald product was dissolved in THF, followed by the addition of IM HC1 solution (2 equiv). The mixture was stirred for 0.5 h. Upon complete consumption of starting material monitored by LCMS, EtOAc and saturated NaHCO3 were added. The phases were separated, and the aqueous phase was further extracted with EA once. The combined organic solution was dried over anhydrous MgSCU and concentrated under reduced pressure.The residue was purified via flash column chromatography, which provided the title compound as colorless oil. tert-Butyl (2-(3-aminophenyl)butan-2-yl)carbamate

[0211] 1H NMR (500 MHz, Methanol-c / 4) 5 7.01 (t, J= 7.8 Hz, 1H), 6.74 (t, J= 2.1 Hz,1H), 6.69 (d, J= 7.9 Hz, 1H), 6.61-6.53 (m, 1H), 1.91 (s, 1H), 1.73 (dq, J= 14.4, 7.3 Hz, 1H), 1.52 (s, 3H), 1.25 (d, J= 126.1 Hz, 9H), 0.76 (t, J= 7.4 Hz, 3H).Zc / 7-Butyl (3-(3-aminophenyl)pentan-3-yl)carbamate

[0212] 1H NMR (500 MHz, Methanol-d4) 5 7.02 (t, J= 7.8 Hz, 1H), 6.74 (d, J= 2.1 Hz,1H), 6.68 (dd, J = 7.7, 1.8 Hz, 1H), 6.56 (dd, J = 7.8, 2.2 Hz, 1H), 1.99 (dt, J = 15.0, 7.4 Hz, 2H), 1.92-1.78 (m, 2H), 1.25 (d, 134.1 Hz, 9H), 0.70 (t, J= 7.3 Hz, 6H). tert- Butyl (l-(3-aminophenyl)cyclobutyl)carbamate

[0213] 1H NMR (500 MHz, Methanol-c / 4) 5 7.03 (t, J = 7.8 Hz, 1H), 6.81 (t, J = 2.0 Hz,1H), 6.76 (dt, J= 7.8, 1.3 Hz, 1H), 6.60-6.54 (m, 1H), 2.47-2.30 (m, 4H), 2.01 (d, J= 13.4 Hz, 1H), 1.83 (h, J= 7.8 Hz, 1H), 1.48- 1.10 (m, 9H). tert-Butyl (l-(3-aminophenyl)cyclopentyl)carbamate

[0214] 1H NMR (500 MHz, Methanol-c / 4) δ 7.00 (t, J= 7.8 Hz, 1H), 6.78 (t, J= 2.1 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 6.55 (d, J= 7.8 Hz, 1H), 2.14 (d, J= 54.0 Hz, 2H), 1.93 (s, 2H), 1.83-1.68 (m, 4H), 1.37 (s, 7H), 1.15 (s, 2H). General procedure of Boc deprotection

[0215] The aniline intermediate was dissolved in 2 mL DCM and 0.5 mL TFA, and stirred at rt for 2 h. Upon complete consumption of starting material monitored by LCMS, 20 mL DCM and 20 mL IM NaOH solution were added. The or ganic solution was dried over anhydrous MgSO4 and concentrated under reduced pressure, which provided the title amine compound as light-yellow oil.General procedure of reductive amination

[0216] The amine intermediate (1 equiv) and 2-(3-chloro-4- (trifluoromethyl)phenyl)acetaldehyde (0.5 equiv, freshly prepared from the corresponding nitrile and DIBAL-H) were added to a 20 mL scintillation vial. After the addition of 3 mL DCM, the solution was stirred for 0.5 h. NaBH(OAc)3 (1.5 equiv) was added and the resulting mixture was further stirred for 1 h. EtOAc and DI water were added. The phases were separated, and the aqueous phase was further extracted with EtOAc once. The combined organic solution was driedover anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified via flash column chromatography, which provided the title compound as light-yellow oil.General procedure of substitution

[0217]

[0218] The aniline intermediate (1 equiv), 3-(3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol- l-yl)piperidine-2, 6-dione (0.75 equiv), TEA (1.1 equiv) were charged to a 8 mb scintillation vial. Upon the addition of 1,4-dioxane (1 mL), the mixture was stirred at 65 °C for 12 h. 15 mL EtOAc was added and filtered through a pad of Celite. The filtrate was collected and concentrated under reduced pressure. The residue was sequentially purified by prep TLC or prep HPLC, which yielded the desired compound as yellow solid.3-(3-((3-(l-(((4-Chloro-3-(trifluoromethyl)benzyl)amino)methyl)cyclobutyl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-1H-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-304)

[0219] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (38 mg, 0.20 mmol), which yielded a yellow solid (9.2 mg, 6%) with 93% purity. 1H NMR (400 MHz, DMSO-d6) 5 11.07 (s, 1H), 9.79 (s, 1H), 7.65 (d, J= 1.8 Hz, 1H), 7.56 (d, J= 8.2 Hz, 1H), 7.45 (dd, J= 8.2, 1.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.24-7.19 (m, 1H), 7.18-7.14 (m, 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.58 (s, 1H), 4.96 (dd, J= 12.9, 5.4 Hz, 1H), 3.66 (s, 2H), 2.86 (ddd, J= 17.0, 13.8, 5.4 Hz, 1H), 2.72 (s, 2H),2.57 (ddd, J = 17.1, 4.5, 2.3 Hz, 1H), 2.44 (dd, ,7 = 13.2, 4.4 Hz, 1H), 2.20 (dd, ,7 = 9.2, 7.2 Hz, 4H), 2.12-1.91 (m, 3H), 1.82-1.70 (m, 1H). MS (ESI) m'z 575.2 (M + H)+.3 -(3 -((3 -( 1 -((2-(3 -Chloro-4-(trifluoromethyl)phenyl)-2- methylpropyl)amino)cyclobutyl)phenyl)amino)-4-methyl-2,5-dioxo-2, 5-dihydro- 177-pyrrol-l- yl)piperidine-2, 6-dione (JWJ-01 -297)

[0220] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (50 mg, 0.13 mmol), which yielded a yellow solid (1.8 mg, 2%) with 98% purity. 1H NMR (400 MHz, DMSO-d6) δ 1 1.12-10.77 (m, 1H), 9.34-9.01 (m, 1H), 7.68 (s, 1H), 7.50 (d, J= 1.7 Hz, 1H), 7.37 (d, J= 8.3 Hz, 1H), 7.20 (dd, J = 9.2, 6.9 Hz, 1H), 6.95 (q, J = 3.8 Hz, 3H), 4.88 (dd, J = 12.9, 5.4 Hz, 1H), 2.81 (ddd, J = 17.0, 13.8, 5.3 Hz, 1H), 2.19 (d, J = 7.4 Hz, 2H), 2.15-2.08 (m, 2H), 2.0 -1.88 (m, 4H), 1.79 (q, J = 7.9, 7.3 Hz, 1H), 1.61-1.48 (m, 1H), 1.40 (s, 3H), 1.16 (s, 8H). MS (ESI) m / z 617.3 (M +H)+.3 -(3 -((3 -( 1 -((2-(3 -Chloro-4-(trifhioromethyl)phenyl)-2- methylpropyl)amino)cyclobutyl)phenyl)amino)-2,5-dioxo-2, 5-dihydro- 177-pyrrol-l- yl)piperidine-2, 6-dione (JWJ-01 -296)

[0221] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (50 mg, 0.13 mmol), which yielded a yellow solid (1.8 mg, 2%) with 98% purity. 1H NMR (400 MHz, DMSO- 6) δ 1 1.07-10.79 (m, 1H),10.05-9.74 (m, 1H), 7.70 (dd, J= 8.3, 2.8 Hz, 1H), 7.51 (d, .7= 2.6 Hz, 1H), 7.39 (d, ,7 = 8.4 Hz, 1H), 7.30-7.23 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 5.52-5.47 (m, 1H), 4.94 (ddd, J= 13.1, 5.5, 2.7 Hz, 1H), 2.85 (ddt, J= 16.1, 7.4, 4.5 Hz, 1H), 2.26 (s, 2H), 2.16 (qt, J = 7.8, 5.5, 4.1 Hz, 2H), 2.08-1.92 (m, 4H), 1.83 (q, J = 8.2 Hz, 1H), 1.67-1.54 (m, 1H), 1.20 (d, J= 2.7 Hz, 8H). MS (ESI) m / z 603.3 (M + H)+.3-(3-((3-(l-((3-Chloro-4-(trifluoromethyl)phenethyl)amino)cyclobutyl)phenyl)amino)-4-methyl-2, 5-dioxo-2,5-dihydro-177-pyrrol-l-yl)piperidine-2, 6-dione (JWI-01-287)

[0222] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (34 mg, 0.093 mmol), which yielded a yellow solid (3.0 mg, 5%) with 99% purity. 1H NMR (400 MHz, DMSO-d6) 5 11.03 (s, 1H), 9.33 (s, 2H), 9.27 (s, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.55 (s, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.29 (t, J= 9.2 Hz, 2H), 7.23 (s, 1H), 7.18 (d, ,7 = 8.1 Hz, 1H), 4.91 (dd, ,7 = 13.0, 5.3 Hz, 1H), 2.92-2.83 (m, 2H), 2.82-2.70 (m, 3H), 2.68-2.52 (m, 5H), 2.01 (d, J = 13.9 Hz, 1H), 1.93 (d, J = 1.6 Hz, 1H), 1.67 (q, .7= 8.8 Hz, 1H), 1.46 (s, 3H). MS (ESI) m / z 589.2 (M + H)+.3-(3-((3-(2-((2-Chloro-4-(trifluoromethyl)phenethyl)amino)butan-2-yl)phenyl)amino)-2,5-dioxo- 2, 5-dihydro-177-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-276)

[0223] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (22 mg, 0.058 mmol), which yielded a yellowsolid (1.6 mg, 5%) with 99% purity. 1H NMR (500 MHz, DMSO-^6) 5 10.98 (s, 1H), 9.73 (s, 1H), 7.72 (s, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.51 (d, J= 8.1 Hz, 1H), 7.37 (s, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 5.50 (d, J = 9.0 Hz, 1H), 4.91 (dd, J= 13.0, 5.3 Hz, 1H), 2.83 (t, J= 7 A Hz, 3H), 2.53 (d, J = 16.7 Hz, 2H), 2.22 (d, J= 27.4 Hz, 1H), 2.01-1.91 (m, 2H), 1.64-1.50 (m, 2H), 1.28 (s, 4H), 0.61 (t, J= 7.5 Hz, 3H). MS (ESI) m / z 577.2 (M + H)+.3-(3-((3-(l-((3-Chloro-4-(trifluoromethyl)phenethyl)amino)cyclobutyl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-177-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-277)

[0224] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (51 mg, 0.14 mmol), which yielded a yellow solid (5.8 mg, 6%) with 99% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.07 (s, 1H), 9.91 (s, 1H), 9.32 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.50 (d, J = 4.3 Hz, 3H), 7.34 (d, J= 8.4 Hz, 2H), 5.88 (s, 1H), 4.98 (dd, J= 13.0, 5.4 Hz, 1H), 2.93-2.81 (m, 6H), 2.69- 2.58 (m, 4H), 2.07-1.96 (m, 2H), 1.76-1.68 (m, 1H). MS (ESI) m z 575.2 (M + H)' .3-(3-((3-(2-((2-Chloro-3-(trifluoromethyl)phenethyl)amino)butan-2-yl)phenyl)amino)-2,5-dioxo- 2, 5-dihydro-1H -pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-275)

[0225] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (23 mg, 0.061 mmol), which yielded a yellow solid (3.5 mg, 8%) with 99% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.08 (s, 1H), 9.90 (s, 1H), 9.42-9.34 (m, 1H), 9.14 (dt, J= 11.0, 4.9 Hz, 1H), 7.75 (d, J= 7.4 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.49 (d, J= 5.6 Hz, 4H), 7.32 (d, J= 7.1 Hz, 1H), 5.87 (s, 1H), 4.98 (dd, J= 13.0, 5.3 Hz, 1H), 3.10 (d, J = 10.7 Hz, 3H), 2.85 (dd, J= 17.8, 4.7 Hz, 1H), 2.65-2.55 (m, 2H), 2.20 (dd, J = 13.3, 7.4 Hz, 1H), 2.00 (dd, J= 13.4, 6.5 Hz, 2H), 1.71 (s, 3H), 0.70 (t, J = 7.3 Hz, 3H). MS (ESI) m / z 577.2 (M + H)+.3-(3-((3-(2-((3,4-Dichlorophenethyl)amino)butan-2-yl)phenyl)amino)-2,5-dioxo-2,5-dihydro- HT-pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01-274)

[0226] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (12 mg, 0.036 mmol), which yielded a yellow solid (1.1 mg, 5%) with 96% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.08 (s, 1H), 9.89 (s, 1H), 9.31-9.19 (m, 1H), 9.08-8.95 (m, 1H), 7.50 (dd, J= 18.6, 6.6 Hz, 4H), 7.45 (s, 1H), 7.32- 7.27 (m, 1H), 7.16 (d, J = 6.2 Hz, 1H), 5.83 (s, 1H), 5.01-4.94 (m, 1H), 3.18-3.05 (m, 2H), 2.92-2.78 (m, 4H), 2.60 (s, 1H), 2.0 -1.96 (m, 2H), 1.70 (s, 3H), 0.69-0.64 (m, 3H). MS (ESI) m / z 543.1 (M + H)+.3-(3-((3-(l-((3-Chloro-4-(trifluoromethyl)phenethyl)amino)cyclopentyl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-1H-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-279)

[0227] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (19 mg, 0.051 mmol), which yielded a yellow solid (3.9 mg, 11%) with 91% purity. 1H NMR (500 MHz, DMSO-c76) δ 11.04 (s, 1H), 9.85 (s, 1H), 9.08 (s, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 19.7 Hz, 2H), 7.44 (d, J = 5.5 Hz, 2H),7.33-7.26 (m, 2H), 5.81 (s, 1H), 4.94 (dd, J = 13.0, 5.4 Hz, 1H), 2.88 (s, 4H), 2.33 (dt, J= 3.8, 1.9 Hz, 2H), 2.22 (dd, J = 13.8, 7.4 Hz, 3H), 1.99-1.90 (m, 1H), 1.90-1.76 (m, 3H), 1.59-1.52 (m, 2H). MS (ESI) m / z 589.2 (M + H)+.3 -(3 -((3 -(2-((2,4-Bi s(trifluoromethy l)phenethyl)amino)butan-2-yl)phenyl )amino)-2, 5 -dioxo-2, 5 - dihydro- 177pyrrol-l-yl)piperidine-2, 6-dione (JWI-01-273)

[0228] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (28 mg, 0.069 mmol), which yielded a yellow solid (4.7 mg, 9%) with 90% purity. 1H NMR (500 MHz, DMSO-c / 6) δ 11.08 (s, 1H), 9.89 (s, 1H), 9.45 (t, J= 10.1 Hz, 1H), 9.25-9.13 (m, 1H), 8.03 (d, J= 8.1 Hz, 1H), 7.96 (s, 1H), 7.69 (d,J = 8.1 Hz, 1H), 7.49 (d, J = 7.8 Hz, 3H), 7.31 (d, J = 7.0 Hz, 1H), 5.87 (s, 1H), 4.98 (dd, J = 13.0, 5.4 Hz, 1H), 3.22-3.11 (m, 3H), 2.92-2.81 (m, 1H), 2.64-2.54 (m, 2H), 2.20 (dd, J= 13.7, 7.3 Hz, 1H), 2.05-1.97 (m, 2H), 1.71 (s, 3H), 0.70 (t, J = 7.3 Hz, 3H). MS (ESI) m / z 611.2 (M + H)+.3-(3-((3-(2-((3,5-Bis(trifluoromethyl)phenethyl)amino)butan-2-yl)phenyl)amino)-2,5-dioxo-2,5- dihydro- I / / pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01 -272)

[0229] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (31 mg, 0.076 mmol), which yielded a yellow solid (5.1 mg, 9%) with 96% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.04 (s, 1H), 9.86 (s, 1H), 9.25-9.10 (m, 1H), 9.06-8.92 (m, 1H), 7.93 (d, J = 14.0 Hz, 3H), 7.45 (d, J= 5.7 Hz, 2H), 7.27 (d, J= 5.7 Hz, 1H), 6.78-6.61 (m, 1H), 5.80 (s, 1H), 4.95 (dd, J= 13.0, 5.4 Hz, 1H), 3.27- 3.13 (m, 1H), 3.11-2.96 (m, 2H), 2.88-2.78 (m, 1H), 2.71 (dd, J = 21.7, 11.0 Hz, 1H), 2.58- 2.52 (m, 1H), 2.12 (ddd, J = 41.1, 13.7, 7.5 Hz, 1H), 2.01-1.82 (m, 2H), 1.64 (d, J = 47.8 Hz, 3H), 0.65 (t, J= 5.1 Hz, 3H). MS (ESI) m / z 611.2 (M + H)+.3 -(3 -((3 -(2-((3 -Chlorophenethyl)amino)butan-2-yl)phenyl)amino)-2, 5 -di oxo-2, 5 -dihydro- 1H- pyrrol - 1 -yl )piperi dine-2, 6-di one (JWJ-01-267)

[0230] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (22 mg, 0.071 mmol), which yielded a yellow solid (3.8 mg, 9%) with 99% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.04 (s, 1H), 9.86 (s, 1H), 9.18 (t, J= 7.6 Hz, 1H), 8.99 (t, J= 11.9 Hz, 1H), 7.45 (d, J= 7.0 Hz, 3H), 7.30-7.24 (m, 4H), 7.10 (d, J= 6.9 Hz, 1H), 5.81 (s, 1H), 4.95 (dd, J= 13.0, 5.4 Hz, 1H), 3.09 (d, J= 9.6 Hz, 1H), 2.83 (dtd, J= 24.9, 14.5, 12.9, 5.6 Hz, 4H), 2.55 (d, J= 17.4 Hz, 1H), 2.18 (d, J = 13 Hz,1H), 1.96 (dd, ,7 = 15.2, 5.1 Hz, 2H), 1.68 (s, 3H), 0.65 (t, ,7 = 7.4 Hz, 3H). MS (ESI) m / z 509.2 (M + H)+.3 -(3 -((3 -(2-((4-Methylphenethyl)amino)butan-2-yl)phenyl)amino)-2, 5 -di oxo-2, 5-dihydro- 177- pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01 -261 )[00231J Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (27 mg, 0.094 mmol), which yielded a yellow solid (2.0 mg, 4%) with 94% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.07 (s, 1H), 9.78 (s, 1H), 7.44 (s, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.1 1 (d, J= 7.8 Hz, 1H), 7.03 (d, J = 2.2 Hz, 4H), 5.59 (s, 1H), 4.97 (dd, J= 13.0, 5.4 Hz, 1H), 3.31 (s, 3H), 2.86 (ddd, J = 17.1, 13.9, 5.3 Hz, 1H), 2.65-2.60 (m, 2H), 2.35-2.29 (m, 1H), 2.22 (s, 3H), 2.04-1.94 (m, 2H), 1.61 (dp, J = 20.9, 7.1 Hz, 2H), 1.31 (s, 3H), 0.63 (t, J = 7.4 Hz, 3H). MS (ESI) m / z 489.2 (M + H)+.3-(3-((3-(2-((4-Methoxyphenethyl)amino)butan-2-yl)phenyl)amino)-2, 5-di oxo-2, 5-dihydro- 177- pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01 -260)

[0232] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (19 mg, 0.062 mmol), which yielded a yellow solid (1.4 mg, 4%) with 93% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.04 (s, 1H), 9.86 (s, 1H), 9.32-9.22 (m, 1H), 9.09-8.96 (m, 1H), 7.44 (s, 2H), 7.29 (d, J = 6.9 Hz, 1H), 7.02 (d, J =8.2 Hz, 3H), 6.79 (d, .7 = 8.0 Hz, 2H), 5.82 (s, 1H), 4.96-4.92 (m, 1H), 3.65 (s, 3H), 2.86-2.77 (m, 3H), 2.77-2.69 (m, 2H), 2.19-2.13 (m, 1H), 1.96 (d, J= 13.8 Hz, 3H), 1.68 (s, 3H), 0.65 (t, J= 7.1 Hz, 3H). MS (ESI) m / z 505.3 (M + H)+.3-(2,5-Dioxo-3-((3-(2-((4-(trifluoromethyl)phenethyl)amino)butan-2-yl)phenyl)amino)-2,5- dihydro- 1H pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-259)

[0233] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (24 mg, 0.071 mmol), which yielded a yellow solid (3.3 mg, 7%) with 96% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.08 (s, 1H), 9.90 (s, 1H), 9.31-9.17 (m, 1H), 9.13-9.00 (m, 1H), 7.64 (d, J = 13 Hz, 2H), 7.48 (s, 2H), 7.41 (d, J = !A Hz, 2H), 7.31 (d, J = 5.2 Hz, 1H), 5.85 (s, 1H), 4.98 (d, J = 18.0 Hz, 1H), 3.14 (d, J = 222 Hz, 1H), 3.03-2.89 (m, 2H), 2.85 (d, J = 17.6 Hz, 1H), 2.67-2.52 (m, 3H), 2.20 (dd, J = 14.3, 7.5 Hz, 1H), 2.00 (dd, J= 11.7, 6.5 Hz, 2H), 1.72 (s, 3H), 0.68 (t, J= 6.2 Hz, 3H). MS (ESI) m / z543.2 (M + H) .3-(2,5-Dioxo-3-((3-(2-(phenethylamino)butan-2-yl)phenyl)amino)-2,5-dihydro-1H -pyrrol-l- yl)piperidine-2, 6-dione (JWJ-01-252)

[0234] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (20 mg, 0.076 mmol), which yielded a yellow solid (2.5 mg, 6%) with 96% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.04 (s, 1H), 9.87 (s,1H), 9.21-9.11 (m, 1H), 9.04-8.91 (m, 1H), 7.45 (s, 2H), 7.28 (d, .7 = 7.4 Hz, 1H), 7.24 (t, J =6.6 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 7.12 (d, J = 13 Hz, 3H), 5.82 (s, 1H), 4.95 (dd, J = 13.0, 5.4 Hz, 1H), 3.09-2.99 (m, 1H), 2.90-2.74 (m, 4H), 2.55 (d, J = 17.5 Hz, 2H), 2.17 (dd, J = 13.5, 7.3 Hz, 1H), 1.96 (dd, J = 12.1, 9.0 Hz, 2H), 1.68 (s, 2H), 0.66 (t, J = 7.3 Hz, 3H). MS (ESI) m'z 475.2 (M + H)+.3-(3-((3-(2-((4-Chloro-3-(trifluoromethyl)phenethyl)amino)butan-2-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-177-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-266)

[0235] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (13 mg, 0.036 mmol), which yielded a yellow solid (1.3 mg, 5%) with 99% purity. 1H NMR (500 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.75 (s, 1H), 7.65 (dd, J = 4.6, 2.0 Hz, 2H), 7.55 (dd, J = 10.1, 8.2 Hz, 2H), 7.45 (dd, J = 8.3, 2.1 Hz, 2H), 7.33 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 4.92 (dd, J = 13.0, 5.5 Hz, 1H), 4.79 (s, 1H), 2.71- 2.68 (m, 3H), 2.52 (d, J = 5.7 Hz, 2H), 2.37-2.32 (m, 2H), 1.94 (dd, J = 9.8, 4.8 Hz, 1H), 1.57 (ddd, J= 18.0, 14.1, 6.9 Hz, 2H), 1.26 (s, 3H), 0.63-0.58 (m, 3H).3-(3-((3-(2-((3-Chloro-4-methoxyphenethyl)amino)butan-2-yl)phenyl)amino)-2,5-dioxo-2,5- dihydro- 17 / pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01 -265)

[0236] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (23 mg, 0.069 mmol), which yielded a yellow solid (1.5 mg, 3%) with 98% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.04 (s, 1H), 9.85 (s, 1H), 9.18 (s, 1H), 8.96 (s, 1H), 7.44 (d, J = 5.8 Hz, 3H), 7.27 (d, J = 5.4 Hz, 1H), 7.22 (s, 1H), 7.07-6.97 (m, 2H), 5.81 (s, 1H), 4.95 (dd, J = 13.0, 5.2 Hz, 1H), 3.75 (s, 3H), 3.06-2.99 (m, 1H), 2.81 (d, J = 5.8 Hz, 2H), 2.72 (d, J = 11.1 Hz, 1H), 2.52 (d, J = 10.4 Hz, 2H), 2.24-2.10 (m, 1H), 1.95 (dd, J = 14.1, 3.3 Hz, 2H), 1.67 (s, 3H), 0.64 (t, J = 6.9 Hz, 3H). MS (ESI) m / z 539.2 (M + H)+.3-(3-((3-(l-(3-Chloro-4-(trifluoromethyl)phenethyl)-1H-l,2,3-triazol-4-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro- 1H -pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01-254)

[0237] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (22 mg, 0.068 mmol), which yielded a yellow solid (4.4 mg, 11%) with 90% purity. 1H NMR (500 MHz, DMSO-d6) δ 11.19-10.80 (m, 1H), 10.14-9.67 (m, 1H), 8.64 (s, 1H), 7.80-7.74 (m, 2H), 7.67 (s, 1H), 7.55 (d, J= 7.7 Hz, 1H), 7.44 (t, J= 7.9 Hz, 1H), 7.37 (t, J = 9.3 Hz, 2H), 5.68 (s, 1H), 4.97 (dd, J = 12.9, 5.4 Hz, 1H), 4.74 (t, J= 7.1 Hz, 2H), 3.31 (s, 2H), 2.92-2.81 (m, 1H), 2.61-2.54 (m, 1H), 1.99 (qt, J= 10.4, 4.6 Hz, 2H). MS (ESI) m / z 573.2 (M + H)+.3-(3-((4-(l-(3-Chloro-4-(trifluoromethyl)phenethyl)-1H-l,2,3-triazol-4-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-1H-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-248)

[0238] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (11 mg, 0.029 mmol), which yielded a yellow solid (5.4 mg, 27%) with 80% purity. 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.89 (s, 1H), 8.51 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 5.80 (s, 1H), 4.94 (dd, J= 12.9, 5.3 Hz, 1H), 4.69 (t, J = 7.0 Hz, 2H), 3.29 (t, J= 7.0 Hz, 2H), 2.86-2.78 (m, 1H), 2.57-2.52 (m, 1H), 2.01-1.92 (m, 2H). MS (ESI) m / z 573.2 (M + H)+.3-(3-((3-(l-(3-Chloro-4-(trifluoromethyl)benzyl)-lJ / -l,2,3-triazol-4-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-1H-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-251)

[0239] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (49 mg, 0.14 mmol), which yielded a yellow solid (7.4 mg, 5%) with 95% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.15 - 10.68 (m, 1H), 10.24 - 9.57 (m, 1H), 8.76 (s, 1H), 7.90 (d, J= 8.2 Hz, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.34 (d, J= 7.9 Hz, 1H), 5.80 (s, 2H), 5.72 - 5.57 (m, 1H), 4.95 (dd, J= 12.9, 5.4 Hz, 1H), 2.91 - 2.80 (m, 1H), 2.60 - 2.53 (m, 1H), 1.97 (qt, J= 10.6, 6.1 Hz, 2H). MS (ESI) m / z 559.2 (M + H)-.3 -(3 -((4-( 1 -(3 -Chloro-4-(trifluoromethyl)benzyl)-1H- 1 ,2,3-triazol-4-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-1H -pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-245)

[0240] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (60 mg, 0.17 mmol), which yielded a yellow solid (5.4 mg, 5%) with 92% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.07 (s, 1H), 9.93 (s, 1H), 8.67 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.86 (d, J= 8.6 Hz, 2H), 7.74 (s, 1H), 7.51 (d, J =8.7 Hz, 2H), 7.45 (d, J = 8.2 Hz, 1H), 5.84 (s, 1H), 5.79 (s, 2H), 4.97 (dd, J= 12.9, 5.4 Hz, 1H), 2.86 (ddd, J = 17.0, 13.1, 4.2 Hz, 1H), 2.58 (d, J = 17.2 Hz, 1H), 2.07-1.95 (m, 1H). MS (ESI) m 'z 559.2 (M + H)+.3-(3-((4-(l-(3-Chloro-4-(trifluoromethyl)phenethyl)piperidin-4-yl)phenyl)amino)-2,5-dioxo-2,5- dihydro- l / / pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-238)

[0241] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (47 mg, 0.12 mmol), which yielded a yellow solid (2.4 mg, 3%) with 97% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.04 (s, 1H), 9.81 (s, 1H), 9.58 (s, 1H), 7.83 (dd, J = 8.3, 2.3 Hz, 1H), 7.71 (d, J = 3.7 Hz, 1H), 7.48 (d, J = 8.2 Hz,1H), 7.37 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 5.69 (d, J = 5.1 Hz, 1H), 4.93 (dd, J =13.0, 5.4 Hz, 1H), 3.63 (s, 2H), 3.39 (t, J= 8.4 Hz, 2H), 3.12 (dd, ,7= 10.7, 5.8 Hz, 2H), 3.06 (s, 2H), 2.84-2.78 (m, 2H), 2.04-1.92 (m, 3H), 1.89-1.74 (m, 3H). MS (ESI) m / z 589.3 (M + H)+.3 -(3 -((3 -( 1 -(3 -Chloro-4-(trifluoromethyl)phenethyl)piperidin-4-yl)phenyl)amino)-2, 5-dioxo-2,5- dihydro- 1 / / pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01 -237)

[0242] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (62 mg, 0.16 mmol), which yielded a yellow solid (3.5 mg, 4%) with 99% purity. 1H NMR (500 MHz, DMSO-d6) δ 10.56 (d, J = 99.4 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.14 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.90 (d, J= 7.7 Hz, 1H), 5.38- 5.25 (m, 1H), 4.86 (dd, J =12.8, 5.5 Hz, 1H), 4.09 (s, 1H), 3.13 (s, 2H), 3.01 (dd, J= 8.9, 5.8 Hz, 2H), 2.87- 2.74 (m, 3H), 2.56 (d, J = 8.0 Hz, 2H), 2.07-2.00 (m, 2H), 1.90 (dd, J = 10.6, 5.3 Hz, 1H), 1.73 (d, J = 12.5 Hz, 2H), 1.58 (tt, J= 14.2, 7.2 Hz, 2H). MS (ESI) m / z 589.3 (M + H)+.3-(3-((3-(l-(3-Chloro-4-(trifluoromethyl)benzyl)piperidin-4-yl)phenyl)amino)-2,5-dioxo-2,5- dihydro- 177pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-235)

[0243] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (66 mg, 0.051 mmol), which yielded a yellow solid (5.0 mg, 5%) with 95% purity. 1H NMR (500 MHz, DMSO-d6) δ 1 1.05-10.44 (m, 1H),7.79 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.49 (d, .7 = 8.1 Hz, 1H), 7.23 (t, ,7= 7.8 Hz, 1H), 7.18 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.93 (d, J= 7.6 Hz, 1H), 5.41 (s, 1H), 4.88 (dd, J= 12.9, 5.4 Hz, 1H), 3.57 (s, 2H), 3.28 (s, 2H), 2.86 (d, J= 11.5 Hz, 2H), 2.84-2.76 (m, 1H), 2.52 (dt, J= 17.6, 3.5 Hz, 2H), 2.07 (td, J= 11.6, 2.5 Hz, 2H), 1.95-1.88 (m, 1H), 1.73 (d, J= 12.5 Hz, 2H), 1.63 (qd, J= 12.3, 3.6 Hz, 2H). MS (ESI) m / z 575.3 (M + H)+.3-(3-((4-(l-(3-Chloro-4-(trifluoromethyl)benzyl)piperidin-4-yl)phenyl)amino)-2,5-dioxo-2,5- dihydro- 177pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-231)

[0244] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (57 mg, 0.16 mmol), which yielded a yellow solid (14.7 mg, 16%) with 99% purity. 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 6.6 Hz, 4H), 5.36 (s, 1H), 4.89 (dd, J = 12.9, 5.4 Hz, 1H), 3.60 (s, 2H), 3.31 (s, 2H), 2.91- 2.86 (m, 2H), 2.86-2.77 (m, 1H), 2.58-2.52 (m, 1H), 2.46 (d, J= 12.4 Hz, 1H), 2.10 (td, J= 11.6, 2.5 Hz, 2H), 1.98-1.92 (m, 1H), 1.78-1.71 (m, 2H), 1.65 (qd, J= 12.2, 3.8 Hz, 2H). MS (ESI) m / z 575.4 (M + H)+.3-(3-((3-(2-((3-Chloro-4-(trifluoromethyl)phenethyl)amino)propan-2-yl)-5- methylphenyl)amino)-2,5-di oxo-2, 5-dihydro-177-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-277)

[0245] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (39 mg, 0.10 mmol), which yielded a yellowsolid (5.7 mg, 9%) with 97% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.06 (s, 1H), 9.68 (s, 1H), 7.72 (d, J= 8.1 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.23 (s, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 5.62 (s, 1H), 4.96 (dd, J = 13.0, 5.4 Hz, 1H), 2.91-2.81 (m, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.58 (d, J = 16.9 Hz, 1H), 2.47 (s, 1H), 2.23 (s, 3H), 2.02-1.96 (m, 1H), 1.32 (s, 6H), 1.23 (s, 2H), 1.17 (t, J= 7.1 Hz, 1H). MS (ESI) m / z 577.3 (M + H)+.3-(3-((3-(2-((3-Chloro-4-(trifluoromethyl)phenethyl)amino)propan-2-yl)-4- methylphenyl)amino)-2, 5-di oxo-2, 5-dihydro- 1 / / -pyrrol - 1 -yl)piperidine-2, 6-dione (JWJ-01-219)

[0246] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (33 mg, 0.089 mmol), which yielded a yellow solid (13.8 mg, 27%) with 94% purity. 1H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.75 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.13 (dd, J = 8.2, 2.2 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 5.57 (d, J = 4.2 Hz, 1H), 4.95 (dd, J = 13.0, 5.4 Hz, 1H), 2.85 (ddd, J = VIA, 13.8, 5.4 Hz, 1H), 2.72 (t, J = 7.0 Hz, 2H), 2.62 - 2.52 (m, 1H), 2.45 (d, J = 7.3 Hz, 3H), 2.35 (s, 3H), 1.99 (s, 2H), 1.42 (s, 6H). MS (ESI) m / z 577.3(M + H)+.N-(3-Chloro-4-(trifluoromethyl)phenethyl)-3-((l-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5- dihydro-1H-pyrrol-3-yl)amino)benzenesulfonamide (JWJ-01-218)

[0247] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (79 mg, 0.16 mmol), which yielded a yellow solid (3.6 mg, 4%) with 91% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.08 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J= 8.2 Hz, 1H), 7.25 (t, J= 7.9 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.24 (s, 1H), 5.75 (s, 1H), 4.96 (dd, J = 13.1, 5.3 Hz, 1H), 4.23 (t, J= 7.9 Hz, 2H), 3.06 (t, J= 7.6 Hz, 2H), 2.86 - 2.78 (m, 1H), 2.36 (d, J= 18.3 Hz, 1H), 1.96 - 1.90 (m, 1H), 1.23 (s, 2H). MS (ESI) / z 585.2 (M + H)+.3-(3-((3-(((3-Chloro-4-(trifluoromethyl)phenethyl)amino)(phenyl)methyl)phenyl)amino)-2,5- di oxo-2, 5-dihydro- 1H-pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01-212)

[0248] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (115 mg, 0.28 mmol), which yielded a yellow solid (13 mg, 8%) with 94% purity. 1H NMR (500 MHz, DM SO- / 6) 5 11.06 (s, 1H), 9.80 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.37 (dd, J = 14.1, 7.8 Hz, 3H), 7.26 (t, J= 7.5 Hz, 3H), 7.22 (d, J= 8.1 Hz, 1H), 7.17 (t, J= 7.3 Hz, 1H), 7.11 (d, J= 7.5 Hz, 1H), 5.62 (s, 1H), 4.96 (dd, J = 13.0, 5.4 Hz, 1H), 4.86 (s, 1H), 2.85 (q, J = 4.8, 2.6 Hz, 3H), 2.73-2.66 (m, 2H), 2.61-2.53 (m, 1H), 2.05-1.93 (m, 2H), 1.23 (s, 1H). MS (ESI) m / z 611.3 (M + H)+.3-(3-((3-(3-((3-Chloro-4-(trifluoromethyl)phenethyl)amino)pentan-3-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro- 1H -pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-208)

[0249] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (44 mg, 0.11 mmol), which yielded a yellow solid (2.0 mg, 11%) with 95% purity. 1H NMR (500 MHz, DMSO-d6) 5 11.07 (s, 1H), 9.87 (s, 1H), 8.86 (s, 2H), 7.74 (d, J= 8.2 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J= 5.6 Hz, 1H), 7.48 (s, 1H), 7.38 - 7.35 (m, 1H), 7.33 (d, 7= 8.2 Hz, 1H), 5.83 (s, 1H), 4.98 (dd, J= 13.0, 5.4 Hz, 1H), 2.99 (dd, J = 9.6, 6.0 Hz, 2H), 2.91 (d, J = 18.3 Hz, 2H), 2.88 - 2.82 (m, 1H), 2.62 - 2.55 (m, 2H), 2.19 (dq, J= 13.9, 6.8 Hz, 2H), 2.12 - 2.05 (m, 2H), 2.02 - 1.96 (m, 1H), 0.83 (t, J = 7.5 Hz, 6H). MS (ESI) m / z 591.3 (M + H)+.3-(3-((3-(2-((3-Chloro-4-(trifluoromethyl)phenethyl)amino)butan-2-yl)phenyl)amino)-2,5-dioxo-2, 5-dihydro-177-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-200)

[0250] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (33 mg, 0.089 mmol), which yielded a yellow solid (5.5 mg, 9%) with 96% purity. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.77 (s, 1H), 7.71 (d, 7= 8.0 Hz, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.34 (d, 7= 8.1 Hz, 1H), 7.26 (t, 7= 7.8 Hz, 1H), 7.22 (d, 7= 8.0 Hz, 1H), 7.08 (d, 7= 7.6 Hz, 1H), 5.59 (s, 1H), 4.97 (dd, 7= 13.0, 5.4 Hz, 1H), 2.86 (ddd, 7 = 16.9, 14.0, 5.5 Hz, 1H), 2.75 (t, J= 13 Hz, 3H), 2.57 (dq, 7= 10.8, 5.3 Hz, 2H), 2.39 (dd, 7 = 11.4, 6.7 Hz, 1H), 1.99 (d, 7 = 6.5 Hz, 2H), 1.59 (ddt, 7= 21.8, 14.7, 7.2 Hz, 2H), 1.31 (s, 3H), 0.63 (q, 7= 8.3, 7.8 Hz, 3H). MS (ESI) m / z 5 13 (M + H)+.3 -(3 -((3 -(2-((3 -(3 -Chloro-4-(trifluoromethyl)phenyl)propyl)amino)propan-2-yl)phenyl)amino)- 2, 5-dioxo-2,5-dihydro-177-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-216)

[0251] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (117 mg, 0.31 mmol), which yielded a yellow solid (8.7 mg, 5%) with 98% purity. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.79 (s, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J= 2.0 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.24 - 7.17 (m, 2H), 5.64 (s, 1H), 4.97 (dd, J = 13.0, 5.4 Hz, 1H), 2.86 (ddd, J = 16.9, 13.8, 5.4 Hz, 1H), 2.69 (t, J= 7.7 Hz, 2H), 2.62 - 2.52 (m, 1H), 2.45 (dd, 13.5, 4.4 Hz, 1H), 2.20 (t, J = 6.8 Hz, 2H), 2.03 - 1.94 (m, 1H), 1.67 (p, J = 7.0 Hz, 2H), 1.35 (s, 6H), 1.23 (s, 1H). MS (ESI) m / z 5113 (M + H)+.3-(3-((3-(2-((3-Chloro-4-(trifluoromethyl)phenethyl)amino)propan-2-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro- 1H -pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-203)

[0252] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (33 mg, 0.092 mmol), which yielded a yellow solid (2.3 mg, 4%) with 99% purity. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.77 (s, 1H), 7.71 (d, J= 8.1 Hz, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.34 (d, J= 8.1 Hz, 1H), 7.27 (t, J= 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (d, J= 7.6 Hz, 1H), 5.61 (s, 1H), 4.97 (dd, J= 13.0, 5.4 Hz, 1H), 2.87 (ddd, J = 17.9, 13.8, 5.4 Hz, 1H), 2.73 (t, J = 7.0 Hz, 2H), 2.62 - 2.54 (m, 1H), 2.47 (d, J= 7.1 Hz, 2H), 2.04 - 1.95 (m, 2H), 1.34 (s, 6H), 1.23 (s, 1H). MS (ESI) m / z 563.3 (M + H)+.3-(3-((4-(l-(4-Chloro-3-(trifluoromethyl)benzyl)piperidin-3-yl)phenyl)amino)-2,5-dioxo-2,5- dihydro- I / / pyrrol- 1 -yl)piperidine-2, 6-dione (JWJ-01-310)

[0253] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (27 mg, 0.072 mmol), which yielded a yellow solid (5.0 mg, 10%) with 98% purity. 1H NMR (400 MHz, DMSO-d6) 5 7.73 (d, J = 1.9 Hz, 1H), 7.66-7.57 (m, 2H), 7.23 (d, J= 8.3 Hz, 2H), 7.18 (d, J= 8.4 Hz, 2H), 5.49 (d, J= 25.8 Hz, 1H), 4.88 (dd, J= 12.8, 5.4 Hz, 1H), 3.54 (d, J= 22 Hz, 2H), 2.85- 2.67 (m, 4H), 2.56-2.50 (m, 1H), 2.05-1.87 (m, 3H), 1.77 (d, J = 12.3 Hz, 1H), 1.67 (d, J = 1H), 1.55 (d, J = 12.8 Hz, 1H), 1.47-1.32 (m, 1H), 1.19 (s, I H). MS (ESI) m z 575,2 (M + H) .3-(3-((3-(3-((4-Chloro-3-(trifluoromethyl)phenethyl)amino)pentan-3-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-1H-pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-300)

[0254] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (27 mg, 0.071 mmol), which yielded a yellow solid (3.5 mg, 7%) with 94% purity. 1H NMR (400 MHz, DMSO-c76) 5 11.08 (s, 1H), 9.88 (s, 1H), 8.85 (s, 1H), 7.68 (dd, J = 5.3, 2.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.53-7.45 (m, 4H), 7.36 (t, J = 4.2 Hz, 1H), 5.82 (s, 1H), 4.98 (dd, J= 13.0, 5.4 Hz, 1H), 2.96 (d, J = 5.9 Hz, 2H),2.94-2.79 (m, 3H), 2.58 (d, .7= 17.8 Hz, 1H), 2.17 (p, J= 7.7 Hz, 2H), 2.11-2.02 (m, 2H), 2.01- 1.93 (m, 1H), 0.82 (t, J= 7.2 Hz, 6H). MS (ESI) m / z 591.3 (M + H)+.3-(3-((3-(3-((Benzylamino)methyl)pentan-3-yl)phenyl)amino)-2,5-di oxo-2, 5-dihydro-177-pyrrol-1 -yl)piperidine-2, 6-dione (JWJ-01-301)

[0255] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (67 mg, 0.24 mmol), which yielded a yellow solid (2.0 mg, 2%) with 91% purity. 1H NMR (400 MHz, DMSO-d6) 5 11.09 (s, 1H), 9.81 (s, 1H), 8.36 (d, J= 8.8 Hz, 2H), 7.50 (dd, J= 6.8, 3.0 Hz, 2H), 7.46-7.41 (m, 3H), 7.37 (d, J= 7.9 Hz, 1H), 7.31 (dd, J= 7.8, 1.8 Hz, 1H), 7.25 (s, 1H), 7.02 (d, J= 7.7 Hz, 1H), 5.64 (s, 1H), 4.99 (dd, J= 13.0, 5.4 Hz, 1H), 4.13 (s, 2H), 3.09 (s, 2H), 2.93-2.81 (m, 1H), 2.59 (d, J = 13.8 Hz, 1H), 2.05-1.96 (m, 1H), 1.69 (q, J= 7.4 Hz, 4H), 0.50 (t, J = 13 Hz, 6H). MS (ESI) m / z 489.2 (M + H)+.3-(3-((3-(3-(((4-Chloro-3-(trifluoromethyl)benzyl)amino)methyl)pentan-3-yl)phenyl)amino)-2,5- di oxo-2, 5-dihydro-1H -pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-303)

[0256] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (45 mg, 0.12 mmol), which yielded a yellow solid (2.9 mg, 4%) with 94% purity. 1H NMR (400 MHz, DMSO-d6) 5 11.08 (s, 1H), 9.80 (s, 1H), 8.46 (s, 2H), 8.02 (d, J = 1.8 Hz, 1H), 7.83-7.76 (m, 2H), 7.38-7.29 (m, 3H), 7.05 (d, J =7.7 Hz, 1H), 5.67 (s, 1H), 4.98 (dd, J= 12.9, 5.4 Hz, 1H), 4.24 (s, 2H), 3.17 (d, .7 = 4.5 Hz, 2H), 2.92-2.81 (m, 1H), 2.58 (d, J = 19.1 Hz, 1H), 2.00 (dd, J = 10.5, 5.2 Hz, 1H), 1.72 (d, J = 7.5 Hz, 4H), 0.58 (t, J= 7.2 Hz, 6H). MS (ESI) m / z 591.3 (M + H)+.3 -(3 -((3 -( 1 -(4-Chl oro-3 -(trifluoromethy l)benzyl)pyrrolidin-2-yl)pheny l)amino)-2, 5 -dioxo-2, 5 - dihydro- 177pyrrol-l-yl)piperidine-2, 6-dione (JWJ-01-308)

[0257] Title compound was generated via general procedure of substitution using corresponding reductive amination intermediate (56 mg, 0.16 mmol), which yielded a yellow solid (8.6 mg, 10%) with 96% purity. 1H NMR (400 MHz, DMSO-i / 6) 5 11.08 (s, 1H), 9.84 (s, 1H), 7.67-7.57 (m, 3H), 7.46 (s, 1H), 7.36-7.26 (m, 2H), 7.16 (d, J = 7.3 Hz, 1H), 5.65 (d, J = 1.9 Hz, 1H), 4.97 (dd, J= 12.9, 5.4 Hz, 1H), 3.71 (d, J= 13.9 Hz, 1H), 3.47 (t, J= 8.1 Hz, 1H), 3.31 (d, J= 14.1 Hz, 1H), 2.99 (t, J= 8.5 Hz, 1H), 2.94-2.81 (m, 1H), 2.58 (d, J= 17.5 Hz, 1H), 2.45 (dd, <7= 13.2, 4.4 Hz, 1H), 2.22 (dq, .7= 21.3, 12.0, 10.4 Hz, 2H), 1.98 (dd, .7= 9.6, 4.2 Hz, 1H), 1.81 (d, J= 9.7 Hz, 2H), 1.63 (t, J= 13.8 Hz, 1H). MS (ESI) m / z 561.2 (M + H)+.REFERENCES REFERRED TO HEREIN1 National Cancer Institute, D. S. R. P.2 National Cancer Institute DCCPS Surveillance Research Program, in Underlying mortality data provided by NCHS (www.cdc.gov / nchs) .3 Cox, A. D., Fesik, S. W., Kimmelman, A. 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[0258] It will be understood from the foregoing description that various modifications and changes may be made in the various embodiments of the present disclosure without departing from their true spirit. The description provided herein is intended for purposes of illustration only and is not intended to be construed in a limiting sense. Thus, while the presently disclosed inventive concepts have been described herein in connection with certain embodiments so that aspects thereof may be more fully understood and appreciated, it is not intended that the presently disclosed inventive concepts be limited to these particular embodiments. On the contrary, it is intended that all alternatives, modifications and equivalents are included within the scope of the presently disclosed inventive concepts as defined herein. Thus the examples described above, which include particular embodiments, will serve to illustrate the practice of the presently disclosed inventive concepts, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of particular embodiments of the presently disclosed inventive concepts only and are presented in the cause of providing what is believed to be a useful and readily understood description of procedures as well as of the principles and conceptual aspects of the inventive concepts. Changes may be made in the construction and formulation of the various components and compositions described herein, the methods described herein or in the steps or the sequence of steps of the methods described herein without departing from the spirit and scope of the presently disclosed inventive concepts.

Claims

What is claimed is:

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound which inhibits or degrades Zinc Finger and BTB Domain Containing 11 (ZBTB11).

2. The method of claim 1, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

3. The method of claim 1 or 2, wherein the cancer is characterized by a K-Ras mutation.

4. The method of any one of claims 1-3, wherein the cancer is a K-Ras inhibitor-resistant cancer.

5. The method of any one of claims 1-3, wherein the cancer is resistant or refractory to treatment with an additional therapeutic intervention in the absence of the compound.

6. The method of claim 5, further comprising administering the additional therapeutic intervention.

7. The method of claim 5 or 6, wherein the additional therapeutic intervention comprises chemotherapy, targeted therapy, immunotherapy, a kinase inhibitor, Ras pathway inhibitors, DNA damaging agents, and / or a PARP inhibitor.

8. The method of any one of claims 1-7, wherein the cancer relies on elevated oxidative phosphorylation for survival.

9. A method of treating a ZB TB 11 -related disease or disorder in a subject in need thereof, comprising administering to the subject a compound which inhibits or degrades Zinc Finger and BTB Domain Containing 11 (ZBTB11).

10. The method of claim 9, wherein ZBTB11 -related disease or disorder is characterized by elevated oxidative phosphorylation.

11. A method of treating a disease or disorder associated with elevated oxidative phosphorylation in a subject in need thereof, comprising administering to the subject a compound which inhibits or degrades Zinc Finger and BTB Domain Containing 11 (ZBTB11).

12. A method of inhibiting oxidative phosphorylation in a subject, comprising administering to the subject a compound which inhibits or degrades Zinc Finger and BTB Domain Containing 11 (ZBTB 11).

13. The method of any one of claims 1-12, wherein the compound is a degrader of ZBTB11.

14. The method of claim 13, wherein the compound binds the E3-ligase CRL4-CRBN and promotes interaction with ZBTB11 by binding at the interface of ZBTB11 and CRBN, leading to ZBTB 11 ubiquitination and degradation.

15. The method of any one of claims 1-14, wherein the compound is a compound of Formula (I):wherein: each X1is independently O or S;X2is a bond, optionally substituted alkylene or heteroalkylene, optionally substituted cycloalkylene or heterocycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, — O — , — N(RA) — , — S — , — C(=O) — , — C(=O)O — , — C(=O)NRA— , — NRAC(=O)—, — NRAC(=O)RA— , — C(=O)RA— , — NRAC(=O)O— , — NRAC(=O)N(RA)—, — OC(=O)— , — OC(=O)O— , — OC(=O)N(RA)— , — S(O)2NRA— , or — NRAS(O)2— ;X3is a bond, optionally substituted alkylene or heteroalkylene, optionally substituted cycloalkylene or heterocycloalkylene, optionally substituted arylene or heteroarylene, — O— , — N(RB)— , — S— , — C(=O)— , — C(=O)O— , — C(=O)NRD— , — NRBC(=0)— , — NRBC(=O)RB— , — C(=O)RB— , — NRBC(=O)O— , — NRBC(=O)N(RA)— , — OC(=O)— , — OC(=O)O— , — OC(=O)N(RB)— , — S(O)2NRB— , or — NRBS(O)2— ;A1is optionally substituted aryl or heteroaryl;A2is optionally substituted aryl or heteroaryl;R1is H, optionally substituted alkyl, halogen, a bond with A1, or optionally substituted alkylene forming a bond with A1; each R2and R3is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, optionally substituted alkylene forming a bond with an RB, or R2and R3are taken together withthe carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl; each R4and R5, when present, is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, or two R4or two R5are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl;1 is 0 or 1; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; each RA, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; andRB, if present, is H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl; or a bond with an optionally substituted alkylene of R2or R3; or a pharmaceutically acceptable salt thereof.

16. The method of claim 15, wherein each X1is O.

17. The method of claim 15 or 16, wherein X2is -NH-.

18. The method of any one of claims 15-17, wherein X3is -NH- or -N(RB)-, wherein RBis a bond with an optionally substituted alkylene of R2or R3.

19. The method of any one of claims 17-18, wherein A1is optionally substituted phenyl or pyridyl.

20. The method of claim 19, wherein A1has the structure21. The method of any one of claims 15-20, wherein A2is optionally substituted phenyl.

22. The method of any one of claims 15-21, wherein A2is substituted by one substituent R6and further optionally substituted by one or more R7, wherein:R6is -CF3 or halogen; and each R7is independently halogen, — CN, — ORC, — S(=O)2RC, — N(RC)2, —substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; and wherein each Rcis independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl.

23. The method of claim 22, wherein R6is -CF3 or chloro.

24. The method of claim 22 or 23, wherein 1 or 2 R7are present and each R7is independently -CF3 or chloro.

26. The method of claim 22, wherein A2is27. The method of any one of claims 15-26, wherein R1is H.

28. The method of any one of claims 15-27, wherein 1 is 1.

29. The method of claim 28, wherein each R2and R3is independently H, methyl, or ethyl, or wherein R2and R3are taken together with the carbon atom to which they are attached to form a cyclobutyl.

30. The method of claim 28, wherein R2is C2 alkylene forming a bond with an RBand R3isH.

31. The method of any one of claims 15-30, wherein n is 0, 1, or 2.

32. The method of any one of claims 15-31, wherein each R4is H.

33. The method of any one of claims 15-32, wherein m is 1 or 2.

34. The method of any one of claims 15-33, wherein each R?is H.

35. The method of any one of claims 1-34, wherein the compound is one provided in Table 1, or a pharmaceutically acceptable salt thereof.

36. A compound having a structure according to Formula (la):Formula (la) wherein: each X1is independently O or S;A2is phenyl substituted by one substituent R6and further optionally substituted by one or more R7, wherein:R6is -CF3; and each R7is independently halogen, — CN, — ORC, — S(=O)2RC, — N(RC)2, — S(=O)2N(RC)2, — C(=O)Rc, — OC(=O)Rc, — C(=O)ORc, — OC(=O)ORc, — C(=0)N(RC)2, — 0C(=0)N(RC)2, — NRCC(=0)N(RC)2, — NRCC(=O)RC, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; and wherein each Rcis independently optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl;R1is H, optionally substituted alkyl, halogen, or optionally substituted alkylene forming a bond with A1; each R2and R3is independently optionally substituted alkyl, optionally substituted alkylene forming a bond with an RB, or R2and R3are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkyl;each R4and R5, when present, is independently H, optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, or two R4or two R?are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl or heterocycloalkylR8is H, optionally substituted alkyl or heteroalkyl, optionally substituted cycloalkyl or heterocycloalkyl, optionally substituted aryl or heteroaryl, -CN, or halogen; m is 1, 2, or 3; n is 0, 1, 2, or 3; andRBis H or a bond with an optionally substituted alkylene of R2or R3; or a pharmaceutically acceptable salt thereof, and37. The compound of claim 36, wherein each X1is O.

38. The compound of claim 36 or 37, wherein A2is substituted 0, 1 or 2 R7.

39. The compound of any one of claims 36-38, wherein each R7is independently chloro or - CF3.

40. The compound of any one of claims 36-39, wherein R1is H.

41. The compound of any one of claims 36-40, wherein R2and R3are each independently methyl, ethyl, propyl, or taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl.

42. The compound of any one of claims 36-41, wherein RBis H.

43. The compound of any one of claims 36-42, wherein n is 0.

44. The compound of any one of claims 36-43, wherein m is 2.

45. The compound of any one of claims 36-44, wherein each R5is H.

46. The compound of any one of claims 36-45, wherein R8is H.

47. The compound of any one of claims 36-46, wherein the compound a structure according to Formula (laa) or Formula (lab), or a pharmaceutically acceptable salt thereof:(lab), wherein,R8is H or Ci-6 alkyl; p is 1, 2 or 3; andR1Ais H or Ci-6 alkyl.

48. The compound of claim 47, wherein R8is H or methyl.

49. The compound of claim 48, wherein R8is H.

50. The compound of any one of claims 47-49, wherein R1Ais H or methyl.

51. The compound of claim 50, wherein R1Ais H.

52. The compound of any one of claims 36-51, wherein A2is optionally substituted phenyl.

53. The compound of any one of claims 36-52, wherein A2is substituted by one substituent R6and further optionally substituted by one or more R7, wherein:R6is -CF3 or halogen; and each R7is independently halogen, — CN, — ORC, — S(=O)2RC, — N(RC)2, — c, —optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl; andwherein each Rcis independently optionally substituted alkyl, optionally substituted cycloalkyl or heterocycloalkyl, or optionally substituted aryl or heteroaryl.

54. The compound of claim 53, wherein R6is -CF3 or chloro.

55. The compound of claim 53 or 54, wherein 1 or 2 R7are present and each R7is independently -CF3 or chloro.

58. The compound of any one of claims 47-57, wherein p is 1 or 2.

59. The compound of any one of claims 47-57, wherein p is 1.

60. A pharmaceutical composition comprising the compound according to any one of claims36-59, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

61. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of claims 36-59, or a pharmaceutical composition of claim 60.

62. The method of claim 61, wherein the compound degrades Zinc Finger and BTB Domain Containing 11 (ZBTB11).

63. The method of claim 61 or 62, wherein the disease or disorder is characterized by elevated oxidative phosphorylation.

64. The method of any one of claims 61-63, wherein the disease or disorder is cancer.

65. The method of claim 64, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

66. The method of any one of claims 64 or 65, wherein the cancer is characterized by a K- Ras mutation.

67. The method of any one of claims 64-66wherein the cancer is a K-Ras inhibitor-resistant cancer.

68. The method of any one of claims 64-67, wherein the cancer relies on elevated oxidative phosphorylation for survival.

69. The method of any one of claims 61-68, wherein the compound binds the E3-ligase CRL4-CRBN and promotes interaction with ZBTB11 by binding at the interface of ZBTB 11 and CRBN, leading to ZBTB 11 ubiquitination and degradation.

70. The method of any one of claims 61-69, wherein the disease or disorder resistant or refractory to treatment with an additional therapeutic intervention in the absence of the compound.

71. The method of any one of claims 61-70, further comprising administering an additional therapeutic intervention.

72. The method of claim 71, wherein the additional therapeutic intervention comprises chemotherapy, targeted therapy, immunotherapy, a kinase inhibitor, Ras pathway inhibitors, DNA damaging agents, and / or a PARP inhibitor.

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