EP4777110A1 - Modulators of bcl6 for use in a method of treating a cancer or an autoimmune disease - Google Patents

Abstract

Provided herein are compounds and compositions thereof for modulating BCL6. In some embodiments, the compounds and compositions are provided for treatment of cancer or an autoimmune disease. In some embodiments, the compounds are of Formula (IA):

Description

MODULATORS OF BCL6 FOR USE IN A METHOD OF TREATING A CANCER OR AN AUTOIMMUNE DISEASE

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority of US Provisional Application No. 63/538,402, filed September 14, 2023, which is incorporated by reference herein in its entirety.

FIELD

[0002] The present disclosure relates generally to compounds, compositions, and methods for preparation and use of the compounds and compositions for treating cancer or an autoimmune disease.

BACKGROUND

[0003] BCL6 (B cell lymphoma 6) is a member of the BTB/POZ-zinc finger family that contains an N-terminal BTB/POZ domain and a zinc finger at the C-terminus. As a transcription factor for T follicular helper (Tfh) cells, BCL6 is required for germinal center (GC) formation of naive B cells and hence antibody affinity maturation. BCL6 was initially discovered as an oncogene in diffuse large B-cell lymphomas (DLBCLs) and its role has been implicated in many types of diseases including B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small lung cancer (NSCLC) (Cardenas et al., Clin Cancer Res 2017, 23, 885- 893). The N-terminal BTB/POZ domain binds to and recruits of co-repressor molecules such as SMRT, NCOR1, and BCOR, to form class I and II histone deacetylase complexes, and the C- terminal zinc fingers bind to specific DNA recognition sequences (Yang et al., Cell Dev. Biol. 2019, 7, 272). Upon binding to its target genes and forming complexes, BCL6 reduces RNA expression of its targets, including several key tumor supressors. Over-expression of BCL6, common in malignanies such as Non-Hodgkin’s lymphoma (NHL), leads to ectopic repression of cell cycle and DNA repair checkpoint proteins, causing unrestricted cell proliferation and tumorgenesis.

[0004] GC reponses are known to result in increased production of pathogenic autoantibodies which are responsible for several diseases, suggesting that methods to suppress or degrade BCL6 hold potential therapeutic applicability. Structural characterization of the cocrystal structures of the BCL6 BTB/POZ domain and co-repressors has shown that binding occurs at the lateral grooves formed by the interface between BCL6 BTB/POZ homodimers (Melnick et al., Mol. Cell Biol. 2002, 22, 1804-1818; Ghetu et al., Mol. Cell. 2008, 29, 384-391). Since then, specific ligands that bind to this site have been investigated, purposed to exploit the binding affinity towards the lateral grooves to render BCL6 as a druggable target.

[0005] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes. Ubiquitination of the protein is accomplished by an E3 ubiquitin ligase that binds to a protein and adds ubiquitin molecules to the protein, thus marking the protein for proteasome degradation. [0006] Harnessing the UPP for therapeutic use has received significant interest (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising therapy uses proteolysis targeting chimeras, commonly referred to as PROTACs, to effect removal of unwanted proteins by protein degradation (Scheepstra et al., Comp. Struct. Biotech. J.2019, 17, 160-176). PROTACS are ligand directed degraders that bring together an E3 ligase and a target protein that is to be degraded. These bivalent molecules usually consist of an E3 ligase ligand connected through a linker moiety to small molecule that binds to the target protein. A PROTAC positions the E3 ligase at the appropriate distance and orientation to the target protein, allowing the latter to be ubiquitinated. The ubiquitinated target protein is subsequently recognized by the proteasome, where it is degraded. [0007] Accordingly, in one aspect, provided herein are compounds that target BCL6 for degradation. SUMMARY [0008] Described herein, in certain embodiments, are compounds and compositions thereof for modulating BCL6. In various embodiments, the compounds and compositions thereof may be used for treatment of cancer. [0009] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. BRIEF DESCRIPTION OF THE FIGURES [0010] FIG.1. Schematic representation of BMS-986458 mechanism as a BCL6-LDD. Compound-induced proximity to the CRBN E3 ligase facilitated the ubiquitination of BCL6 resulting in degradation by the 26S proteasome. In DLBCL, the loss of BCL6 leads to cell cycle arrest, loss of DNA damage repair, and eventual cell death through apoptosis. [0011] FIG.2. BCL6 protein levels evaluated by MSD-ECL assay following treatment with BMS-986458 in (A) OCI-LY-1 and (B) WSU-DLCL-2 at 2 h and 4 h, respectively. The relative BCL6 protein levels (C) and 5-day proliferation response (D) were independently assessed for both diastereomers, BMT-648592 (filled circles) and BMT-648599 (filled diamonds), relative to BMS-986458 (1:1 mixture) (filled squares) in OCI-LY-1. OCI-LY-1 cells treated with 10 nM BMS-986458 achieved full degradation of BCL6 within 2 h (F) and, when dosed at 10 nM, maintained greater that 90% BCL6 degradation for 5 days (G) as demonstrated by Western blot. The 5-day anti-proliferative response to BMS-986458 observed in OCI-LY-1 parental control was not observed in OCI-LY-1 CRBN-/- (H). Concentrations listed in µM. Abbreviations: DC50, concentration at half max degradation; DMSO, dimethyl sulfoxide, POC, percentage of DMSO control. [0012] FIG.3. Mass spectrometry proteomic analysis of OCI-LY-1 cells treated with BMS- 986458. Volcano plots demonstrating high substrate specificity of compound induced degradation at 4h treatment (A). BCL6 degradation is maintained at 24 h, however levels of downstream functional effectors are also impacted (B). Historic neo-substrates associated with CRBN-based degradation mechanisms (IKZF1, IKZF2, IKZF3, ZFP91, CSNK1A1, GSPT1) highlighted in blue. Statistical robustness threshold established where FDR p-value < 0.05, highlighted yellow and red squares. Cut-off for meaningful biological impact established at log- fold change = +/- 1, vertical dotted red lines. Concentrations listed in µM. Abbreviations: FDR, false discovery rate. [0013] FIG.4. Acute and Delayed Antiproliferative Response Following BMS-986458 Treatment. AUC values (μM • h) describing the anti-proliferative response to BMS-986458 over 5 day (diagonal fill) and 10 day (solid fill) treatments across equivalent dose range (0.015-100 nM).10 day DRCs have been adjusted by proliferation factor obtained following 5-day treatment on DMSO only control. Activity was assessed using CTG luminescent cell viability assay. GCB COO indicated by (*). [0014] FIG.5. Apoptotic and Anti-proliferative Response to BMS-986458 in Acute and Delayed Responsive Cell Lines. Viability (triangle data points, solid regression; left axis) and apoptosis (round data points, dotted regression; right axis) following exposure to BMS-896458 dose range up to 40 nM for 5 days in six DLBCL cell line models representing both acute and delayed response classification. Apoptotic activity was assessed using flow cytometry. Abbreviations: PoC, percentage of control; FC, flow cytometry; AUC, area under the concentration-time curve. [0015] FIG.6. Correlation of BMS-986458 Anti-proliferative Response to BCL6 Expression Levels. Ranked 10-day AUC values from DLBCL panel cell lines responses to BMS-986458 (6A). Ten-day AUC < 7 μM • h threshold used to define delayed sensitive versus resistant models as indicated by solid black line. Ranked BMS-986458 sensitivity represented by BCL6 baseline protein expression levels (6B). [0016] FIG.7. Anti-proliferative and Apoptotic Response of Doxorubicin-resistant DLBCL Models to BMS-986458. Viability and apoptosis curves following exposure to serially diluted doxorubicin or BMS-986458 for 5 days in three acquired-doxorubicin resistance (dashed lines) and corresponding matching parental DLBCL cell lines (solid lines) (A). Western protein analysis of DLBCL models of acquired doxorubicin resistance and their corresponding matching parental line in response to a 10 nM single dose BMS-986458 over a 72 h treatment period (B). Abbreviations: DoxR, doxorubicin resistant. [0017] FIG.8. Plasma/Tumor Exposure and Percent BCL6 Degradation in OCI-LY- 1 Xenografts following BID x 5 or BID x 3 Dosing with 30 mg/kg BMS-986458. Female CB.17- SCID mice with OCI-LY-1 tumors of approximately 500 mm³ were dosed with BMS-986458 twice daily at 30 mg/kg for five consecutive days (BID×5, AP9506) or three consecutive days (BID×3, AP9721) (n = 4/time point). Plasma and tumor samples were harvested at 6, 10, and 14 h post last dose to determine BMS-986458 concentrations. Tumors were processed to detect BCL6 levels with western blots (top panel images). Plasma (blue line) and tumor (red line) concentrations of BMS-986458 (left axis) are represented in graphs on the bottom panel. Green bars represent percent BCL6 degradation in BMS-986458 treated tumors compared with vehicle. Percent BCL6 degradation was calculated relative to the vehicle control (0% BCL6 degradation). Statistical analysis was performed using a one-way analysis of variance with Dunnett’s multiple comparisons test with all treatment groups and the data shown are in comparison with the vehicle control group. Results are presented as mean values with error bars representing standard error of the mean. Abbreviations: BCL6, B cell lymphoma 6; h, hours; BIDx5, twice daily dosing for 5 consecutive days; BIDx3, twice daily dosing for 3 consecutive days; ****p < 0.0001. [0018] FIG.9. Anti-tumor Activity of BMS-986458 in a OCI-LY-1 Xenograft Model with Twice Daily Dosing (BID) for 21 Consecutive Days (Study AP9776). Female CB.17-SCID mice were inoculated with 5 x 10⁶ OCI-LY-1 tumor cells in 1:1 Matrigel into the right flank. Mice were randomized into treatment groups (n = 9/group) at the time of treatment initiation. Test 3 article treatment started on Day 19 when average tumor volumes were approximately 196 mm . Tumor volume reduction is calculated as the center difference in average tumor volume between BMS-986458-treated mice and vehicle-treated mice. Day 37, the final tumor measurement day. Results are presented as mean values with error bars representing SEM. Statistical analysis was performed using a two-way analysis of variance with Bonferroni’s multiple comparisons test with all the treatment groups and the data shown are in comparison with vehicle control group. Abbreviations: BID, twice daily dosing; Vehicle, 10% Captisol in 25 mM citrate buffer, pH 3; ****p < 0.0001. [0019] FIG.10. BCL6 Degradation in OCI-LY-1 Tumors Treated with Twice Daily Dosing for 21 Consecutive Days of BMS-986458 Collected at 6 h (A), 10 h (B), and 14 h (C) Following 3 the Final Dose. started on Day 19 when average tumor volumes were approximately 196 mm . Three days after the final tumor measurement, on Day 40, each BMS-986458-treated group (n = 9) was split into three cohorts of 3 mice each for PD and PK sampling. Tumors were collected at 6, 10, and 14 h following the final dose and were split in half for PD and PK analysis. For PD analysis, tumors were processed into lysates and analyzed by western blot for degradation of BCL6 protein (top panels, blot images). Plasma and tumor BMS-986458 concentrations and BCL6 degradation are depicted in bottom panel (graphs). Results are presented as mean integrated intensity values with error bars representing standard error of the mean. Statistical analysis was performed using a one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons test with all the treatment groups and the data shown are in comparison with vehicle control group. Abbreviations: BID, Twice daily dosing; Vehicle, 10% Captisol in 25 mM citrate buffer, pH3; ****p < 0.0001 Female CB.17-SCID mice were inoculated with 5 x 10⁶ OCI-LY-1 tumor cells in 1:1 Matrigel into the right flank. [0020] FIG.11. BMS-986458 Treatment Induces Loss of Follicular T-Helper Cell Identity and Perturbation of Cytokine Secretion. Phenotypic response to BMS-986458 was evaluated in iTfh isolated from PBMCs from three independent healthy donors. A shows the treatment schedule followed to induce iTfh differentiation from naive CD4+CD45RA+ T-cells and timing of flow analysis using gating strategy shown (B). Analysis of iTfh at day 4 showing induction of BCL6 expression, expression of Tfh surface markers CXCR5/PD1 and secretion of canonical Tfh cytokine IL-21 (C). BMS-986458 dose and time-dependent modulation BCL6 protein and Tfh phenotype acquired through loss of CXCR5+PD1+ as determined by flow cytometry (D-F). IL-10 and IL-121 secretion was assessed at day 4 and day 8, respectively post-BMS-986458 treatment using ECL-MSD (Panel G). Non-linear regression analysis was performed using GraphPad Prism v9.4.0. Significance of donor variation in all assays was evaluated using 2-way ANOVA, significance = p-value > 0.05 (Panel H). Abbreviations: ActA, Activin A; iTfh, T- follicular helper cells; D4, Day 4; DMSO, dimethyl sulfoxide; ns, not significant. [0021] FIG.12. BMS-986458 Treatment Does Not Impact Ex Vivo Neutrophil Viability or Maturation Dynamics. CD34+ cells derived from HD bone marrow were exposed to BMS- 986458 at concentrations indicated for 14 days refreshing treatment and cell culture media every two days. Neutrophil maturation stages were assessed over time by flow cytometry. Data represent the mean percentage of cells within each myeloid population across three donors. Abbreviations: DMSO, dimethyl sulfoxide. [0022] FIG 13A. Flowchart of BOIN Design in Part A1 Stage 1 of Example B4. [0023] FIG.13B. Flowchart of TITE-BOIN12 Design in Part A1 Stage 2 of Example B4. DETAILED DESCRIPTION Definitions [0024] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of”. Consequently, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention. [0025] The term “consisting of” means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term “consisting of” excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved. [0026] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive. [0027] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms “about” and “approximately” mean ± 20%, ± 10%, ± 5%, or ± 1% of the indicated range, value, or structure, unless otherwise indicated. [0028] “Amino” refers to the -NH₂ radical. [0029] “Cyano” refers to the -CN radical. [0030] “Nitro” refers to the -NO2 radical. [0031] “Oxa” refers to the -O- radical. [0032] “Oxo” refers to the =O radical. [0033] “Thioxo” refers to the =S radical. [0034] “Imino” refers to the =N-H radical. [0035] “Oximo” refers to the =N-OH radical. [0036] “Hydrazino” refers to the =N-NH2 radical. [0037] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅ alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1- C₄ alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^a, -OC(O)- N(R^a)₂, -N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)_tOR^a (where t is 1 or 2), -S(O)_tR^a (where t is 1 or 2) and -S(O)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0038] “Alkyl-OH” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by -OH. For example, “C1-C6 alkyl-OH” refers to a C₁-C₆ alkyl which is substituted by one or more -OH groups. An alkyl-OH may contain multiple hydroxy groups that are attached to the same carbon atom or to multiple carbon atoms. [0039] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above. [0040] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^a, -OC(O)- N(R^a)₂, -N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)_tOR^a (where t is 1 or 2), -S(O)_tR^a (where t is 1 or 2) and -S(O)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0041] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^a, -OC(O)- N(R^a)₂, -N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)_tOR^a (where t is 1 or 2), -S(O)tR^a (where t is 1 or 2) and -S(O)tN(R^a)2 (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0042] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C₁-C₄ alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C₁ alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a)C(O)OR^a, -OC(O)- N(R^a)₂, -N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)_tOR^a (where t is 1 or 2), -S(O)_tR^a (where t is 1 or 2) and -S(O)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0043] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^ –electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)2, -R^b-N(R^a)2, -R^b-C(O)R^a, -R^b-C(O)OR^a, -R^b-C(O)N(R^a)₂, -R^b-O-R^c-C(O)N(R^a)₂, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)tR^a (where t is 1 or 2), -R^b-S(O)tR^a (where t is 1 or 2), -R^b-S(O)tOR^a (where t is 1 or 2) and -R^b-S(O)tN(R^a)2 (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0044] “Aralkyl” refers to a radical of the formula -R^c-aryl where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group. [0045] “Aralkenyl” refers to a radical of the formula -R^d-aryl where R^d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group. [0046] “Aralkynyl” refers to a radical of the formula -R^e-aryl, where R^e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain. [0047] “Carbocyclyl” refers to a stable non aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl may be saturated, (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as “carbocyclyl”. Examples of monocyclic carbocyclyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl”. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -OC(O)- N(R^a)₂, -N(R^a)C(O)R^a, -N(R^a)S(O)_tR^a (where t is 1 or 2), -S(O)tOR^a (where t is 1 or 2), -S(O)tR^a (where t is 1 or 2) and -S(O)tN(R^a)2 (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0048] “Carbocyclylalkyl” refers to a radical of the formula -R^c-carbocyclyl where R^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above. [0049] “Carbonyl” refers to a radical of the formula -C(O)R¹⁰R²⁰, wherein R¹⁰ and R²⁰ is independently selected from -OH, halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -R^a, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)2, -C(O)R^a, -C(O)OR^a, -C(O)N(R^a)2, -N(R^a) C(O)OR^a, -OC(O)- N(R^a)2, -N(R^a)C(O)R^a, -N(R^a)S(O)tR^a (where t is 1 or 2), -S(O)tOR^a (where t is 1 or 2), -S(O)_tR^a (where t is 1 or 2) and -S(O)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0050] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents. [0051] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group has one to six carbon atoms and is substituted by one or more halo radicals (C1-C6 haloalkyl), or the haloalkyl group has one to five carbon atoms and is substituted by one or more halo radicals (C1-C5 haloalkyl), or the haloalkyl group has one to three carbon atoms and is substituted by one or more halo radicals (C₁-C₃ haloalkyl). The halo radicals may be all the same or the halo radicals may be different. Unless specifically stated otherwise, a haloalkyl group is optionally substituted. [0052] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group. [0053] “Heterocyclyl” refers to a stable 3 to 18 membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, 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, and 1,1 dioxo thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(O)R^a, -R^b-C(O)OR^a, -R^b-C(O)N(R^a)₂, -R^b-O-R^c-C(O)N(R^a)₂, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)tR^a (where t is 1 or 2), -R^b-S(O)tR^a (where t is 1 or 2), -R^b-S(O)tOR^a (where t is 1 or 2) and -R^b-S(O)tN(R^a)2 (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0054] “N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. [0055] “C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2- morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like. [0056] “Heterocyclylalkyl” refers to a radical of the formula -R^c-heterocyclyl where R^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group. [0057] “Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-R^c heterocyclyl where R^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group. [0058] “Heteroaryl” refers to a radical derived from a 3 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(O)-R^a, -R^b-OC(O)-OR^a, -R^b-OC(O)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(O)R^a, -R^b-C(O)OR^a, -R^b-C(O)N(R^a)2, -R^b-O-R^c-C(O)N(R^a)2, -R^b-N(R^a)C(O)OR^a, -R^b-N(R^a)C(O)R^a, -R^b-N(R^a)S(O)tR^a (where t is 1 or 2), -R^b-S(O)tR^a (where t is 1 or 2), -R^b-S(O)_tOR^a (where t is 1 or 2) and -R^b-S(O)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0059] “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals. [0060] “C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals. [0061] “Heteroarylalkyl” refers to a radical of the formula -R^c-heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group. [0062] “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-R^c heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group. [0063] Embodiments of the disclosure are meant to encompass pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein, such as the compounds of Formula (I). [0064] As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride, formic, and mesylate salts. Others are well-known in the art, see for example, Remington’s Pharmaceutical Sciences, 18^th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19^th eds., Mack Publishing, Easton PA (1995). [0065] As used herein and unless otherwise indicated, the term “stereoisomer” or “stereoisomerically pure” means one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The compounds disclosed herein can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof. [0066] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011). [0067] “Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other: . [0068] As readily understood by one skilled in the art, a wide variety of functional groups and other stuctures may exhibit tautomerism and all tautomers of compounds of Formula (I) are within the scope of the present disclosure. [0069] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. [0070] It should also be noted the compounds disclosed herein can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I), sulfur-35 (³⁵S), or carbon-14 (¹⁴C), or may be isotopically enriched, such as with deuterium (²H), carbon-13 (¹³C), or nitrogen-15 (¹⁵N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the compounds disclosed herein, for example, the isotopologues are deuterium, carbon-13, and/or nitrogen-15 enriched compounds. As used herein, “deuterated”, means a compound wherein at least one hydrogen (H) has been replaced by deuterium (indicated by D or ²H), that is, the compound is enriched in deuterium in at least one position. [0071] The disclosure also includes “deuterated analogs” of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. When multiple deuterium atoms are present in a compound, the deuterium atoms may be on the same portion of the molecule (for example, on a single alkyl group or on a single ring) or on different portions of the molecule (for example, on separate alkyl groups or separate rings). Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. [0072] It is understood that, independently of stereoisomerical or isotopic composition, each compound disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Equally, it is understood that the isotopic composition may vary independently from the stereoisomerical composition of each compound referred to herein. Further, the isotopic composition, while being restricted to those elements present in the respective compound or salt thereof disclosed herein, may otherwise vary independently from the selection of the pharmaceutically acceptable salt of the respective compound. [0073] It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight. [0074] “Treating” as used herein, means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is a cancer, as described herein, or a symptom thereof. [0075] “Preventing” as used herein, means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is a cancer, as described herein, or symptoms thereof. [0076] The term “effective amount” in connection with a compound disclosed herein means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein. [0077] The term “subject” or “patient” as used herein include an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. In one embodiment, a subject is a human having or at risk for having A BCL6 mediated disease, or a symptom thereof. [0078] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment. Compounds [0079] In one aspect, provided herein is a compound of Formula (IA): or a pharmaceutically acceptable salt thereof, wherein: X¹ and X² are each independently N or CH, provided that at least one of X¹ and X² is N; R^1a and R^1b are each independently H, halo, or C₁-C₆ alkyl; R^2a and R^2b are each independently H, C₁-C₆ alkyl, -O(C₁-C₆ alkyl), -OH, halo, C₁-C₆ haloalkyl, or C1-C6 alkyl-OH, or R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₅ cycloalkyl, or R^2a and R^2b are taken together to form oxo; or R^1a and R^2a are taken together to form a bridging C2-C3 alkylene; R^3a and R^3b are each independently H, halo, or C₁-C₆ alkyl; R^4a and R^4b are each independently H, halo, or C₁-C₆ alkyl, or R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₅ cycloalkyl; R^5a and R^5b are each independently H, halo, or C₁-C₆ alkyl; w is 0 or 1; R⁶ is H or C1-C6 alkyl; R⁷ is H or C₁-C₆ alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R⁸ is Cl or -CN; R⁹ is F; X³ is N or CH; z is 0 or 1; R^10a and R^10b are each independently H or halo; R¹¹ is H, C₁-C₆ alkyl, -(C₁-C₆ alkylene)-(5- to 6-membered heterocyclyl), -(C₁-C₆ alkylene)- O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R¹² is H, halo, or C₁-C₆ alkyl; R¹³ is H or halo; R¹⁴ is H or C1-C6 alkyl; X⁴ is N or CR¹⁵; R¹⁵ is H or C₁-C₆ alkyl; X⁵ and X⁶ are each independently N or CH; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium. [0080] In a further aspect, provided herein is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X¹ and X² are each independently N or CH, provided that at least one of X¹ and X² is N; R^1a and R^1b are each independently H, halo, or C₁-C₆ alkyl; R^2a and R^2b are each independently H, C₁-C₆ alkyl, -OH, halo, or C₁-C₆ alkyl-OH, or R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₅ cycloalkyl, or R^2a and R^2b are taken together to form oxo; or R^1a and R^2a are taken together to form a bridging C2-C3 alkylene; R^3a and R^3b are each independently H, halo, or C1-C6 alkyl; R^4a and R^4b are each independently H, halo, or C₁-C₆ alkyl, or R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl; R^5a and R^5b are each independently H, halo, or C₁-C₆ alkyl; w is 0 or 1; R⁶ is H or C1-C6 alkyl; R⁷ is H or C₁-C₆ alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R⁸ is Cl or -CN; R⁹ is F; X³ is N or CH; z is 0 or 1; R^10a and R^10b are each independently H or halo; R¹¹ is H, C₁-C₆ alkyl, -(C₁-C₆ alkylene)-(5- to 6-membered heterocyclyl), -(C₁-C₆ alkylene)- O(C₁-C₆ alkyl), C₁-C₆ haloalkyl, C₁-C₆ alkyl-OH, or -(C₁-C₆ alkylene)-NH(C₁-C₆ alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R¹² is H, halo, or C1-C6 alkyl; R¹³ is H or halo; R¹⁴ is H or C1-C6 alkyl; X⁴ is N or CR¹⁵; R¹⁵ is H or C₁-C₆ alkyl; X⁵ and X⁶ are each independently N or CH; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium. [0081] In some embodiments, X¹ is CH and X² is N. In some embodiments, X¹ is N and X² is CH. In some embodiments, X¹ and X² are both N. [0082] In some embodiments, R^1a is H, halo, or C1-C6 alkyl. In some embodiments, R^1a is H, halo, or C₁-C₃ alkyl. In some embodiments, R^1a is H, F, Cl, Br, I, or C₁-C₃ alkyl. In some embodiments, R^1a is H, F, Cl, Br, I, methyl, ethyl, or propyl. [0083] In some embodiments, R^1a is H. [0084] In some embodiments, R^1a is halo. In some embodiments, R^1a is F, Cl, Br, or I. In some embodiments, R^1a is F. [0085] In some embodiments, R^1a is C1-C6 alkyl. In some embodiments, R^1a is C1-C3 alkyl. In some embodiments, R^1a is methyl, ethyl, or propyl. In some embodiments, R^1a is methyl. [0086] In some embodiments, R^1b is H, halo, or C₁-C₆ alkyl. In some embodiments, R^1b is H, halo, or C1-C3 alkyl. In some embodiments, R^1b is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R^1b is H, F, Cl, Br, I, methyl, ethyl, or propyl. [0087] In some embodiments, R^1b is H. [0088] In some embodiments, R^1b is halo. In some embodiments, R^1b is F, Cl, Br, or I. In some embodiments, R^1b is F. [0089] In some embodiments, R^1a and R^1b are each independently H, halo, or C₁-C₃ alkyl. In some embodiments, R^1a and R^1b are each independently H, F, Cl, Br, I, methyl, ethyl, or propyl. In some embodiments, R^1a and R^1b are each independently H or -CH3. [0090] In some embodiments, R^1b is C1-C6 alkyl. In some embodiments, R^1b is C1-C3 alkyl. In some embodiments, R^1b is methyl, ethyl, or propyl. In some embodiments, R^1b is methyl. [0091] In some embodiments, R^2a is H, C1-C6 alkyl, -O(C1-C6 alkyl), -OH, halo, C1-C6 haloalkyl, or C1-C6 alkyl-OH. In some embodiments, R^2a is H, C1-C3 alkyl, -O(C1-C3 alkyl), - OH, F, Cl, Br, I, C1-C3 haloalkyl, or C1-C3 alkyl-OH. In some embodiments, R^2a is H, methyl, ethyl, propyl, -OCH₃, -OH, F, Cl, Br, I, -CF₃, -CHF₂, -CCl₃, -CH₂OH, -(CH₂CH₂)OH, or -(CH₂CH₂CH₂)OH. [0092] In some embodiments, R^2a is H. [0093] In some embodiments, R^2a is C1-C6 alkyl. In some embodiments, R^2a is C1-C3 alkyl. In some embodiments, R^2a is methyl, ethyl, or propyl. In some embodiments, R^2a is methyl. [0094] In some embodiments, R^2a is -O(C1-C6 alkyl). In some embodiments, R^2a is -O(C1- C3 alkyl). In some embodiments, R^2a is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R^2a is -OCH₃. [0095] In some embodiments, R^2a is -OH. [0096] In some embodiments, R^2a is halo. In some embodiments, R^2a is F, Cl, Br, or I. In some embodiments, R^2a is F. [0097] In some embodiments, R^2a is C₁-C₆ haloalkyl. In some embodiments, R^2a is C₁-C₆ haloalkyl containing 1-13 halogen atoms. In some embodiments, R^2a is C1-C3 haloalkyl. In some embodiments, R^2a is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R^2a is -CF₃, -CHF₂, -CH₂F, -CCl₃, -CHCl₂, -CH₂Cl, -CF₂Cl, -CFCl₂, -CH₂CF₃, -CH2CHF2, or -CH2CCl3. In some embodiments, R^2a is -CF3. [0098] In some embodiments, R^2a is C1-C6 alkyl-OH. In some embodiments, R^2a is C1-C3 alkyl-OH. In some embodiments, R^2a is -CH₂OH, -(CH₂CH₂)OH, or -(CH₂CH₂CH₂)OH. In some embodiments, R^2a is -CH₂OH. [0099] In some embodiments, R^2b is H, C1-C6 alkyl, -OH, halo, or C1-C6 alkyl-OH. In some embodiments, R^2b is H, C₁-C₃ alkyl, -OH, F, Cl, Br, I, or C₁-C₃ alkyl-OH. In some embodiments, R^2b is H, methyl, ethyl, propyl, -OH, F, Cl, Br, I, -CH₂OH, -(CH₂CH₂)OH, or -(CH2CH2CH2)OH. [00100] In some embodiments, R^2b is H. [00101] In some embodiments, R^2b is C₁-C₆ alkyl. In some embodiments, R^2b is C₁-C₃ alkyl. In some embodiments, R^2b is methyl, ethyl, or propyl. In some embodiments, R^2b is methyl. [00102] In some embodiments, R^2b is -O(C1-C6 alkyl). In some embodiments, R^2b is -O(C1- C₃ alkyl). In some embodiments, R^2b is -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, or -OCH(CH₃)₂. In some embodiments, R^2b is -OCH₃. [00103] In some embodiments, R^2b is -OH. [00104] In some embodiments, R^2b is halo. In some embodiments, R^2b is F, Cl, Br, or I. In some embodiments, R^2b is F. [00105] In some embodiments, R^2b is C1-C6 haloalkyl. In some embodiments, R^2b is C1-C6 haloalkyl containing 1-13 halogen atoms. In some embodiments, R^2b is C1-C3 haloalkyl. In some embodiments, R^2b is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R^2b is -CF₃, -CHF₂, -CH₂F, -CCl₃, -CHCl₂, -CH₂Cl, -CF₂Cl, -CFCl₂, -CH₂CF₃, -CH₂CHF₂, or -CH₂CCl₃. In some embodiments, R^2b is -CF₃. [00106] In some embodiments, R^2b is C1-C6 alkyl-OH. In some embodiments, R^2b is C1-C3 alkyl-OH. In some embodiments, R^2b is -CH2OH, -(CH2CH2)OH, or -(CH2CH2CH2)OH. In some embodiments, R^2b is -CH₂OH. [00107] In some embodiments, R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl. In some embodiments, R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₄ cycloalkyl. In some embodiments, R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro cyclobutyl. [00108] In some embodiments, R^2a and R^2b are taken together to form oxo. [00109] In some embodiments, R^1a and R^1b are both H, and at least one of R^2a and R^2b is other than H. [00110] In some embodiments, R^1a and R^2a are taken together to form a bridging C2-C3 alkylene. In some embodiments, R^1a and R^2a are taken together to form a bridging ethylene. [00111] In some embodiments, R^3a is H, halo, or C1-C6 alkyl. In some embodiments, R^3a is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R^3a is H, F, Cl, Br, I, methyl, ethyl, or propyl. [00112] In some embodiments, R^3a is H. [00113] In some embodiments, R^3a is halo. In some embodiments, R^3a is F, Cl, Br, or I. In some embodiments, R^3a is F. [00114] In some embodiments, R^3a is C₁-C₆ alkyl. In some embodiments, R^3a is C₁-C₃ alkyl. In some embodiments, R^3a is methyl, ethyl, or propyl. In some embodiments, R^3a is methyl. [00115] In some embodiments, R^3b is H, halo, or C1-C6 alkyl. In some embodiments, R^3b is H, F, Cl, Br, I, or C₁-C₃ alkyl. In some embodiments, R^3b is H, F, Cl, Br, I, methyl, ethyl, or propyl. [00116] In some embodiments, R^3b is H. [00117] In some embodiments, R^3b is halo. In some embodiments, R^3b is F, Cl, Br, or I. In some embodiments, R^3b is F. [00118] In some embodiments, R^3b is C1-C6 alkyl. In some embodiments, R^3b is C1-C3 alkyl. In some embodiments, R^3b is methyl, ethyl, or propyl. In some embodiments, R^3b is methyl. [00119] In some embodiments, R^4a is H, halo, or C₁-C₆ alkyl. In some embodiments, R^4a is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R^4a is H, F, Cl, Br, I, methyl, ethyl, or propyl. [00120] In some embodiments, R^4a is H. [00121] In some embodiments, R^4a is halo. In some embodiments, R^4a is F, Cl, Br, or I. In some embodiments, R^4a is F. [00122] In some embodiments, R^4a is C1-C6 alkyl. In some embodiments, R^4a is C1-C3 alkyl. In some embodiments, R^4a is methyl, ethyl, or propyl. In some embodiments, R^4a is methyl. [00123] In some embodiments, R^4b is H, halo, or C₁-C₆ alkyl. In some embodiments, R^4b is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R^4b is H, F, Cl, Br, I, methyl, ethyl, or propyl. [00124] In some embodiments, R^4b is H. [00125] In some embodiments, R^4b is halo. In some embodiments, R^4b is F, Cl, Br, or I. In some embodiments, R^4b is F. [00126] In some embodiments, R^4b is C₁-C₆ alkyl. In some embodiments, R^4b is C₁-C₃ alkyl. In some embodiments, R^4b is methyl, ethyl, or propyl. In some embodiments, R^4b is methyl. [00127] In some embodiments, R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl. In some embodiments, R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₄ cycloalkyl. In some embodiments, R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro cyclobutyl. [00128] In some embodiments, R^3a, R^3b, R^4a, and R^4b are each H. [00129] In some embodiements, at least one of R^3a and R^3b is other than H, and at least one of R^4a and R^4b is other than H. [00130] In some embodiments, R^5a is H, halo, or C₁-C₆ alkyl. In some embodiments, R^5a is H, F, Cl, Br, I, or C₁-C₃ alkyl. In some embodiments, R^5a is H, F, Cl, Br, I, methyl, ethyl, or propyl. [00131] In some embodiments, R^5a is H. [00132] In some embodiments, R^5b is H, halo, or C₁-C₆ alkyl. In some embodiments, R^5b is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R^5b is H, F, Cl, Br, I, methyl, ethyl, or propyl. [00133] In some embodiments, R^5b is H. [00134] In some embodiments, R^5a and R^5b are each H. [00135] In some embodiments, at least one of R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, and R^5b is other than H. [00136] In some embodiments, one, two, or three of R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, and R^5b is other than H. [00137] In some embodiments, one or two of R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, and R^5b is other than H. [00138] In some embodiments, w is 0. In some embodiments, w is 1. [00139] In some embodiments, is: . [00140] In some embodiments, x and y are each 0. In some embodiments, x is 0 and y is 1. In some embodiments, x is 1 and y is 0. [00141] In some embodiments, R⁶ is H or C1-C6 alkyl. In some embodiments, R⁶ is H or C1- C₃ alkyl. In some embodiments, R⁶ is H, methyl, ethyl, or propyl. [00142] In some embodiments, R⁶ is H. [00143] In some embodiments, R⁶ is C1-C6 alkyl. In some embodiments, R⁶ is C1-C3 alkyl. In some embodiments, R⁶ is methyl, ethyl, or propyl. In some embodiments, R⁶ is methyl. [00144] In some embodiments, x is 0, y is 1, and R⁶ is H. [00145] In some embodiments, x is 0, y is 1, and R⁶ is C1-C6 alkyl. In some embodiments, x is 0, y is 1, and R⁶ is C₁-C₃ alkyl. In some embodiments, x is 0, y is 1, and R⁶ is methyl. [00146] In some embodiments, R⁷ is H or C₁-C₆ alkyl. In some embodiments, R⁷ is H or C₁- C3 alkyl. In some embodiments, R⁷ is H, methyl, ethyl, or propyl. [00147] In some embodiments, R⁷ is H. [00148] In some embodiments, R⁷ is C1-C6 alkyl. In some embodiments, R⁷ is C1-C3 alkyl. In some embodiments, R⁷ is methyl, ethyl, or propyl. In some embodiments, R⁷ is methyl. [00149] In some embodiments, x is 1, y is 0, and R⁷ is H. [00150] In some embodiments, x is 1, y is 0, and R⁷ is C1-C6 alkyl. In some embodiments, x is 1, y is 0, and R⁷ is C1-C3 alkyl. In some embodiments, x is 1, y is 0, and R⁷ is methyl. [00151] In some embodiments, R⁸ is Cl. In some embodiments, R⁸ is -CN. [00152] In some embodiments, R⁹ is F. [00153] In some embodiments, X³ is N. In some embodiments, X³ is CH. [00154] In some embodiments, z is 0. In some embodiments, z is 1. [00155] In some embodiments, R^10a is H or halo. In some embodiments, R^10a is H, F, Cl, Br, or I. [00156] In some embodiments, R^10a is H. [00157] In some embodiments, R^10a is halo. In some embodiments, R^10a is H, F, Cl, Br, or I. In some embodiments, R^10a is F. [00158] In some embodiments, R^10b is H or halo. In some embodiments, R^10b is H, F, Cl, Br, or I. [00159] In some embodiments, R^10b is H. [00160] In some embodiments, R^10b is halo. In some embodiments, R^10b is H, F, Cl, Br, or I. In some embodiments, R^10b is F. [00161] In some embodiments, R¹¹ is H, C₁-C₆ alkyl, -(C₁-C₆ alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C₁-C₆ alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S. In some embodiments, R¹¹ is H, C₁-C₃ alkyl, -(C₁-C₃ alkylene)-(5- to 6-membered heterocyclyl), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH, or -(C1-C3 alkylene)-NH(C1-C3 alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S. In some embodiments, R¹¹ is H, C₁-C₃ alkyl, -(C₁-C₃ alkylene)-(5- to 6-membered heterocyclyl), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH, or -(C1-C3 alkylene)-NH(C1-C3 alkyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O. In some embodiments, R¹¹ is H, methyl, ethyl, propyl, -CD₃, -(CH₂)-(5- to 6-membered heterocyclyl), -(CH₂CH₂)-(5- to 6-membered heterocyclyl), -(CH₂CH₂CH₂)-(5- to 6-membered heterocyclyl), -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH₂CH₂CH₂OCH₂CH₂CH₃, -(CH₂)₃CF₃, -(CH₂)₃CHF₂, -(CH₂)₃CH₂F, -CH₂CF₂CH₃, -CH2CHFCH3, -CH2CF2CH3, -CH2CH2CF3, -CH2CH2CF2(CH3), -CH2CH2CF(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH(OH)(CH3), -CH2CH2C(OH)(CH3)2, -CH2-N(H)CH3, -CH2-N(H)CH2CH3, -CH2-N(H)CH2CH2CH3, -CH2CH2-N(H)CH3, -CH₂CH₂-N(H)CH₂CH₃, -CH₂CH₂-N(H)CH₂CH₂CH₃, -CH₂CH₂CH₂-N(H)CH₃, -CH₂CH₂CH₂-N(H)CH₂CH₃, or -CH₂CH₂CH₂-N(H)CH₂CH₂CH₃, wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O. [00162] In some embodiments, R¹¹ is H. [00163] In some embodiments, R¹¹ is C₁-C₆ alkyl. In some embodiments, R¹¹ is C₁-C₃ alkyl. In some embodiments, R¹¹ is methyl, ethyl, propyl, or -CD3. In some embodiments, R¹¹ is -CH3. In some embodiments, R¹¹ includes one or more deuterium atoms. In some embodiments, R¹¹ is -CD₃. In some embodiments, R¹¹ is -CH₂CH₃. In some embodiments, R¹¹ is -CH(CH₃)₂. [00164] In some embodiments, R¹¹ is -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S. In some embodiments, R¹¹ is -(C₁-C₃ alkylene)-(5- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S. In some embodiments, R¹¹ is -(C1-C3 alkylene)-(5- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N, and O. In some embodiments, R¹¹ is . [00165] In some embodiments, R¹¹ is -(C₁-C₆ alkylene)-O(C₁-C₆ alkyl). In some embodiments, R¹¹ is -(C1-C3 alkylene)-O(C1-C3 alkyl). In some embodiments, R¹¹ is -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH₂CH₂OCH₂CH₂CH₃, -CH₂CH₂CH₂OCH₃, -CH₂CH₂CH₂OCH₂CH₃, or -CH2CH2CH2OCH2CH2CH3. In some embodiments, R¹¹ is -CH2CH2OCH3. [00166] In some embodiments, R¹¹ is C1-C6 haloalkyl. In some embodiments, R¹¹ is C1-C5 haloalkyl. In some embodiments, R¹¹ is -CF₃, -CH₂CH₂F₃, -(CH₂)₂CHF₃, -(CH₂)₃CF₃, -CH2CF(CH3)2, -CH2CF2CH3, -CH2CF3, -CH2CH2CF(CH3)2, -CH2CH2CF2CH3 or -CH2CH2CF3. In some embodiments, R¹¹ is-(CH2)3CF3, -CH2CF2CH3, -CH2CH2CF(CH3)2, or -CH2CF(CH3)2. [00167] In some embodiments, R¹¹ is C₁-C₆ alkyl-OH. In some embodiments, R¹¹ is C₁-C₅ alkyl-OH. In some embodiments, R¹¹ is -CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH2CH2CH(OH)(CH3), or -CH2CH2C(OH)(CH3)2. In some embodiments, R¹¹ is -CH2CH2C(OH)(CH3)2. [00168] In some embodiments, R¹¹ is -(C₁-C₆ alkylene)-NH(C₁-C₆ alkyl). In some embodiments, R¹¹ is -(C1-C3 alkylene)-NH(C1-C3 alkyl). In some embodiments, R¹¹ is -CH2-N(H)CH3, -CH2-N(H)CH2CH3, -CH2-N(H)CH2CH2CH3, -CH2CH2-N(H)CH3, -CH₂CH₂-N(H)CH₂CH₃, -CH₂CH₂-N(H)CH₂CH₂CH₃, -CH₂CH₂CH₂-N(H)CH₃, -CH2CH2CH2-N(H)CH2CH3, or -CH2CH2CH2-N(H)CH2CH2CH3. In some embodiments, R¹¹ is -CH2CH2N(H)CH3. [00169] In some embodiments, is: . [00170] In some embodiments, R¹² is H, halo, or C1-C6 alkyl. In some embodiments, R¹² is H, F, Cl, Br, I, or C₁-C₃ alkyl. In some embodiments, R¹² is H, F, Cl, Br, I, methyl, ethyl, or propyl. [00171] In some embodiments, R¹² is H. [00172] In some embodiments, R¹² is halo. In some embodiments, R¹² is F, Cl, Br, or I. In some embodiments, R¹² is F. [00173] In some embodiments, R¹² is C1-C6 alkyl. In some embodiments, R¹² is C1-C3 alkyl. In some embodiments, R¹² is methyl, ethyl, or propyl. In some embodiments, R¹² is methyl. [00174] In some embodiments, is: [00175] In some embodiments, R¹³ is H or halo. In some embodiments, R¹³ is H, F, Cl, Br, or I. [00176] In some embodiments, R¹³ is H. [00177] In some embodiments, R¹³ is halo. In some embodiments, R¹³ is F, Cl, Br, or I. In some embodiments, R¹³ is F. [00178] In some embodiments, R¹⁴ is H or C₁-C₆ alkyl. In some embodiments, R¹⁴ is H or C1-C3 alkyl. In some embodiments, R¹⁴ is H, methyl, ethyl, or propyl. [00179] In some embodiments, R¹⁴ is H. [00180] In some embodiments, R¹⁴ is C₁-C₆ alkyl. In some embodiments, R¹⁴ is C₁-C₃ alkyl. In some embodiments, R¹⁴ is methyl, ethyl, or propyl. In some embodiments, R¹⁴ is methyl. [00181] In some embodiments, R¹⁴ is H. In some embodiments, R¹⁴ is methyl. [00182] In some embodiments, X⁴ is N. In some embodiments, X⁴ is CR¹⁵. [00183] In some embodiments, R¹⁵ is H or C₁-C₆ alkyl. In some embodiments, R¹⁵ is H or C1-C3 alkyl. In some embodiments, R¹⁵ is H, methyl, ethyl, or propyl. [00184] In some embodiments, R¹⁵ is H. [00185] In some embodiments, R¹⁵ is C₁-C₆ alkyl. In some embodiments, R¹⁵ is C₁-C₃ alkyl. In some embodiments, R¹⁵ is methyl, ethyl, or propyl. In some embodiments, R¹⁵ is methyl. [00186] In some embodiments, X⁵ is N. In some embodiments, X⁵ is CH. [00187] In some embodiments, X⁶ is N. In some embodiments, X⁶ is CH. [00188] In some embodiments, is a single bond. In some embodiments, is a double bond. [00189] In some embodiments, :

. [00190] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (II): wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁷, R⁸, R⁹, R^10a, R^10b, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X¹, X², X³, X⁴, X⁵, X⁶, w, z, and are as described for Formula (IA) or Formula (I). [00191] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IIa): wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X¹, X², X³, X⁴, X⁵, X⁶, w, z, and are as described for Formula (IA) or Formula (I). [00192] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IIb):

wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁷, X¹, X², and w are as described for Formula (IA) or Formula (I). [00193] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IIc): wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R⁷, X¹, and X² are as described for Formula Formula (IA) or (I). [00194] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (III): wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁶, R⁸, R⁹, R^10a, R^10b, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X¹, X², X³, X⁴, X⁵, X⁶, w, z, and are as described for Formula (IA) or Formula (I). [00195] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IIIa): wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁶, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X¹, X², X³, X⁴, X⁵, X⁶, w, z, and are as described for Formula Formula (IA) or (I). [00196] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IIIb): wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, and R¹¹ are as described for Formula (IA) or Formula (I). [00197] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IV):

wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁸, R⁹, R^10a, R^10b, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X¹, X², X³, X⁴, X⁵, X⁶, w, z, and are as described for Formula (IA) or Formula (I). [00198] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IVa): wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X¹, X², X³, X⁴, X⁵, X⁶, w, z, and are as described for Formula (IA) or Formula (I). [00199] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IVb):

wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, X¹, X², and w are as described for Formula (IA) or Formula (I). [00200] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IVc): wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, X¹, and X² are as described for Formula (IA) or Formula (I). [00201] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IVd):

wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, and R^4b are as described for Formula (IA) or Formula (I). [00202] It is understood that any of the compounds described herein can include replacement of one or more hydrogen atoms by deuterium. Any one or more of the substituents of Formula (IA) or Formula (I) can be deuterated, such as one or more of X¹, X², X³, X⁵, X⁶, R^1a, R^1b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁶, R⁷, R^10a, R^10b, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵. For example, in some embodiments, R¹¹ is a deuterated group, such as -CD3. [00203] In the descriptions herein, it is understood that all descriptions, variations, embodiments, or aspects of Formula (IA) or Formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed. It is also understood that all descriptions, variations, embodiments, or aspects of Formula (IA) or Formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments, or aspects of Formula (IA) or Formula (I), where applicable, apply equally to any of the formulae as detailed herein, such as Formulae (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), and (IVd), and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae. [00204] In some embodiments, provided is a compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. Although certain compounds described in the present disclosure, including in Table 1, are presented as specific stereoisomers and/or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 1, are herein described. Table 1.

or a pharmaceutically acceptable salt thereof. [00205] All compounds of Formula (IA) or Formula (I) that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of Formula (IA) or Formula (I) can be converted to their free base or acid form by standard techniques. Methods of Synthesis [00206] The compounds described herein can be made using conventional organic syntheses and commercially available starting materials, or the methods provided herein. By way of example and not limitation, compounds of Formula (I-a) through Formula (I-h) can be prepared as outlined in Schemes 1-4, as well as in the Examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and Examples to arrive at the desired products.

Scheme 1. wherein X³, R⁸, R⁹, R^10a, R^10b R¹¹, R¹², and z are as defined for Formula (IA) or Formula (I); LGi is a leaving group, such as OTs, OMs, or I; and

LG2 and LG3 are independently a leaving group, such as F or Cl.

Scheme 2. wherein X⁵, X⁶, R⁶, and R⁷ are as defined for Formula (IA) or Formula (I); LG4 is a leaving group, such as Br or Cl; ¥ is H, Ci-Ce alkyl, 6- or 7 membered heterocyclyl, or Boc, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; PG is a protecting group such as Boc; R^b represents R^la, R^2a, R^3a, R^4a, R^5a, R^2b, R^3b, R^4b, and R^5b, as defined for Formula (IA) or Formula (I); X is CH, CH2, N, NH, or NBoc; X’ is

CH, CH₂, N, or NH; is 6- or 7-membered heterocyclyl; and Bn is benzyl.

Scheme 3. wherein PG is a protecting group, such as Fmoc or Boc; LG4 is a leaving group, such as Br or Cl; R⁶ is as defined for Formula (IA) or Formula (I); and Y is H, C₁-C₆ alkyl, 6- or 7 membered heterocyclyl, or Boc, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S.

Scheme 4.

wherein X³, X⁴, R⁶, R⁸, R⁹, R^10a, R^10b R¹¹, R¹², R¹³, z are as defined for Formula (IA) or Formula (I); LG3 is a leaving group, such as OTs, OMs, F,

X² NH

Cl, or I; R^b represents R^la, R^2a, R^3a, R^4a, R^5a, R^2b, R^3b, R^4b, or R^5b, as defined for Formula (IA) or Formula (I); and ' is 6- or 7-membered heterocyclyl.

[00207] As outlined in Scheme 1, compounds of Formula (i-1) that contain an oxindole motif can be synthesized from coupling the indole derivatives a with intermediate compounds b to form intermediate compounds c, which are then nitrated to form intermediate compounds d. The nitro group is reduced to form intermediate compounds e, followed by coupling to intermediate f to form compounds of Formula (i-1).

[00208] Scheme 2 provides two routes for synthesizing compounds of Formula (i-2) that contain a glutarimide motif. Indazole derivatives g can be coupled to intermediate compounds h to afford intermediate compounds i. Deprotection and further reduction of intermediate compounds i forms intermediate compounds j, which are subjected to deprotection to form compounds of Formula (i-2). Alternatively, indazole derivatives g can be coupled to intermediate compounds k to afford intermediate compounds 1. Deprotection and further reduction of intermediate compounds 1 forms intermediate compounds i, which are subjected to deprotection of the amine to form compounds of Formula (i-2).

[00209] Scheme 3 provides the synthesis of compounds of Formula (i-2) that contain a dihydrouridine motif. Indazole derivatives n can be coupled to intermediate compounds h to afford intermediate compounds o, which are deprotected to form intermediate compounds p and subsequently deprotected to form compounds of Formula (i-2).

[00210] Scheme 4 provides multiple routes for synthesizing various compounds of Formula (IA) or Formula (I). The compounds of Formula (i-1) can be coupled to various derivations of compounds of Formula (i-2) (denoted as Formula (i-2a) through Formula (i-2h)) to afford the compounds of Formula (La) through Formula (I-h).

Methods of Use

[00211] Embodiments of the present disclosure provide a method for modulating BCL6 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). Modulation (e.g., inhibition or activation) of BCL6 can be assessed and demonstrated by a wide variety of ways known in the art. Kits and commercially available assays can be utilized for determining whether and to what degree BCL6 has been modulated (e.g., inhibited or activated).

[00212] In one aspect, provided herein is a method of modulating BCL6 comprising contacting BCL6 with an effective amount of a compound of Formula (IA) or Formula (I) or any embodiment or variation thereof. In some embodiments, the compound of Formula (IA) or Formula (I) inhibits BCL6. In some embodiments, the compound of Formula (IA) or Formula (I) causes degradation of BCL6. [00213] In some embodiments, a compound of Formula (IA) or Formula (I) modulates the activity of BCL6 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, a compound of Formula (IA) or Formula (I) modulates the activity of BCL6 by about 1-100%, 5-100%, 10- 100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55- 100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 5- 95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5- 35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%. [00214] Also provided in certain embodiments of the present disclosure is a method for degrading BCL6 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). Degradation of BCL6 can be assessed and demonstrated by a wide variety of ways known in the art. Kits and commercially available assays, including cell-based assays, can be utilized for determining whether and to what degree BCL6 has been degraded. [00215] In one aspect, provided herein is a method of degrading BCL6 comprising contacting BCL6 with an effective amount of a compound of Formula (IA) or Formula (I) or any embodiment or variation thereof. In some embodiments, the compound of Formula (IA) or Formula (I) partially degrades BCL6. In some embodiments, the compound of Formula (IA) or Formula (I) fully degrades BCL6. [00216] In some embodiments, a compound of Formula (IA) or Formula (I) degrades BCL6 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, a compound of Formula (IA) or Formula (I) degrades BCL6 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25- 100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70- 100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5- 75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5- 15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%. [00217] In another aspect, provided herein is a method for treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). In some embodiments, provided herein is a method for preventing a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). Non-limiting examples of a cancer include squamous- cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, renal cell carcinomas, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, cancer of the head, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, leukemia, benign lymphoma, malignant lymphoma, Burkitt's lymphoma, Non-Hodgkin's lymphoma (NHL), benign melanoma, malignant melanomas, myeloproliferative diseases, sarcomas, Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, stomach cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratocarcinomas, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T- cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Diffuse Large B-cell Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, Waldenstroms Macroglobulinemia, Chronic Lymphocytic leukemia (CLL), Small Lymphocytic Lymphoma (SLL), intravascular large B-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, and non-small cell lung cancer. [00218] In some embodiments, the cancer is a lymphoma, such as a B-cell lymphoma. In some embodiments, the cancer is a non-Hodgkin lymphoma, such as a B-cell non-Hodgkin lymphoma. In some embodiments, the lymphoma is diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma, marginal zone lymphoma (e.g., mucosa- associated lymphoid tissue lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), Burkitt lymphoma, or lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia). In some embodiments, the cancer is diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL). In some embodiments, the cancer is DLBCL (e.g., relapsed and/or refractory DLBCL). In some embodiments, the cancer is FL (e.g., relapsed and/or refractory FL). [00219] In some embodiments, the cancer is relapsed and/or refractory. [00220] In some embodiments, a compound of Formula (IA) or (I) is administered as a first- line therapy. In other embodiments, a compound of Formula (IA) or (I) is administered as a non-firstline therapy (e.g., as a second-line or subsequent therapy, such as a salvage therapy). [00221] In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof diminishes the extent of the cancer (such as tumor size, tumor growth rate, metastasis) in the subject. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof stabilizes the cancer (prevents or delays the worsening of the cancer). In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof delays the occurrence or recurrence of the cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof slows the progression of the cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof provides a partial remission of the cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof provides a total remission of the cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof decreases the dose of one or more other medications required to treat the cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof enhances the effect of another medication used to treat the cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof delays the progression of the cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof increases the quality of life of the subject having a cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof prolongs survival of a subject having a cancer. [00222] In some aspects, provided herein is a method of slowing progression of a cancer in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. In some embodiments, provided herein is a method of stabilizing a cancer in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. In some embodiments, the method prevents the progression of the cancer. In some embodiments, the method delays the progression of the cancer. In some embodiments, the method provides a partial or total remission of the cancer. [00223] In another aspect, provided herein is a method of delaying the occurrence or recurrence of a cancer in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. [00224] In further aspects, provided herein is a method of decreasing the dose of one or more other medications required to treat a cancer in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. In some embodiments, provided herein is a method of enhancing the effect of another medication used to treat a cancer in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. [00225] Also provided here is a method of delaying the progression of a cancer in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. In some embodiments, the method increases the quality of life of the subject having a cancer. In some embodiments, the method prolongs survival of the subject having a cancer. [00226] In a further aspect, provided herein is a method for treating an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). In some embodiments, provided herein is a method for preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). Autoimmune diseases can be divided into two categories. Organ-specific autoimmune diseases occur when the immune system targets specific cells, tissues, or organs. Generalized autoimmune diseases occur when the immune system attacks the body without discriminating among different types of tissues or target cells. Exemplary organ-specific autoimmune diseases include atopic dermatitis, asthma, insulin dependent diabetes, Hashimoto's thyroiditis, Grave's disease, Pernicious anemia, Myasthenia gravis, Pemphigus vulgaris, and Crohn's disease. Exemplary generalized autoimmune diseases include Systemic lupus erythematosus (SLE), Rheumatoid arthritis, Scleroderma, Sarcoidosis, and Guillain-Barré Syndrome (GBS). The present disclosure encompasses treatment of all types of autoimmune disease, including organ-specific and general autoimmune diseases, including, but not limited to, lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohn's Disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain- Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjögren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, and Wegener's granulomatosis. [00227] In another aspect, provided herein is a method for treating a TH17-related condition, such as a TH17-related autoimmune condition, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). [00228] In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof diminishes or reduces the symptoms of the autoimmune disease (such as inflammation, chronic fever, malaise, joint pains, myalgias, and fatigue) in the subject. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof shortens or reduces the duration of a symptom of the autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof eliminates the symptoms of the autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof delays the occurrence or recurrence of the autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof slows the progression of the autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof decreases the dose of one or more other medications required to treat the autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof enhances the effect of another medication used to treat the autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof delays the progression of the autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof increases the quality of life of the subject having an autoimmune disease. [00229] In some aspects, provided herein is a method of slowing progression of an autoimmune disease in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. In some embodiments, provided herein is a method of stabilizing an autoimmune disease in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. In some embodiments, the method prevents the progression of the autoimmune disease. In some embodiments, the method delays the progression of the autoimmune disease. In some embodiments, the method increases the quality of life of the subject having an autoimmune disease. [00230] In further aspects, provided herein is a method of decreasing the dose of one or more other medications required to treat an autoimmune disease in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. In some embodiments, provided herein is a method of enhancing the effect of another medication used to treat an autoimmune disease in a subject, the method comprising administering a compound of Formula (IA) or Formula (I) to the subject. [00231] In some embodiments of any of the methods described herein, a compound of Formula (IA) or (I) is administered on one or more treatment cycles, e.g., three or more treatment cycles, six or more treatment cycles, 12 or more treatment cycles, 15 or more treatment cycles, 18 or more treatment cycles, or 24 or more treatment cycles. In a particular embodiment, a treatment cycle is a 28-day treatment cycle. [00232] In some embodiments, a compound of Formula (IA) or (I) is administered daily on each day of a 28-day treatment cycle, e.g., the compound of Formula (IA) or (I) is administered once or twice daily on each day of a 28-day treatment cycle. In some embodiments, a compound of Formula (IA) or (I) is administered daily on days 1-14 of a 28-day treatment cycle and is not administered on days 15-28 of the 28-day treatment cycle, e.g., the compound of Formula (IA) or (I) is administered once or twice daily on days 1-14 of a 28-day treatment cycle. In some embodiments, a compound of Formula (IA) or (I) is administered daily on days 1-21 of a 28-day treatment cycle and is not administered on days 22-28 of the 28-day treatment cycle, e.g., the compound of Formula (IA) or (I) is administered once or twice daily on days 1-21 of a 28-day treatment cycle. [00233] Administration of a compound of Formula (IA) or (I) can be continued in accordance with the methods described herein indefinitely, or until clinically significant disease progression, unacceptable toxicity, or a decision to discontinue administration is otherwise reached. In some embodiments, administration of a compound of Formula (IA) or (I) continues for up to three years, e.g., up to to two years, and is discontinued thereafter. [00234] In some embodiments of any of the methods described herein, a compound of Formula (IA) or (I) is administered in combination with an additional therapy. Accordingly, some embodiments further comprise administering to the subject an additional therapy, such as an additional therapeutic agent. In some embodiments, the additional therapy is a standard of care (SOC). [00235] Current SOC for DLBCL is CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), administered in combination with rituximab (R-CHOP). SOC for second-line relapsed/refractory DLBCL is high-dose chemotherapy followed by autologous stem cell transplantation (autoSCT). CAR-T cell therapies have also been used to treat relapsed/refractory DLBCL. SOC for FL is anti-CD20 immunotherapy with or without chemotherapy. [00236] In some embodiments, the additional therapy comprises an anti-lymphoma therapy (e.g., anti-lymphoma agent). Anti-lymphoma therapies include SOC for DLBCL and FL described herein, as well as cytotoxic agents, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants. Anti-lymphoma agents include SOC agents for DLBCL and FL described herein (e.g., cyclophosphamide, doxorubicin, vincristine, prednisolone, rituximab), as well as cytotoxic agents and anti-CD20 antibodies. [00237] Rituximab is a recombinant chimeric murine/human antibody directed against the CD20 antigen, a hydrophobic transmembrane protein located on normal pre-B and mature B lymphocytes. Following binding, rituximab triggers a cytotoxic immune response against CD20- positive cells. Rituximab is indicated for several oncologic and non-oncologic treatments. For example, rituximab is indicated for the treatment of patients with: (i) previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or other anthracycline based chemotherapy regimens; (ii) previously untreated follicular, CD20-positive B-cell NHL in combination with CVP (cyclophosphamide, vincristine, prednisolone) chemotherapy; and/or (iii) relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent. For example, rituximab is indicated for the treatment of patients with: (i) CD20 positive diffuse large B-cell non-Hodgkin lymphoma in combination with CHOP chemotherapy; (ii) previously untreated patients with stage III-IV FL in combination with chemotherapy; (iii) stage III-IV FL who are chemoresistant or are in their second or subsequent relapse after chemotherapy as a monotherapy; and/or (iv) adult patients with FL responding to induction therapy, as maintenance therapy. Rituximab is also a component of most salvage chemoimmunotherapy regimens (e.g., R-ICE, R-DHAP, R- ESHAP, R-gemcitabine/oxaliplatin), and is listed as a treatment option for second (and subsequent) line treatment of B-cell lymphoma in the NCCN and European Society of Medical Oncology (ESMO) guidelines, and is routinely used in standard practice in these settings. In addition, in the US and EU, rituximab is indicated for use in combination with lenalidomide in the treatment of relapsed/refractory FL. [00238] In some embodiments, the method further comprises administering to the subject an anti-CD20 antibody (e.g., a therapeutically effective amount of an anti-CD20 antibody), such as rituximab. In a particular embodiment, the method further comprises administering to the subject rituximab (e.g., a therapeutically effective amount of rituximab). For example, some embodiments comprise administering rituximab intravenously (e.g., as an intravenous (IV) infusion). Some embodiments comprise administering about 375 mg/m² rituximab. Some embodiments comprise administering about 375 mg/m² rituximab intravenously (e.g., as an IV infusion). In some embodiments, rituximab is administered concurrently with or up to 2 hours after the compound of Formula (IA) or (I). Some embodiments comprise administering rituximab once every 28 days (e.g., on day 1 of a 28-day cycle). In some embodiments, rituximab is administered once every 28 days (e.g., on Day 1 of a 28-day cycle) for up to 12 months, e.g., for up to 6 months. Pharmaceutical Compositions and Routes of Administration [00239] The compounds provided herein can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. [00240] The compounds disclosed herein can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., methylcellulose, polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compounds of Formula (IA) or Formula (I) in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject’s body weight to about 10 mg/kg of a subject’s body weight in unit dosage for both oral and parenteral administration. [00241] The dose of a compound of Formula (IA) or Formula (I) to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner. In general, the compounds disclosed herein can be administered one to four times a day in a dose of about 0.001 mg/kg of a subject’s body weight to about 10 mg/kg of a subject’s body weight, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration. In one embodiment, the dose is about 0.001 mg/kg of a subject’s body weight to about 5 mg/kg of a subject’s body weight, about 0.01 mg/kg of a subject’s body weight to about 5 mg/kg of a subject’s body weight, about 0.05 mg/kg of a subject’s body weight to about 1 mg/kg of a subject’s body weight, about 0.1 mg/kg of a subject’s body weight to about 0.75 mg/kg of a subject’s body weight or about 0.25 mg/kg of a subject’s body weight to about 0.5 mg/kg of a subject’s body weight. In one embodiment, one dose is given per day. In any given case, the amount of the compound of Formula (IA) or Formula (I) administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration. [00242] In some embodiments, a compound of Formula (IA) or Formula (I) is administered to a subject at a dose of about 0.01 mg/day to about 750 mg/day, about 0.1 mg/day to about 375 mg/day, about 0.1 mg/day to about 150 mg/day, about 0.1 mg/day to about 75 mg/day, about 0.1 mg/day to about 50 mg/day, about 0.1 mg/day to about 25 mg/day, or about 0.1 mg/day to about 10 mg/day. In some embodiments, a compound of Formula (IA) or Formula (I) is administered to a subject at a dose of about 10 mg/day to about 750 mg/day, once daily or twice daily. [00243] In a particular embodiment, a compound of Formula (IA) or (I) is administered to a subject at a dose of about 20 mg/day, about 40 mg/day, about 80 mg/day, about 160 mg/day, about 260 mg/day, about 400 mg/day, or about 640 mg/day, once daily (QD) or twice daily (BID). In further embodiments, administration is QD. Alternatively, administration is BID. [00244] In another embodiment, provided herein are unit dosage formulations that comprise between about 0.1 mg and 500 mg, about 1 mg and 250 mg, about 1 mg and about 100 mg, about 1 mg and about 50 mg, about 1 mg and about 25 mg, or between about 1 mg and about 10 mg of a compound of Formula (IA) or Formula (I). [00245] In a particular embodiment, provided herein are unit dosage formulations comprising about 0.1 mg or 100 mg of a compound of Formula (IA) or Formula (I). In some embodiments, a unit dosage formulation comprises about 10 mg to about 100 mg of a compound of Formula (IA) or Formula (I). In some embodiments, a unit dosage formulation comprises about 20 mg of a compound of Formula (IA) or (I) (e.g., Compound 70, or a pharmaceutically acceptable salt thereof). In some embodiments, a unit dosage formulation comprises about 80 mg of a compound of Formula (IA) or (I) (e.g., Compound 70, or a pharmaceutically acceptable salt thereof). [00246] In another embodiment, provided herein are unit dosage formulations that comprise 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a compound of Formula (IA) or Formula (I). [00247] A compound of Formula (IA) or Formula (I) can be administered once, twice, three, four or more times daily. In a particular embodiment, doses of 100 mg or less are administered as a once daily dose and doses of more than 100 mg are administered twice daily in an amount equal to one half of the total daily dose. In some embodiments, a compound of Formula (IA) or (I) is administered once daily. In some embodiments, a compound of Formula (IA) or (I) is administered twice daily. [00248] A compound of Formula (IA) or Formula (I) can be administered orally. In one embodiment, when administered orally, a compound of Formula (IA) or Formula (I) is administered with a meal and water. In another embodiment, the compound of Formula (IA) or Formula (I) is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or a suspension. Alternatively, in one embodiment, when administered orally, a compound of Formula (IA) or (I) is administered to a subject in a fasted state. For example, in some embodiments, the compound of Formula (IA) or (I) is administered to a subject that has had nothing to eat or drink except water for at least about 2 hours prior to administration of the compound of Formula (IA) or (I). In some embodiments, the fasted state begins at least about 2 hours prior to administration of the compound of Formula (IA) or (I) and continues for at least about 1 hour after administration of the compound of Formula (IA) or (I). [00249] The compounds disclosed herein can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition. [00250] In another embodiment, provided herein are compositions comprising an effective amount of a compound of Formula (IA) or Formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition. [00251] In some embodiments, a pharmaceutical composition comprises a compound of Formula (IA) or (I) and two or more of: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate. In some embodiments, the pharmaceutical composition comprises anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate. [00252] In some embodiments, a composition is in the form of a dispersion (e.g., a spray dried dispersion). The composition may optionally be coated with a film, for example, that resists dissolution for a predictable period of time. [00253] A compound of Formula (IA) or (I) can be present in a composition in any effective amount. In some embodiments, a compound of Formula (IA) or (I) is present in a composition at 1% weight/weight (w/w) to 75% w/w, 5% w/w to 50% w/w, 10% w/w to 40% w/w, 30% w/w to 40% w/w, about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, or about 50% w/w. In a particular embodiment, a pharmaceutical composition comprises about 35% w/w of a compound of Formula (IA) or (I). [00254] The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like. In some embodiments, the composition is in the form of a tablet or capsule. In some embodiments, the composition is in the form of a tablet, e.g., a film-coated tablet. In some embodiments, the composition is in the form of a capsule. [00255] Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing a compound of Formula (IA) or Formula (I) with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. [00256] Tablets can be prepared by direct compression, by wet granulation, by dry granulation, or by spray drying. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders. [00257] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation. [00258] When it is desired to administer a compound of Formula (IA) or Formula (I) as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use. [00259] The effect of the compound of Formula (IA) or Formula (I) can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the compound of Formula (IA) or Formula (I) can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the compound of Formula (IA) or Formula (I) in oily or emulsified vehicles that allow it to disperse slowly in the serum. In some embodiments, a tablet or capsule is formulated for enteric release, for example, by formulation of a compound of Formula (IA) or (I) with Eudragit L100-55. [00260] It is understood that the pharmaceutical compositions described herein may include a mixture of compounds of Formula (IA) or Formula (I), including a racemic mixture of any of the compounds described herein. Numbered Embodiments [00261] The compounds useful in accordance with the present disclosure are further described by the following embodiments. The features of each of the embodiments are combinable with any of the other embodiments where appropriate and practical. [00262] Embodiment P1. A compound of Formula (IA): or a pharmaceutically acceptable salt thereof, wherein: X¹ and X² are each independently N or CH, provided that at least one of X¹ and X² is N; R^1a and R^1b are each independently H, halo, or C1-C6 alkyl; R^2a and R^2b are each independently H, C₁-C₆ alkyl, -O(C₁-C₆ alkyl), -OH, halo, C₁-C₆ haloalkyl, or C1-C6 alkyl-OH, or R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₅ cycloalkyl, or R^2a and R^2b are taken together to form oxo; or R^1a and R^2a are taken together to form a bridging C2-C3 alkylene; R^3a and R^3b are each independently H, halo, or C₁-C₆ alkyl; R^4a and R^4b are each independently H, halo, or C₁-C₆ alkyl, or R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl; R^5a and R^5b are each independently H, halo, or C₁-C₆ alkyl; w is 0 or 1; R⁶ is H or C1-C6 alkyl; R⁷ is H or C₁-C₆ alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R⁸ is Cl or -CN; R⁹ is F; X³ is N or CH; z is 0 or 1; R^10a and R^10b are each independently H or halo; R¹¹ is H, C₁-C₆ alkyl, -(C₁-C₆ alkylene)-(5- to 6-membered heterocyclyl), -(C₁-C₆ alkylene)- O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R¹² is H, halo, or C₁-C₆ alkyl; R¹³ is H or halo; R¹⁴ is H or C1-C6 alkyl; X⁴ is N or CR¹⁵; R¹⁵ is H or C₁-C₆ alkyl; X⁵ and X⁶ are each independently N or CH; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium. [00263] Embodiment P2. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X¹ and X² are each independently N or CH, provided that at least one of X¹ and X² is N; R^1a and R^1b are each independently H, halo, or C₁-C₆ alkyl; R^2a and R^2b are each independently H, C₁-C₆ alkyl, -OH, halo, or C₁-C₆ alkyl-OH, or R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl, or R^2a and R^2b are taken together to form oxo; or R^1a and R^2a are taken together to form a bridging C₂-C₃ alkylene; R^3a and R^3b are each independently H, halo, or C1-C6 alkyl; R^4a and R^4b are each independently H, halo, or C₁-C₆ alkyl, or R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl; R^5a and R^5b are each independently H, halo, or C1-C6 alkyl; w is 0 or 1; R⁶ is H or C1-C6 alkyl; R⁷ is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R⁸ is Cl or -CN; R⁹ is F; X³ is N or CH; z is 0 or 1; R^10a and R^10b are each independently H or halo; R¹¹ is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)- O(C₁-C₆ alkyl), C₁-C₆ haloalkyl, C₁-C₆ alkyl-OH, or -(C₁-C₆ alkylene)-NH(C₁-C₆ alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R¹² is H, halo, or C1-C6 alkyl; R¹³ is H or halo; R¹⁴ is H or C1-C6 alkyl; X⁴ is N or CR¹⁵; R¹⁵ is H or C₁-C₆ alkyl; X⁵ and X⁶ are each independently N or CH; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium. [00264] Embodiment P3. The compound of embodiment P1 or P2, or a pharmaceutically acceptable salt thereof, wherein: X¹ is CH; and X² is N. [00265] Embodiment P4. The compound of embodiment P1 or P2, or a pharmaceutically acceptable salt thereof, wherein: X¹ is N; and X² is CH. [00266] Embodiment P5. The compound of embodiment P1 or P2, or a pharmaceutically acceptable salt thereof, wherein: X¹ and X² are each N. [00267] Embodiment P6. The compound of any one of embodiments P1-P5, or a pharmaceutically acceptable salt thereof, wherein: R^1a and R^1b are each independently H, halo, or C₁-C₃ alkyl. [00268] Embodiment P7. The compound of embodiment P6, or a pharmaceutically acceptable salt thereof, wherein: R^1a and R^1b are each independently H or -CH₃. [00269] Embodiment P8. The compound of any one of embodiments P1-P7, or a pharmaceutically acceptable salt thereof, wherein: R^2a and R^2b are each independently H, C₁-C₃ alkyl, -O(C₁-C₃ alkyl), -OH, halo, C₁-C₃ haloalkyl, or C₁-C₃ alkyl-OH, or R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C3-C4 cycloalkyl, or R^2a and R^2b are taken together to form oxo. [00270] Embodiment P9. The compound of embodiment P8, or a pharmaceutically acceptable salt thereof, wherein: R^2a and R^2b are each independently H, -CH₃, -OCH₃, -OH, F, -CF₃, or -CH₂OH, or R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro cyclobutyl, or R^2a and R^2b are taken together to form oxo. [00271] Embodiment P10. The compound of any one of embodiments P1-P9, or a pharmaceutically acceptable salt thereof, wherein R^1a and R^1b are each H, and at least one of R^2a and R^2b is other than H. [00272] Embodiment P11. The compound of any one of embodiments P1-P9, or a pharmaceutically acceptable salt thereof, wherein: R^1a and R^2a are taken together to form a bridging ethylene. [00273] Embodiment P12. The compound of any one of embodiments P1-P11, or a pharmaceutically acceptable salt thereof, wherein: R^3a and R^3b are each independently H, halo, or C1-C3 alkyl. [00274] Embodiment P13. The compound of embodiment P12, or a pharmaceutically acceptable salt thereof, wherein: R^3a and R^3b are each independently H, F, or -CH3. [00275] Embodiment P14. The compound of any one of embodiments P1-P13, or a pharmaceutically acceptable salt thereof, wherein: R^4a and R^4b are each independently H, halo, or C₁-C₃ alkyl, or R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₄ cycloalkyl. [00276] Embodiment P15. The compound of embodiment P14, or a pharmaceutically acceptable salt thereof, wherein: R^4a and R^4b are each independently H, F, or -CH3, or R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro cyclobutyl. [00277] Embodiment P16. The compound of any one of embodiments P1-P15, or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3b, R^4a, and R^4b are each H. [00278] Embodiment P17. The compound of any one of embodiments P1-P15, or a pharmaceutically acceptable salt thereof, wherein at least one of R^3a and R^3b is other than H, and at least one of R^4a and R^4b is other than H. [00279] Embodiment P18. The compound of any one of embodiments P1-P17, or a pharmaceutically acceptable salt thereof, wherein: w is 0. [00280] Embodiment P19. The compound of any one of embodiments P1-P17, or a pharmaceutically acceptable salt thereof, wherein: w is 1. [00281] Embodiment P20. The compound of embodiment P19, or a pharmaceutically acceptable salt thereof, wherein: R^5a and R^5b are each independently H, halo, or C1-C3 alkyl. [00282] Embodiment P21. The compound of embodiment P20, or a pharmaceutically acceptable salt thereof, wherein: R^5a and R^5b are each H. [00283] Embodiment P22. The compound of any one of embodiments P1-P21, or a pharmaceutically acceptable salt thereof, wherein at least one of R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, and R^5b is other than H. [00284] Embodiment P23. The compound of embodiment P22, or a pharmaceutically acceptable salt thereof, wherein one or two of R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, and R^5b is other than H. [00285] Embodiment P24. The compound of any one of embodiments P1-P23, or a pharmaceutically acceptable salt thereof, wherein . [00286] Embodiment P25. The compound of any one of embodiments P1-P24, or a pharmaceutically acceptable salt thereof, wherein: x is 1; y is 0; and R⁷ is H or C1-C3 alkyl. [00287] Embodiment P26. The compound of embodiment P25, or a pharmaceutically acceptable salt thereof, wherein: R⁷ is H or -CH3. [00288] Embodiment P27. The compound of any one of embodiments P1-P24, or a pharmaceutically acceptable salt thereof, wherein: x is 0; y is 1; and R⁶ is H or C1-C3 alkyl. [00289] Embodiment P28. The compound of embodiment P27, or a pharmaceutically acceptable salt thereof, wherein: R⁶ is H or -CH3. [00290] Embodiment P29. The compound of any one of embodiments P1-P24, or a pharmaceutically acceptable salt thereof, wherein: x and y are each 0. [00291] Embodiment P30. The compound of any one of embodiments P1-P29, or a pharmaceutically acceptable salt thereof, wherein: R⁸ is Cl. [00292] Embodiment P31. The compound of any one of embodiments P1-P29, or a pharmaceutically acceptable salt thereof, wherein: R⁸ is -CN. [00293] Embodiment P32. The compound of any one of embodiments P1-P31, or a pharmaceutically acceptable salt thereof, wherein: X³ is CH. [00294] Embodiment P33. The compound of any one of embodiments P1-P31, or a pharmaceutically acceptable salt thereof, wherein: X³ is N. [00295] Embodiment P34. The compound of any one of embodiments P1-P33, or a pharmaceutically acceptable salt thereof, wherein: [00296] z is 0. [00297] Embodiment P35. The compound of any one of embodiments P1-P33, or a pharmaceutically acceptable salt thereof, wherein: z is 1. [00298] Embodiment P36. The compound of any one of embodiments P1-P35, or a pharmaceutically acceptable salt thereof, wherein: R^10a and R^10b are each independently H or F. [00299] Embodiment P37. The compound of any one of embodiments P1-P36, or a pharmaceutically acceptable salt thereof, wherein: R¹¹ is H, C1-C3 alkyl, -(C1-C3 alkylene)-(6-membered heterocyclyl), -(C1-C3 alkylene)-O(C1- C₃ alkyl), C₁-C₅ haloalkyl, C₁-C₅ alkyl-OH, or -(C₁-C₃ alkylene)-NH(C₁-C₃ alkyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O. [00300] Embodiment P38. The compound of embodiment P37, or a pharmaceutically acceptable salt thereof, wherein: R¹¹ is H, -CH₃, -CD₃, -CH₂CH₃, -CH(CH₃)₂, -CH₂CH₂OCH₃, -CH₂CH₂OH, -CH2CH2C(OH)(CH3)2, -CH2CH2N(H)CH3, -(CH2)3CF3, -CH2CF2CH3, -CH₂CH₂CF(CH₃)₂, -CH₂CF(CH₃)₂, or . [00301] Embodiment P39. The compound of any one of embodiments P1-P38, or a pharmaceutically acceptable salt thereof, wherein

. [00302] Embodiment P40. The compound of any one of embodiments P1-P39, or a pharmaceutically acceptable salt thereof, wherein: R¹² is H, halo, or C1-C3 alkyl. [00303] Embodiment P41. The compound of embodiment P40, or a pharmaceutically acceptable salt thereof, wherein: R¹² is H, F, or -CH₃. [00304] Embodiment P42. The compound of any one of embodiments P1-P41, or a pharmaceutically acceptable salt thereof, wherein is: . [00305] Embodiment P43. The compound of any one of embodiments P1-P42, or a pharmaceutically acceptable salt thereof, wherein: R¹³ is H or F. [00306] Embodiment P44. The compound of any one of embodiments P1-P43, or a pharmaceutically acceptable salt thereof, wherein: R¹⁴ is H or C₁-C₃ alkyl. [00307] Embodiment P45. The compound of embodiment P44, or a pharmaceutically acceptable salt thereof, wherein: R¹⁴ is H or -CH₃. [00308] Embodiment P46. The compound of any one of embodiments P1-P45, or a pharmaceutically acceptable salt thereof, wherein: X⁴ is N. [00309] Embodiment P47. The compound of any one of embodiments P1-P45, or a pharmaceutically acceptable salt thereof, wherein: X⁴ is CR¹⁵; and R¹⁵ is H or C₁-C₃ alkyl. [00310] Embodiment P48. The compound of embodiment P47, or a pharmaceutically acceptable salt thereof, wherein: X⁴ is CR¹⁵; and R¹⁵ is H or -CH3. [00311] Embodiment P49. The compound of any one of embodiments P1-P48, or a pharmaceutically acceptable salt thereof, wherein: X⁵ is N. [00312] Embodiment P50. The compound of any one of embodiments P1-P48, or a pharmaceutically acceptable salt thereof, wherein: X⁵ is CH. [00313] Embodiment P51. The compound of any one of embodiments P1-P50, or a pharmaceutically acceptable salt thereof, wherein: X⁶ is N. [00314] Embodiment P52. The compound of any one of embodiments P1-P50, or a pharmaceutically acceptable salt thereof, wherein: X⁶ is CH. [00315] Embodiment P53. The compound of any one of embodiments P1-P52, or a pharmaceutically acceptable salt thereof, wherein: is a single bond. [00316] Embodiment P54. The compound of any one of embodiments P1-P52, or a pharmaceutically acceptable salt thereof, wherein: is a double bond. [00317] Embodiment P55. The compound of any one of embodiments P1-P54, or a pharmaceutically acceptable salt thereof, wherein is: . [00318] Embodiment P56. The compound of any one of embodiments P1-P55, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II), (III), or (IV): . [00319] Embodiment P57. The compound of embodiment P56, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIIb): . [00320] Embodiment P58. A compound selected from the compounds of Table 1 and pharmaceutically acceptable salts thereof. [00321] Embodiment P59. A pharmaceutical composition comprising the compound of any one of embodiments P1-P58, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [00322] Embodiment P60. A method of degrading B-cell lymphoma 6 protein (BCL6) comprising contacting BCL6 with an effective amount of the compound of any one of embodiments P1-P58, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment P59. [00323] Embodiment P61. A method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments P1-P58, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment P59. [00324] Embodiment P62. The method of embodiment P61, wherein the cancer is lymphoma. [00325] Embodiment P63. The method of embodiment P62, wherein the lymphoma is Diffuse Large B-Cell Lymphoma. [00326] Embodiment P64. A method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments P1-P58, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment P59. [00327] Embodiment P65. The method of embodiment P64, wherein the autoimmune disease is selected from atopic dermatitis, asthma, lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohns Disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjögren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, and Wegener's granulomatosis. [00328] Embodiment P66. A pharmaceutical composition comprising a compound of the following formula: or an isomer thereof, or a pharmaceutically acceptable salt of the foregoing, and two or more of: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate. [00329] Embodiment P67. The pharmaceutical composition of embodiment P66, wherein the , or a pharmaceutically acceptable salt thereof. [00330] Embodiment P68. The pharmaceutical composition of embodiment P66 or P67, comprising anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate. [00331] Embodiment P69. The pharmaceutical composition of any one of embodiments P66- P68, comprising about 35% weight/weight (w/w) of the compound (70), or an isomer therof, or a pharmaceutically acceptable salt of the foregoing. [00332] Embodiment P70. The pharmaceutical composition of any one of embodiments P66- P69, formulated for oral administration. [00333] Embodiment P71. The pharmaceutical composition of embodiment P70, formulated for enteric release. [00334] Embodiment P72. A unit dosage formulation comprising a pharmaceutical composition of any one of embodiments P66-P71, wherein the compound (70), or an isomer thereof, or a pharmaceutically acceptable salt of the foregoing, is present in the unit dosage form in an amount of from about 10 mg to about 100 mg. [00335] Embodiment P73. The unit dosage formulation of embodiment P72, comprising about 20 mg or about 80 mg of the compound (70), or an isomer thereof, or a pharmaceutically acceptable salt of the foregoing. [00336] Embodiment P74. The unit dosage formulation of embodiment P72 or P73, in the form of a tablet. [00337] Embodiment P75. The unit dosage formulation of embodiment P74, wherein the tablet is film-coated. [00338] Embodiment P76. A method of treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti- CD20 antibody and the compound of any one of embodiments P1-P58, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of embodiments P59 and P66-P71, or the unit dosage formulation of any one of embodiments P72-P75. [00339] Embodiment P77. A method of treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments P1-P58, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of embodiments P59 and P66-P71, or the unit dosage formulation of any one of embodiments P72-P75, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered: (i) daily on each day of a 28-day cycle; or (ii) on days 1-14 of a 28-day cycle and is not administered on days 15-28 of the 28-day cycle: or (iii) on days 1-21 of a 28-day cycle and is not administered on days 22-28 of the 28-day cycle. [00340] Embodiment P78. A method of treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject the compound of any one of embodiments P1-P58, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of embodiments P59 and P66-P71, or the unit dosage formulation of any one of embodiments P72-P75, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily or twice daily at a dose of about 20 mg/day, about 40 mg/day, about 80 mg/day, about 160 mg/day, about 260 mg/day, about 400 mg/day, or about 640 mg/day. [00341] Embodiment P79. The method of embodiment P76 or P77, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily or twice daily at a dose of about 20 mg/day, about 40 mg/day, about 80 mg/day, about 160 mg/day, about 260 mg/day, about 400 mg/day, or about 640 mg/day. [00342] Embodiment P80. The method of any one of embodiments P76-P79, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily. [00343] Embodiment P81. The method of any one of embodiments P76-P79, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to the subject twice daily. [00344] Embodiment P82. The method of any one of embodiments P76-P81, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered: (i) daily on each day of a 28-day cycle; or (ii) on days 1-14 of a 28-day cycle and is not administered on days 15-28 of the 28-day cycle: or (iii) on days 1-21 of a 28-day cycle and is not administered on days 22- 28 of the 28-day cycle. [00345] Embodiment P83. The method of embodiment P82, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered daily on each day of a 28-day cycle. [00346] Embodiment P84. The method of embodiment P82, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of a 28-day cycle and is not administered on days 15-28 of the 28-day cycle. [00347] Embodiment P85. The method of embodiment P82, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of a 28-day cycle and is not administered on days 22-28 of the 28-day cycle. [00348] Embodiment P86. The method of any one of embodiments P77-P85, further comprising administering to the subject an anti-CD20 antibody. [00349] Embodiment P87. The method of embodiment P76 or P86, wherein the anti-CD20 antibody is rituximab. [00350] Embodiment P88. The method of embodiment P87, wherein rituximab is administered intravenously. [00351] Embodiment P89. The method of embodiment P87 or P88, wherein about 375 mg/m² rituximab is administered once every 28 days. [00352] Embodiment P90. The method of any one of embodiments P87-P89, wherein rituximab is administered on day 1 of a 28-day treatment cycle and the compound, or a pharmaceutically acceptable salt thereof, is administered: (i) daily on each day of the 28-day treatment cycle; or (ii) on days 1-14 of the 28-day treatment cycle and is not administered on days 15-28 of the 28-day treatment cycle: or (iii) on days 1-21 of the 28-day treatment cycle and is not administered on days 22-28 of the 28-day treatment cycle. [00353] Embodiment P91. The method of any one of embodiments P76-P90, wherein the method is a method of treating a cancer. [00354] Embodiment P92. The method of embodiment P91, wherein the cancer is a lymphoma. [00355] Embodiment P93. The method of embodiment P92, wherein the lymphoma is a B cell lymphoma. [00356] Embodiment P94. The method of embodiment P92 or P93, wherein the lymphoma is a non-Hodgkin lymphoma. [00357] Embodiment P95. The method of any one of embodiments P92-P94, wherein the lymphoma is diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, or lymphoplasmacytic lymphoma. [00358] Embodiment P96. The method of embodiment P95, wherein the lymphoma is diffuse large B cell lymphoma or follicular lymphoma. [00359] Embodiment P97. The method of any one of embodiments P91-P96, wherein the cancer is relapsed or refractory. EXAMPLES [00360] The following Examples are presented by way of illustration, not limitation. Compounds are named using the automatic name generating tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products. [00361] Salts of the compounds described herein can be prepared by standard methods, such as inclusion of an acid (for example TFA, formic acid, or HCl) in the mobile phases during chromatography purification, or stirring of the products after chromatography purification, with a solution of an acid (for example, aqueous HCl). [00362] The following abbreviations may be relevant for the application. Abbreviations ACN, MeCN acetonitrile AcOH acetic acid anh anhydrous atm atmospheric pressure BF3OEt2 boron trifluoride etherate BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BOC tert-butyloxycarbonyl CBM Cereblon Binding Moiety Cbz-Cl benzyl chloroformate CDI 1,1'-carbonyldiimidazole CPhos 2′-(dicyclohexylphosphanyl)-N²,N²,N⁶,N⁶-tetramethyl[1,1′- biphenyl]-2,6-diamine DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMEDA 1,2-dimethylethylenediamine DMF dimethylformamide DMSO dimethyl sulfoxide EDC ethylene dichloride eq or equiv equivalents ESI electrospray ionization Et3N triethylamine Et2O diethyl ether EtOAc or EA ethyl acetate EtOH ethanol FA formic acid h or hrs hour HATU N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N- oxide hex hexanes HPLC high pressure liquid chromatography iPrOH isopropanol Josiphos Pd G3 {(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert- butylphosphine}[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate LCMS liquid chromatography mass spectrometry LHDMS lithium bis(trimethylsilyl)amide M molarity mCPBA meta-chloroperoxybenzoic acid MeOH methanol MeTHF 2-methyltetrahydrofuran min minute MS mass spectrometry N normality NaOtBu sodium tert-butoxide NBS N-bromosuccinimide NIS N-iodosuccinimide NMP N-methyl-2-pyrrolidone oMe mesylate oTs tosylate Pd₂dba₃ tris(dibenzylideneacetone)dipalladium(0) Pd-Ruphos-G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-(2'- amino-1,1'-biphenyl))palladium(II) methanesulfonate PE, pet ether petroleum ether quant. quantitative RBF round bottom flask rt or RT room temperature Rt retention time SFC supercritical fluid chromatography SM starting material SNAr nucleophilic aromatic substitution TBAB tetrabutylammonium bromide tBuOH tert-butanol TEA trimethylamine TFA trifluoro acetic acid THF tetrahydrofuran TLC thin layer chromatography xantphos XPhos Pd G3 Synthetic Examples General Procedure 1: First SNAr onto pyrimidine. [00363] To a -40 °C mixture of 5-amino-1-methylindolin-2-one (1 eq) in dry tetrahydrofuran [0.4M] was added DIPEA (1.1 eq). A solution of 5-chloro-2,4-difluoropyrimidine (1 eq) in dry tetrahydrofuran [1.5M] was slowly added to the above mixture and allowed to slowly warm to rt. The reaction mixture was stirred at rt for 16 h. After this time, the reaction mixture was filtered and washed with acetonitrile. The solid was dried under vacuum to afford the title compound as a tan solid. General Procedure 2: Buchwald Coupling of Amine to Indazole CBM. [00364] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1a (1.1 eq), amine (1.0 eq), Ruphos-Pd-G3 (0.20 equiv.) and NaOtBu (1.5 eq) in 1,4-dioxane [0.3M] was heated to 90 °C for 16 h and then cooled to rt. The mixture was filtered on celite and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound. General Procedure 3: Methylation of amine [00365] To a solution of amine (1.0 eq, 14.2 mmol) in DMF [0.15M] was added NaH (4.4 eq), and stirred at 0 °C for 1 h. To the mixture was added iodomethane (2.8 eq) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16hr. The reaction mixture was then quenched with water, and extracted with EA. The extracts were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EA (15:1) to obtain the title compound. General Procedure 4: Reduction of CBM with Hydrogen. [00366] A mixture of indazole intermediate (1.0 equiv.) and Pd/C (10 wt. % palladium; 40% by weight) in EtOH:THF (1:1.5; [0.05M]) was subjected to hydrogen (1 atm) at 50 °C for 4 h. The mixture was degassed with nitrogen and filtered through Celite. The filter cake was washed sequentially with EtOH and THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford title compound. General Procedure 5: BOC Deprotection with HCl or TFA. [00367] To a solution of BOC protected amine (1.0 eq) in 1,4-dioxane [0.3 M] was added 4N HCl in 1,4-dioxane (14 eq.), and the reaction mixture was stirred at rt for 12 h. The volatiles were evaporated under reduced pressure to afford title compound (quant.) as a solid, which was used in the next step without further purification. General Procedure 6: SNAr of Decorated TBM with CBM. [00368] A solution of amine hydrochloride (1.0 eq), the chloro/fluoro pyrimidine (1.0 eq), N,N-diisopropylethylamine (3 to 5 eq) in DMSO [0.1-0.2 M] was stirred at 80 °C for 2 hr. The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fractions containing clean product were combined and lyophilized to afford the title compounds. [00369] Example i-1. Synthesis of Intermediate 1: 3-(1-Methyl-6-(4- (methylamino)piperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride [00370] Step 1: Synthesis of tert-Butyl (1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl- 1H-indazol-6-yl)piperidin-4-yl)(methyl)carbamate. 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-indazole (300 mg, 0.6000 mmol), tert-butyl N-methyl-N-(piperidin-4-yl)carbamate (192.72 mg, 0.9000 mmol), cesium carbonate (390.68 mg, 1.2 mmol), and RuPhos-Pd-G3 (50.14 mg, 0.0600 mmol) were added to a 1 dram vial and purged with nitrogen for 1 min. After which, 1,4-dioxane (0.8 mL) was added and the reaction mixture was stirred at 100 °C for overnight. Product was purified from crude mixture using column chromatography (10 g SNAP cartridge, 0-7% Methanol/ DCM 25 CV, 7% methanol/ DCM 10 CV) to give the title compound (106 mg, 0.1673 mmol, 27.8% yield) as a white solid. MS (ESI) m/z 634.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6 ) δ ppm 7.89 (d, J=8.19 Hz, 1 H), 7.26 - 7.51 (m, 11 H), 6.88 (d, J=1.59 Hz, 1 H), 6.82 (dd, J=9.17, 1.96 Hz, 1 H), 6.57 (d, J=8.19 Hz, 1 H), 5.44 (d, J=13.57 Hz, 4 H), 3.97 (s, 3 H), 3.87 (br d, J=12.59 Hz, 2 H), 2.77 (br t, J=11.55 Hz, 2 H), 2.70 (s, 3 H), 1.71 - 1.89 (m, 2 H), 1.61 - 1.70 (m, 2 H), 1.42 (s, 9 H). [00371] Step 2: Synthesis of tert-butyl (1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)piperidin-4-yl)(methyl)carbamate. Tert-butyl N-[1-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-6-yl]-4-piperidyl]-N-methyl-carbamate (106 mg, 0.1700 mmol) and ethanol (4.1813 mL) were dissolved in a 40 mL vial equipped with a sir bar. The mixture was purged with nitrogen and palladium on carbon (17.8 mg, 0.1700 mmol) was added. The mixture was purged again with nitrogen and then hydrogen. The reaction stirred under a balloon of hydrogen overnight. The slurry was filtered through celite and concentrated. The residue was loaded onto a SNAP25G column and purified with 0-50% EtOAC/hex with 2-5% MeOH additive to give the title compound (50 mg, 0.110 mmol, 65.6% yield) as yellow oil. [00372] Step 3: Synthesis of 3-(1-Methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol- 3-yl)piperidine-2,6-dione hydrochloride. Tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]-4-piperidyl]-N-methyl-carbamate (50 mg, 0.1100 mmol) was added to a vial equipped with a stir bar and dichloromethane (1 mL) was added. HCl 4 N in 1,4-dioxane (0.4400 mmol) was then added to the mixture and stirred for 2 hours. The stir bar was removed and the solvent was removed in vacuo to give the title compound (42 mg, 0.107 mmol, 97.6% yield) as an off white solid. Example i-2. Synthesis of Intermediate 2: 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol- 3-yl)piperidine-2,6-dione hydrochloride [00373] Step 1: Synthesis of 6-bromo-3-iodo-1-methyl-indazole. To a solution of^6- bromo-1-methyl-indazole (8.00 g, 37.9 mmol) in^DMF (100 mL) was added NIS (25.58 g, 113.7 mmol). The reaction mixture was heated to^150 °C for on and then cooled to rt. The volatiles were evaporated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexane to afford^the title compound (4.95 g, 14.7 mmol, 39% yield) as a solid. ^MS (ESI) [M+H]⁺^336.90. [00374] Step 2: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole. To a solution of^6-bromo-3-iodo-1-methyl-indazole (2. g, 5.94 mmol)^in 1,4-Dioxane (30 mL)^and water (3 mL)^was added (2,6-dibenzyloxy-3-pyridyl)boronic acid (1.99 g, 5.94 mmol), potassium phosphate (3.78 g, 17.81 mmol)^and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (0.43 g, 0.5900 mmol) under N₂, then the mixture was stirred at^80 °C^for 17 hrs under N₂. LCMS showed the reactant was consumed completely, and desired MS as main peak. The reaction was then cooled to room temperature and filtered. The filtrate was^extracted^with ethyl acetate (3x 40 mL), washed with^brine(2x 40 mL), dried over anhydrous Na₂SO₄^and concentrated under reduced pressure.^The crude was purified by column chromatography (silica, gradient: 0-30% Ethyl acetate in ptroleum ether) to the title compound (2.1 g, 4.20 mmol, 71% yield)^as a pale yellow solid. MS (ES) [M+H]⁺^500.3.¹H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.62 (d, J= 8.7 Hz, 1H), 7.50 – 7.24 (m, 10H), 7.12 (dd, J= 8.7, 1.4 Hz, 1H), 6.60 (d, J= 8.1 Hz, 1H), 5.45 (s, 2H), 5.43 (s, 2H), 4.05 (s, 3H). [00375] Step 3: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of^6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazole (4.0 g, 7.99 mmol),^tert-butyl 4-aminopiperidine-1-carboxylate (1.92 g, 9.59 mmol), XPhos-Pd-G3 (1.35 g, 1.6 mmol)and^Cs2CO3 (5.2 g, 15.99 mmol) in1,4-Dioxane (53.292 mL)was heated to 110 °C for 28 h and then cooled to rt. The mixture was filtered through Celite and washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-90% ethyl acetate in hexane to afford^tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (2.81 g, 4.53 mmol, 57% yield)as a solid.^MS (ESI) [M+H]⁺:^620.4;^¹H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.45 – 7.42 (m, 2H), 7.39 – 7.27 (m, 7H), 7.25 – 7.22 (m, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 8.8, 1.9 Hz, 1H), 6.31 (d, J = 1.7 Hz, 1H), 5.46 (s, 2H), 5.38 (s, 2H), 4.06 (br, 2H), 3.98 (s, 3H), 3.73 (br, 1H), 3.57 – 3.46 (m, 2H), 3.00 (t, J = 11.9 Hz, 2H), 2.10 (dd, J = 13.0, 2.8 Hz, 2H), 1.48 (s, 9H). [00376] Step 4: Synthesis of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]amino]piperidine-1-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (600 mg, 0.970 mmol) and Pearlman's Catalyst (167 mg, 0.240 mmol) in THF (5 mL) and Ethanol (3 mL) was subjected to hydrogenation at 1 atm and 50 °C for 4 h. At this time, only the alkene product was observed. Additional^Pearlman's Catalyst (33.4 mg, 0.0500 mmol) was added and the mixture was^subjected to hydrogenation at 1 atm and 50 °C for 24 h.^The mixture was filtered through Celite and washed with MeOH:MeCN (1:1 ratio, 3 x 50.0 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]amino]piperidine-1-carboxylate (495 mg, 0.9496 mmol, 98.085% yield) as a solid.^ MS (ESI) [M+H]⁺: 442.4;^¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.52 (dd, J = 8.8, 1.8 Hz, 1H), 6.43 (s, 1H), 5.79 (d, J = 8.2 Hz, 1H), 4.18 (dd, J = 8.7, 5.2 Hz, 1H), 3.93 – 3.86 (m, 2H), 3.81 (s, 3H), 2.96 (br, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.30 – 2.20 (m, 1H), 2.18 – 2.11 (m, 1H), 1.94 (d, J = 11.0 Hz, 2H), 1.41 (s, 9H), 1.30 – 1.19 (m, 3H). [00377] Step 5: Synthesis of 3-[1-Methyl-6-(4-piperidylamino)indazol-3-yl]piperidine- 2,6-dione hydrochloride salt. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]amino]piperidine-1-carboxylate (1.22 g, 2.76 mmol) in 1,4-dioxane (20 mL) was added hydrogen chloride 4N in 1, 4 dioxane (3.45 mL, 13.8 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The solid was collected by filtration to give title compound (1.0 g, 2.65 mmol, 96% yield) as white solid. MS (ESI) m/z 342.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1 H), 9.01 (br d, J=2.45 Hz, 1 H), 8.76 - 8.95 (m, 1 H), 7.48 (br s, 1 H), 6.72 (br s, 3 H), 4.21 - 4.30 (m, 1 H), 3.87 (s, 3 H), 3.63 - 3.75 (m, 1 H), 3.32 (br d, J=12.59 Hz, 2 H), 2.99 (br d, J=10.39 Hz, 2 H), 2.55 - 2.69 (m, 2 H), 2.22 - 2.34 (m, 1 H), 2.07 - 2.22 (m, 3 H), 1.72 (br s, 2 H). Example i-3. Synthesis of Intermediate 3: 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine- 2,6-dione [00378] Step 1: Synthesis of tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- indazol-6-yl)carbamate.3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (160g, 320 mmol) was taken in 1,4-Dioxane (1600 mL) in a 3000ml multineck RBF fitted with reflux condenser under N₂ atm with mechanical stirring. Next, tert-butyl carbamate (56.2 g, 480 mmol) was added , followed by K2CO3 (133 g, 959 mmol) and then purged for 5 minutes, followed by addition of XPhos Pd G2 (25.2 g, 32.0 mmol), purged again for 5 minutes and then refluxed at 110 °C for overnight. The reaction mixture was filtered through a celite bed, washing with ethyl acetate. The filtrate obtained was evaporated to give crude product which was purified using ISCO in silica gel with PE/EtOAc as eluant to give the title compound (148 g, 275 mmol, 86 % yield) as white solid. MS (ESI) m/z 537.30 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.5 (s, 1H), 7.89 – 7.91 (m, 1H), 7.28 - 7.54 (m, 12 H), 6.94 (d, 1 H), 6.58 (d, 1 H), 5.41-5.45 (d, 4 H), 3.96 (s, 3 H), 1.50 (s, 9 H), 1.37 (s, 1H). [00379] Step 2: Synthesis of tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol- 6-yl)carbamate. To a flask was added tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl- 1H-indazol-6-yl)carbamate (25 g, 46.6 mmol) and THF (500 mL). This mixture was purged with nitrogen for 5 min and then palladium on carbon (24.79 g, 23.29 mmol) was added and then stirred under H₂ atmosphere overnight at 55 °C. After this time, the reaction mixture was filtered through celite washing with THF (2 L) and then the filtrate obtained was evaporated to give the title compound (15.69 g, 43.8 mmol, 94 % yield) as white solid. MS (ESI) m/z 359.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 9.54 (s, 1H), 7.82 (m, 1H), 7.55 - 7.57 (d, 1 H), 7.04 (d, 1 H), 4.30 (m, 1 H), 3.90 (s, 3 H), 2.30 – 2.70 (m, 2 H) 2.13 – 2.37 (m, 2 H), 1.36 (s, 9H). [00380] Step 3: Synthesis of 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione, HCl salt. tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)carbamate (25 g, 69.8 mmol) was dissolved in 1,4-Dioxane (250 mL) in a 2 L RBF under magnetic stirring. HCl (4M in dioxane) (250 mL, 69.8 mmol) was added slowly and then the reaction was stirred at RT for 48 hours. After this time, the mixture was filtered and then the solids obtained were taken up in methanol and then stirred well for 20 minutes and then filtered again to give the title compound (18 g, 57.2 mmol, 82 % yield) as pale yellow solid. MS (ESI) m/z 259.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.80 - 7.82 (d, 1 H), 7.53 (s, 1 H), 7.08 - 7.11 (d 1 H), 4.39 - 4.43 (m, 1 H), 3.99 (s, 3 H), 2.50 – 2.73 (m, 2 H), 2.38 – 2.40 (m, 1 H), 2.18 - 2.36 (m, 1 H). Example i-4. Synthesis of Intermediate 4: 3-(1-methyl-6-(methyl(piperidin-4-yl)amino)-1H- indazol-3-yl)piperidine-2,6-dione hydrochloride [00381] Step 1: Synthesis of tert-Butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazole (500 mg, 1 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol), RuPhos-Pd-G3 (83 mg, 0.1000 mmol) and Cs2CO3 (651 mg, 2 mmol) in 1,4- dioxane (5 mL) was heated to 90 °C for 18 h and then cooled to rt. The mixture was filtered through Celite and washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (550 mg, 89%) as a solid.¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.45 – 7.41 (m, 2H), 7.39 – 7.24 (m, 8H), 6.49 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 8.7, 1.9 Hz, 1H), 6.31 (d, J = 1.7 Hz, 1H), 5.46 (s, 2H), 5.38 (s, 2H), 4.13 – 4.03 (m, 2H), 3.98 (s, 3H), 3.73 (s, 1H), 3.57 – 3.50 (m, 1H), 3.00 (t, J = 12.1 Hz, 2H), 2.10 (d, J = 10.8 Hz, 2H), 1.48 (s, 9H), 1.43 – 1.35 (m, 2H). MS (ESI) [M+H]⁺ 620.5. [00382] Step 2: Synthesis of tert-Butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]-methyl-amino]piperidine-1-carboxylate. To a solution of tert-butyl 4-[[3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino] piperidine-1-carboxylate (550 mg, 0.89 mmol) in DMSO (3.6 mL) and acetic acid (0.9 mL) were sequentially added aqueous solution of formaldehyde (0.13 mL, 1.8 mmol) and NaBH(OAc)3 (282 mg, 1.3 mmol). The reaction mixture was stirred at rt for 1 h. Water (10 mL) and EtOAc (25 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of NaHCO₃ (5 mL), water (3 x 5 mL), brine (5 mL), dried on Na2SO4, filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (467 mg, 83% yield) as a solid.¹H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.40 – 7.30 (m, 5H), 7.29 – 7.23 (m, 3H), 6.72 (dd, J = 9.3, 2.1 Hz, 1H), 6.50 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 5.47 (s, 2H), 5.38 (s, 2H), 4.25 (s, 2H), 4.01 (s, 3H), 3.80 (td, J = 10.8, 5.3 Hz, 1H), 2.84 (s, 3H), 2.83 – 2.74 (m, 2H), 1.81 – 1.64 (m, 4H), 1.49 (s, 9H). MS (ESI) [M+H]⁺ 635.5. [00383] Step 3: tert-Butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-methyl- amino] piperidine-1-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate (467 mg, 0.74 mmol) and 20% Pd(OH)2/C (117 mg, 25 wt%) in THF (7 mL) and EtOH (7 mL) was subjected to hydrogenation at 1 atm and 50 °C for 2 h. The mixture was filtered through Celite, washed with a mixture of MeCN and MeOH (1:1, 3 x 10 mL), and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–20% MeOH in DCM to afford the title compound (258 mg, 77%) as a solid.¹H NMR (500 MHz, DMSO) δ 10.83 (s, 1H), 7.46 (d, J = 9.0 Hz, 1H), 6.87 (dd, J = 9.2, 2.0 Hz, 1H), 6.65 (d, J = 1.9 Hz, 1H), 4.23 (dd, J = 9.0, 5.1 Hz, 1H), 4.09 – 3.99 (m, 2H), 3.98 – 3.91 (m, 1H), 3.87 (s, 3H), 2.86 (br s, 2H), 2.76 (s, 3H), 2.64 – 2.56 (m, 2H), 2.33 – 2.25 (m, 1H), 2.21 – 2.13 (m, 1H), 1.67 – 1.54 (m, 4H), 1.41 (s, 9H). MS (ESI) [M+H]⁺ 456.3. [00384] Step 4: Synthesis of 3-[1-Methyl-6-[methyl(4-piperidyl)amino]indazol-3- yl]piperidine-2,6-dione;hydrochloride. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate (258 mg, 0.57 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in 1,4-dioxane (1.42 mL, 5.66 mmol). The reaction mixture was heated to 100 °C for 3 h then cooled to rt. The volatiles were evaporated under reduced pressure. Et₂O (5 x mL) was added and the resulting precipitate was collected by filtration, washed with 1,4-dioxane (3 x 1 mL) and Et₂O (10 x 2 mL) then dried under vacuum to afford the title compound (217 mg, 92%) as a solid.¹H NMR (400 MHz, D2O) δ 7.93 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.56 (dd, J = 10.8, 4.2 Hz, 1H), 4.18 – 4.09 (m, 1H), 4.07 (s, 3H), 3.61 (d, J = 12.6 Hz, 2H), 3.33 (s, 3H), 3.11 (t, J = 12.9 Hz, 2H), 2.91 – 2.79 (m, 2H), 2.61 – 2.48 (m, 1H), 2.44 – 2.35 (m, 1H), 2.28 (d, J = 12.0 Hz, 2H), 2.05 – 1.90 (m, 2H). Note: exchangeable protons not observed, contains < 1 wt% 1,4-dioxane. MS (ESI) [M+H]⁺ 356.2. Example i-5. Synthesis of Intermediate 5: 5-amino-1-(2-morpholinoethyl)indolin-2-one [00385] Step 1: Synthesis of 1-(2-morpholinoethyl)-5-nitroindolin-2-one. To a stirred solution of triphenylphosphine (1.104 g, 4.21 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (1.091 mL, 5.61 mmol) dropwise at 0 °C under nitrogen and stirred for 20 min. Then 2-morpholinoethan-1-ol (736 mg, 5.61 mmol) was added and stirred for 15 min. Subsequently, 5-nitroindolin-2-one (500 mg, 2.81 mmol) was added and slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to afford the crude product which was purified by flash column chromatography on silica gel with 60- 80% ethyl acetate/pet ether to afford the title compound (273 mg, 0.937 mmol, 24% yield) as an off-white solid. MS (ESI) [M+H]⁺ 292.0. [00386] Step 2: Synthesis of 5-amino-1-(2-morpholinoethyl)indolin-2-one. To a stirred suspension of 1-(2-morpholinoethyl)-5-nitroindolin-2-one (300 mg, 1.030 mmol) in ethanol (5.0 mL) and THF (5.0 mL) was added 10% Pd/C (150 mg) under nitrogen at 25 °C. The reaction mixture was stirred under hydrogen atmosphere for 8 h. The reaction mixture was filtered through celite and the celite pad was washed with ethanol (2 x 50 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (280 mg, 1.071 mmol, 45% yield) as a grey liquid. The crude product was used for the next step without further purification. MS (ESI) [M+H]⁺ 262.2. Example i-6. Synthesis of Intermediate 6: 5-amino-1-(4,4,4-trifluorobutyl)indolin-2-one [00387] Step 1: Synthesis of 5-amino-1-(4,4,4-trifluorobutyl)indolin-2-one The synthesis of the title compound was accomplished analogously to Intermediate 5 and using 4,4,4- trifluorobutan-1-ol as the starting material. Example i-7. Synthesis of Intermediate 7: 5-amino-6-fluoro-1-methylindolin-2-one [00388] Step 1: Synthesis of 6-fluoro-1-methyl-5-nitroindolin-2-one. To a solution of 6- fluoro-1-methylindolin-2-one (100 mg, 0.605 mmol) in TFA (1 mL) was added to sodium nitrate (51.5 mg, 0.605 mmol) at 0 °C, The reaction mixture was allow warm to room temperature and stirred for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was then quenched with saturate sodium bicarbonate (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated. The crude was purified by silica gel column chromatography (0-100 % ethyl acetate in hexane) to afford the title compound (100 mg, 0.476 mmol, 79 % yield) as white solid; MS (ESI) m/z 211.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (br d, J=7.46 Hz, 1 H), 6.95 - 7.10 (m, 1 H), 3.63 (s, 2 H), 3.28 - 3.33 (m, 43 H), 3.24 (s, 3 H). [00389] Step 2: Synthesis of 5-amino-6-fluoro-1-methylindolin-2-one. A suspension of 6- fluoro-1-methyl-5-nitroindolin-2-one (100 mg, 0.476 mmol) in methanol (10 mL) was stirred with palladium on carbon (50.6 mg, 0.476 mmol) under hydrogen (1 atm) at room temperature for 2 h. The reaction mixture was filtered. Concentration of the filtrate under reduced pressure afforded the title compound (80 mg, 0.444 mmol, 93 % yield) as off-white solid; MS (ESI) m/z 181.2 [M+H]⁺. Example i-8. Synthesis of Intermediate 8: 5-amino-7-fluoro-1-methylindolin-2-one [00390] Step 1: Synthesis of 7-fluoro-1-methylindolin-2-one. To a suspension of 7- fluoroindolin-2-one (0.400 g, 2.65 mmol) in water (10 mL) was added sodium hydroxide 1N (3.97 mL, 3.97 mmol) and dimethyl sulfate (0.379 mL, 3.97 mmol), The reaction mixture was stirred at 120 °C for 40 min. LCMS indicated the reaction was incomplete with 20% SM remaining. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered over celite, and concentrated. The crude was purified by silica gel column chromatography (0-50 % ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound 7-fluoro-1-methylindolin- 2-one (0.3 g, 1.82 mmol, 69 % yield) as yellow solid; MS (ESI) m/z 331.2 [M+H]⁺. [00391] Step 2: Synthesis of 5-amino-7-fluoro-1-methylindolin-2-one. The synthesis of the title compound was accomplished analogously to Intermediate 7 using 7-fluoro-1- methylindolin-2-one as the starting material. Example i-9. Synthesis of Intermediate 9: 5-amino-4-fluoro-1-methylindolin-2-one [00392] Step 1: Synthesis of 4-fluoro-1-methylindolin-2-one. To a suspension of 4- fluoroindolin-2-one (1.0 g, 6.62 mmol) in water (18 mL) was added sodium hydroxide 1N (9.92 mL, 9.92 mmol) and dimethyl sulfate (0.695 mL, 7.28 mmol), The reaction mixture was stirred at 120 °C for 40 min. LCMS indicated the reaction was incomplete with 20% SM remaining. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered over celite, and concentrated. The crude was purified by silica gel column chromatography (0-50 % ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (1.48 g, 100 %) as white solid; MS (ESI) m/z 166.2 [M+H]⁺. [00393] Step 2: Synthesis of 4-fluoro-1-methyl-5-nitroindolin-2-one. To a -30 °C solution of 4-fluoro-1-methylindolin-2-one (0.68 g, 4.12 mmol) in sulfuric acid (10 mL) was added nitric acid 90% (0.195 mL, 4.53 mmol) in sulfuric acid 98 (1 mL) slowly. The reaction mixture was stirred at -30 °C and allowed warm to 0 °C over 30 min. The reaction mixture was poured onto 100 g ice, then extracted with ethyl acetate (3 X 25 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered over celite, and concentrated. The crude was purified by silica gel column chromatography (0-100 % ethyl acetate in hexane) to afford the title compound 4-fluoro-1-methyl-5-nitroindolin-2-one (0.260 g, 1.24 mmol, 30.0 % yield) as yellow solid; MS (ESI) m/z 211.2 [M+H]⁺. [00394] Step 3: Synthesis of 5-amino-4-fluoro-1-methylindolin-2-one. The suspension of 4-fluoro-1-methyl-5-nitroindolin-2-one (60 mg, 0.285 mmol) in methanol (10 mL) was stirred with palladium on carbon (30.4 mg, 0.285 mmol) under hydrogen (1 atm) at room temperature for 2 h. The reaction mixture was filtered. Concentration of the elute under reduced pressure afforded the title compound (44 mg, 0.244 mmol, 86 % yield) as white solid; MS (ESI) m/z 181.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.68 (t, J = 8.56 Hz, 1H), 6.54 (d, J = 8.07 Hz, 1H), 4.76 (s, 2H), 3.52 (s, 2H), 3.04 (s, 3H). Example i-10. Synthesis of Intermediate 10: 5-amino-1-isopropylindolin-2-one [00395] Step 1: Synthesis of 1-isopropyl-5-nitroindolin-2-one A solution of 2-(2-fluoro-5- nitrophenyl)acetic acid (0.5 g, 2.51 mmol), propan-2-amine (0.445 g, 7.53 mmol) in DMSO (4 mL) was stirred at 60 °C for 15 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (0-100 % ethyl acetate in hexane in hexane). Concentration of the desired fractions under reduced pressure afforded the 2-(2- (isopropylamino)-5-nitrophenyl)acetic acid (0.528 g, 87 %) as yellow solid. The solid 2-(2- (isopropylamino)-5-nitrophenyl)acetic acid (0.528 g) was then stirred with 2 N HCl 10 mL at room temperature for 15 hours. The resulting solid was collected by filtration to give the title compound (0.45 g, 2.043 mmol, 81 % yield) as yellow solid; MS (ESI) m/z 221.2 [M+H]⁺. [00396] Step 2: Synthesis of 5-amino-1-isopropylindolin-2-one The suspension of 1- isopropyl-5-nitroindolin-2-one (450 mg, 2.043 mmol) in methanol (10 mL) was stirred with palladium on carbon (217 mg, 2.043 mmol) under hydrogen (1 atm) at room temperature for 15 h. The reaction mixture was filtered. Concentration of the elute under reduced pressure afforded the title compound 5-amino-1-isopropylindolin-2-one (350 mg, 1.840 mmol, 90 % yield) as off- white solid; MS (ESI) m/z 191.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.80 (d, J=8.31 Hz, 1 H), 6.55 (d, J=1.96 Hz, 1 H), 6.43 (dd, J=8.31, 2.32 Hz, 1 H), 4.72 (br s, 2 H), 4.45 (spt, J=6.99 Hz, 1 H), 3.35 (s, 2 H), 1.34 (d, J=7.09 Hz, 6 H). Example i-11. Synthesis of Intermediate 11: 5-amino-1-ethylindolin-2-one [00397] Step 1: Synthesis of 5-amino-1-ethylindolin-2-one The synthesis of the title compound was accomplished analogously to Intermediate 10 and using ethanamine hydrochloride as the starting material. Example i-12. Synthesis of Intermediate 12: 5-amino-1-(2-hydroxyethyl)indolin-2-one [00398] Step 1: Synthesis of 5-amino-1-(2-hydroxyethyl)indolin-2-one The synthesis of the title compound was accomplished analogously to Intermediate 10 and using 2- aminoethanol as the starting material. Example i-13. Synthesis of Intermediate 13: 5-amino-1-(2-methoxyethyl)indolin-2-one [00399] Step 1: Synthesis of 2-(2-((2-methoxyethyl)amino)-5-nitrophenyl)acetic acid. To a solution of 2-(2-fluoro-5-nitrophenyl) acetic acid (1, 500 mg, 2.51 mmol) in THF (5.0 mL) was added 2-methoxyethan-1-amine (2, 377mg, 5.02mmol) and DIPEA (0.877 mL, 5.02 mmol) under nitrogen at 25 °C. The reaction mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (550 mg, 0.543 mmol, 21% yield) as yellow solid. [00400] Step 2: Synthesis of 1-(2-methoxyethyl)-5-nitroindolin-2-one. To a solution of 2- (2-((2-methoxyethyl)amino)-5-nitrophenyl)acetic acid (550 mg, 2.16 mmol) in water (2.0 mL) was added 1.5 N HCl (3.0 mL). The reaction mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was slowly poured in sodium bicarbonate solution at 0 °C and extracted with ethyl acetate. The combine organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (240 mg, 0.95 mmol, 44% yield) as a light brown solid. [00401] Step 3: Synthesis of 5-amino-1-(2-methoxyethyl) indolin-2-one. To a stirred solution of 1-(2-methoxyethyl)-5-nitroindolin-2-one (240 mg, 0.945 mmol) in ethanol (10 mL) was added 10% Pd/C (101 mg) under nitrogen at 25 °C. The reaction mixture was stirred under hydrogen atmosphere for 8 h. The reaction mixture was filtered through celite and the celite pad was washed with ethanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (200 mg, 0.563 mmol, 59% yield). The product was used for the next step without further purification. MS (ESI) m/z 207.2 [M+H]⁺. Example i-14. Synthesis of Intermediate 14: 5-amino-1-methyl-1,3-dihydro-2H- pyrrolo[2,3-b]pyridin-2-one [00402] Step 1: Synthesis of 3,3-dibromo-1-methyl-5-nitro-1,3-dihydro-2H-pyrrolo[2,3- b]pyridin-2-one. To a stirred solution of 1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (800 mg, 3.66 mmol) in t-Butanol (1 mL) and water (1 mL). was added NBS (1.37 g, 7.68 mmol) at 0 °C. the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was monitored by TLC and LCMS. When the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3x 100 ml). The combined organic layers were evaporated to obtain crude title compound that was used without further purification. [00403] Step 2: Synthesis of 5-amino-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2- one To a stirred solution of 3,3-dibromo-1-methyl-5-nitro-1,3-dihydro-2H-pyrrolo[2,3- b]pyridin-2-one (1.4 g, 3.99 mmol) in AcOH (20 mL) was added zinc dust (1.30 g, 20.0 mmol) and the reaction mixture was stirred at 25 °C for 6 h. The reaction mixture was monitored by TLC and LCMS. After this time, the reaction mixture was evaporated. The resulting reside was basified by using NaOH solution (100 ml) and extracted with 10% MeOH in DCM. The organic fraction was evaporated to obtained the title compound which was used without further purification. MS (ESI) m/z 164.1 [M+H]⁺. Example i-15. Synthesis of Intermediate 15: 6-amino-1-(3-hydroxy-3-methylbutyl)indolin- 2-one [00404] Step 1: Synthesis of 2-methyl-4-(6-nitro-1H-indol-1-yl)butan-2-ol To a stirred solution of 6-nitro-1H-indole (1, 1.0 g, 6.17 mmol) in DMF (10 mL) was added compound 3- hydroxy-3-methylbutyl 4-methylbenzenesulfonate (2, 2.30 g, 8.02 mmol) and cesium carbonate (3.01 g, 9.25 mmol) at 25 °C. The reaction mixture was heated to 120 °C for 16 h. The reaction mixture was then cooled to room temperature and treated with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound which was purified by flash column chromatography on silica with 20-30% ethyl acetate/pet ether to afford the title compound (1.4 g, 5.44 mmol, 88% yield) as a brown semi solid. MS (ESI) m/z 249.1 [M+H]⁺. [00405] Step 2: Synthesis of 3,3-dibromo-1-(3-hydroxy-3-methylbutyl)-6-nitroindolin-2- one. To a stirred solution of 2-methyl-4-(6-nitro-1H-indol-1-yl)butan-2-ol (100 mg, 0.380 mmol) in t-BuOH (1 mL) and water (1.0 mL) was added NBS (142 mg, 0.797 mmol) at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 2 h. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (150 mg, 94% yield). The crude product was used for the next step without further purification. [00406] Step 3: Synthesis of 6-amino-1-(3-hydroxy-3-methylbutyl)indolin-2-one. To a stirred solution of 3,3-dibromo-1-(3-hydroxy-3-methylbutyl)-6-nitroindolin-2-one (150 mg) in AcOH (3.0 mL) was added zinc dust (116 mg, 1.78 mmol) at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude compound. The crude was purified by flash column chromatography on silica with 6% methanol/DCM to afford the title compound (100 mg, 0.333 mmol, 87% yield) as a brown gummy solid. MS (ESI) m/z 235.2 [M+H]⁺. Example i-16. Synthesis of Intermediate 16: 6-amino-1-(3-hydroxy-3-methylbutyl)-3,3- dimethylindolin-2-one [00407] Step 1: Synthesis of N-(2-Bromo-5-nitro-phenyl)-2-methyl-prop-2-enamide. To a solution of 2-bromo-5-nitro-aniline (1.00 g, 4.61 mmol) in DMA (20 mL) was added 2- methylprop-2-enoyl chloride (0.45 mL, 4.61 mmol) and the reaction mixture was stirred at rt for 12 h. Water (5.0 mL) was added and the resulting precipitate was collected by filtration, washed with water (20 mL), then dried under vacuum to afford the title compound (950 mg, 72%) as a solid.¹H NMR (400 MHz, DMSO d6): δ 9.69 (s, 1H), 8.44 (s, 1H), 8.00 (d, J = 1.2 Hz, 2H), 5.97 (s, 1H), 5.63 (s, 1H), 2.00 (s, 3H). MS (ESI) [M+H]⁺ 285.1. [00408] Step 2: Synthesis of 3,3-Dimethyl-6-nitro-indolin-2-one. To a solution of N-(2- bromo-5-nitro-phenyl)-2-methyl-prop-2-enamide (950 mg, 3.33 mmol) in DMF (33 mL) were added sequentially triethylamine (1.16 mL, 8.33 mmol), TBAB (1.07 g, 3.33 mmol) and Pd(OAc)₂ (15.0 mg, 0.07 mmol) under nitrogen, and the reaction mixture was stirred at 80 °C for 1 h. HCOONa (227 mg, 3.33 mmol) was added and the reaction mixture was stirred at 80 °C for 12 h. Water (5 mL) and ethyl acetate (15 mL) were added and the layers were separated. The organic layer was washed with brine (3 x 10 mL), dried on Na2SO4, filtered and concentrated under reduced pressure. Et₂O (5 mL) was added and the resulting precipitate was collected by filtration and dried under vacuum to afford the title compound (180 mg, 26%) as a solid.¹H NMR (400 MHz, DMSO d6): δ 10.75 (s, 1H), 7.90 (dd, J = 8.2, 2.1 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 1.30 (s, 6H). MS (ESI) [M+H]⁺ 207.0. [00409] Step 3: Synthesis of 1-(3-Hydroxy-3-methyl-butyl)-3,3-dimethyl-6-nitro-indolin- 2-one. To a solution of 3,3-dimethyl-6-nitro-indolin-2-one (180 mg, 0.87 mmol) in DMF (3 mL) were added sequentially (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (271 mg, 1.05 mmol) and K₂CO₃ (362 mg, 2.62 mmol), and the reaction mixture was stirred at 80 °C for 12 h. Water (10 mL) and ethyl acetate (60 mL) were added and the layers were separated. The organic layer was washed with brine (10 mL), dried on Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (145 mg, 57%) as a solid.¹H NMR (500 MHz, DMSO d6): δ 7.96 (dd, J = 8.1, 2.1 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 4.50 (s, 1H), 3.86 – 3.78 (m, 2H), 1.69 – 1.62 (m, 2H), 1.31 (s, 6H), 1.17 (s, 6H). MS (ESI) [M+H]⁺ 275.2. [00410] Step 4: Synthesis of 6-Amino-1-(3-hydroxy-3-methyl-butyl)-3,3-dimethyl- indolin-2-one. A mixture of 1-(3-hydroxy-3-methyl-butyl)-3,3-dimethyl-6-nitro-indolin-2-one (145 mg, 0.50 mmol) and Pd(OH)₂/C (70.0 mg, 0.10 mmol) in iPrOH (3 mL) was subjected to hydrogenation (1 atm) at rt for overnight. The mixture was filtered through Celite and washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to afford the title compound (125 mg, 96%) as a solid which was used directly in the next step without further purification. MS (ESI) [M+H]⁺ 263.2. Example i-17. Synthesis of Intermediate 17: tert-butyl (2-(5-amino-2-oxoindolin-1- yl)ethyl)(methyl)carbamate [00411] Step 1: Synthesis of 1-(2-(methylamino)ethyl)-5-nitroindolin-2-one To a stirred solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (1, 1.0 g, 5.02 mmol) in THF (30 mL) was added tert-butyl (2-aminoethyl)(methyl)carbamate (2, 1.750 g, 10.04 mmol) and DIPEA (1.754 mL, 10.04 mmol) under nitrogen at 25 °C. The reaction mixture was heated to 65 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to afford the crude as brown liquid. The crude was dissolved in water (20 mL) and 6.0 N HCl (6 ml, 36.0 mmol) was added dropwise at 25 °C. The reaction mixture was heated to 65 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and neutralized with sodium bicarbonate and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (400 mg, 0.909 mmol, 18% yield) that was used in the next step without further purification. [00412] Step 2: Synthesis of tert-butyl methyl(2-(5-nitro-2-oxoindolin-1- yl)ethyl)carbamate. To a stirred solution of 1-(2-(methylamino)ethyl)-5-nitroindolin-2-one (400 mg, 0.909 mmol) in DCM (10 mL) was added DIPEA (0.397 mL, 2.272 mmol) and Boc- anhydride (0.422 mL, 1.818 mmol) dropwise at 0 °C under nitrogen. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude compound which was purified by flash column chromatography on silica gel with 20-40% ethyl acetate/pet ether to afford the title compound (240 mg, 0.697 mmol, 77% yield). [00413] Step 3: Synthesis of tert-butyl (2-(5-amino-2-oxoindolin-1- yl)ethyl)(methyl)carbamate. To a stirred solution of tert-butyl methyl(2-(5-nitro-2-oxoindolin- 1-yl)ethyl)carbamate (240 mg, 0.716 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was added 10% Pd/C (120 mg) under nitrogen at 25 °C. The reaction mixture was stirred under hydrogen atmosphere for 6 h. The reaction mixture was filtered through celite and the celite pad was washed with ethanol (2 x 50 mL). The filtrate was concentrated under reduced pressure to obtain compound 5 (200 mg, 0.504 mmol, 70% yield) as a dark brown liquid. The crude product was used for the next step without further purification. Example i-18. Synthesis of Intermediate 18: 5-amino-1-(2,2-difluoropropyl)indolin-2-one [00414] Step 1: Synthesis of 2,2-difluoropropyl 4-methylbenzenesulfonate. To a solution of 2,2-difluoropropan-1-ol (1, 1.0 g, 10.4 mmol) in DCM (10 mL) was added triethylamine (2.18 mL, 15.61 mmol) at 25 °C. The mixture was cooled to 0 °C and 4-dimethylaminopyridine (0.127 g, 1.041 mmol) followed by 4-methylbenzenesulfonyl chloride (2.381 g, 12.49 mmol) were added. The reaction mixture was slowly warmed up to 25 °C and stirred for 16 h. The resulting reaction mixture was added to water (25 mL) and was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (2.0 g, 7.95 mmol, 76 % yield) as an off white solid. The crude product was used for the next step without further purification. MS (ESI) m/z 268.0 [M+H₂O]. [00415] Step 2: Synthesis of 1-(2,2-difluoropropyl)-5-nitro-1H-indole. To a solution of 2,2-difluoropropyl 4-methylbenzenesulfonate (931 mg, 3.70 mmol) in DMF (5 mL) at 25 °C was added cesium carbonate (1507 mg, 4.63 mmol) and 5-nitro-1H-indole (3, 500.0 mg, 3.08 mmol). The mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was quenched by the addition of water (15 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to give crude product. The crude was purified by flash column chromatography on silica with 35-40% ethyl acetate/pet ether to afford the title compound (250.0 mg, 0.997 mmol, 32% yield) as a pale-yellow solid. MS (ESI) m/z 240.9 [M+H]⁺. [00416] Step 3: Synthesis of 3,3-dibromo-1-(2,2-difluoropropyl)-5-nitroindolin-2-one. To a solution of 1-(2,2-difluoropropyl)-5-nitro-1H-indole (250.0 mg, 0.997 mmol) in tert-butanol (2.5 mL, 26.1 mmol) and water (2.5 mL) at 0 °C, NBS (373 mg, 2.094 mmol) was added in portion wise. The reaction mixture was slowly warmed to 25 °C and stirred for 6 h. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (350.0 mg, 0.619 mmol, 62% yield) as a pale-yellow solid. MS (ESI) m/z 415.0 [M+H]⁺. [00417] Step 4: Synthesis of 5-amino-1-(2,2-difluoropropyl)indolin-2-one. To a stirred solution of 3,3-dibromo-1-(2,2-difluoropropyl)-5-nitroindolin-2-one (350.0 mg, 0.619 mmol) in acetic acid (5.0 mL), zinc dust (202 mg, 3.10 mmol) was slowly added at 25 °C and stirring was continued for 6 h. The reaction mixture was concentrated under reduced pressure and diluted by the addition of water (15 mL). The resulting residue was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (150.0 mg, 0.299 mmol, 48% yield) as a brown solid. The crude product was used for the next step without further purification. MS (ESI) m/z 227.0 [M+H]⁺. Example i-19. Synthesis of Intermediate 19: 5-amino-1-(3-fluoro-3-methylbutyl)indolin-2- one [00418] Step 1: Synthesis of 5-amino-1-(3-fluoro-3-methylbutyl)indolin-2-one. The title compound was synthesized analogously to Intermediate 18 using 3-fluoro-3-methylbutan-1-ol as starting material. Example i-20. Synthesis of Intermediate 20: 5-amino-1-(2-fluoro-2-methylpropyl)indolin-2- one [00419] Step 1: Synthesis of 2-fluoro-2-methylpropyl trifluoromethanesulfonate. To a stirred mixture of trifluoromethanesulfonic anhydride (2.75 mL, 16.28 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (2.26 mL, 19.5 mmol) at -10 °C slowly and then a solution of 2-fluoro-2-methylpropan-1-ol (1.50 g, 16.3 mmol) in DCM (35 mL) was added dropwise. The reaction mixture was stirred for 4 h at 0 °C. The reaction mixture was concentrated under reduced pressure to obtain residue. The residue was dissolved in DCM and washed with 1.0 N HCl solution, followed by saturated bicarbonate solution and then washed with brine. The organic phase dried over sodium sulphate, filtered, and concentrated to afford the title compound (2.5 g, 11.2 mmol, 68% yield) as a brown liquid. The crude product was used in the next step without purification. [00420] Step 2: Synthesis of 1-(2-fluoro-2-methylpropyl)-5-nitro-1H-indole. To a stirred solution of 5-nitro-1H-indole (700 mg, 4.32 mmol) in DMF (10 mL) was added compound 2- fluoro-2-methylpropyl trifluoromethanesulfonate (2419 mg 10.79 mmol). The reaction mixture was heated to 100 °C and stirred for 4 h. The reaction mixture was poured in ice cold water extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to afford the title compound (600 mg, 2.41 mmol, 56% yield). The crude product was used for the next step without purification. MS (ESI) m/z 237.1 [M+H]⁺. [00421] Synthesis of 5-amino-1-(2-fluoro-2-methylpropyl)indolin-2-one. To a stirred solution 1-(2-fluoro-2-methylpropyl)-5-nitro-1H-indole (100 mg, 0.423 mmol) in t-butanol (2.0 mL) was added bromine (0.218 mL, 4.23 mmol) at 0 °C and the reaction mixture was stirred for 5 min. Then water (2 mL) was added slowly and warmed to 25 °C and stirred for 4 h. The reaction mixture was treated with water and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford 110 mg of the crude material. This residue was dissolved in acetic acid (3.5 mL) and zinc powder (88 mg, 1.34 mmol) was added and stirred for 1 h at 25 °C. The reaction mixture was concentrated under reduced pressure to get crude product. The crude was dissolved in ethyl acetate and treated with sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford the title compound compound (55 mg, 0.132 mmol, 49% yield). The crude product was used for the next step without purification. Example i-21. Synthesis of Intermediate 21: 5-amino-1-(2,2,2-trifluoroethyl)indolin-2-one [00422] Step 1: Synthesis of 5-nitro-1-(2,2,2-trifluoroethyl)indoline-2,3-dione. To a solution of 5-nitroindoline-2,3-dione (0.96 g, 5.00 mmol) in DMF (35.0 mL) cooled to 0 °C was added NaH (60% dispersion in mineral oil, 220.0 mg, 5.50 mmol). After stirring for 45 min at 0 °C, 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.28 g, 5.50 mmol) was added. The reaction mixture was warmed to rt for 1 h. A saturated aqueous solution of NH₄Cl (300.0 mL) and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 20-70% ethyl acetate in hexane to afford the title compound (910.0 mg, 66%) as a solid.¹H NMR (500 MHz, DMSO) δ 8.60 (dd, J = 8.8, 2.5 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 4.77 (q, J = 9.3 Hz, 2H). [00423] Step 2: Synthesis of 5-amino-1-(2,2,2-trifluoroethyl)indoline-2,3-dione. A mixture of 5-nitro-1-(2,2,2-trifluoroethyl)indoline-2,3-dione (548..0 mg, 2.00 mmol) and 10% Pd/C (106.0 mg, 0.10 mmol) in methanol (25.0 mL) was shaken in a Parr flask at 50 psi hydrogen atmosphere at rt for 1 h. The mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (450.0 mg, 92%) as a solid, which was used in next step without further purification. MS (ESI) [M+H]⁺ 247.1. [00424] Step 3: Synthesis of 5-amino-1-(2,2,2-trifluoroethyl)indolin-2-one. A mixture of 5-amino-1-(2,2,2-trifluoroethyl)indoline-2,3-dione (450.0 mg, 1.84 mmol) and hydrazine hydrate (65%, 10.0 mL, 133.0 mmol) was heated to 115 °C for 1 h and then cooled to rt. The volatiles were evaporated under reduced pressure. The material was purified by reverse phase chromatography (C18), using a gradient of 10-70% acetonitrile and water (ammonium formate buffer pH4) to afford the title compound (150.0 mg, 35%) as a solid.¹H NMR (500 MHz, DMSO) δ 6.79 (d, J = 8.3 Hz, 1H), 6.57 (s, 1H), 6.47 (dd, J = 8.3, 2.1 Hz, 1H), 4.81 (s, 2H), 4.47 (q, J = 9.5 Hz, 2H), 3.54 (s, 2H). MS (ESI) [M+H]⁺ 231.1. Example i-22. Synthesis of Intermediate 22: benzyl 4-amino-5-methylcycloheptane-1- carboxylate [00425] Step 1: Synthesis of 1-benzyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate To a stirred solution of benzyl 4-oxopiperidine-1-carboxylate (2.5 g, 10.72 mmol) and ethyl 2-diazoacetate (9.78 g, 12.86 mmol) in THF (50 mL) was added BF3OEt2 (1.358 mL, 10.72 mmol) at -25 °C. The reaction mixture stirred at 25 °C for 4 h. After, the reaction mixture was basified with sodium bicarbonate solution (100 ml) and the organics were extracted with EtOAc (3 x 100 ml). The combined organic fractions were dried and concentrated to give the crude material. This was purified by Combi-flash Column chromatography with product eluting at 15% EA in PE. Fractions containing product were combined and concentrated to give 1-benzyl 4-ethyl 5- oxoazepane-1,4-dicarboxylate (3.5 g, 3.40 mmol, 31.7 % yield) as an colourless liquid. (ESI) [M+H]⁺ 320.0, RT=2.15. [00426] Step 2: Synthesis of 1-benzyl 4-ethyl 4-methyl-5-oxoazepane-1,4-dicarboxylate To a stirred solution of 1-benzyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (3.5 g, 10.96 mmol) in DMF (8 mL). was added Cs2CO3 (7.14 g, 21.92 mmol) and MeI (1.371 mL, 21.92 mmol) at 0 °C. The reaction mixture warmed to room temperature and stirred at 25 °C for 6h. The reaction mixture was evaporated to obtained the crude material which was purified by combi-flash column chromatography. The product eluted at 25-30% EA in PE and fractions containing product were combined and concentrating giving 1-benzyl 4-ethyl 4-methyl-5-oxoazepane-1,4- dicarboxylate (2.5 g, 76%) as a colorless liquid.¹H NMR (400 MHz, DMSO) δ 7.35 (br m, 5H), 5.07 (br m, 2H), 4.15 ( br m, 2H), 3.68 (m, 2H), 3.40 (br m, 1H), 2.81 (br m, 2H), 2.15 (br m, 1H), 1.59 (br m, 1H), 1.19 – 1.24 (br m, 6H). MS (ESI) [M+H]⁺ 334.1 [00427] Step 3: Synthesis of benzyl 4-methyl-5-oxoazepane-1-carboxylate To a stirred solution of 1-benzyl 4-ethyl 4-methyl-5-oxoazepane-1,4-dicarboxylate (2.5 g, 5.70 mmol) in MeOH (20 mL) and water (20 mL). was added KOH (0.959 g, 17.10 mmol) at 25 °C. The reaction mixture stirred at 60 °C for 4 h. After, the reaction mixture was diluted with water (50 ml) and extracted with DCM (2 x 100 ml). This was purified via reverse phase prep HPLC with a gradient of 2-98% MeCN in 5mm Ammonium formate pH 3.3. Fractions containing the desired product were combined and concentrated giving benzyl 4-methyl-5-oxoazepane-1- carboxylate (1.50 g, 80%) as a yellow oil.¹H NMR (400 MHz, DMSO) δ 7.31 - 7.39 (m, 5H), 5.07 (s, 2H), 3.82 - 3.98 (m, 2H), 3.46 (m, 1H), 3.34 (m, 1H), 3.19 (m, 1H), 3.01 (m, 1H).2.59 (m, 1H), 1.66 (m, 1H), 1.30 (m, 1H), 0.95 (d, 2H). MS (ESI) [M+H]⁺ 262.2 [00428] Step 4: Synthesis of benzyl 4-amino-5-methylazepane-1-carboxylate To a stirred solution of benzyl 4-methyl-5-oxoazepane-1-carboxylate (1.0 g, 3.02 mmol) in 2-propanol (20 mL) was added ammonium acetate (4.66 g, 60.5 mmol) and NaCNBH₄ (1.140 g, 18.14 mmol) at 25 °C. The reaction mixturer was stirred at 50 °C for 3h and was monitored by TLC and LCMS. After, the reaction mixture was diluted with water (80ml) and extracted with DCM (3 x 80ml). The organic fractions were concentrated to give benzyl 4-amino-5-methylazepane-1-carboxylate (700 mg, 65%) as a yellow solid. MS (ESI) [M+H]⁺ 263.2, RT= 0.78 Example i-23. Synthesis of Intermediate 23: benzyl 4-amino-3-methylazepane-1- carboxylate [00429] Step 1: Synthesis of 1-benzyl 3-ethyl 4-oxoazepane-1,3-dicarboxylate To a stirred solution of benzyl 3-oxopiperidine-1-carboxylate (5.0 g, 21.43 mmol) and ethyl 2-diazoacetate (21.20 g, 27.9 mmol) in THF (50 mL), was added BF3OEt2 (2.72 mL, 21.43 mmol) at -78 °C. The reaction mixture warmed to room temperature and stirred at 25 °C for 4h. After, the reaction mixture was basified with sodium bicarbonate solution (100 ml) and the organics were extracted with EtOAc (3 x 100 ml). The combined organic fractions were dried and concentrated to give the crude material. This was purified by Combi-flash Column chromatography with product eluting at 20-30% EA in PE. Fractions containing product were combined and concentrated to give 1-benzyl 3-ethyl 4-oxoazepane-1,3-dicarboxylate (4.5 g, 10.00 mmol, 46.7 % yield) as a colourless liquid. (ESI) [M+H]⁺ 320.1, RT=2.11 [00430] Step 2: Synthesis of 1-benzyl 3-ethyl 3-methyl-4-oxoazepane-1,3-dicarboxylate To a stirred solution of 1-benzyl 3-ethyl 4-oxoazepane-1,3-dicarboxylate (4.0 g, 10.02 mmol) in DMF (1 mL). was Cs2CO3 (6.53 g, 20.04 mmol) and MeI (1.253 mL, 20.04 mmol) at 0 °C. and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture warmed to room temperature and stirred at 25 °C for 6 h. The reaction mixture was evaporated to obtained the crude material which was purified by combi-flash column chromatography. The product eluted at 20% EtOAc in PE and fractions containing product were combined and concentrating to obtain 1-benzyl 3-ethyl 3-methyl-4-oxoazepane-1,3-dicarboxylate (2.2 g, 5.61 mmol, 56.0 % yield) as an colourless liquid.¹H NMR (400 MHz, DMSO) δ 7.32 - 7.40 (m, 5H), 5.08 (s, 2H), 3.34 – 4.04 (m, 6H), 2.71 (m, 2H), 1.64 – 1.78 (m, 3H).1.10 - 1.24 (m, 5H). MS (ESI) [M+H]⁺ 334.2 [00431] Step 3: Synthesis of benzyl 3-methyl-4-oxoazepane-1-carboxylate To a stirred solution of 1-benzyl 3-ethyl 3-methyl-4-oxoazepane-1,3-dicarboxylate (1.0 g, 2.55 mmol) in MeOH (7.5 mL) and H₂O (7.5 mL) was added KOH (0.429 g, 7.65 mmol) and the reaction mixture was stirred at 60 °C for 2h. the reaction mixture was monitored by TLC and LCMS. The reaction mixture stirred at 60 °C for 4 h. After, the reaction mixture was diluted with water (50 ml) and extracted with DCM (2 x 100 ml). This was purified via reverse phase prep HPLC with a gradient of 2-98% MeCN in 5mm Ammonium formate pH 3.3. Fractions containing the desired product were combined and concentrated giving benzyl 3-methyl-4-oxoazepane-1- carboxylate (550 mg, 76%) as a yellow oil.¹H NMR (400 MHz, DMSO) δ 7.29 - 7.37 (m, 5H), 5.08 (s, 2H), 3.33 – 4.04 (m, 6H), 2.51 (m, 2H), 1.99 (m, 1H), 1.76 (m, 1H), 1.64 (m, 1H).1.09 - 1.23 (m, 6H). MS (ESI) [M+H]⁺ 262.1 [00432] Step 4: Synthesis of benzyl 4-amino-3-methylazepane-1-carboxylate To a stirred solution of benzyl 3-methyl-4-oxoazepane-1-carboxylate (100 mg, 0.352 mmol) in 2-Propanol (4 mL), was added ammonium acetate (543 mg, 7.04 mmol) and NaCNBH₄ (133 mg, 2.112 mmol) at 25 °C. The reaction mixture stirred at 50 °C for 3 h. After, the reaction mixture was diluted with water and extracted with EtOAC. The organic fractions were concentrated to give benzyl 4-amino-3-methylazepane-1-carboxylate (100 mg, 40%) as a yellow solid. MS (ESI) [M+H]⁺ 263.2, RT=1.35. Example S1. Synthesis of 3-(6-((5-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-5-azaspiro[3.5]nonan-8-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (1) [00433] Step 1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1- methylindolin-2-one. To a solution of 5-amino-1-methylindolin-2-one (2.0 g, 12.3 mmol) in tetrahydrofuran (32 mL) was added DIPEA (2.37 ml, 13.6 mmol) at -40 °C. A solution of 5- chloro-2,4-difluoropyrimidine (1.86 g, 12.3 mmol) in dry tetrahydrofuran (8 mL) was slowly added to the above mixture and allowed to slowly warm to rt. The reaction mixture was stirred at rt for 16 h. After this time, the reaction mixture was filtered and washed with acetonitrile (~50 mL). The solid was dried under vacuum to afford the title compound as a tan solid. MS (ESI) [M+H]⁺ 293.1. [00434] Step 2: Synthesis of tert-Butyl 8-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]amino]-5-azaspiro[3.5]nonane-5-carboxylate. To a solution of 3-(6-amino-1-methyl- indazol-3-yl)piperidine-2,6-dione hydrochloride (200 mg, 0.68 mmol), tert-butyl 8-oxo-5- azaspiro[3.5]nonane-5-carboxylate (201 mg, 0.81 mmol), and AcOH (1 mL) in DMSO (5 mL), was added decaborane (38 mg, 0.34 mmol). The reaction mixture was stirred for 5 h at rt and the volatiles were evaporated under reduced pressure. The residue was purified by reverse phase chromatography (C18) using a gradient of 0–80% MeCN and 10 mM ammonium formate in water to afford title compound (325 mg, 76%) as a solid. MS (ESI) [M+H]⁺ 482.3.¹H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.52 – 6.40 (m, 1H), 6.48 (br s, 1H), 5.78 (d, J = 8.7 Hz, 1H), 4.18 (dd, J = 8.8, 5.2 Hz, 1H), 3.82 (s, 3H), 3.73 – 3.68 (m, 2H), 2.75 – 2.68 (m, 1H), 2.62 – 2.59 (m, 2H), 2.30 – 2.13 (m, 4H), 1.98 – 1.86 (m, 4H), 1.72 – 1.60 (m, 3H), 1.40 (s, 9H), 1.06 – 0.98 (m, 1H). [00435] Step 3: Synthesis of 3-[6-(5-Azaspiro[3.5]nonan-8-ylamino)-1-methyl-indazol-3- yl]piperidine-2,6-dione 2,2,2-trifluoroacetic acid. To a solution of tert-butyl 8-[[3-(2,6-dioxo- 3-piperidyl)-1-methyl-indazol-6-yl]amino]-5-azaspiro[3.5]nonane-5-carboxylate (325 mg, 0.67 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.31 mL, 4.1 mmol), and the reaction mixture was stirred for 18 h at rt. The volatiles were evaporated under reduced pressure to afford title compound as a solid, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 382.3.¹H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.98 (d, J = 8.5 Hz, 1H), 8.75 – 8.71 (m, 1H), 7.37 (d, J = 8.7 Hz, 1H), 6.55 (dd, J = 8.7, 1.8 Hz, 1H), 6.51 (br s, 1H), 4.19 (dd, J = 8.9, 5.1 Hz, 1H), 3.83 (s, 3H), 3.63 – 3.57 (m, 1H), 3.30 – 3.27 (m, 1H), 3.02 – 2.96 (m, 1H), 2.63 – 2.60 (m, 2H), 2.36 (d, J = 12.9 Hz, 1H), 2.30 – 2.23 (m, 4H), 2.17 – 2.12 (m, 2H), 2.01 – 1.97 (m, 1H), 1.95 – 1.87 (m, 2H), 1.63 – 1.58 (m, 1H), 1.40 – 1.32 (m, 1H). [00436] Step 4: Synthesis of 3-[6-[[5-[5-Chloro-4-[(1-methyl-2-oxo-indolin-5- yl)amino]pyrimidin-2-yl]-5-azaspiro[3.5]nonan-8-yl]amino]-1-methyl-indazol-3- yl]piperidine-2,6-dione. To a solution of 3-[6-(5-azaspiro[3.5]nonan-8-ylamino)-1-methyl- indazol-3-yl]piperidine-2,6-dione 2,2,2-trifluoroacetic acid (20 mg, 40 µmol) in NMP (0.7 mL) was added 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one5-((5-chloro-2- fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (11 mg, 40 µmol) under N2 (1 atm). The reaction mixture was heated to 160 °C for 18 h and then cooled to rt. The crude reaction mixture was purified by reverse phase chromatography (C18) using a gradient of 0–100% MeCN and water (containing 0.1% formic acid) to afford title compound (13 mg, 44%) as a solid. LCMS: C34H36ClN9O3 requires 653.3, found 654.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.62 (s, 1H), 8.01 (s, 1H), 7.39 (s, 1H), 7.38 – 7.36 (m, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.48 – 6.45 (m, 2H), 5.65 (d, J = 8.8 Hz, 1H), 4.25 (d, J = 12.1 Hz, 1H), 4.17 (dd, J = 8.9, 5.1 Hz, 1H), 3.83 –3.80 (m, 1H), 3.81 (s, 3H) 3.51 – 3.50 (m, 2H), 3.09 (s, 3H), 2.88 (t, J = 10.0 Hz, 1H), 2.62 – 2.59 (m, 2H), 2.38 –2.34 (m, 2H), 2.26 – 2.24 (m, 1H), 2.19 – 2.12 (m, 2H), 1.96 –1.88 (m, 3H), 1.67 – 1.56 (m, 3H), 1.07 – 0.99 (m, 1H). Example S2. Synthesis of 3-(6-(8-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-5-azaspiro[3.5]nonan-5-yl)-1-methyl-1H-indazol- 3-yl)piperidine-2,6-dione (2) [00437] Step 1: Synthesis of 2-[2-bis-[3,5-bis-(Trifluoromethyl)phenyl]phosphanyl-3,6- dimethoxy-phenyl]-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine [2-[2- (methylamino)phenyl]phenyl]-methylsulfonyloxy-palladium. A mixture of (2'-methylamino- 1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer (406 mg, 0.53 mmol) and 2-[2-bis-[3, 5-bis-(trifluoromethyl)phenyl]phosphanyl-3,6-dimethoxy-phenyl]-N1,N1,N3,N3-tetramethyl- benzene-1,3-diamine (800 mg, 1.06 mmol) was evacuated and backfilled with argon. DCM (5 mL) was added via syringe and the mixture was stirred at rt for 2 h. The reaction mixture was diluted with Et₂O (5 mL) and filtered. The filtrate was concentrated, and pentane (5 mL) was added to the residue and the mixture was concentrated under reduced pressure to afford the title compound (1.08 g, 90%) as a yellow solid.¹H NMR (500 MHz, MeOD-d4) δ 8.38 (s, 1H), 8.13 (s, 1H), 8.00 (t, J = 8.1 Hz, 1H), 7.74 (d, J = 11.2 Hz, 2H), 7.62 (d, J = 11.4 Hz, 2H), 7.59 – 7.55 (m, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 7.5, 1.4 Hz, 1H), 7.34 – 7.28 (m, 3H), 7.25 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.16 – 7.13 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.84 (t, J = 7.7 Hz, 1H), 6.33 – 6.29 (m, 1H), 3.71 (s, 3H), 3.42 (s, 3H), 2.78 (s, 6H), 2.69 (s, 3H), 2.61 – 2.54 (m, 1H), 2.15 (dd, J = 5.9, 2.9 Hz, 3H), 2.09 (s, 6H).¹⁹F NMR (471 MHz, MeOD-d₄) δ – 64.20, –64.42.³¹P NMR (203 MHz, MeOD-d₄) δ 33.80. [00438] Step 2: Synthesis of tert-Butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]carbamate. A mixture of 6-bromo-3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazole (600 mg, 1.20 mmol), tert-butyl N-(5- azaspiro[3.5]nonan-8-yl)carbamate (375 mg, 1.56 mmol), NaOtBu (288 mg, 3.0 mmol), 2-[2- bis-[3,5-bis-(Trifluoromethyl)phenyl]phosphanyl-3,6-dimethoxy-phenyl]-N1,N1,N3,N3- tetramethyl-benzene-1,3-diamine [2-[2-(methylamino)phenyl]phenyl]-methylsulfonyloxy- palladium (137 mg, 0.12 mmol) in cyclopentyl methyl ether (12 mL) was heated to 85 °C for 4 h and then cooled to rt. The mixture was filtered through celite and washed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–60% EtOAc in hexanes to afford the title compound (600 mg, 76%) as a solid. MS (ESI) [M+H]⁺ 660.2.¹H NMR (400 MHz, DMSO- d6) δ 7.88 (d, J = 8.1 Hz, 1H), 7.50 – 7.43 (m, 3H), 7.42 – 7.32 (m, 5H), 7.32 – 7.25 (m, 3H), 6.79 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 1.5 Hz, 1H), 6.62 (dd, J = 9.0, 1.8 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.42 (s, 2H), 3.95 (s, 3H), 3.69 – 3.57 (m, 1H), 3.51 – 3.43 (m, 1H), 3.12 – 3.00 (m, 1H), 2.17 – 2.04 (m, 4H), 1.98 – 1.89 (m, 1H), 1.80 – 1.68 (m, 2H), 1.59 – 1.48 (m, 2H), 1.38 (s, 9H), 1.27 – 1.16 (m, 1H). [00439] Step 3: Synthesis of tert-Butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]-N-methyl-carbamate. To an ice-cold solution of tert-butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8- yl]carbamate (1.05 g, 1.59 mmol) and NaH (159 mg, 3.98 mmol, 60% dispersion in mineral oil) in DMF (6 mL) was added iodomethane (198 µL, 3.18 mmol), and the mixture was stirred at rt for 2 h. Another batch was prepared using the same procedure. Water (50 mL) was added and the combined mixture was extracted with EtOAc (3 x 75 mL). The organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (C18) using a gradient of 20–100% MeCN and 10 mM ammonium formate in water to afford the title compound (700 mg, 65% combined yield) as a solid. MS (ESI) [M+H]⁺ 674.4. [00440] Step 4: Synthesis of tert-Butyl N-[5-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol- 6-yl]-5-azaspiro[3.5]nonan-8-yl]-N-methyl-carbamate. A mixture of tert-butyl N-[5-[3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]-N-methyl-carbamate (700 mg, 1.04 mmol) and Pearlman's catalyst (365 mg, 0.26 mmol) in EtOH (15 mL) and THF (15 mL) was stirred under a hydrogen atmosphere (1 atm) at 50 °C for 2 h. The mixture was filtered through celite, washing with MeOH (3 x 15 mL) and the filtrate was concentrated to afford the title compound (425 mg, 83%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 496.2.¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H), 6.77 – 6.73 (m, 1H), 4.30 – 4.22 (m, 1H), 3.89 (s, 3H), 3.62 – 3.53 (m, 1H), 3.16 – 3.05 (m, 1H), 2.70 – 2.57 (m, 5H), 2.38 – 2.25 (m, 1H), 2.19 – 2.07 (m, 4H), 2.06 – 1.93 (m, 2H), 1.93 – 1.81 (m, 1H), 1.78 – 1.67 (m, 1H), 1.62 – 1.31 (m, 4H), 1.41 (s, 9H). [00441] Step 5: Synthesis of 3-[1-Methyl-6-[8-(methylamino)-5-azaspiro[3.5]nonan-5- yl]indazol-3-yl]piperidine-2,6-dione hydrochloride. To a solution of tert-butyl N-[5-[3-(2,6- dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]-N-methyl-carbamate (425 mg, 0.86 mmol) in DCM (4 mL) was added 4N HCl in 1,4-dioxane (4 mL, 16 mmol), and the mixture was stirred for 4 h at rt. The resulting precipitate was collected by filtration, washed with Et2O (2 x 5 mL), and dried under vacuum to afford the title compound(340 mg, 92%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 396.3.¹H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.08 (br s, 2H), 7.56 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 6.87 (dd, J = 8.8, 1.4 Hz, 1H), 4.27 (dd, J = 8.8, 5.2 Hz, 1H), 3.92 (s, 3H), 3.60 (dt, J = 13.6, 3.2 Hz, 1H), 3.43 – 3.32 (m, 1H), 3.25 – 3.16 (m, 1H), 2.68 – 2.63 (m, 2H), 2.56 (t, J = 5.3 Hz, 3H), 2.49 – 2.43 (m, 1H), 2.39 – 2.29 (m, 1H), 2.27 – 2.20 (m, 2H), 2.20 – 2.13 (m, 2H), 2.13 – 2.04 (m, 2H), 1.96 – 1.89 (m, 1H), 1.82 – 1.70 (m, 1H), 1.64 – 1.53 (m, 2H). [00442] Step 6: Synthesis of 3-[6-[8-[[5-Chloro-4-[(1-methyl-2-oxo-indolin-5- yl)amino]pyrimidin-2-yl]-methyl-amino]-5-azaspiro[3.5]nonan-5-yl]-1-methyl-indazol-3- yl]piperidine-2,6-dione. To a mixture of 3-[1-methyl-6-[8-(methylamino)-5- azaspiro[3.5]nonan-5-yl]indazol-3-yl]piperidine-2,6-dione hydrochloride (46.5 mg, 0.11 mmol) and DIPEA (110 µL, 0.61 mmol) in DMSO (1 mL) at rt was added 5-((5-chloro-2- fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (30 mg, 0.10 mmol), and the reaction mixture was heated to 80 °C for 16 h. The crude reaction mixture was purified by preparative HPLC (BEH column, C18), using a gradient of 48–58% MeCN and 10 mM ammonium formate in water to afford the title compound (14.9 mg, 22%) as a solid. LCMS: C₃₄H₃₆ClN₉O₃ requires 667.3, found 668.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.49 (br s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.56 (s, 1H), 7.54 – 7.49 (m, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.80 – 6.76 (m, 2H), 4.89 – 4.80 (m, 1H), 4.26 (dd, J = 8.6, 5.2 Hz, 1H), 3.91 (s, 3H), 3.57 (d, J = 13.3 Hz, 1H), 3.54 (s, 2H), 3.15 (s, 3H), 2.89 (s, 3H), 2.74 – 2.60 (m, 2H), 2.40 – 2.30 (m, 1H), 2.27 – 2.16 (m, 2H), 2.13 – 2.05 (m, 2H), 2.01 – 1.88 (m, 3H), 1.69 – 1.55 (m, 2H), 1.55 – 1.41 (m, 2H). Note: one CH obscured by water signal. Example S3. Synthesis of 3-(6-(((trans)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)cyclohexyl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (3) [00443] The title compound was synthesized analogously to Example S2 using trans-tert- butyl N-(4-aminocyclohexyl)carbamate as the starting material. Isolated title compound as an off-white solid (36.7 mg, 0.05 mmol, 20.6% yield). LCMS: C₃₃H₃₆ClN₉O₃ requires 641, found 642 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.14 (s, 1H), 7.60 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 6.55 (s, 1H), 4.30 (s, 1H), 4.22 (dd, J = 9.0, 5.1 Hz, 1H), 3.86(s,3H), 3.59 (s, 2H), 3.36 (s, 1H), 3.15 (s, 3H), 2.95 (s, 3H), 2.62 (s, 2H), 2.28 (s, 1H), 2.20 – 2.09 (m, 3H), 1.76 (d, J = 11.8 Hz, 1H), 1.70 (s, 3H), 1.25 (s, 2H). Example S4. Synthesis of 3-(6-((2R,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-2-methylpiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (4) [00444] Step 1: Synthesis of N-[(2R,4R)-1-[3-(2,6-Dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]-2-methyl-4-piperidyl]carbamate. The title compound was synthesized according to General Procedure 2 using tert-butyl N-[(2R,4R)-2-methyl-4-piperidyl]carbamate as the reactant in toluene at 110 °C for 18 h. The title compound was isolated by reverse phase chromatography (C18) using a gradient of 30–100% MeCN and 10 mM ammonium formate in water (700 mg, 86%) as a solid. LCMS: C38H43N5O4 requires 633.3, found 635.9 [M+H]⁺. [00445] Step 2: Synthesis of tert-Butyl N-[(2R,4R)-1-[3-(2,6-Dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]-2-methyl-4-piperidyl]-N-methyl-carbamate. To a solution of tert-butyl N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-2-methyl-4- piperidyl]carbamate (800 mg, 1.26 mmol) in DMF (13 mL) cooled to 0 °C was added NaH (151 mg, 3.8 mmol), and the reaction mixture was stirred at 0 °C for 15 min. Iodomethane (0.24 mL, 3.79 mmol) was added, the reaction mixture was warmed to rt and stirred for 1 h. The reaction was diluted by the dropwise addition of water (5 mL). Water (50 mL) and EtOAc (100 mL) were added and the layers were separated. The organic layer was washed with water (5 x 20 mL), brine (50 mL), dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18) using a gradient of 30–100% MeCN and 10 mM ammonium formate in water to afford title compound (700 mg, 86%) as a solid. LCMS: C₃₉H₄₅N₅O₄ requires 647.4, found 648.4 [M+H]⁺. [00446] Step 3: Synthesis of 3-(6-((2R,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-2-methylpiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The synthesis of the title compound was accomplished using General Procedures 4, 5, and 6 with tert-Butyl N-[(2R,4R)-1-[3-(2,6-Dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]-2-methyl-4-piperidyl]-N-methyl-carbamate as the starting material. The crude residue was purified by reverse phase chromatography (C18) using a gradient of 10–70% MeCN and 10 mM ammonium formate in water to afford title compound (19 mg, 25%) as a solid. LCMS C33H36ClN9O3 requires 641.3, found 642.3[M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.60 (s, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 6.98 – 6.89 (m, 2H), 4.59 (br s, 1H), 4.33 (dd, J = 9.5, 4.9 Hz, 1H), 3.97 (s, 3H), 3.59 (s, 2H), 3.28 – 3.21 (m, 2H), 3.10 (s, 3H), 2.96 (s, 3H), 2.81 (br s, 1H), 2.68 – 2.59 (m, 2H), 2.38 – 2.31 (m, 1H), 2.22 – 2.13 (m, 1H), 1.95 – 1.86 (m, 1H), 1.76 (d, J = 10.6 Hz, 1H), 1.70 – 1.58 (m, 2H), 0.93 (d, J = 5.7 Hz, 3H). Example S5. Synthesis of 3-(6-(4-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methyl-6-oxopiperazin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (5) [00447] Step 1: Synthesis of 6-methylpiperazin-2-one. To a stirred solution of 6- methylpiperazin-2-one (1.0 g, 8.76 mmol) and triethylamine (1.83 mL, 13.14 mmol) in CH2Cl2 (20 mL) was added Boc-anhydride (2.24 mL, 9.64 mmol) under nitrogen at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 3 h. The reaction mixture was treated with 0.5 N HCl (2.0 mL), water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound compound (1.81 g, 8.43 mmol, 96 % yield) as an off-white solid. The crude product was used for the next step without further purification. [00448] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl- 1H-indazol-6-yl)-3-methyl-5-oxopiperazine-1-carboxylate. A stirred solution of 6- methylpiperazin-2-one (750 mg, 3.49 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1- methyl-1H-indazole (1.50 g, 3.00 mmol) in DMF (10 mL) was degassed with nitrogen for 5 min. Then copper(I)iodide (571 mg, 3.00 mmol), K2CO3 (621 mg, 4.50 mmol) and N1,N2- dimethylethane-1,2-diamine (264 mg, 3.00 mmol) were added and degassed for 10 min. The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and treated with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude compound. The crude was purified by flash column chromatography on silica with 80-100% ethyl acetate/pet ether to afford the title compound (650 mg, 0.779 mmol, 26% yield) as an off-white solid. MS (ESI) m/z 634.8 [M+H]⁺. [00449] Step 3: Synthesis of 3-(6-(4-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methyl-6-oxopiperazin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione The synthesis of the title compound was accomplished using General Procedures 4, 5, and 6 beginning with tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)-3-methyl-5-oxopiperazine-1-carboxylate as starting material. LCMS C₃₁H₃₀ClN₉O₄ requires 627.2, found 628.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s, 1H), 8.83 (s, 1H), 8.10 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.55-7.53 (m, 2H), 7.01 - 6.96 (m, 2H), 4.58 - 4.50 (m, 1H), 4.39 (dd, J = 5.1 Hz and 10.2 Hz, 1H), 4.24 - 4.16 (m, 2H), 4.25 - 4.07 (m, 1H), 3.98 (s, 3H), 3.90 - 3.83 (m, 1H), 3.55 (s, 2H), 3.12 (s, 3H), 2.73 - 2.66 (m, 2H), 2.66 - 2.61 (m, 1H), 2.43 - 2.36 (m, 1H), 1.07 (d, J = 6.3 Hz, 3H). [00450] Examples in Table 2 below have been made according to the general procedures outlined in the table beginning with their respective commercial starting materials and intermediates found within this document.

Table 2.

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

y ( )

Example S52. Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (52) [00451] Step 1: Synthesis of 3-(6-((1-(5-Chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione. 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6-dione (40.3 mg, 0.120 mmol), 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (28.8 mg, 0.100 mmol), N,N-diisopropylethylamine (0.03 mL, 0.2000 mmol) and DMSO (0.1969 mL) were added to a 1 dram vial equipped with a stir bar and heated to 80 °C for overnight. The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fraction containing clean product were combined and lyphilized to give the title compound (3.0 mg, 0.0049 mmol, 4.9% yield) as an off white solid. LCMS C₃₁H₃₂ClN₉O₃ requires 613.2, found 614.2 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz) δ 10.7-10.8 (m, 1H), 8.5-8.6 (m, 1H), 7.95 (s, 1H), 7.45 (s, 2H), 7.2-7.3 (m, 1H), 6.8-6.9 (m, 1H), 6.4-6.5 (m, 3H), 5.7-5.7 (m, 1H), 4.2-4.4 (m, 2H), 4.0-4.1 (m, 1H), 3.75 (s, 3H), 3.5-3.6 (m, 1H), 3.4-3.5 (m, 2H), 3.03 (s, 5H), 2.5-2.6 (m, 1H), 2.0-2.2 (m, 3H), 1.9-2.0 (m, 2H), 1.2-1.3 (m, 2H). Example S53. Synthesis of rel-(R)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (single isomer, stereochemistry not determined) (53) [00452] Step 1: Synthesis of rel-(R)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione. The product of Example S52 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 11.0 min. LCMS C31H32ClN9O3 requires 614.2, found 614.2 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz) δ 10.7-10.8 (m, 1H), 8.5-8.6 (m, 1H), 7.95 (s, 1H), 7.45 (s, 2H), 7.2-7.3 (m, 1H), 6.8-6.9 (m, 1H), 6.4-6.5 (m, 3H), 5.7-5.7 (m, 1H), 4.2-4.4 (m, 2H), 4.0-4.1 (m, 1H), 3.75 (s, 3H), 3.5-3.6 (m, 1H), 3.4-3.5 (m, 2H), 3.03 (s, 5H), 2.5-2.6 (m, 1H), 2.0-2.2 (m, 3H), 1.9-2.0 (m, 2H), 1.2-1.3 (m, 2H). Example S54. Synthesis of rel-(S)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (single isomer, stereochemistry not determined) (54) [00453] Step 1: Synthesis of rel-(S)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione. The product of Example S52 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5 μ column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 18.9 min. LCMS C31H32ClN9O3 requires 614.2, found 614.2 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz) δ 10.7-10.8 (m, 1H), 8.5-8.6 (m, 1H), 7.95 (s, 1H), 7.45 (s, 2H), 7.2-7.3 (m, 1H), 6.8-6.9 (m, 1H), 6.4-6.5 (m, 3H), 5.7-5.7 (m, 1H), 4.2-4.4 (m, 2H), 4.0-4.1 (m, 1H), 3.75 (s, 3H), 3.5-3.6 (m, 1H), 3.4-3.5 (m, 2H), 3.03 (s, 5H), 2.5-2.6 (m, 1H), 2.0-2.2 (m, 3H), 1.9-2.0 (m, 2H), 1.2-1.3 (m, 2H). Example S55. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4- b]pyridin-3-yl)piperidine-2,6-dione (55) [00454] Step 1: Synthesis of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine. To a 0 °C solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (1 g, 3.58 mmol) in DMF (20 mL) was added sodium hydride (0.150 g, 3.76 mmol), The reaction mixture was stiired for 30 min. Then sodium hydride (0.150 g, 3.76 mmol) was added dropwise. The reaction mixtre was allowed to warm to room temperature and stirred and stirred for another hour. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered over celite, and concentrated. The crude was purified by silica gel column chromatography (0-100 % ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (0.75 g, 2.56 mmol, 71 % yield) as white solid; MS (ESI) m/z 293.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (s, 1 H), 7.92 (s, 1 H), 4.06 (d, J=0.98 Hz, 3 H). [00455] Step 2: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H- pyrazolo[3,4-b]pyridine. The solution of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4- b]pyridine (500 mg, 1.704 mmol), (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (628 mg, 1.874 mmol) and sodium carbonate (379 mg, 3.58 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was stirred with tetrakis(triphenylphosphine)palladium(0) (197 mg, 0.170 mmol) at 100 °C for 15 h. After this tie, the reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered over celite, and concentrated. The crude was purified by silica gel column chromatography (0-50 % ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (520 mg, 1.14 mmol, 67 % yield) as white solid; MS (ESI) m/z 456.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (d, J=8.44 Hz, 1 H), 8.02 (d, J=8.07 Hz, 1 H), 7.45 - 7.51 (m, 2 H), 7.28 - 7.44 (m, 8 H), 7.11 (d, J=8.44 Hz, 1 H), 6.62 (d, J=8.19 Hz, 1 H), 5.49 (s, 2 H), 5.44 (s, 2 H), 4.04 (s, 3 H). [00456] Step 3: Synthesis of tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-hydroxypiperidine-1-carboxylate. To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.094 mmol), RuPhos Pd G3 (92 mg, 0.109 mmol) and tert-butyl (3R,4R)-4-amino-3- hydroxypiperidine-1-carboxylate (237 mg, 1.094 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (713 mg, 2.189 mmol). The reaction mixture was degassed with argon for 1 min and then stirred at 100 °C for 15 h. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered over celite, and concentrated. The crude was purified by silica gel column chromatography (0-100 % ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the crude. The crude was further purified by reveres-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% TFA in water 0.1% TFA, over 30 min). Fraction containing clean product were combined and lyphilized to give the title compound (120 mg, 0.188 mmol, 17 % yield) as white solid; MS (ESI) m/z 636.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J=8.07 Hz, 1 H), 7.65 (d, J=8.93 Hz, 1 H), 7.43 - 7.50 (m, 2 H), 7.28 - 7.43 (m, 8 H), 6.97 (d, J=7.09 Hz, 1 H), 6.56 (d, J=8.07 Hz, 1 H), 6.24 (d, J=8.93 Hz, 1 H), 5.46 (s, 2 H), 5.39 - 5.44 (m, 2 H), 5.18 (d, J=4.65 Hz, 1 H), 3.71 - 3.98 (m, 6 H), 3.40 (tt, J=9.00, 4.63 Hz, 1 H), 2.94 (br d, J=1.47 Hz, 1 H), 2.69 - 2.85 (m, 1 H), 1.99 - 2.15 (m, 1 H), 1.41 (s, 9 H), 1.24 - 1.34 (m, 1 H). [00457] Step 4: Synthesis of 3-(6-(((3R,4R)-3-hydroxypiperidin-4-yl)amino)-1-methyl- 1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione. The solution of tert-butyl (3R,4R)-4- ((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3- hydroxypiperidine-1-carboxylate (0.120 g, 0.188 mmol) in ethanol (10 mL) was stirred with palladium on carbon 10% w/w (0.020 g, 0.019 mmol) under hydrogen (1 atm) at 50 °C for 15 h. The reaction mixture was filtered through celite, the filtrate was concentrated and the residue was then stirrer with 1 mL TFA in DCM (1 mL) for 30 min at room temperature. The volatiles were removed under reduced pressure to give the desired product (67 mg, 0.187 mmol, 99 % yield) as TFA salt which was used without further purification. [00458] Step 5: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4- b]pyridin-3-yl)piperidine-2,6-dione. A solution of 3-(6-(((3R,4R)-3-hydroxypiperidin-4- yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione (68 mg, 0.190 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (55.5 mg, 0.190 mmol) in DMSO (3 mL) was added DIPEA (0.10 mL, 0.57 mmol). The reaction mixtre was stirred at 80 °C for 16 hours. The reaction mixture was filtered and purified by reveres-phased semi- preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fraction containing clean product were combined and lyphilized to give the title compound (3.7 mg, 5.86 µmol, 3.09 % yield) as white solid; MS (ESI) m/z 630.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1 H), 8.68 (s, 1 H), 8.02 (s, 1 H), 7.65 (d, J=8.68 Hz, 1 H), 7.54 (s, 1 H), 7.50 (dd, J=8.44, 2.20 Hz, 1 H), 6.99 (br d, J=7.21 Hz, 1 H), 6.94 (d, J=8.44 Hz, 1 H), 6.37 (d, J=8.80 Hz, 1 H), 5.16 (dd, J=5.07, 1.77 Hz, 1 H), 4.39 - 4.53 (m, 1 H), 4.24 - 4.38 (m, 1 H), 4.14 (dd, J=9.35, 5.07 Hz, 1 H), 3.89 - 4.02 (m, 1 H), 3.77 (s, 3 H), 3.54 (s, 2 H), 3.44 (tt, J=9.25, 4.88 Hz, 1 H), 3.29 (s, 1 H), 3.11 (s, 3 H), 3.05 (br t, J=11.19 Hz, 1 H), 2.88 (dd, J=12.78, 9.60 Hz, 1 H), 2.55 - 2.64 (m, 2 H), 2.21 - 2.31 (m, 1 H), 2.06 - 2.20 (m, 2 H), 1.26 - 1.42 (m, 1 H). [00459] Example S56. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3,3-difluoro-1-methyl- 2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (56) [00460] Step 1: Synthesis of 3,3-difluoro-5-nitroindolin-2-one. To a -78 °C suspension of 5-nitroindoline-2,3-dione (2.2 g, 11.5 mmol) in dichloromethane (50 mL) was added diethylaminosulfur trifluoride (4.06 g, 25.2 mmol) dropwise. The reaction mixture was allowed warm up to room temperature and stirred for 2 days. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered over celite, and concentrated. The crude was purified by silica gel column chromatography (0-75% ethyl acetate in hexane ). Concentration of the desired fractions under reduced pressure afforded the title compound 3,3-difluoro-5-nitroindolin-2-one (1.52 g, 7.10 mmol, 62.0 % yield) as yellow solid; MS (ESI) m/z 215.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.89 (br s, 1 H), 8.56 - 8.60 (m, 1 H), 8.43 (d, J=8.78 Hz, 1 H), 7.20 (d, J=8.68 Hz, 1 H). [00461] Step 2: Synthesis of 3,3-difluoro-1-methyl-5-nitroindolin-2-one. To a solution of 3,3-difluoro-5-nitroindolin-2-one (0.53 g, 2.475 mmol) in DMF (1 mL) as added DBU (0.485 mL, 3.22 mmol) followed by iodomethane (0.185 mL, 2.97 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 50 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered over celite, and concentrated. The crude was purified by silica gel column chromatography (0-80% ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (0.339 g, 1.485 mmol, 60 % yield) as yellow solid; MS (ESI) m/z 229.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (d, J=1.96 Hz, 1 H), 8.54 (d, J=8.91 Hz, 1 H), 7.46 (d, J=8.80 Hz, 1 H), 3.25 (s, 3 H). [00462] Step 3: Synthesis of 5-amino-3,3-difluoro-1-methylindolin-2-one. A suspension of 3,3-difluoro-1-methyl-5-nitroindolin-2-one (360 mg, 1.578 mmol) in ethanol (15 mL) was stirred under hydrogen (45 psi) at room temperature for 15 h. To the reaction mixture was filtered over celite. Concentration of the filtrate under reduced pressure afforded the title compound (300 mg, 1.514 mmol, 96 % yield) as yellow solid; MS (ESI) m/z 199.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.90 (d, J=8.44 Hz, 1 H), 6.87 (d, J=1.96 Hz, 1 H), 6.75 (d, J=7.91 Hz, 1 H), 5.22 (s, 2 H), 3.09 (s, 3 H). [00463] Step 4: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3,3-difluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The synthesis of the title compound was accomplished using General Procedures 1 and 6 using 5-amino-3,3-difluoro-1-methylindolin-2-one and 3-(1- methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride as staring materials. The reaction mixture was filtered and purified by reveres- phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fraction containing clean product were combined and lyphilized to give the title compound (8 mg, 0.012 mmol, 23.46 % yield) as yellow solid; MS (ESI) m/z 664.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1 H), 8.94 (s, 1 H), 8.03 - 8.14 (m, 2 H), 7.77 (br d, J=8.56 Hz, 1 H), 7.31 (d, J=8.80 Hz, 1 H), 7.21 (d, J=8.44 Hz, 1 H), 6.51 (br d, J=8.80 Hz, 1 H), 6.44 (s, 1 H), 5.70 (br d, J=8.80 Hz, 1 H), 4.47 (br s, 2 H), 4.17 (dd, J=8.62, 5.07 Hz, 1 H), 3.81 (s, 3 H), 3.17 (s, 3 H), 3.04 (br t, J=12.10 Hz, 1 H), 2.65 - 2.76 (m, 1 H), 2.56 - 2.63 (m, 2 H), 2.19 - 2.31 (m, 1 H), 2.11 - 2.19 (m, 1 H), 2.06 (br d, J=10.64 Hz, 1 H), 1.46 - 1.66 (m, 1 H), 1.07 - 1.28 (m, 2 H), 0.96 (d, J=6.36 Hz, 3 H). Example S57. Synthesis of 3-[6-[[(3S,4R)-1-[5-Chloro-4-[(1-methyl-2-oxo-indolin-5- yl)amino]pyrimidin-2-yl]-3-(hydroxymethyl)-4-piperidyl]amino]-1-methyl-indazol-3- yl]piperidine-2,6-dione (57) [00464] Step 1: Synthesis of tert-Butyl O5-ethyl 4-[[(1R)-1-phenylethyl]amino]-3,6- dihydro-2H-pyridine-1,5-dicarboxylate. To a solution of O1-tert-butyl O3-ethyl 4- oxopiperidine-1,3-dicarboxylate (22 g, 81 mmol) and (1R)-1-phenylethanamine (12.5 mL, 97.2 mmol) in toluene (400 mL) was added PTSA (1.39 g, 8.1 mmol) and the mixture was heated to reflux with a Dean-Stark trap for 18 h. The mixture was cooled to rt, washed with a saturated aqueous solution of NaHCO₃ (2 x 200 mL) and brine (2 x 200 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated. The residue was filtered on a pad of silica, rinsed with DCM (2 x 100 mL) and concentrated to afford the title compound (30.2 g, 99%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 375.2. ¹H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 7.5 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.26 – 7.18 (m, 3H), 4.66 – 4.54 (m, 1H), 4.24 – 4.14 (m, 2H), 4.07 (br s, 2H), 3.48 – 3.35 (m, 1H), 3.35 – 3.24 (m, 1H), 2.39 (dd, J = 13.0, 6.2 Hz, 1H), 2.09 – 2.00 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H), 1.29 (t, J = 7.0 Hz, 3H). [00465] Step 2: Synthesis of tert-butyl O3-ethyl (3S,4R)-4-[[(1R)-1- phenylethyl]amino]piperidine-1,3-dicarboxylate and tert-butyl O3-ethyl (3R,4S)-4-[[(1R)- 1-phenylethyl]amino]piperidine-1,3-dicarboxylate To a solution of tert-butyl O5-ethyl 4- [[(1R)-1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylate (15 g, 40.1 mmol) in MeCN (200 mL) and AcOH (100 mL) cooled to 0 °C was added portion-wise sodium triacetoxyborohydride (34 g, 160 mmol) over 2 h, and the reaction mixture was stirred at 0 °C for 2 h. The mixture was then cooled to –10 °C and slowly treated with a 1M aqueous solution of NaOH (100 mL), a 4M aqueous solution of NaOH (100 mL), a 6M aqueous solution of NaOH (100 mL), followed by a 50% aqueous solution of NaOH (50 mL). The mixture was warmed to rt and the layers were separated. The aqueous layer was extracted with DCM (3 x 80 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–50% EtOAc in hexanes to afford a 4:1 mixture of title compounds (14.8 g, 98%) as an oil. A portion (7 g) of the 4:1 mixture of title compounds was separated by SFC to afford tert-butyl O3-ethyl (3S,4R)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate (3.7 g) as an oil and title compound tert-butyl O3-ethyl (3R,4S)-4-[[(1R)-1- phenylethyl]amino]piperidine-1,3-dicarboxylate (1.1 g) as an oil. [00466] Step 3: Synthesis of tert-butyl (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1- phenylethyl]amino]piperidine-1-carboxylate. To a solution of tert-butyl O3-ethyl (3S,4R)-4- [[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate (500 mg, 1.33 mmol) in THF (3 mL) was added LiBH₄ (1.33 mL, 2.66 mmol), and the mixture was heated to reflux for 2 h, then cooled to rt. Ice-water (10 mL) was added and the mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (3 x 30 mL). The combined organic fractions were dried over Na₂SO₄, filtered, and concentrated to afford the title compound (404 mg, 91%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 335.3. [00467] Step 4: Synthesis of tert-Butyl (3S,4R)-3-[[tert-butyl (dimethyl)silyl]oxymethyl]- 4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate. To a solution of tert-butyl (3S,4R)- 3-(hydroxymethyl)-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate (404 mg, 1.21 mmol) in DCM (5 mL) was added sequentially tert-butylchlorodimethylsilane (218 mg, 1.45 mmol) and imidazole (123 mg, 1.81 mmol), and the reaction mixture was stirred at rt for 3 h. Water (15 mL) and Et₂O (20 mL) were added and the layers were separated. The aqueous layer was washed with Et2O (3 x 10 mL) and the combined organic fractions were dried over Na2SO4, filtered, and concentrated to afford the title compound (540 mg, 99%) as an oil, which was used in the next step without further purification. Note: SFC analysis confirmed the presence of only one diastereomer. MS (ESI) [M+H]⁺ 449.4.¹H NMR (400 MHz, DMSO-d₆) δ 7.35 – 7.26 (m, 4H), 7.23 – 7.16 (m, 1H), 3.86 – 3.68 (m, 3H), 3.68 – 3.54 (m, 1H), 3.48 (t, J = 9.6 Hz, 1H), 2.89 – 2.68 (m, 1H), 2.81 (dd, J = 13.1, 3.2 Hz, 1H), 2.59 – 2.52 (m, 1H), 1.82 – 1.72 (m, 1H), 1.36 (s, 9H), 1.34 – 1.27 (m, 1H), 1.26 – 1.18 (m, 1H), 1.22 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.07 (d, J = 3.1 Hz, 6H). [00468] Step 5: Synthesis of tert-butyl (3S,4R)-4-amino-3-[[tert- butyl(dimethyl)silyl]oxymethyl]piperidine-1-carboxylate. A mixture of tert-butyl (3S,4R)-3- [[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate (530 mg, 1.18 mmol), ammonium formate (596 mg, 9.45 mmol) and Pd/C (126 mg, 0.12 mmol) in EtOH (15 mL) was heated to 65 °C for 2 h. The mixture was filtered through celite and washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure to afford the title compound (320 mg, 79%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 345.3.¹H NMR (400 MHz, DMSO-d6) δ 3.61 (dd, J = 10.2, 4.9 Hz, 1H), 3.49 – 3.41 (m, 2H), 3.39 – 3.24 (m, 3H), 3.23 – 3.08 (m, 1H), 3.06 – 2.98 (m, 1H), 1.71 – 1.55 (m, 2H), 1.55 – 1.44 (m, 1H), 1.40 – 1.33 (m, 1H), 1.38 (s, 9H), 0.89 – 0.84 (m, 9H), 0.06 – 0.01 (m, 6H). [00469] Step 6: Synthesis of tert-butyl (3S, 4R)-3-[[tert-butyl(dimethyl) silyl] oxymethyl]- 4-[[3-(2, 6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl] amino] piperidine-1-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (471 mg, 0.94 mmol), tert-butyl (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silyl] oxymethyl]piperidine-1-carboxylate (270 mg, 0.78 mmol), Cs₂CO₃ (638 mg, 1.96 mmol) and RuPhos Pd G3 (98.3 mg, 0.12 mmol) in 1,4-dioxane (7 mL) was heated to 90 °C for 16 h and then cooled to rt. The residue was purified by column chromatography on silica gel using a gradient of 0–50% EtOAC in hexanes to afford the title compound (458 mg, 67%) as a solid. Note: the reaction was repeated and the crude residue combined before purification. MS (ESI) [M+H]⁺ 764.4.¹H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.1 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.42 – 7.26 (m, 9H), 6.55 (d, J = 7.9 Hz, 1H), 6.52 (dd, J = 9.0, 1.9 Hz, 1H), 6.45 (d, J = 1.3 Hz, 1H), 5.78 (d, J = 8.6 Hz, 1H), 5.44 (s, 2H), 5.41 (s, 2H), 3.88 (s, 3H), 3.85 – 3.77 (m, 1H), 3.67 – 3.61 (m, 1H), 3.60 – 3.41 (m, 4H), 3.39 – 3.32 (m, 1H), 2.10 – 2.00 (m, 1H), 1.67 – 1.53 (m, 2H), 1.41 (s, 9H), 0.82 (s, 9H), –0.05 (d, J = 15.0 Hz, 6H). [00470] Step 7: Synthesis of tert-Butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]- 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (458 mg, 0.60 mmol) and Pearlman's catalyst (210 mg, 0.15 mmol) in EtOH (10 mL) and THF (10 mL) was subjected to hydrogenation (1 atm) at 50 °C for 2 h. The mixture was filtered through celite and washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure to afford the title compound (350 mg, quant.) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 586.4. [00471] Step 8: Synthesis of 3-[6-[[(3S,4R)-3-(Hydroxymethyl)-4-piperidyl]amino]-1- methyl-indazol-3-yl]piperidine-2,6-dione dihydrochloride. To a solution of tert- butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]amino]piperidine-1-carboxylate (350 mg, 0.60 mmol) in DCM (2.5 mL) was added 4N HCl in 1,4-dioxane (1.5 mL, 6.0 mmol) and the mixture was stirred for 2 h at rt. The resulting precipitate was collected by filtration, washed with Et₂O (3 x 5 mL) and dried under vacuum to afford the title compound (250 mg, 77%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 372.2.¹H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.89 – 8.68 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 6.66 (dd, J = 8.8, 1.7 Hz, 1H), 6.51 (s, 1H), 4.18 (dd, J = 9.0, 5.1 Hz, 1H), 3.99 – 3.92 (m, 1H), 3.82 (s, 3H), 3.51 – 3.41 (m, 2H), 3.27 – 3.15 (m, 2H), 3.15 – 3.04 (m, 2H), 2.67 – 2.54 (m, 2H), 2.32 – 2.21 (m, 2H), 2.18 – 2.10 (m, 1H), 1.98 – 1.89 (m, 1H), 1.87 – 1.78 (m, 1H). [00472] Step 9: Synthesis of 3-[6-[[(3S,4R)-1-[5-Chloro-4-[(1-methyl-2-oxo-indolin-5- yl)amino]pyrimidin-2-yl]-3-(hydroxymethyl)-4-piperidyl]amino]-1-methyl-indazol-3- yl]piperidine-2,6-dione. To a mixture of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl) amino]-1- methyl-indolin-2-one (35 mg, 0.12 mmol) and DIPEA (0.10 mL, 0.60 mmol) in DMF (2 mL) at rt was added 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidyl]amino]-1-methyl-indazol-3- yl]piperidine-2,6-dione dihydrochloride (77.8 mg, 0.14 mmol), and the reaction mixture was heated to 80 °C for 2 h. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (BEH column, C18) using a gradient of 31−41% MeCN and 10 mM ammonium formate in water to afford the title compound (22.1 mg, 28%) as a solid. LCMS C₃₂H₃₄ClN₉O₄ requires 643.2, found 644.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H), 8.61 (s, 1H), 8.00 (s, 1H), 7.75 – 7.57 (m, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.9 Hz, 1H), 6.48 (s, 1H), 5.85 (d, J = 8.5 Hz, 1H), 4.46 (s, 1H), 4.18 (dd, J = 8.4, 5.1 Hz, 1H), 3.96 – 3.85 (m, 2H), 3.81 (s, 3H), 3.80 – 3.75 (m, 1H), 3.75 – 3.63 (m, 2H), 3.52 (s, 2H), 3.51 – 3.46 (m, 1H), 3.09 (s, 3H), 2.66 – 2.55 (m, 2H), 2.31 – 2.21 (m, 1H), 2.20 – 2.11 (m, 1H), 2.11 – 2.02 (m, 1H), 1.79 – 1.69 (m, 1H), 1.67 – 1.56 (m, 1H). Example S58. Synthesis of 3-(6-(((3R,4S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-(hydroxymethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (58) [00473] Step 1: Synthesis of 3-(6-(((3R,4S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-(hydroxymethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The title compound was synthesized analogously to Example S57 beginning with the other diastereomer isolated from Example S57, Step 2. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 44–54% MeCN and 10 mM ammonium formate in water to afford title compound (5.5 mg, 14%) as a solid. LCMS C32H34ClN9O4 requires 643.2, found 644.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO- d6) δ 8.61 (s, 1H), 8.00 (s, 1H), 7.66 (br s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.8, 1.7 Hz, 1H), 6.48 (s, 1H), 5.85 (d, J = 8.5 Hz, 1H), 4.18 (dd, J = 8.8, 5.1 Hz, 1H), 3.92 – 3.84 (m, 2H), 3.81 (s, 3H), 3.80 – 3.74 (m, 1H), 3.52 (s, 2H), 3.51 – 3.46 (m, 2H), 3.39 – 3.29 (m, 2H), 3.09 (s, 3H), 2.63 – 2.57 (m, 2H), 2.30 – 2.19 (m, 1H), 2.19 – 2.11 (m, 1H), 2.11 – 2.01 (m, 1H), 1.78 – 1.69 (m, 1H), 1.67 – 1.52 (m, 1H). Example S59. Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-pyrazolo[4,3- b]pyridin-3-yl)piperidine-2,6-dione (59) [00474] Step 1: Synthesis of 6-Bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine. To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (3.75 g, 18.9 mmol) in MeCN (90 mL) was added NIS (5.11 g, 22.7 mmol). The reaction mixture was heated to 85 °C for 18 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–15% EtOAc in hexanes to afford title compound (6.05 g, 98%) as a solid. MS (ESI) [M+H]⁺ 324.0. [00475] Step 2: Synthesis of 6-Bromo-3-iodo-1-methyl-pyrazolo[4,3-b]pyridine. The title compound was synthesized analogously to General Procedure 3 using 6-Bromo-3-iodo-1H- pyrazolo[4,3-b]pyridine as the starting material. [00476] Step 3: Synthesis of 6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- pyrazolo[4,3-b]pyridine. A mixture of 6-bromo-3-iodo-1-methyl-pyrazolo[4,3-b]pyridine (900 mg, 2.66 mmol), (2,6-dibenzyloxy-3-pyridyl)boronic acid (5.36 g, 7.99 mmol, intermediate provided by Celgene), Pd(PPh3)2Cl2 (374 mg, 0.53 mmol) and a 2M aqueous solution of Na2CO3 (2.66 mL, 5.33 mmol) in 1,4-dioxane (18 mL) was heated to 80 °C for 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–20% EtOAc in hexanes to afford title compound (835 mg, 62%) as a solid. MS (ESI) [M+H]⁺ 502.2. [00477] Step 4: Synthesis of tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- pyrazolo[4,3-b]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate. The title compound was synthesized according to General Procedure 2 using 6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-pyrazolo[4,3-b]pyridine and tert-butyl N-methyl-N-(4-piperidyl)carbamate as starting materials in toluene. [00478] Step 5: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-pyrazolo[4,3- b]pyridin-3-yl)piperidine-2,6-dione. The synthesis of the title compound was accomplished using General Procedures 4, 5, and 6 using tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-pyrazolo[4,3-b]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate as the starting material. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 44–54% MeCN and 10 mM ammonium formate in water to afford title compound (5.4 mg, 12%) as a solid. LCMS C31H33ClN10O3 requires 628.2, found 629.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.89 – 10.82 (m, 1H), 8.59 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 4.28 (dd, J = 9.8, 5.2 Hz, 1H), 3.97 – 3.91 (m, 5H), 3.55 (s, 2H), 3.28 (s, 2H), 3.08 (s, 3H), 2.92 (s, 3H), 2.87 – 2.72 (m, 2H), 2.72 – 2.64 (m, 1H), 2.62 – 2.55 (m, 1H), 2.22 – 2.10 (m, 1H), 1.97 – 1.84 (m, 2H), 1.76 – 1.66 (m, 2H). Example S60. Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-pyrazolo[4,3- c]pyridin-3-yl)piperidine-2,6-dione (60) [00479] Step 1: 6-Bromo-3-iodo-1H-pyrazolo[4,3-c]pyridine To a solution of 6-bromo- 1H-pyrazolo[4,3-c]pyridine (3.5 g, 17.7 mmol) in MeCN (177 mL) was added NIS (7.95 g, 35.4 mmol). The reaction mixture was heated to 85 °C for 18 h and then cooled to rt. Water (50 mL) was added and the resulting precipitate was collected by filtration, washed with water (50 mL), DCM (50 mL), and dried under vacuum to afford the title compound (6.21 g, quant.) as a solid. MS (ESI) [M+H]⁺ 325.8.¹H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.57 (s, 1H). [00480] Step 2: 6-Bromo-3-iodo-1-methyl-pyrazolo[4,3-c]pyridine. To a mixture of 6- bromo-3-iodo-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.31 mmol) in DMF (2 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 31 mg, 0.77 mmol), and the reaction mixture was stirred at 0 °C for 15 min. A solution of iodomethane (50 µL, 0.77 mmol) in DMF (1 mL) was added and the reaction was warmed to rt and stirred for 2 h. Water (20 mL) and DCM (20 mL) were added, and the layers were separated. The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic fractions were washed with brine (40 mL), dried over MgSO4, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 10–35% EtOAc in hexanes to afford the title compound (46 mg, 44%) as a solid.¹H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.0 Hz, 1H), 8.09 (d, J = 1.0 Hz, 1H), 4.05 (s, 3H). [00481] Step 3: 6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3- c]pyridine. A mixture of 6-bromo-3-iodo-1-methyl-pyrazolo[4,3-c]pyridine (100 mg, 0.30 mmol), (2,6-dibenzyloxy-3-pyridyl)boronic acid (595 mg, 0.89 mmol), Pd(PPh3)2Cl2 (41.5 mg, 60 µmol) and a 2M aqueous solution of Na₂CO₃ (300 µL, 0.59 mmol) in 1,4-dioxane (1.5 mL) was heated to 80 °C for 16 h and then cooled to rt. Water (40 mL) and EtOAc (40 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic fractions were washed with brine (40 mL), dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–15% EtOAc in hexanes to afford the title compound (99.0 mg, 67%) as a solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J = 1.0 Hz, 1H), 8.09 – 7.96 (m, 2H), 7.49 – 7.44 (m, 2H), 7.43 – 7.39 (m, 2H), 7.38 – 7.33 (m, 3H), 7.33 – 7.24 (m, 3H), 6.63 (d, J = 8.2 Hz, 1H), 5.52 (s, 2H), 5.44 (s, 2H), 4.06 (s, 3H). [00482] Step 4: tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3- c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate. A mixture of 6-bromo-3-(2,6-dibenzyloxy- 3-pyridyl)-1-methyl-pyrazolo[4,3-c]pyridine (1.44 g, 2.87 mmol), tert-butyl N-methyl-N-(4- piperidyl)carbamate (677 mg, 3.16 mmol), RuPhos-Pd-G3 (480 mg, 0.57 mmol) and NaOtBu (552 mg, 5.74 mmol) in 1,4-dioxane (58 mL) was heated to 90 °C for 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–40% EtOAc in hexanes to afford the title compound (1.08 g, 59%) as a solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (d, J = 1.0 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.43 – 7.33 (m, 5H), 7.33 – 7.23 (m, 3H), 6.72 (d, J = 1.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 5.51 (s, 2H), 5.40 (s, 2H), 4.47 (d, J = 12.6 Hz, 2H), 3.93 (s, 3H), 2.82 (t, J = 12.5 Hz, 2H), 2.72 – 2.66 (m, 1H), 2.64 (s, 3H), 1.80 – 1.52 (m, 4H), 1.40 (s, 9H). [00483] Step 5: tert-Butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-pyrazolo[4,3- c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate. A mixture of tert-butyl N-[1-[3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate (1.59 g, 1.88 mmol) and Pd(OH)₂/C (200 mg, 0.38 mmol) in THF (12.5 mL) and EtOH (12.5 mL) was subjected to hydrogenation (1 atm) at rt for 2 h. The mixture was filtered through celite and washed with DMF (60 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (927 mg, quant.) as a solid. MS (ESI) [M+H]⁺ 457.4. [00484] Step 6: 3-[1-Methyl-6-[4-(methylamino)-1-piperidyl]pyrazolo[4,3-c]pyridin-3- yl]piperidine-2,6-dione hydrochloride. To a solution of tert-butyl N-[1-[3-(2,6-dioxo-3- piperidyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate (927 mg, 2.03 mmol) in DCM (40.6 mL) was added 4N HCl in 1,4-dioxane (5.08 mL, 20.3 mmol), and the reaction mixture was stirred at rt for 16 h. The reaction was diluted with Et₂O (20 mL), filtered and rinsed with Et2O (2 x 10 mL) to afford the title compound (688 mg, 86%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 357.3.¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.06 (s, 2H), 8.91 (s, 1H), 7.17 (s, 1H), 4.51 (dd, J = 10.9, 4.9 Hz, 1H), 4.33 (d, J = 13.3 Hz, 2H), 3.97 (s, 3H), 3.36 – 3.17 (m, 1H), 3.07 (t, J = 12.6 Hz, 2H), 2.77 – 2.60 (m, 2H), 2.56 (t, J = 5.4 Hz, 3H), 2.48 – 2.38 (m, 1H), 2.25 – 2.15 (m, 1H), 2.14 (d, J = 13.4 Hz, 2H), 1.75 – 1.57 (m, 2H). [00485] Step 7: 3-[6-[4-[[5-Chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2- yl]-methyl-amino]-1-piperidyl]-1-methyl-pyrazolo[4,3-c]pyridin-3-yl]piperidine-2,6-dione To a solution of 3-[1-methyl-6-[4-(methylamino)-1-piperidyl]pyrazolo[4,3-c]pyridin-3- yl]piperidine-2,6-dione hydrochloride (50 mg, 0.13 mmol) in DMSO (1.6 mL) were added sequentially 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (34 mg, 0.12 mmol) and DIPEA (0.2 mL, 1.16 mmol). The reaction mixture was heated to 100 °C for 18 h and then cooled to rt. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 44–54% MeCN and 10 mM ammonium formate in water to afford the title compound (18.6 mg, 25%) as a solid. LCMS C31H33ClN10O3 requires 628.2, found 629.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 8.11 – 7.84 (m, 1H), 7.64 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.74 (s, 1H), 4.53 (d, J = 12.9 Hz, 2H), 4.35 – 4.25 (m, 1H), 3.98 – 3.82 (m, 3H), 3.54 (s, 1H), 3.30 – 3.26 (m, 3H), 3.09 (s, 2H), 2.91 –2.73 (m, 4H), 2.73 – 2.54 (m, 3H), 2.41 – 2.29 (m, 1H), 2.23 – 2.13 (m, 1H), 1.82 – 1.59 (m, 4H). Example S61. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-6- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (61) [00486] Step 1: Synthesis of 1-methyl-6-nitroindoline-2,3-dione. To a stirred solution of 6- nitroindoline-2,3-dione (1.0 g, 5.20 mmol) in DMF (20 mL) was added sodium hydride (0.312 g, 7.81 mmol) at 0 ºC under nitrogen and stirred for 10 min. Methyl iodide (0.651 mL, 10.41 mmol) was added to the reaction mixture and slowly warmed to 25 ºC. The reaction mixture was stirred for 1 h, treated with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound which was purified by flash column chromatography on silica gel with 40-50% ethyl acetate/pet ether to afford the title compound (320 mg, 1.531 mmol, 29% yield) as an off-white solid. [00487] Step 2: Synthesis of 1-methyl-6-nitroindolin-2-one. To a stirred solution of 1- methyl-6-nitroindoline-2,3-dione (200 mg, 0.957 mmol) in n-butanol (5.0 mL) was added hydrazine hydrate (144 mg, 2.87 mmol) at 25 °C. The reaction was heated 80 °C and stirred for 4 h. Then the reaction mixture was cooled to 25 °C and added triethylamine (0.533 mL, 3.83 mmol) and stirred at 80 °C for 14 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude compound which was purified by flash column chromatography on silica gel with 35-45% ethyl acetate/pet ether to afford the title compound (40 mg, 0.171 mmol, 18% yield) as an off-white solid. LCMS found 193.2 [M+H]⁺, Rt 1.686 min [00488] Step 3: Synthesis of 6-amino-1-methylindolin-2-one. To a stirred solution of 1- methyl-6-nitroindolin-2-one (40 mg, 0.171 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was added 10% Pd/C (20 mg) under nitrogen at 25 °C. The reaction mixture was stirred under hydrogen atmosphere for 6 h. The reaction mixture was filtered through celite and the celite pad was washed with ethanol (2 x 20 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (35 mg, crude) which was used for the next step without further purification.¹H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 8.4 Hz, 1H), 6.20-6.18 (m, 2H), 5.11 (brs, 2H), 3.32 (s, 2H), 3.02 (s, 3H). [00489] Step 4: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-6- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The synthesis of the title compound was accomplished using General Procedures 1 and 6 using 6-amino-1-methylindolin-2-one and 3-(1-methyl-6-(((3R,4R)-3- methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. The crude material was purified by preparative HPLC to afford the title compound (18 mg, 0.028 mmol, 17% yield) as an off-white solid. LCMS C32H34ClN9O3 requires 627.3, found 628.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 8.99 (s, 1H), 8.12 (s, 1H), 7.42 (s, 1H), 7.32 (d, J = 8.80 Hz, 1H), 7.26 (d, J = 9.20 Hz, 1H), 7.21 (d, J = 8.00 Hz, 1H), 6.52 (dd, J = 8.80, 1.60 Hz, 1H), 6.45 (s, 1H), 5.79 (brs, 1H), 4.55-4.47 (m, 2H), 4.19-4.16 (m, 1H), 3.81 (s, 3H), 3.12-3.06 (m, 4H), 2.75-2.70 (m, 1H), 2.66-2.58 (m, 3H), 2.28-2.19 (m, 1H), 2.16-2.08 (m, 2H), 1.62-1.53 (m, 1H), 1.25-1.18 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). Example S62. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4- b]pyridin-3-yl)piperidine-2,6-dione (62) [00490] Step 1.6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine To a 0 °C solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (2 g, 7.16 mmol) in DMF (20 mL) was added sodium hydride (0.301 g, 7.51 mmol), The reaction mixture was stirred for 30 min and then sodium hydride (0.301 g, 7.51 mmol) was added dropwise. The reaction mixtre was allowed to warm to rt and stirred for 1 h. The reaction mixture was treated with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100 % ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (1.7 g, 5.79 mmol, 81 % yield) as white solid; MS (ESI) m/z 293.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO- d6) δ ppm 7.99 (d, J=8.31 Hz, 1 H), 7.32 (d, J=8.31 Hz, 1 H), 4.03 (s, 3 H). [00491] Step 2. tert-butyl (3R,4R)-4-((3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-6- yl)amino)-3-methylpiperidine-1-carboxylate The solution of 6-chloro-3-iodo-1-methyl-1H- pyrazolo[3,4-b]pyridine (500 mg, 1.704 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.607 mL, 3.41 mmol) in DMSO (1 mL) was added tert-butyl (3R,4R)-4-amino-3-methylpiperidine-1- carboxylate (365 mg, 1.704 mmol). The reaction mixtre stirred at 120 °C for 48 h. The reaction mixture was filtered and purified by reveres-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fractions containing clean product were combined and lyphilized to give the title compound (250 mg, 0.530 mmol, 31.1 % yield) as white solid. MS (ESI) m/z 472.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.33 (dd, J=8.68, 1.71 Hz, 1 H), 7.18 (br d, J=7.83 Hz, 1 H), 6.33 - 6.46 (m, 1 H), 3.86 - 4.05 (m, 2 H), 3.81 (d, J=1.83 Hz, 4 H), 2.79 - 2.99 (m, 1 H), 2.56 - 2.64 (m, 1 H), 1.98 (br d, J=12.35 Hz, 1 H), 1.47 - 1.63 (m, 1 H), 1.41 (d, J=1.71 Hz, 9 H), 1.17 - 1.32 (m, 1 H), 0.88 (br d, J=4.89 Hz, 3 H). [00492] Step 3. tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidine-1-carboxylate. The solution of tert- butyl (3R,4R)-4-((3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidine- 1-carboxylate (250 mg, 0.530 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (243 mg, 0.583 mmol) and sodium bicarbonate (98 mg, 1.167 mmol) in mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) was stirred with tetrakis(triphenylphosphine)palladium(0) (61.3 mg, 0.053 mmol) at 80 °C for 15 h. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the crude product, which further purified by reveres-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fraction containing clean product were combined and lyphilized to give the title compound as a white solid (110 mg, 0.173 mmol, 32.7 % yield). MS (ESI) m/z 372.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.94 (d, J=8.07 Hz, 1 H), 7.64 (d, J=8.80 Hz, 1 H), 7.43 - 7.51 (m, 2 H), 7.36 - 7.42 (m, 4 H), 7.26 - 7.36 (m, 4 H), 6.92 (d, J=8.19 Hz, 1 H), 6.55 (d, J=8.19 Hz, 1 H), 6.19 (d, J=8.93 Hz, 1 H), 5.46 (s, 2 H), 5.41 (s, 2 H), 3.86 - 3.99 (m, 2 H), 3.81 - 3.85 (m, 3 H), 3.69 - 3.81 (m, 1 H), 2.75 - 3.07 (m, 1 H), 1.91 - 2.07 (m, 1 H), 1.45 - 1.64 (m, 1 H), 1.41 (s, 9 H), 1.24 - 1.32 (m, 2 H), 0.88 (d, J=6.60 Hz, 3 H). [00493] Step 4. 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H- pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione. The solution of tert-butyl (3R,4R)-4-((3- (2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3- methylpiperidine-1-carboxylate (0.105 g, 0.165 mmol) in ethanol (10 mL) was stirred with palladium on carbon 10% w/w (0.018 g, 0.017 mmol) under hydrogen (1 atm) at 50 °C for 15 h. The reaction mixture was filter over celite, the elute was concentrected and the residue was then stirred at rt with 1 mL TFA in DCM (1 mL) for 30 min. The TFA and solvent were removed under reduced pressure to give the desired product 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin- 4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione (60 mg, 0.168 mmol, quant yield) as TFA salt which was use without further purification. [00494] Step 5.3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4- b]pyridin-3-yl)piperidine-2,6-dione The synthesis of the title compound was accomplished using General Procedures 6 using 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H- pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione hydrochloride (40 mg, 0.102 mmol) and 5-((5- chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (29.8 mg, 0.102 mmol). The reaction mixture was filtered and purified by reveres-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fraction containing clean product were combined and lyphilized to give the title compound as a white solid (13 mg, 0.02 mmol, 19.4%). MS (ESI) m/z 628.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1 H), 8.66 (s, 1 H), 8.02 (s, 1 H), 7.63 (d, J=8.80 Hz, 1 H), 7.57 (s, 1 H), 7.52 (dd, J=8.44, 2.08 Hz, 1 H), 6.87 - 6.98 (m, 2 H), 6.31 (d, J=8.80 Hz, 1 H), 4.48 (br s, 2 H), 4.13 (dd, J=9.35, 5.07 Hz, 1 H), 3.82 - 3.95 (m, 1 H), 3.77 (s, 3 H), 3.53 (s, 2 H), 3.06 - 3.15 (m, 3 H), 2.92 - 3.03 (m, 1 H), 2.64 - 2.73 (m, 1 H), 2.52 - 2.64 (m, 2 H), 2.21 - 2.31 (m, 1 H), 2.09 - 2.19 (m, 1 H), 2.02 (br d, J=9.29 Hz, 1 H), 1.54 - 1.67 (m, 1 H), 1.21 - 1.37 (m, 1 H), 0.93 (d, J=6.48 Hz, 3 H). Example S63. Synthesis of 3-(6-((1-(5-chloro-4-((2-oxoindolin-5-yl)amino)pyrimidin-2- yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (63) [00495] Step 1: Synthesis of 3-(6-((1-(5-chloro-4-((2-oxoindolin-5-yl)amino)pyrimidin-2- yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione. The title compound was synthesized analogously to Example S62 above using 3-[1-methyl-6-(4- piperidylamino)indazol-3-yl]piperidine-2,6-dione and 5-aminoindolin-2-one as starting materials. LCMS C30H30ClN9O3 requires 599.2, found 600.0 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz) δ 10.8-10.9 (m, 1H), 10.3-10.4 (m, 1H), 8.0-8.1 (m, 1H), 7.4-7.5 (m, 1H), 7.3-7.4 (m, 2H), 6.8-6.8 (m, 1H), 6.4-6.6 (m, 2H), 4.2-4.4 (m, 2H), 4.1-4.2 (m, 1H), 3.9-4.0 (m, 2H), 3.84 (s, 3H), 3.6-3.7 (m, 1H), 3.49 (s, 2H), 3.1-3.2 (m, 2H), 2.6-2.6 (m, 2H), 2.2-2.3 (m, 1H), 2.1-2.2 (m, 1H), 2.0-2.1 (m, 2H), 1.3-1.4 (m, 2H). Example S64. Synthesis of 3-(6-((1-(5-Chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (64) [00496] Step 1: Synthesis of 3-(6-((3,3-Difluoropiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione hydrochloride. A mixture of 3-(6-amino-1-methyl-indazol- 3-yl)piperidine-2,6-dione (500 mg, 1.94 mmol), tert-butyl 3,3-difluoro-4-oxopiperidine-1- carboxylate hydrate (500.9 mg, 2.13 mmol) and decaborane(14) (108.54 mg, 0.9700 mmol) was stirred in DMSO (5 mL) and acetic acid (0.22 mL, 3.87 mmol) at ambient temperature. After 2 hours, the reaction was complete according to LCMS. The reaction was diluted with methanol (1 mL) which resulted in bubbling. After 10 min, the bubbling subsided and the solution was diluted with ethyl acetate, washed with water and then brine, dried (sodium sulfate), filtered and concentrated. The resulting solid was triturated with diethyl ether. The resulting solid was then purified using silica gel chromatography using 4% methanol and a gradient of 0-50% ethyl acetate in hexanes. The resulting intermediate tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate (230 mg, 0.4817 mmol, 24.8% yield) was isolated and treated with 2 mL 4 N HCL in 1,4-dioxane and stirred for 3 h. After this time, the reaction mixture was concentrated to give the title compound (270 mg, 0.6524 mmol, 33.7% yield) as a light yellow powder. [00497] Step 2: Synthesis of 3-(6-((1-(5-Chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione 3-{6-[(3,3-difluoropiperidin-4-yl)amino]-1-methyl-1H-indazol-3- yl}piperidine-2,6-dione hydrochloride (278 mg, 0.650 mmol), 5-((5-chloro-2-fluoropyrimidin-4- yl)amino)-1-methylindolin-2-one (172 mg, 0.590 mmol), N,N-diisopropylethylamine (0.2 mL, 1.17 mmol) and DMSO (1.17 mL) were added to a 1 dram vial equipped with a stir bar and heated to 80 °C for 15 hours. The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fraction containing clean product were combined and lyphilized to give the title compound (12 mg, 0.0184 mmol, 3.14 % yield). ¹H NMR (DMSO-d6, 400 MHz) δ 10.8-10.9 (m, 1H), 8.8-8.9 (m, 1H), 8.2-8.2 (m, 1H), 8.0-8.1 (m, 1H), 7.4-7.5 (m, 2H), 7.3-7.4 (m, 1H), 6.9-7.0 (m, 1H), 6.6-6.7 (m, 2H), 5.9-6.1 (m, 1H), 4.6-4.8 (m, 1H), 4.4-4.5 (m, 1H), 4.2-4.3 (m, 2H), 3.8-3.9 (m, 3H), 3.4-3.6 (m, 3H), 3.2-3.3 (m, 1H), 3.1-3.1 (m, 3H), 2.6-2.7 (m, 2H), 2.5-2.6 (m, 4H), 2.2-2.3 (m, 1H), 2.1-2.2 (m, 1H), 1.9-2.0 (m, 1H), 1.5-1.7 (m, 1H). Example S65. Synthesis of 1-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (65) [00498] Step 1: Synthesis of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate. To a solution of 1-(6- amino-1-methyl-indazol-3-yl) hexahydropyrimidine-2,4-dione (900 mg, 3.47 mmol), tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (980 mg, 4.17 mmol) in acetic acid (5 mL) and DMSO (25 mL) was added Decaborane(14) (195 mg, 1.74 mmol) and the mixture was stirred for 6 h at rt. Volatiles were removed and the residue was purified by reverse phase chromatography (C18) with a gradient of 20–100% MeCN and 10 mM ammonium formate in water to afford the title compound (450 mg, 27%) as a solid. MS (ESI) [M–H]^– 477.3. [00499] Step 2: Synthesis of 1-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione. The title compound was synthesized according to General Procedures 5 and 6 using tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate as the starting material. LCMS C30H29ClF2N10O3 requires 650.2, found 651.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.82 (s, 1H), 8.06 (s, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 8.4, 2.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.9, 1.9 Hz, 1H), 6.61 (d, J = 1.8 Hz, 1H), 6.05 (d, J = 9.2 Hz, 1H), 4.77 – 4.63 (m, 1H), 4.49 – 4.36 (m, 1H), 4.33 – 4.17 (m, 1H), 3.87 (t, J = 6.7 Hz, 2H), 3.81 (s, 3H), 3.55 – 3.51 (m, 2H), 3.58 – 3.44 (m, 1H), 3.28 – 3.18 (m, 1H), 3.11 (s, 3H), 2.72 (t, J = 6.7 Hz, 2H), 2.03 – 1.95 (m, 1H), 1.70 – 1.57 (m, 1H). Example S66. Synthesis of 3-(6-(((R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (66) [00500] Step 1: Synthesis of tert-butyl 3,3-difluoro-4-(((R)-1- phenylethyl)amino)piperidine-1-carboxylate. A mixture of tert-butyl 3,3-difluoro-4-oxo- piperidine-1-carboxylate (3.53 g, 15.0 mmol) and (1R)-1-phenylethanamine (2.18 g, 18.0 mmol) in toluene (35 mL) was heated to reflux with a Dean-Stark trap for 18 h. The mixture was cooled to rt and the volatiles were removed under reduced pressure. DCM (35 mL) was added, followed by sodium triacetoxyborohydride (7.15 g, 33.7 mmol) portion wise over 1 h. The mixture was heated to 50 °C for 18 h. Another batch of sodium triacetoxyborohydride (3.56 g, 16.8 mmol) was added and the reaction mixture was heated to 50 °C for another 6 h. The mixture was cooled to rt and the volatiles were removed under reduced pressure. A 2M solution of Na₂CO₃ (50 mL) was added and the mixture was stirred for 1 h at rt, followed by the addition of EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 0–3% MeOH in DCM to afford the title compound (4.21 g, 82%) as an oil.¹H NMR (500 MHz, Methanol-d4) δ 7.29 – 7.35 (m, 4H), 7.20 – 7.25 (m, 1H), 5.48 (s, 1H), 4.08 (q, J = 6.7 Hz, 1H), 4.04 (br s, 1 H), 3.73 – 3.79 (m, 1H), 3.17 (br s, 1H), 2.91 (br s, 1H), 2.70 – 2.80 (m, 1H), 1.65 – 1.72 (m, 1H), 1.45 – 1.50 (m, 1H), 1.44 (s, 9H), 1.31 (d, J = 6.62 Hz, 3H). [00501] Step 2: Synthesis of tert-Butyl (4R)-3, 3-difluoro-4-[[(1R)-1-phenylethyl] amino] piperidine-1-carboxylate 4-methyl benzenesulfonic acid salt. To a solution of tert-butyl 3,3- difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate (4.21 g, 12.4 mmol) in EtOH (50 mL) at rt was added 4-methylbenzenesulfonic acid hydrate (2.35 g, 12.4 mmol), and the mixture was heated to 60 °C for 1 h. The volatiles were removed under reduced pressure to afford a mixture of diastereomers as solids.The crude mixture of intermediates (6.07 g) was dissolved in a 10:1 mixture of acetone:EtOH (68.5 mL) and the mixture was heated to reflux. The flask was removed from the oil bath and left to stand overnight. The precipitated solid was filtered, rinsed with cold acetone (2 x 1 mL) and dried to afford the first crop of the title compound which was carried forward. [00502] Step 3: Synthesis of tert-Butyl (4R)-3,3-difluoro-4-[[(1R)-1- phenylethyl]amino]piperidine-1-carboxylate. The compound tert-Butyl (4R)-3,3-difluoro-4- [[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate 4-methyl benzenesulfonic acid salt (1.99 g, 3.88 mmol) was partitioned between EtOAc (50 mL) and a saturated aqueous solution of NaHCO3 (50 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (1.30 g, 98%) as an oil. MS (ESI) [M+H]⁺ 341.3.¹H NMR (400 MHz, DMSO-d6) δ 7.36 – 7.27 (m, 4H), 7.26 – 7.15 (m, 1H), 4.01 – 3.95 (m, 1H), 3.94 – 3.80 (m, 1H), 3.66 – 3.54 (m, 1H), 3.29 – 3.20 (m, 1H), 3.04 – 2.91 (m, 1H), 2.71 – 2.64 (m, 1H), 2.37 (t, J = 7.2 Hz, 1H), 1.64 – 1.58 (m, 1H), 1.38 (s, 9H), 1.22 (d, J = 6.6 Hz, 3H). [00503] Step 4: Synthesis of tert-Butyl (4R)-4-amino-3,3-difluoro-piperidine-1- carboxylate. A mixture of tert-butyl (4R)-3,3-difluoro-4-[[(1SR)-1- phenylethyl]amino]piperidine-1-carboxylate (1.29 g, 3.79 mmol) and 10% Pd/C (202 mg, 0.19 mmol) in EtOH (41 mL) was shaken in a Parr flask under hydrogen atmosphere (50 psi) at rt for 18 h. The mixture was filtered on Celite and washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford title compound (845 mg, 94%) as an oil, which was used in the next step without further purification. MS (ESI) [M-butene]+ 181.0. [α]D +0.19° (c = 0.142, EtOH).¹H NMR (400 MHz, Methanol-d4) δ 4.22 – 4.12 (m, 1H), 3.96 (dt, J = 13.7, 4.0 Hz, 1H), 3.25 – 3.15 (m, 1H), 3.14 – 3.00 (m, 2H), 1.93 – 1.82 (m, 1H), 1.59 – 1.48 (m, 1H), 1.46 (s, 9H). [00504] Step 5: Synthesis of tert-Butyl (4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate. To a degassed mixture of 6- bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (200 mg, 0.40 mmol), tert-butyl (4R)- 4-amino-3,3-difluoro-piperidine-1-carboxylate (123 mg, 0.520 mmol) and tBuONa (57.7 mg, 0.60 mmol) in THF (2 mL) at rt was added tBuXPhos-Pd-G3 (33.9 mg, 40 µmol). The reaction vessel was sealed and the reaction mixture was heated to 80 °C for 18 h and cooled to rt. DCM (10 mL) was added and the mixture was filtered on Celite and rinsed with DCM (3 x 10 mL). The volatiles were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–60% of EtOAc in hexanes to afford the title compound (200 mg, 76%) as a solid. MS (ESI) [M+H]⁺ 657.6.¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (d, J = 8.1 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.42 – 7.23 (m, 9H), 6.59 (s, 1H), 6.58 – 6.52 (m, 2H), 6.00 (d, J = 9.1 Hz, 1H), 5.44 (s, 2H), 5.41 (s, 2H), 4.25 – 4.08 (m, 2H), 3.97 – 3.92 (m, 1H), 3.89 (s, 3H), 3.50 – 3.36 (m, 1H), 3.19 – 3.00 (m, 1H), 1.97 – 1.87 (m, 1H), 1.65 – 1.52 (m, 1H), 1.42 (s, 9H). [00505] Step 6: Synthesis of 3-(6-(((R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 4, 5, and 6 using tert-Butyl (4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate as the starting material. LCMS C31H30ClF2N9O3 requires 649.2, found 650.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.51 (s, 1H), 7.47 (dd, J = 8.4, 2.1 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 8.8, 1.8 Hz, 1H), 6.62 (s, 1H), 6.00 (d, J = 8.9 Hz, 1H), 4.75 – 4.64 (m, 1H), 4.41 (d, J = 11.6 Hz, 1H), 4.26 – 4.13 (m, 2H), 3.82 (s, 3H), 3.60 – 3.42 (m, 3H), 3.23 (t, J = 11.7 Hz, 1H), 3.11 (s, 3H), 2.65 – 2.55 (m, 2H), 2.30 – 2.22 (m, 1H), 2.20 – 2.11 (m, 1H), 2.04 – 1.94 (m, 1H), 1.70 – 1.52 (m, 1H). Example S67. Synthesis of 3-(6-(((S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (67) [00506] Step 1: Synthesis of 3-(6-(((S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione The title compound was synthesized analogously to Example S66 starting using (1S)-1-phenylethanamine in Step 1. LCMS C31H30ClF2N9O3 requires 649.2, found 650.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H), 8.82 (s, 1H), 8.06 (s, 1H), 7.51 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 6.00 (d, J = 9.0 Hz, 1H), 4.78 – 4.63 (m, 1H), 4.47 – 4.33 (m, 1H), 4.30 – 4.18 (m, 2H), 3.82 (s, 3H), 3.60 – 3.45 (m, 3H), 3.26 – 3.19 (m, 1H), 3.11 (s, 3H), 2.69 – 2.57 (m, 2H), 2.31 – 2.23 (m, 1H), 2.15 (dd, J= 12.8, 5.9 Hz, 1H), 2.05 – 1.92 (m, 1H), 1.70 – 1.56 (m, 1H). Example S68. Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (68) [00507] Step 1: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 2, 4, 5, and 6 using tert-butyl (3,3-difluoropiperidin-4-yl)carbamate as starting material. LCMS C₃₁H₃₀ClF₂N₉O₃ requires 649, found 650 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 10.8-10.9 (m, 1H), 8.5-8.7 (m, 1H), 7.9-8.1 (m, 1H), 7.6-7.8 (m, 1H), 7.4-7.6 (m, 2H), 7.2-7.4 (m, 1H), 6.9-7.0 (m, 3H), 4.2-4.4 (m, 1H), 4.0-4.2 (m, 1H), 3.92 (s, 4H), 3.56 (s, 2H), 3.3-3.3 (m, 1H), 3.1-3.2 (m, 3H), 3.0-3.1 (m, 1H), 2.9-2.9 (m, 1H), 2.7-2.7 (m, 1H), 2.6-2.7 (m, 1H), 2.2-2.3 (m, 1H), 2.1-2.2 (m, 1H), 1.9-2.0 (m, 2H). Example S69. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-ethyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (69) [00508] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-ethyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-1-ethylindolin-2-one and 3-(1-methyl-6-(((3R,4R)-3- methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. LCMS C₃₃H₃₆ClN₉O₃ requires 641.3, found 642.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 9.03 (br s, 1H), 8.09 (s, 1H), 7.55 (s, 1H), 7.50 (dd, J = 8.50, 1.90 Hz, 1H), 7.31 (d, J = 8.68 Hz, 1H), 7.01 (d, J = 8.44 Hz, 1H), 6.51 (dd, J = 8.68, 1.59 Hz, 1H), 6.45 (s, 1H), 5.54 - 6.00 (m, 1H), 4.39 (br d, J = 7.70 Hz, 2H), 4.17 (dd, J = 8.68, 5.14 Hz, 1H), 3.81 (s, 3H), 3.68 (q, J = 7.09 Hz, 2H), 3.54 (s, 2H), 3.25 - 3.37 (m, 1H), 3.08 (br t, J = 12.10 Hz, 1H), 2.75 (br t, J = 12.41 Hz, 1H), 2.54 - 2.64 (m, 2H), 2.20 - 2.31 (m, 1H), 2.04 - 2.19 (m, 2H), 1.52 - 1.69 (m, 1H), 1.16 - 1.27 (m, 1H), 1.13 (t, J = 7.09 Hz, 3 H), 0.97 (d, J = 6.48 Hz, 3H). Example S70. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (70) [00509] Step 1: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate (Intermediate 24). A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.92 g, 3.84 mmol), tert- butyl (3R,4R)-4-amino-3-methyl-piperidine-1-carboxylate (685 mg, 3.20 mmol), RuPhos Pd G3 (668.6 mg, 0.80 mmol) and Cs2CO3 (1.25 g, 3.84 mmol) in 1,4-dioxane (15 mL) was heated to 90 °C for 20 h. The mixture was cooled to rt, filtered through celite and washed with EtOAc (4 x 30 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–40% EtOAc in hexanes to afford title compound (1.37 g, 68%) as a solid. MS (ESI) [M+H]⁺ 634.1.¹H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.1 Hz, 1H), 7.50 – 7.46 (m, 1H), 7.46 – 7.25 (m, 10H), 6.54 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 5.70 (d, J = 8.9 Hz, 1H), 5.44 (s, 2H), 5.40 (s, 2H), 3.97 – 3.89 (m, 2H), 3.88 (s, 3H), 3.24 – 3.14 (m, 1H), 2.99 – 2.87 (m, 1H), 2.05 – 2.01 (m, 1H), 2.01 – 1.98 (m, 1H), 1.57 – 1.47 (m, 1H), 1.41 (s, 9H), 1.17 – 1.08 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H). [00510] Step 2: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate. A mixture of tert-butyl (3R,4R)-4- [[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1- carboxylate (1.40 g, 2.21 mmol) and Pd(OH)2/C (1.18 g, 1.10 mmol) in MeOH (25 mL) and THF (75 mL) was hydrogenated under H2 (1 atm) at 50 °C for 9 h. The mixture was filtered through celite and washed with MeOH (2 x 50 mL) and THF (2 x 100 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–5% MeOH in DCM to afford title compound (695 mg, 69%) as a solid. MS (ESI) [M+H]⁺ 456.3.¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.8, 1.7 Hz, 1H), 6.40 (s, 1H), 5.72 (d, J = 8.9 Hz, 1H), 4.17 (dd, J = 8.7, 5.2 Hz, 1H), 3.98 – 3.88 (m, 2H), 3.80 (s, 3H), 3.26 – 3.14 (m, 1H), 3.00 – 2.86 (m, 1H), 2.65 – 2.56 (m, 3H), 2.34 – 2.20 (m, 1H), 2.18 – 2.09 (m, 1H), 2.05 – 1.94 (m, 1H), 1.60 – 1.46 (m, 1H), 1.41 (s, 9H), 1.22 – 1.05 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H). [00511] Step 3: Synthesis of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H- indazol-3-yl)piperidine-2,6-dione hydrochloride. To a solution of tert-butyl (3R,4R)-4-[[3- (2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate (8 g, 17.6 mmol) in ethyl acetate (35 mL) was added 4M HCl in ethyl acetate (35 mL) at 25 °C. After addition, the reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was filtered to offer the title compound (8 g, 100% yield) as an off-white solid. MS (ESI) [M+H]⁺ 356.2.400 MHz MeOD δ: 8.04 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.59- 4.55 (m, 1H), 4.11 (s, 3H), 3.75-7.71 (m, 1H), 3.49-3.46 (m,2 H), 3.20-3.15 (m, 1H), 3.03 (s, 2H), 2.93-2.89 (m, 1H), 2.83-2.81 (m, 2H), 2.52-2.48 (m, 1H), 2.40-2.35 (m, 1H), 2.30-2.26 (m, 1H), 2.20-2.15 (m, 1H), 2.02 (s, 1H), 1.80-1.75 (m, 1H), 1.24-1.22 (m, 3H). [00512] Step 4: Synthesis of 3-[6-[[(3R,4R)-1-[5-Chloro-4-[(1-methyl-2-oxo-indolin-5- yl)amino]pyrimidin-2-yl]-3-methyl-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine- 2,6-dione. To a solution of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H- indazol-3-yl)piperidine-2,6-dione hydrochloride (50.0 mg, 0.130 mmol) in DMSO (0.50 mL) was added sequentially 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (41.1 mg, 0.140 mmol) and DIPEA (90 μL, 0.510 mmol), and was heated to 80 °C for 2 h. The reaction mixture was cooled to rt and was purified directly by preparative HPLC (BEH column, C18) using a gradient of 44–54% MeCN and 10 mM ammonium formate in water to afford the title compound (13.5 mg, 16%) as a solid. LCMS C₃₂H₃₄ClN₉O₃ requires 627.3, found 628.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.65 (s, 1H), 8.02 (s, 1H), 7.57 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 6.43 (s, 1H), 5.68 (d, J = 9.1 Hz, 1H), 4.53 – 4.39 (m, 2H), 4.17 (dd, J = 8.7, 5.2 Hz, 1H), 3.81 (s, 3H), 3.53 (s, 2H), 3.27 – 3.21 (m, 1H), 3.10 (s, 3H), 3.02 (t, J = 12.2 Hz, 1H), 2.76 – 2.65 (m, 1H), 2.64 – 2.56 (m, 2H), 2.32 – 2.19 (m, 1H), 2.18 – 2.09 (m, 1H), 2.10 – 2.02 (m, 1H), 1.65 – 1.51 (m, 1H), 1.21 – 1.11 (m, 1H), 0.97 (d, J = 6.5 Hz, 3H). Example S71. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (71) [00513] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The product of Example S70 was then separated using preparatory HPLC with a Regis Whelk-O1 RR or SS column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C. The title compound elutes as the first peak, Rt = 10.01 min. LCMS C32H34ClN9O3 requires 627.3, found 628.4 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz) δ 10.7-10.9 (m, 1H), 8.5-8.8 (m, 1H), 7.9-8.1 (m, 1H), 7.5-7.7 (m, 2H), 7.2-7.4 (m, 1H), 6.9-7.1 (m, 1H), 6.4-6.7 (m, 2H), 5.6-5.7 (m, 1H), 4.4-4.7 (m, 2H), 4.0-4.3 (m, 1H), 3.8-3.9 (m, 3H), 3.4-3.6 (m, 2H), 2.9-3.2 (m, 4H), 2.7-2.8 (m, 2H), 2.0-2.3 (m, 5H), 1.5-1.6 (m, 1H), 1.1-1.3 (m, 1H), 0.8-1.1 (m, 3H). Example S72. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (72) [00514] Step 1: Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione The product of Example S70 was then separated using preparatory HPLC with a Regis Whelk-O1 RR or SS column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C. The title compound elutes as the second peak, Rt = 14.87 min. LCMS C32H34ClN9O3 requires 627.3, found 628.4 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz) δ 10.7-10.9 (m, 1H), 8.6-8.8 (m, 1H), 7.9-8.1 (m, 1H), 7.5-7.7 (m, 2H), 7.2-7.4 (m, 1H), 6.9-7.0 (m, 1H), 6.3-6.6 (m, 2H), 5.6-5.9 (m, 1H), 4.4-4.6 (m, 2H), 4.1-4.4 (m, 1H), 3.8-3.9 (m, 3H), 3.5-3.6 (m, 2H), 2.9-3.2 (m, 4H), 2.7-2.8 (m, 2H), 2.0-2.3 (m, 5H), 1.5-1.7 (m, 1H), 1.1-1.3 (m, 1H), 0.9-1.0 (m, 3H) Example S73. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (73) [00515] Step 1: Synthesis of tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]-methyl-amino]-3-methyl-piperidine-1-carboxylate. To an ice-cold solution of tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]- 3-methyl-piperidine-1-carboxylate (1.55 g, 2.45 mmol) and 60% NaH dispersion in mineral oil (245 mg, 6.11 mmol) in DMF (20 mL) was added iodomethane (305 µL, 4.89 mmol), and the mixture was stirred at rt for 48 h. Another batch was prepared using the same procedure. Water (50 mL) was added to the combined mixtures and the layers separated. The aqueous layer was extracted with EtOAc (3 x 75 mL). The combined organic fractions were washed with brine (20 mL), dried over MgSO₄, filtered and concentrated. The residue was purified by reverse phase chromatography (C18) using a gradient of 20–100% MeCN and 10 mM ammonium formate in water to afford the title compound (700 mg, 44%) as a solid. MS (ESI) [M+H]⁺ 649.34.¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (d, J = 8.1 Hz, 1H), 7.47 (dd, J = 8.7, 7.1 Hz, 3H), 7.43 – 7.23 (m, 8H), 6.78 (dd, J = 9.4, 2.0 Hz, 1H), 6.61 (d, J = 1.9 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.40 (s, 2H), 4.05 – 3.99 (m, 2H), 3.94 (s, 3H), 3.65 – 3.59 (m, 1H), 2.92 – 2.85 (m, 1H), 2.75 (s, 3H), 2.60 – 2.54 (m, 1H), 1.72 – 1.77 (m, 1H), 1.60 – 1.54 (m, 2H), 1.42 (s, 9H), 0.75 (d, J = 6.5 Hz, 3H). [00516] Step 2: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 4, 5, and 6 using tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]-methyl-amino]-3-methyl-piperidine-1-carboxylate as the starting material. LCMS C₃₂H₃₄ClN₉O₃ requires 641.3, found 642.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.62 (s, 1H), 7.98 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 9.1 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.59 (s, 1H), 4.58 – 4.51 (m, 2H), 4.19 (dd, J = 8.9, 5.2 Hz, 1H), 3.83 (s, 3H), 3.74 – 3.65 (m, 1H), 3.49 (s, 2H), 3.07 (s, 3H), 2.97 – 2.90 (m, 1H), 2.69 (s, 3H), 2.63 – 2.57 (m, 3H), 2.30 – 2.23 (m, 1H), 2.16 – 2.09 (m, 1H), 1.86 – 1.76 (m, 1H), 1.60 – 1.53 (m, 2H), 0.77 (d, J = 6.5 Hz, 3H). Example S74. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxo-2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl- 1H-indazol-3-yl)piperidine-2,6-dione (74) [00517] Step 1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyl-1,3- dihydro-2H-pyrrolo[2,3-b]pyridin-2-one. To a stirred solution of 5-amino-1-methyl-1,3- dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.2 g, 1.18 mmol) in EtOH (30 mL) was added DIPEA (0.617 mL, 3.53 mmol) and 5-chloro-2,4-difluoropyrimidine (0.266 g, 1.765 mmol) at -25 °C. The reaction was allowed to slowly warm to rt after 1 hr and then the reaction was stirred at 25 °C for 16h . After this time, the reaction mixture was evaporated. The crude residue was purified by silica gel chromatography using 50-100% EtOAc in PE to obtain the title compound (190 mg, 0.252 mmol, 21.44 % yield) as an pale yellow solid. MS (ESI) m/z 294.0 [M+H]⁺. [00518] Step 2: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxo-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione. To a stirred solution of 5-((5-chloro-2- fluoropyrimidin-4-yl)amino)-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (80 mg, 0.104 mmol) and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3- yl)piperidine-2,6-dione (49.1 mg, 0.104 mmol) in DMSO (1 mL) was added DIPEA (0.054 mL, 0.311 mmol) and the reaction mixture was stirred at 90 °C for 4h. The reaction mixture was purified by preparatory HPLC to obtain the title compound (30 mg, 0.047 mmol, 45.8 % yield) as an off white solid. LCMS C31H33ClN10O3 requires 628.2, found 629.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.85 (s, 1H), 8.36 (d, J = 2.00 Hz, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.31 (d, J = 8.80 Hz, 1H), 6.44-6.52 (m, 2H), 5.69 (d, J = 8.80 Hz, 1H), 4.44 (d, J = 9.20 Hz, 2H), 4.17 (q, J = 5.20 Hz, 1H), 3.82 (s, 3H), 3.61 (s, 2H), 3.13 (s, 3H), δ 3.02 (t, J = Hz, 1H), 2.53-2.68 (m, 3H), 2.33 (t, J = 1.60 Hz, 1H), 2.25 (t, J = 6.00 Hz, 1H), 2.06-2.17 (m, 2H), 1.58 (d, J = 4.80 Hz, 1H), 1.15-1.17 (m, 1H), 0.96 (d, J = 6.40 Hz, 3H). Example S75. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2-oxoindolin- 5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (75) [00519] Step 1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl) amino)-1-(2- methoxyethyl) indolin-2-one. To a stirred solution of 5-amino-1-(2-methoxyethyl) indolin-2- one (200 mg, 0.97 mmol) in THF (5 mL) was added DIPEA (0.254 mL, 1.46 mmol) and 5- chloro-2,4-difluoropyrimidine (219 mg, 1.46 mmol) under nitrogen atmosphere at -45 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to obtain crude. The crude product was purified by flash column chromatography on silica gel with 30% ethyl acetate/pet ether to afford the title compound (80 mg, 0.210 mmol, 21% yield) as an off-white solid. MS: 337.0 [M+H]⁺. [00520] Step 2: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2- oxoindolin-5-yl) amino) pyrimidin-2-yl)-3-methylpiperidin-4-yl) amino)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione. To a stirred solution 3-(1-methyl-6-(((3R,4R)-3- methylpiperidin-4-yl) amino)-1H-indazol-3-yl) piperidine-2,6-dione (117 mg, 0.238 mmol) in DMSO (2.0 mL) was added 5-((5-chloro-2-fluoropyrimidin-4-yl) amino)-1-(2-methoxyethyl) indolin-2-one (80 mg, 0.238 mmol) and DIPEA (0.166 mL, 0.95 mmol) at 25 ºC. The reaction mixture was heated to 80 °C stirred for 4 h. The crude was purified by Prep-HPLC to afford the title compound (24 mg, 0.028 mmol, 25% yield). LCMS C₃₄H₃₈ClN₉O₄ requires 671.3, found 672.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 8.67 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 7.50 (d, J = 8.40 Hz, 1H), 7.31 (d, J = 8.80 Hz, 1H), 7.01 (d, J = 8.40 Hz, 1H), 6.51 (dd, J = 1.6 Hz and 8.8 Hz, 1H), 6.44 (s, 1H), 5.71 (d, J = 9.20 Hz, 1H), 4.51-4.44 (m, 2H), 4.18 (dd, J = 5.2 Hz and 8.4 Hz, 1H), 3.84-3.82 (m, 2H), 3.82 (s, 3H), 3.56-3.52 (m, 4H), 3.22 (s, 3H), 3.05-2.99 (m, 1H), 2.68-2.65 (m, 1H), 2.62-2.58 (m, 2H), 2.28-2.23 (m, 1H), 2.17-2.06 (m, 2H), 1.60-1.57 (m, 1H), 1.18-1.16 (m, 1H), 0.97 (d, J = 6.40 Hz, 3H). Example S76. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (76) [00521] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione The product of Example S75 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C, isolated as the first eluting peak, Rt = 9.85 min. LCMS C₃₄H₃₈ClN₉O₄ requires 671.3, found 672.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO- d6) δ (ppm) = 10.81 (s, 1H), 8.65 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 7.49 (dd, J = 2.0, 8.5 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.50 (dd, J = 1.7, 8.8 Hz, 1H), 6.43 (d, J = 1.1 Hz, 1H), 5.69 (d, J = 8.9 Hz, 1H), 4.53 - 4.40 (m, 2H), 4.17 (dd, J = 5.2, 8.7 Hz, 1H), 3.86 - 3.79 (m, 5H), 3.58 - 3.48 (m, 4H), 3.21 (s, 3H), 3.06 - 2.96 (m, 1H), 2.73 - 2.56 (m, 3H), 2.35 - 2.01 (m, 4H), 1.63 - 1.50 (m, 1H), 1.23 - 1.10 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H). Example S77. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (77) [00522] Step 1: Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione The product of Example S75 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C isolated as the second eluting peak, Rt = 13.85 min. LCMS C34H38ClN9O4 requires 671.3, found 672.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.81 (s, 1H), 8.65 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 7.49 (dd, J = 2.1, 8.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.50 (dd, J = 1.7, 8.8 Hz, 1H), 6.43 (d, J = 1.2 Hz, 1H), 5.69 (d, J = 9.2 Hz, 1H), 4.52 - 4.41 (m, 2H), 4.17 (dd, J = 5.2, 8.7 Hz, 1H), 3.86 - 3.79 (m, 5H), 3.58 - 3.48 (m, 4H), 3.21 (s, 3H), 3.07 - 2.96 (m, 1H), 2.73 - 2.56 (m, 3H), 2.34 - 2.02 (m, 4H), 1.63 - 1.53 (m, 1H), 1.22 - 1.10 (m, 1H), 0.97 (d, J = 6.5 Hz, 3H). Example S78. Synthesis of 3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (78) [00523] Step 1: Synthesis of tert-butyl (3R,5R)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)-3,5-dimethylpiperazine-1-carboxylate. A stirred solution of 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (2.335 g, 4.67 mmol) and tert-butyl (3R,5R)-3,5-dimethylpiperazine-1-carboxylate (1.0 g, 4.67 mmol) in toluene (25 ml) was degassed with nitrogen for 15 min. Then sodium tert-butoxide (0.673 g, 7.00 mmol) and CPhos- Pd-G3 (0.188 g, 0.233 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 8 h. The reaction mixture was cooled to room temperature and treated with water (150 mL) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude compound. The crude was purified by flash column chromatography on silica with 35- 40% ethyl acetate/pet ether to afford the title compound (950 mg, 1.364 mmol, 29% yield) as an off-white solid. MS (ESI) m/z 634.8 [M+H]⁺. [00524] Step 2: Synthesis of tert-butyl (3R,5R)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl)-3,5-dimethylpiperazine-1-carboxylate. To a stirred solution of tert-butyl (3R,5R)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,5- dimethylpiperazine-1-carboxylate (950 mg, 1.364 mmol) in ethanol (20 mL) and THF (20 mL) was added 20% palladium hydroxide on carbon (192 mg) under nitrogen. The reaction mixture was stirred under hydrogenation pressure at 25 °C for 8 h. The reaction mixture was filtered through celite pad and the celite pad was washed with 1:1 mixture of acetonitrile and methanol (3 x 25 mL). The filtrate was concentrated under reduced pressure to afford the crude compound. The crude was purified by flash column chromatography on silica with 5% MeOH/DCM to afford the title compound (330 mg, 0.719 mmol, 52.7 % yield) as an off-white solid. MS (ESI) m/z 456.2 [M+H]⁺. [00525] Step 3: Synthesis of 3-(6-((2R,6R)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione, TFA salt. To a stirred solution of tert-butyl (3R,5R)-4-(3- (2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3,5-dimethylpiperazine-1-carboxylate (250 mg, 0.450 mmol) in DCM (5 mL) was added TFA (0.34 mL) at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with diethyl ether and dried under reduced pressure to afford the title compound (220 mg, 0.410 mmol, 91% yield) as an off-white solid. The crude product was used for the next step without further purification. MS (ESI) m/z 356.0 [M+H]⁺. [00526] Step 4: Synthesis of 3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. To a stirred solution of 3-(6-((2R,6R)-2,6-dimethylpiperazin-1-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione, TFA salt (70 mg, 0.137 mmol) and 5-((5-chloro- 2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (40.2 mg, 0.137 mmol) in DMSO (1 mL) was added DIPEA (0.096 mL, 0.549 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 6 h. The reaction mixture was cooled to room temperature and purified by Prep- HPLC to afford the title compound (26 mg, 0.040 mmol, 29% yield) as an off-white solid. LCMS C32H34ClN9O3 requires 627.3, found 628.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 8.72 (s, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.57-7.52 (m, 2H), 7.01 (s, 1H), 6.96 (d, J = 8.40 Hz, 1H), 6.87 (d, J = 8.80 Hz, 1H), 4.31-4.27 (m, 1H), 3.92 (s, 3H), 3.93-3.90 (m, 2H), 3.81-3.77 (m, 2H), 3.69-3.65 (m, 2H), 3.57 (s, 2H), 3.12 (s, 3H), 2.67-2.64 (m, 2H), 2.33-2.30 (m, 1H).2.19-2.15 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H). Example S79. Synthesis of (R)-3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (79) [00527] Step 1: Synthesis of (R)-3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione The product of Example S78 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 10.08 min. LCMS C₃₂H₃₄ClN₉O₃ requires 627.3, found 628.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.86 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.00 (d, J = 1.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.86 (dd, J = 1.6, 8.9 Hz, 1H), 4.28 (dd, J = 5.1, 9.5 Hz, 1H), 3.91 (s, 5H), 3.82 - 3.73 (m, 2H), 3.67 (dd, J = 5.3, 12.8 Hz, 2H), 3.56 (s, 2H), 3.12 (s, 3H), 2.69 - 2.58 (m, 2H), 2.38 - 2.26 (m, 1H), 2.21 - 2.10 (m, 1H), 0.95 (d, J = 6.2 Hz, 6H). Example S80. Synthesis of (S)-3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (80) [00528] Step 1: Synthesis of (S)-3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione The product of Example S78 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 13.90 min. LCMS C32H34ClN9O3 requires 627.3, found 628.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.86 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.00 (d, J = 1.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.86 (dd, J = 1.6, 8.9 Hz, 1H), 4.28 (dd, J = 5.2, 9.4 Hz, 1H), 3.91 (s, 5H), 3.82 - 3.74 (m, 2H), 3.67 (dd, J = 5.3, 12.7 Hz, 2H), 3.56 (s, 2H), 3.12 (s, 3H), 2.70 - 2.56 (m, 2H), 2.37 - 2.29 (m, 2H), 2.22 - 2.12 (m, 1H), 0.95 (d, J = 6.1 Hz, 6H). Example S81. Synthesis of 3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (81) [00529] Step 1: Synthesis of tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylate. A mixture of 6-bromo-3-(2, 6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.9 g, 3.80 mmol), tert-butyl (2S,4R)-4-amino-2- methyl-piperidine-1-carboxylate hydrochloride (1.05 g, 4.18 mmol) and tBuXPhos-Pd-G3 (302 mg, 0.380 mmol) and NaOtBu (912 mg, 9.49 mmol) in MeTHF (38 mL) was evacuated and refilled with nitrogen for 3 cycles. The mixture was heated to 85 °C for 1.5 h and cooled to rt. DCM (30 mL) was added and the mixture was filtered on a Celite pad and rinsed with DCM (3X30 mL). The volatiles were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–60% of EtOAc in hexanes to afford the title compound (2.01 g, 84%) as a solid. MS (ESI) [M+H]⁺ 634.1.¹H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 6.9 Hz, 2H), 7.42 – 7.21 (m, 9H), 6.55 (d, J = 8.1 Hz, 1H), 6.47 – 6.36 (m, 2H), 5.66 (d, J = 8.3 Hz, 1H), 5.44 (s, 2H), 5.41 (s, 2H), 4.45 – 4.33 (m, 1H), 3.89 (s, 3H), 3.88 – 3.86 (m, 1H), 3.76 – 3.62 (m, 1H), 3.01 (t, J = 13.9 Hz, 1H), 2.05 (d, J = 11.5 Hz, 1H), 1.87 – 1.83 (m, 1H), 1.48 – 1.43 (m, 1H), 1.41 (s, 9H), 1.23 (d, J= 7.0 Hz, 3H), 1.16 – 1.05 (m, 1H). [00530] Step 2: Synthesis of 3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 4, 5, and 6 using tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylate as the starting material. LCMS C₃₂H₃₄ClN₉O₃ requires 627.3, found 628.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H), 8.63 (s, 1H), 8.01 (s, 1H), 7.55 (s, 1H), 7.54 – 7.46 (m, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.52 (dd, J = 8.8, 1.7 Hz, 1H), 6.47 (s, 1H), 5.67 (d, J = 8.3 Hz, 1H), 4.91 (br s, 1H), 4.48 (br s, 1H), 4.18 (dd, J = 8.8, 5.1 Hz, 1H), 3.83 (s, 3H), 3.81 – 3.74 (m, 1H), 3.54 (s, 2H), 3.11 (s, 3H), 3.06 (td, J = 13.1, 1.7 Hz, 1H), 2.66 – 2.56 (m, 2H), 2.31 – 2.22 (m, 1H), 2.17 – 2.08 (m, 2H), 1.92 (d, J = 11.3 Hz, 1H), 1.47 (td, J = 13.0, 5.7 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H), 1.15 (td, J = 13.9, 5.3 Hz, 1H). Example S82. Synthesis of (R)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (82) [00531] Step 1: Synthesis of (R)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The product of Example S81 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 11.30 min. LCMS C32H34ClN9O3 requires 627.3, found 628.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.81 (s, 1H), 8.62 (s, 1H), 8.01 (s, 1H), 7.61 - 7.42 (m, 2H), 7.33 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.62 - 6.40 (m, 2H), 5.67 (br d, J = 8.5 Hz, 1H), 5.09 - 4.32 (m, 2H), 4.18 (dd, J = 5.1, 8.8 Hz, 1H), 3.91 - 3.69 (m, 4H), 3.54 (s, 2H), 3.11 (s, 4H), 2.31 - 2.06 (m, 3H), 1.91 (br d, J = 10.5 Hz, 1H), 1.46 (dt, J = 5.2, 11.9 Hz, 1H), 1.26 (br d, J = 6.7 Hz, 3H), 1.20 - 1.09 (m, 1H). Example S83. Synthesis of (S)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (83) [00532] Step 2: Synthesis of (S)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The product of Example S81 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 19.77 min. LCMS C₃₂H₃₄ClN₉O₃ requires 627.3, found 628.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.81 (br s, 1H), 8.62 (br s, 1H), 8.01 (br s, 1H), 7.65 - 7.44 (m, 2H), 7.33 (br d, J = 8.8 Hz, 1H), 6.93 (br d, J = 8.1 Hz, 1H), 6.58 - 6.39 (m, 2H), 5.67 (br d, J = 8.5 Hz, 1H), 5.13 - 4.32 (m, 2H), 4.31 - 4.10 (m, 1H), 3.97 - 3.71 (m, 4H), 3.54 (br s, 2H), 3.11 (br s, 4H), 2.33 - 2.08 (m, 3H), 1.97 - 1.86 (m, 1H), 1.55 - 1.41 (m, 1H), 1.26 (br d, J = 6.6 Hz, 3H), 1.20 - 1.07 (m, 1H). Example S84. Synthesis of 3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (84) [00533] Step 1: Synthesis of tert-Butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylate. A mixture of 6-bromo-3-(2, 6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.9 g, 3.80 mmol, intermediate provided by Celgene), tert-butyl (2S,4R)-4-amino-2-methyl-piperidine-1-carboxylate hydrochloride (1.05 g, 4.18 mmol) and tBuXPhos-Pd-G3 (302 mg, 0.380 mmol) and NaOtBu (912 mg, 9.49 mmol) in MeTHF (38 mL) was evacuated and refilled with nitrogen for 3 cycles. The mixture was heated to 85 °C for 1.5 h and cooled to rt. DCM (30 mL) was added and the mixture was filtered on a Celite pad and rinsed with DCM (3 X 30 mL). The volatiles were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–60% of EtOAc in hexanes to afford the title compound (2.01 g, 84%) as a solid. MS (ESI) [M+H]⁺ 634.1.¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 6.9 Hz, 2H), 7.42 – 7.21 (m, 9H), 6.55 (d, J = 8.1 Hz, 1H), 6.47 – 6.36 (m, 2H), 5.66 (d, J = 8.3 Hz, 1H), 5.44 (s, 2H), 5.41 (s, 2H), 4.45 – 4.33 (m, 1H), 3.89 (s, 3H), 3.88 – 3.86 (m, 1H), 3.76 – 3.62 (m, 1H), 3.01 (t, J = 13.9 Hz, 1H), 2.05 (d, J = 11.5 Hz, 1H), 1.87 – 1.83 (m, 1H), 1.48 – 1.43 (m, 1H), 1.41 (s, 9H), 1.23 (d, J= 7.0 Hz, 3H), 1.16 – 1.05 (m, 1H). [00534] Step 2: Synthesis of tert-Butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylate. To a solution of tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-2-methyl- piperidine-1-carboxylate (525 mg, 0.83 mmol) in DMSO (6.5 mL) was added sequentially a formaldehyde solution (0.53 mL, 7.09 mmol, 37%) and decaborane (152 mg, 1.24 mmol). The mixture was stirred at rt for 2 h. Water (25 mL) was added, and the precipitated solid was collected by filtration. The residue was purified by column chromatography on silica gel using a gradient of 0–50% EtOAc in hexanes to afford the title compound (449 mg, 84%) as a solid. MS (ESI) [M+H]⁺ 648.7; ¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (d, J = 8.1 Hz, 1H), 7.51 – 7.44 (m, 3H), 7.42 – 7.36 (m, 4H), 7.36 – 7.24 (m, 4H), 6.77 (dd, J = 9.3, 2.0 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 5.48 – 5.41 (m, 2H), 5.41 (s, 2H), 4.51 – 4.36 (m, 1H), 4.10 (t, J = 11.9 Hz, 1H), 4.00 – 3.86 (m, 4H), 3.17 – 2.96 (m, 1H), 2.75 (s, 3H), 1.83 – 1.72 (m, 1H), 1.70 – 1.55 (m, 2H), 1.48 (d, J = 13.3 Hz, 1H), 1.41 (s, 9H), 1.25 – 1.19 (m, 3H). [00535] Step 3: Synthesis of tert-Butyl (2S,4R)-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylate. A mixture of tert- butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-methyl-amino]-2- methyl-piperidine-1-carboxylate (446 mg, 0.69 mmol) and Pearlman’s catalyst (96.7 mg, 0.340 mmol) in THF (9 mL) and EtOH (9 mL) was stirred under a hydrogen atmosphere (1 atm) at 50 °C for 6 h and cooled to rt. The mixture was filtered on a pad of Celite and rinsed with THF (3 x 30 mL). The volatiles were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 10–100% of EtOAc in hexanes to afford the title compound (303 mg, 94%) as a solid. MS (ESI) [M+H]⁺ 470.3.¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.48 (d, J = 9.0 Hz, 1H), 6.88 (dd, J = 9.2, 1.9 Hz, 1H), 6.64 (d, J = 1.7 Hz, 1H), 4.49 – 4.36 (m, 1H), 4.24 (dd, J = 8.9, 5.1 Hz, 1H), 4.18 – 4.08 (m, 1H), 3.99 – 3.91 (m, 1H), 3.86 (s, 3H), 3.15 – 2.97 (m, 1H), 2.75 (s, 3H), 2.68 – 2.55 (m, 2H), 2.33 – 2.23 (m, 1H), 2.22 – 2.12 (m, 1H), 1.84 – 1.71 (m, 1H), 1.71 – 1.55 (m, 2H), 1.49 (d, J = 12.1 Hz, 1H), 1.41 (s, 9H), 1.25 – 1.17 (m, 3H). [00536] Step 4: Synthesis of 3-[1-Methyl-6-[methyl-[(2S,4R)-2-methyl-4- piperidyl]amino]indazol-3-yl]piperidine-2,6-dione hydrochloride. To a solution of tert-butyl (2S,4R)-4-[[3-(2, 6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl- piperidine-1-carboxylate (400 mg, 0.85 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4- dioxane (2.13 mL, 8.52 mmol), and the mixture was stirred at rt for 15 h. The volatiles were evaporated under reduced pressure and the residue was triturated in Et₂O (10 mL) to afford title compound (295 mg, 85%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]⁺ 370.3.¹H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.12 (br s, 1H), 9.05 – 8.83 (m, 1H), 7.71 (br s, 1H), 7.21 (br s, 1H), 4.40 – 4.30 (m, 1H), 4.27 – 3.98 (m, 6H), 3.95 (s, 3H), 3.89 – 3.73 (m, 1H), 3.34 – 3.24 (m, 1H), 3.22 – 3.11 (m, 1H), 3.07 – 2.85 (m, 2H), 2.75 – 2.55 (m, 2H), 2.42 – 2.29 (m, 1H), 2.19 – 2.11 (m, 1H), 1.35 (d, J = 5.4 Hz, 3H). [00537] Step 5: Synthesis of 3-[6-[[(2S,4R)-1-[5-Chloro-4-[(1-methyl-2-oxo-indolin-5- yl)amino]pyrimidin-2-yl]-2-methyl-4-piperidyl]-methyl-amino]-1-methyl-indazol-3- yl]piperidine-2,6-dione. To a solution of 3-[1-methyl-6-[methyl-[(2S,4R)-2-methyl-4- piperidyl]amino]indazol-3-yl]piperidine-2,6-dione hydrochloride (64.1 mg, 0.16 mmol) in DMF (2 mL) and DMSO (0.5 mL) added was sequentially 5-[(5-chloro-2-fluoro-pyrimidin-4-yl) amino]-1-methyl-indolin-2-one (42 mg, 0.14 mmol) and DIPEA (0.2 mL, 1.15 mmol). The mixture was heated to 100 °C for 18 h and then cooled to rt. The volatiles were removed under reduced pressure and the residue was purified by using a gradient of 20–75% MeCN and 10 mM ammonium formate in water to afford the title compound (47 mg, 48%) as a solid. LCMS C33H36ClN9O3 requires 641.3, found 642.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.63 (s, 1H), 8.01 (s, 1H), 7.56 (br s, 1H), 7.52 – 7.43 (m, 2H), 6.96 – 6.85 (m, 2H), 6.65 (d, J = 1.6 Hz, 1H), 5.17 – 4.78 (m, 1H), 4.72 – 4.36 (m, 1H), 4.29 – 4.16 (m, 2H), 3.87 (s, 3H), 3.54 (s, 2H), 3.15 – 3.03 (m, 4H), 2.75 (s, 3H), 2.68 – 2.54 (m, 2H), 2.34 – 2.26 (m, 1H), 2.17 (td, J = 11.9, 6.0 Hz, 1H), 1.86 – 1.71 (m, 2H), 1.71 – 1.52 (m, 2H), 1.25 (d, J = 6.8 Hz, 3H). Example S85. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)-3- methylpiperidine-2,6-dione (85) [00538] Step 1: Synthesis of 6-bromo-1-methyl-indazole-3-carbaldehyde To a solution of 6-bromo-1H-indazole-3-carbaldehyde (5.000 g, 22.22 mmol, 1.00 eq) in Dimethyl Formamide (50 mL) was added cesium carbonate (14.480 g, 44.44 mmol, 2.00 eq) and iodomethane (3.780 g, 26.66 mmol, 1.7 mL, 1.20 eq) the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature. The mixture was filtered and the filtrate was added ethyl acetate (100 mL) and water (50 mL) and organic layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). Combined extracts were washed with sat brine (50 mL), dried over magnesium sulfate, filtered and the filtrate were concentrated to give the product. The residue was purified by silica gel column (5~10% ethyl acetate in petroleum ether). The title compound (3.500 g, 14.64 mmol, 65.9% yield) was obtained as a white solid. LCMS: 240.9[M+H]⁺ [00539] Step 2: Synthesis of (6-bromo-1-methyl-indazol-3-yl) methanol To a solution of 6-bromo-1-methyl-indazole-3-carbaldehyde (2.800 g, 11.71 mmol, 1.00 eq) in ethyl alcohol (40 mL) was added sodium borohydride (0.886 g, 23.42 mmol, 2.00 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. 6-bromo-1-methyl-indazole-3-carbaldehyde was consumed and desired mass was detected by LCMS. The mixture was filtered and the filtrate under pressure was added ethyl acetate (50 mL) and water (50 mL) and organic layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). Combined extracts were washed with sat brine (50 mL), dried over magnesium sulfate, filtered and the filtrate were concentrated to give the title compound (3.000 g, crude) as a white solid. LCMS: 242.0 [M+H]⁺ [00540] Step 3: Synthesis of 6-bromo-3-(chloromethyl)-1-methyl-1H-indazole To a solution of (6-bromo-1-methyl-indazol-3-yl) methanol (3.000 g, 12.44 mmol, 1.00 eq) in dichloromethane (50 mL) was added thionyl chloride (2.960 g, 24.89 mmol, 1.8 mL, 2.00 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. (6-bromo-1-methyl-indazol-3-yl) methanol was consumed and desired mass was detected by LCMS. The mixture was concentrated under pressure. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column (5~20% ethyl acetate in petroleum ether. The title compound (1.600 g, 6.16 mmol, 49.5% yield) was obtained as a yellow solid. LCMS: 260.9[M+1]+.¹H NMR (400MHz, chloroform-d) δ, 7.69 (d, J =8.8 Hz, 1H), 7.59 (s, 1H), 7.31 (m, J =1.2, 8.4 Hz, 1H), 4.93 (s, 2H), 4.02 (s, 3H) [00541] Step 4: Synthesis of 2-(6-bromo-1-methyl-1H-indazol-3-yl)acetonitrile To a solution of 6-bromo-3-(chloromethyl)-1-methyl-1H-indazole (1.95 g, 7.51 mmol) in DMF (25.05 ml) was added sodium cyanide (0.479 g, 9.77 mmol) the mixture was stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature, and ethyl acetate (100 mL) and water (50 mL) were added. The aqueous phase was extracted with ethyl acetate (50mL x 2). Combined extracts were washed with sat brine (50mL), dried over magnesium sulfate, filtered and concentrated to give the (1.867 g, 7.47 mmol, 99 % yield)) as a yellow solid. Used as is in the following step. LCMS: 249.8 [M+H]⁺. [00542] Step 5: Synthesis of 2-(6-bromo-1-methyl-1H-indazol-3-yl)propanenitrile To a solution of 2-(6-bromo-1-methyl-1H-indazol-3-yl)acetonitrile (1.867 g, 7.47 mmol) in Tetrahydrofuran (46.7 ml) was added potassium tert-butoxide (1.005 g, 8.96 mmol) at -20 °C, After the mixture was stirred at -20 °C for 30 min, a solution of iodomethane (0.467 ml, 7.47 mmol) was added dropwise. The mixture stirred overnight while warming to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified with 20% EtOAc in hexanes and the title compound (0.5885 g, 2.228 mmol, 29.8 % yield) was obtained as a yellow oil. LCMS: 265.1 [M+H]⁺.¹H NMR (chloroform-d, 400 MHz) δ 7.6-7.8 (m, 1H), 7.5- 7.6 (m, 1H), 7.3-7.5 (m, 1H), 4.3-4.4 (m, 1H), 4.39 (s, 1H), 3.9-4.1 (m, 5H), 1.6-1.9 (m, 3H) [00543] Step 6: Synthesis of tert-butyl 4-(6-bromo-1-methyl-1H-indazol-3-yl)-4- cyanopentanoate To a solution of 2-(6-bromo-1-methyl-1H-indazol-3-yl)propanenitrile (0.300 g, 1.136 mmol) and tert-butyl acrylate (0.333 ml, 2.272 mmol) in toluene (4.54 ml) was added potassium carbonate (0.314 g, 2.272 mmol)) and N-benzyl-N,N-diethylethanaminium chloride (0.026 g, 0.114 mmol). The mixture was stirred for 12 h at 65 °C. After cooling, the mixture was filtered and the filtrate was concentrated. The residue was further purified by prep-TLC (20% ethyl acetate in hexanes). (0.212 g, 0.540 mmol, 47.6 % yield) was obtained as a yellow oil. LCMS: 336.1 (M-^tBu+H)⁺.¹H NMR (chloroform-d, 400 MHz) δ 7.84 (s, 1H), 7.8-7.9 (m, 1H), 7.57 (s, 1H), 7.5-7.7 (m, 1H), 7.30 (s, 1H), 7.3-7.3 (m, 1H), 4.00 (s, 3H), 2.3-2.6 (m, 4H), 1.87 (s, 3H), 1.41 (s, 9H) [00544] Step 7: Synthesis of tert-butyl (3R,4R)-4-((3-(5-(tert-butoxy)-2-cyano-5- oxopentan-2-yl)-1-methyl-1H-indazol-6-yl)amino)-3-methylpiperidine-1-carboxylate A 0.5- 2 mL microwave vial was charged with tert-butyl 4-(6-bromo-1-methyl-1H-indazol-3-yl)-4- cyanopentanoate (25 mg, 0.064 mmol), bis(dibenzylideneacetone)palladium(0) (0.366 mg, 0.637 µmol), sodium tert-butoxide (12.25 mg, 0.127 mmol), 2,2'-Bis(diphenylphosphino)-1,1'- binaphthalene (1.190 mg, 1.912 µmol), tert-butyl (3R,4R)-4-amino-3-methylpiperidine-1- carboxylate (20.49 mg, 0.096 mmol) and PhMe (319 µL). This was sparged with N2 for five minutes then heated overnight at 80 °C overnight. This was filtered through a celite plug, rinsing with EtOAc and DCM to give the crude product. This was purified via normal phase chromatography with MeOH in DCM. This title compound was obstained as a yellow solid. LCMS: 470.0 [M+H]⁺.¹H NMR (chloroform-d, 400 MHz) δ 7.5-7.8 (m, 1H), 6.1-6.6 (m, 2H), 4.0-4.2 (m, 3H), 3.7-3.9 (m, 3H), 3.0-3.2 (m, 2H), 2.8-3.0 (m, 3H), 2.3-2.7 (br m, 2H), 2.0-2.2 (m, 3H), 1.6-1.8 (m, 3H), 1.47 (s, 11H), 1.2-1.3 (m, 8H), 0.9-1.1 (m, 3H), 0.8-0.9 (m, 2H), 0.8- 0.9 (m, 2H) [00545] Step 8: Synthesis of 5-amino-4-(6-(((3R,4R)-1-(tert-butoxycarbonyl)-3- methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)-4-methyl-5-oxopentanoic acid To a mixture of tert-butyl (3R,4R)-4-((3-(5-(tert-butoxy)-2-cyano-5-oxopentan-2-yl)-1-methyl-1H- indazol-6-yl)amino)-3-methylpiperidine-1-carboxylate (32.3 mg, 0.061 mmol) in DMSO (307 µL) and Ethanol (307 µL) was added sodium hydroxide (123 µL, 0.123 mmol) and hydrogen peroxide (126 µL, 1.229 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 12 hrs. tert-Butyl 4-(6-bromo-1-methyl-1H-indazol-3-yl)-4-cyanopentanoate was consumed and desired mass was detected by LCMS. The mixture was quenched with saturated ammonium chloride aqueous solution. The pH was adjusted to 5 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL x 2), Then the organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure The title compound (30 mg, 0.062 mmol, 100 % yield)) was obtained as a white solid. LCMS: 488.20 [M+H]⁺. ¹H NMR (chloroform-d, 400 MHz) δ 7.4-7.5 (m, 1H), 6.4-6.5 (m, 1H), 6.2-6.3 (m, 1H), 5.9-6.0 (m, 1H), 4.6-4.9 (m, 2H), 3.9-4.0 (m, 3H), 3.1-3.2 (m, 2H), 2.7-2.9 (m, 3H), 2.2-2.5 (m, 2H), 2.1-2.2 (m, 1H), 2.0-2.1 (m, 1H), 1.5-1.6 (m, 2H), 1.47 (s, 9H), 1.2-1.4 (m, 7H), 1.0-1.1 (m, 3H) [00546] Step 9: Synthesis of tert-butyl (3R,4R)-3-methyl-4-((1-methyl-3-(3-methyl-2,6- dioxopiperidin-3-yl)-1H-indazol-6-yl)amino)piperidine-1-carboxylate To a solution of 5- amino-4-(6-(((3R,4R)-1-(tert-butoxycarbonyl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)-4-methyl-5-oxopentanoic acid (30 mg, 0.062 mmol) in THF (615 µL) was added CDI (29.9 mg, 0.185 mmol) and DMAP (0.752 mg, 6.15 µmol) and the mixture was stirred for 12 h at 70 °C. The mixture was filtered and the filtrate was concentrated. This was purified via reverse phase (accq prep) with a gradient of 0-100% acetonitrile in water. The fractions were conctentrated to give the title compound (21.89 mg, 0.047 mmol, 76 % yield) as a white solid. LCMS: 470.0 [M+H]⁺.¹H NMR (chloroform-d, 400 MHz) δ 7.86 (s, 1H), 7.8-8.1 (m, 1H), 7.5- 7.7 (m, 1H), 6.4-6.6 (m, 1H), 6.2-6.3 (m, 1H), 4.0-4.2 (m, 2H), 3.87 (s, 3H), 3.0-3.2 (m, 1H), 2.5-3.0 (m, 5H), 2.0-2.3 (m, 2H), 2.01 (s, 3H), 1.6-1.7 (m, 2H), 1.47 (s, 9H), 1.2-1.3 (m, 2H), 1.0-1.1 (m, 3H) [00547] Step 10: Synthesis of 3-methyl-3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4- yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione A 2 dram vial charged with tert-butyl (3R,4R)-3-methyl-4-((1-methyl-3-(3-methyl-2,6-dioxopiperidin-3-yl)-1H-indazol-6- yl)amino)piperidine-1-carboxylate (21.89 mg, 0.047 mmol) in DCM (466 µL) and hydrochloric acid (4 M in dioxane) (58.3 µL, 0.233 mmol) was added dropwise. This stirred at room temperature for 1 hour. After, the solution was concentrated to give the title compound (17.22 mg, 0.047 mmol, 100 % yield) as a white solid. Used as is in the next step. LCMS: 370.5 [M+H]⁺. [00548] Step 11: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)-3- methylpiperidine-2,6-dione A solution of 3-methyl-3-(1-methyl-6-(((3R,4R)-3- methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione (17 mg, 0.046 mmol), 5-((5- chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (13.47 mg, 0.046 mmol), DIPEA (0.020 mL, 0.115 mmol) in DMSO (0.5 mL) was stirred at 80 °C for 2 hours. After, the reaction was quenched with 10% formic acid in DMSO and filtered through a syringe filter. The crude material was purified by preparative HPLC to afford the the title compound (30 mg, 0.045 mmol, 23% yield) as an off-white solid. LCMS C₃₁H₃₀ClFN₁₀O₃ requires 642.2, found 642.8 [M+H]⁺; ¹H NMR (chloroform-d, 400 MHz) δ 7.98 (s, 1H), 7.76 (s, 1H), 7.7-7.8 (m, 1H), 7.5- 7.6 (m, 2H), 7.4-7.5 (m, 1H), 6.9-7.1 (m, 1H), 6.7-6.8 (m, 1H), 6.4-6.6 (m, 1H), 6.2-6.3 (m, 1H), 4.5-4.7 (m, 2H), 3.88 (s, 3H), 3.6-3.8 (m, 1H), 3.4-3.6 (m, 2H), 3.21 (s, 3H), 3.0-3.1 (m, 1H), 2.8-2.9 (m, 1H), 2.7-2.8 (m, 2H), 2.5-2.7 (m, 1H), 2.2-2.3 (m, 1H), 2.0-2.1 (m, 1H), 1.75 (s, 3H), 1.6-1.7 (m, 1H), 1.2-1.4 (m, 1H), 1.0-1.1 (m, 3H) Example S86. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[4,3- c]pyridin-3-yl)piperidine-2,6-dione (86) [00549] Step 1. 6-chloro-3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridine To a 0 °C solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1 g, 3.58 mmol) in DMF (20 mL) was added sodium hydride (0.150 g, 3.76 mmol), The reaction mixture was stiired for 30 min. Then sodium hydride (0.150 g, 3.76 mmol) was added dropwise. The reaction mixtre was allowed to warm to rt and stirred for another 1 h. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound as a white solid (0.75 g, 2.56 mmol, 71.4 % yield). MS (ESI) m/z 293.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 1 H), 7.92 (s, 1 H), 4.06 (d, J=0.98 Hz, 3 H). [00550] Step 2.3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrazolo[4,3- c]pyridine The solution of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridine (415 mg, 1.414 mmol), (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (521 mg, 1.555 mmol) and sodium bicarbonate (261 mg, 3.11 mmol) in mixed solvent of DME (10 mL) and water (2 mL) was stirred with tetrakis(triphenylphosphine)palladium(0) (163 mg, 0.141 mmol) at 100 °C for 15 h. The reaction mixture was treated with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound as a white solid (300 mg, 0.657 mmol, 46.4% yield). MS (ESI) m/z 457.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (d, J=0.98 Hz, 1 H), 8.02 (d, J=8.19 Hz, 1 H), 7.86 (d, J=0.98 Hz, 1 H), 7.26 - 7.49 (m, 10 H), 6.63 (d, J=8.19 Hz, 1 H), 5.52 (s, 2 H), 5.44 (s, 2 H), 4.02 - 4.08 (m, 3 H). [00551] Step 3. tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)-3-methylpiperidine-1-carboxylate To a solution of 3- (2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridine (400 mg, 0.875 mmol), RuPhos Pd G3 (73.2 mg, 0.088 mmol) and tert-butyl (3R,4R)-4-amino-3- methylpiperidine-1-carboxylate (188 mg, 0.875 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (570 mg, 1.751 mmol). The reaction mixture was purged with argon for 1 min and them stirred at 100 °C for 15 h. LCMS indicated the reaction was complete. The reaction mixture was treated with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded a solid that was further purified by reveres- phased semi-preparative HPLC (10-100% acetonitrile + 0.1% TFA in water 0.1% TFA, over 30 min). Fraction containing clean product were combined and lyphilized to give the title compound as a white solid (95 mg, 0.150 mmol, 17.1% yield). MS (ESI) m/z 635.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (br s, 1 H), 7.96 (d, J=8.07 Hz, 1 H), 7.23 - 7.51 (m, 10 H), 6.59 (d, J=8.07 Hz, 1 H), 6.34 (br s, 1 H), 5.49 (s, 2 H), 5.41 (s, 2 H), 3.93 (br s, 2 H), 3.87 (s, 3 H), 3.44 - 3.56 (m, 1 H), 2.88 (br s, 1 H), 2.51 - 2.62 (m, 1 H), 1.92 (br d, J=9.66 Hz, 1 H), 1.52 - 1.63 (m, 1 H), 1.41 (s, 9 H), 1.16 - 1.29 (m, 1 H), 0.89 (d, J=6.48 Hz, 3 H). [00552] Step 4. 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H- pyrazolo[4,3-c]pyridin-3-yl)piperidine-2,6-dione A solution of tert-butyl (3R,4R)-4-((3-(2,6- bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-3- methylpiperidine-1-carboxylate (0.095 g, 0.150 mmol) in ethanol (10 mL) was stirred with palladium on carbon 10% w/w (0.016 g, 0.015 mmol) under hydrogen (1 atm) at 80 °C for 15 h. The reaction mixture was filtered through celite, the elute was concentrected and the residue was then stirred at rt with 1 mL TFA in DCM (1 mL) for 30 min. The TFA and solvent was removed under reduced pressure to give the desired product as TFA salt which was use without further purification (53 mg, 0.149 mmol, 99% yield). [00553] Step 5. 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[4,3- c]pyridin-3-yl)piperidine-2,6-dione The synthesis of the title compound was accomplished using General Procedures 6 using 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H- pyrazolo[4,3-c]pyridin-3-yl)piperidine-2,6-dione (53 mg, 0.149 mmol) and 5-((5-chloro-2- fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (43.5 mg, 0.149 mmol). The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fraction containing clean product were combined and lyophilized to give the title compound as white solid (7.7 mg, 0.012 mmol, 8.23% yield). MS (ESI) m/z 628.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1 H), 8.65 (s, 1 H), 8.49 (d, J=0.86 Hz, 1 H), 8.01 (s, 1 H), 7.57 (s, 1 H), 7.52 (dd, J=8.50, 1.90 Hz, 1 H), 6.94 (d, J=8.44 Hz, 1 H), 6.23 - 6.31 (m, 2 H), 4.42 - 4.59 (m, 2 H), 4.28 (dd, J=9.84, 5.07 Hz, 1 H), 3.78 (s, 3 H), 3.55 - 3.66 (m, 1 H), 3.53 (s, 2 H), 3.10 (s, 3 H), 2.89 - 3.04 (m, 1 H), 2.54 - 2.65 (m, 2 H), 2.35 - 2.41 (m, 1 H), 2.09 - 2.23 (m, 1 H), 1.98 (br d, J=10.39 Hz, 1 H), 1.54 - 1.72 (m, 1 H), 1.16 - 1.37 (m, 1 H), 0.93 (d, J=6.36 Hz, 3 H). Example S87. Synthesis of (R)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (87) [00554] Step 1: Synthesis of (R)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The product of Example S84 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% ACN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 13.41 min. LCMS C33H36ClN9O3 requires 641.3, found 642.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.84 (s, 1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.56 (br s, 1H), 7.52 - 7.45 (m, 2H), 6.96 - 6.88 (m, 2H), 6.65 (d, J = 1.6 Hz, 1H), 4.24 (dd, J = 8.9, 5.1 Hz, 2H), 3.87 (s, 3H), 3.54 (s, 2H), 3.15 - 3.04 (m, 4H), 2.75 (s, 3H), 2.69 - 2.58 (m, 2H), 2.37 - 2.06 (m, 2H), 1.86 - 1.52 (m, 4H), 1.25 (br d, J = 6.8 Hz, 3H). Example S88. Synthesis of (S)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (88) [00555] Step 1: Synthesis of (S)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The product of Example S84 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MECN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 23.26 min. LCMS C33H36ClN9O3 requires 641.3, found 642.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃SOCD₃, 298 K) δ (ppm) = 10.84 (s, 1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.56 (br s, 1H), 7.53 - 7.44 (m, 2H), 6.96 - 6.87 (m, 2H), 6.65 (d, J = 1.6 Hz, 1H), 4.24 (dd, J = 9.1, 5.1 Hz, 2H), 3.87 (s, 3H), 3.54 (s, 2H),3.15 - 3.04 (m, 4H), 2.75 (s, 3H), 2.68 - 2.58 (m, 2H), 2.36 - 2.09 (m, 2H), 1.88 - 1.51 (m, 4H), 1.24 (br d, J = 7.0 Hz, 3H). Example S89. Synthesis of 3-(6-((1-(5-chloro-4-((1-ethyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (89) [00556] Step 1: Synthesis of 3-(6-((1-(5-chloro-4-((1-ethyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione. The title compound was synthesized according to General Procedures 1 and 6 using 5- amino-1-ethylindolin-2-one and 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol-3- yl)piperidine-2,6-dione as starting materials. LCMS C₃₂H₃₄ClN₉O₃ requires 627.3, found 628.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ 8.64 (s, 1H), 8.44 (br, 1H), 8.01 (s, 1H), 7.54 (s, 1H), 7.54 – 7.49 (m, 1H), 7.32 (d, J= 8.7 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.52 (dd, J= 8.8, 1.7 Hz, 1H), 6.46 (s, 1H), 5.82 – 5.73 (m, 1H), 4.42 – 4.35 (m, 2H), 4.18 (dd, J= 8.8, 5.1 Hz, 1H), 3.82 (s, 3H), 3.67 (q, J= 7.2 Hz, 2H), 3.53 (s, 2H), 3.11 (t, J= 11.3 Hz, 2H), 2.64 – 2.56 (m, 2H), 2.30 – 2.21 (m, 1H), 2.18 – 2.10 (m, 1H), 2.04 – 1.94 (m, 2H), 1.36 – 1.26 (m, 2H), 1.13 (t, J= 7.1 Hz, 3H). Example S90. Synthesis of (R)-3-(6-((1-(5-chloro-4-((1-ethyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (90) [00557] Step 1: Synthesis of (R)-3-(6-((1-(5-chloro-4-((1-ethyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione. The product of Example S89 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MECN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 11.16 min. LCMS C32H34ClN9O3 requires 627.3, found 628.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ 10.81 (s, 1H), 8.63 (s, 1H), 8.01 (s, 1H), 7.60 - 7.47 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.52 (dd, J = 1.5, 8.8 Hz, 1H), 6.46 (s, 1H), 5.76 (d, J = 8.2 Hz, 1H), 4.38 (br d, J = 13.4 Hz, 2H), 4.18 (dd, J = 5.1, 8.8 Hz, 1H), 3.82 (s, 3H), 3.71 - 3.59 (m, 3H), 3.53 (s, 2H), 3.11 (br t, J = 11.0 Hz, 2H), 2.62 - 2.58 (m, 2H), 2.30 - 2.21 (m, 1H), 2.19 - 2.09 (m, 1H), 2.00 (br d, J = 9.4 Hz, 2H), 1.38 - 1.26 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H) Example S91. Synthesis of (S)-3-(6-((1-(5-chloro-4-((1-ethyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (91) [00558] Step 1: Synthesis of (S)-3-(6-((1-(5-chloro-4-((1-ethyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione. The product of Example S89 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 18.20 min. LCMS C32H34ClN9O3 requires 627.3, found 628.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ 10.81 (s, 1H), 8.63 (s, 1H), 8.02 (s, 1H), 7.58 - 7.50 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.55 - 6.49 (m, 1H), 6.46 (s, 1H), 5.76 (d, J = 8.3 Hz, 1H), 4.43 - 4.35 (m, 2H), 4.18 (dd, J = 5.2, 8.9 Hz, 1H), 3.82 (s, 3H), 3.71 - 3.59 (m, 3H), 3.53 (s, 2H), 3.11 (br t, J = 11.2 Hz, 2H), 2.62 - 2.58 (m, 2H), 2.32 - 2.20 (m, 1H), 2.19 - 2.11 (m, 1H), 2.00 (br d, J = 8.6 Hz, 2H), 1.37 - 1.27 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H). Example S92. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((6-fluoro-1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (92) [00559] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((6-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-6-fluoro-1-methylindolin-2-one and 3-(1-methyl-6- (((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. LCMS C₃₂H₃₃ClFN₉O₃ requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ ppm 10.81 (s, 1H), 8.58 (s, 1H), 8.00 (s, 1H), 7.27 - 7.33 (m, 2H), 7.02 (d, J = 10.64 Hz, 1H), 6.49 (dd, J = 8.80, 1.59 Hz, 1H), 6.40 (s, 1H), 5.67 (d, J = 9.05 Hz, 1H), 4.33 (br s, 2H), 4.16 (dd, J = 8.74, 5.32 Hz, 1H), 3.80 (s, 3H), 3.53 (s, 2H), 3.23 (br d, J = 5.38 Hz, H), 3.10 (s, 3 H), 2.91 (br t, J = 11.74 Hz, 1H), 2.54 - 2.64 (m, 3H), 2.19 - 2.30 (m, 1H), 2.09 - 2.19 (m, 1H), 1.99 (br d, J = 10.15 Hz, 1H), 1.45 - 1.56 (m, 1H), 1.10 (br d, J = 13.33 Hz, 1H), 0.90 (br d, J = 6.48 Hz, 3H). Example S93. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((6-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (93) [00560] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((6-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The product of Example S92 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 8.86 min. LCMS C₃₂H₃₃ClFN₉O₃ requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ ppm 10.80 (s, 1H), 8.57 (s, 1H), 8.00 (s, 1H), 7.36 - 7.27 (m, 2H), 7.02 (d, J = 10.6 Hz, 1H), 6.49 (dd, J = 1.5, 8.8 Hz, 1H), 6.40 (s, 1H), 5.66 (d, J = 9.1 Hz, 1H), 4.42 - 4.25 (m, 2H), 4.16 (dd, J = 5.1, 8.8 Hz, 1H), 3.80 (s, 3H), 3.53 (s, 2H), 3.23 (dq, J = 3.9, 9.7 Hz, 1H), 3.10 (s, 3H), 2.96 - 2.87 (m, 1H), 2.64 - 2.57 (m, 3H), 2.31 - 2.19 (m, 1H), 2.18 - 2.09 (m, 1H), 1.99 (br d, J = 10.0 Hz, 1H), 1.58 - 1.43 (m, 1H), 1.17 - 1.04 (m, 1H), 0.90 (br d, J = 6.3 Hz, 3H). Example S94. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((6-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (94) [00561] Step 1: Synthesis of (s)-3-(6-(((3R,4R)-1-(5-chloro-4-((6-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The product of Example S92 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 12.57 min. LCMS C₃₂H₃₃ClFN₉O₃ requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ ppm10.80 (s, 1H), 8.57 (s, 1H), 8.00 (s, 1H), 7.35 - 7.27 (m, 2H), 7.02 (d, J = 10.6 Hz, 1H), 6.49 (dd, J = 1.7, 8.8 Hz, 1H), 6.40 (s, 1H), 5.66 (d, J = 9.1 Hz, 1H), 4.45 - 4.23 (m, 2H), 4.16 (dd, J = 5.2, 8.8 Hz, 1H), 3.80 (s, 3H), 3.53 (s, 2H), 3.27 - 3.17 (m, 1H), 3.10 (s, 3H), 2.97 - 2.86 (m, 1H), 2.61 - 2.57 (m, 3H), 2.29 - 2.19 (m, 1H), 2.18 - 2.09 (m, 1H), 1.99 (br d, J = 9.9 Hz, 1H), 1.55 - 1.47 (m, 1H), 1.17 - 1.04 (m, 1H), 0.90 (br d, J = 6.3 Hz, 3H). Example S95. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((7-fluoro-1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (95) [00562] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((7-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-7-fluoro-1-methylindolin-2-one and 3-(1-methyl-6- (((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. LCMS C₃₂H₃₃ClFN₉O₃ requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ ppm 10.81 (s, 1H), 8.79 (s, 1H), 8.06 (s, 1H), 7.61 (br d, J = 13.57 Hz, 1H), 7.43 (s, 1 H), 7.31 (d, J = 8.80 Hz, 1H), 6.41 - 6.61 (m, 2H), 5.70 (d, J = 8.93 Hz, 1H), 4.40 - 4.59 (m, 2H), 4.17 (dd, J = 8.68, 5.26 Hz, 1H), 3.81 (s, 3H), 3.61 (s, 2H), 3.26 (d, J = 2.45 Hz, H), 3.01 - 3.11 (m, 1H), 2.69 - 2.78 (m, 1H), 2.56 - 2.64 (m, 2H), 2.19 - 2.30 (m, 1H), 2.04 - 2.18 (m, 2H), 1.53 - 1.67 (m, 1H), 1.11 - 1.26 (m, 1H), 0.99 (d, J = 6.48 Hz, 3H). Example S96. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((7-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (96) [00563] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((7-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The product of Example S95 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 10.48 min. LCMS C32H33ClFN9O3 requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ ppm 10.81 (s, 1H), 8.79 (s, 1H), 8.06 (s, 1H), 7.62 (br d, J = 13.1 Hz, 1H), 7.44 (br s, 1H), 7.31 (br d, J = 8.6 Hz, 1H), 6.51 (br d, J = 8.8 Hz, 1H), 6.45 (s, 1H), 5.70 (br d, J = 8.0 Hz, 1H), 4.58 - 4.41 (m, 2H), 4.25 - 4.12 (m, 1H), 3.82 (br s, 3H), 3.62 (br s, 2H), 3.27 (br s, 3H), 3.14 - 3.02 (m, 1H), 2.83 - 2.69 (m, 1H), 2.64 - 2.59 (m, 1H), 2.33 - 2.04 (m, 3H), 1.69 - 1.55 (m, 1H), 1.31 - 1.13 (m, 1H), 0.99 (br d, J = 5.6 Hz, 3H) Example S97. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((7-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (97) [00564] Step 1: Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((7-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione The product of Example S95 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 15.07 min. LCMS C₃₂H₃₃ClFN₉O₃ requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ ppm10.81 (s, 1H), 8.79 (s, 1H), 8.07 (s, 1H), 7.62 (br d, J = 14.2 Hz, 1H), 7.44 (br s, 1H), 7.32 (br d, J = 8.7 Hz, 1H), 6.52 (br d, J = 8.9 Hz, 1H), 6.45 (s, 1H), 5.70 (br d, J = 8.7 Hz, 1H), 4.49 (br t, J = 13.4 Hz, 2H), 4.18 (dd, J = 5.3, 8.4 Hz, 1H), 3.82 (s, 3H), 3.62 (s, 2H), 3.27 (br s, 3H), 3.07 (t, J = 12.2 Hz, 1H), 2.82 - 2.69 (m, 1H), 2.66 - 2.57 (m, 2H), 2.31 - 2.08 (m, 3H), 1.66 - 1.57 (m, 1H), 1.29 - 1.13 (m, 1H), 1.00 (d, J = 6.3 Hz, 3H). Example S98. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((4-fluoro-1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (98) [00565] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((4-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-4-fluoro-1-methylindolin-2-one and 3-(1-methyl-6- (((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. LCMS C₃₂H₃₃ClFN₉O₃ requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1 H), 8.64 (s, 1 H), 8.01 (s, 1 H), 7.35 (t, J=7.95 Hz, 1 H), 7.29 (d, J=8.80 Hz, 1 H), 6.84 (d, J=8.31 Hz, 1 H), 6.49 (dd, J=8.86, 1.53 Hz, 1 H), 6.40 (s, 1 H), 5.67 (d, J=8.93 Hz, 1 H), 4.21 - 4.48 (m, 2 H), 4.12 - 4.21 (m, 1 H), 3.79 (s, 3 H), 3.53 - 3.70 (m, 2 H), 3.23 (qd, J=9.78, 3.79 Hz, 1 H), 3.13 (s, 3 H), 2.86 - 2.98 (m, 1 H), 2.52 - 2.63 (m, 3 H), 2.19 - 2.31 (m, 1 H), 2.08 - 2.19 (m, 1 H), 1.93 - 2.05 (m, 1 H), 1.43 - 1.60 (m, 1 H), 0.99 - 1.17 (m, 1 H), 0.79 - 0.96 (m, 3 H). Example S99. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((4-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (99) [00566] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((4-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The product of Example S98 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 8.56 min. LCMS C₃₂H₃₃ClFN₉O₃ requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (br s, 1H), 9.99 - 9.96 (m, 1H), 8.63 (br s, 1H), 8.00 (s, 1H), 7.39 - 7.26 (m, 2H), 6.84 (br d, J = 8.1 Hz, 1H), 6.49 (br d, J = 8.5 Hz, 1H), 6.40 (br s, 1H), 5.66 (br d, J = 8.8 Hz, 1H), 4.45 - 4.22 (m, 2H), 4.16 (br dd, J = 4.9, 8.5 Hz, 1H), 3.79 (s, 3H), 3.70 - 3.51 (m, 2H), 3.26 - 3.18 (m, 1H), 3.12 (s, 3H), 2.96 - 2.87 (m, 1H), 2.67 - 2.55 (m, 3H), 2.29 - 2.19 (m, 1H), 2.18 - 2.10 (m, 1H), 1.99 (br d, J = 10.1 Hz, 1H), 1.54 - 1.43 (m, 1H), 1.15 - 1.04 (m, 1H), 0.89 (br s, 3H). Example S100. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((4-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (100) [00567] Step 1: Synthesis of(S)-3-(6-(((3R,4R)-1-(5-chloro-4-((4-fluoro-1-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The product of Example S98 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 12.25 min. LCMS C32H33ClFN9O3 requires 645.2, found 646.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.63 (br s, 1H), 8.00 (s, 1H), 7.46 - 7.20 (m, 2H), 6.84 (br d, J = 8.2 Hz, 1H), 6.49 (br d, J = 8.8 Hz, 1H), 6.40 (br s, 1H), 5.66 (br d, J = 8.7 Hz, 1H), 4.42 - 4.21 (m, 2H), 4.16 (br dd, J = 5.0, 8.3 Hz, 1H), 3.79 (s, 3H), 3.72 - 3.52 (m, 2H), 3.27 - 3.19 (m, 1H), 3.12 (s, 3H), 2.97 - 2.87 (m, 1H), 2.59 (br d, J = 4.5 Hz, 3H), 2.29 - 2.19 (m, 1H), 2.18 - 2.07 (m, 1H), 1.99 (br d, J = 10.8 Hz, 1H), 1.57 - 1.42 (m, 1H), 1.18 - 1.02 (m, 1H), 0.89 (br s, 3H). Example S101. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-morpholinoethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (101) [00568] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-morpholinoethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-1-(2-morpholinoethyl)indolin-2-one and 3-(1-methyl-6- (((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. LCMS C₃₇H₄₃ClN₁₀O₄ requires 726.3, found 727.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.70 (s, 1H), 8.04 (s, 1H), 7.64-7.53 (m, 2H), 7.31 (d, J = 8.80 Hz, 1H), 7.13-7.00 (m, 1H), 6.50 (d, J = 8.80 Hz, 1H), 6.45 (s, 1H), 5.70 (d, J = 8.40 Hz, 1H), 4.52- 4.45 (m, 2H), 4.19-4.16 (m, 1H), 4.08-3.90 (m, 2H), 3.81 (s, 3H), 3.65-3.45 (m, 6H), 3.40-3.35 (m, 1H), 3.19-3.11 (s, 1H), 3.05-2.95 (m, 1H), 2.71-2.60 (m, 1H), 2.59-2.54 (m, 2H), 2.46-2.42 (m, 1H), 2.31-2.22 (m, 1H), 2.19-2.08 (m, 2H), 1.62-1.55 (m, 1H), 1.21-1.15 (m, 1H), 0.98 (d, J = 6.0 Hz, 3H). Example S102. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-morpholinoethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (102) [00569] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-morpholinoethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The product of Example S101 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak. LCMS C37H43ClN10O4 requires 726.3, found 727.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.64 (s, 1H), 8.02 (s, 1H), 7.56 (br s, 1H), 7.50 (br d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.50 (dd, J = 1.5, 8.9 Hz, 1H), 6.43 (s, 1H), 5.68 (d, J = 8.9 Hz, 1H), 4.51 - 4.41 (m, 2H), 4.17 (dd, J = 5.2, 8.6 Hz, 1H), 3.81 (s, 3H), 3.76 (br t, J = 6.5 Hz, 2H), 3.56 - 3.48 (m, 5H), 3.02 (br t, J = 12.3 Hz, 1H), 2.73 - 2.57 (m, 4H), 2.42 (br s, 3H), 2.30 - 2.01 (m, 4H), 1.64 - 1.51 (m, 1H), 1.23 - 1.11 (m, 1H), 0.96 (br d, J = 6.4 Hz, 3H). Example S103. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-morpholinoethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (103) [00570] Step 1: Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-morpholinoethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The product of Example S101 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak. LCMS C37H43ClN10O4 requires 726.3, found 727.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.65 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 7.50 (br d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.99 (br d, J = 8.5 Hz, 1H), 6.50 (dd, J = 1.5, 8.8 Hz, 1H), 6.43 (s, 1H), 5.68 (d, J = 9.1 Hz, 1H), 4.46 (br s, 2H), 4.17 (dd, J = 5.2, 8.8 Hz, 1H), 3.81 (s, 3H), 3.76 (br t, J = 6.2 Hz, 2H), 3.52 (br d, J = 16.2 Hz, 6H), 3.02 (br t, J = 12.6 Hz, 1H), 2.74 - 2.56 (m, 4H), 2.42 (br s, 3H), 2.31 - 2.03 (m, 3H), 1.63 - 1.53 (m, 1H), 1.22 - 1.12 (m, 1H), 0.97 (br d, J = 6.3 Hz, 3H). Example S104. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-(methylamino)ethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (104) [00571] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-(methylamino)ethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 1, 6, and 5 using tert-butyl (2-(5-amino-2-oxoindolin-1-yl)ethyl)(methyl)carbamate and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6- dione as starting materials. LCMS C₃₄H₃₉ClN₁₀O₃ requires 670.3, found 672.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 8.67 (s, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.51 (d, J = 8.40, 1.60 Hz, 1H), 7.32 (d, J = 8.40 Hz, 1H), 7.01 (d, J = 8.40 Hz, 1H), 6.50 (dd, J = 8.80, 1.60 Hz, 1H), 6.45 (s, 1H), 5.69-5.58 (m, 1H), 4.55-4.47 (m, 2H), 4.19-4.16 (m, 1H), 3.81 (s, 3H), 3.80-3.75 (m, 2H), 3.53 (s, 2H), 3.05-2.96 (s, 1H), 2.85-2.75 (m, 2H), 2.72-2.65 (m, 1H), 2.62-2.55 (m, 2H), 2.36 (s, 3H), 2.28-2.20 (m, 2H), 2.19-2.05 (m, 1H), 1.62-1.53 (m, 1H), 1.25- 1.18 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). [00572] Example S105. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2- (methylamino)ethyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4- yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (105) [00573] The product of Example S104 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 18.13 min. LCMS C34H39ClN10O3 requires 670.3, found 672.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO- d6): δ 10.80 (s, 1H), 8.64 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 7.50 (dd, J = 1.8, 8.5 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.50 (dd, J = 1.7, 8.8 Hz, 1H), 6.44 (s, 1H), 5.68 (d, J = 9.1 Hz, 1H), 4.53 - 4.41 (m, 2H), 4.17 (dd, J = 5.1, 8.8 Hz, 1H), 3.81 (s, 3H), 3.71 (t, J = 6.4 Hz, 2H), 3.52 (s, 2H), 3.07 - 2.96 (m, 1H), 2.73 - 2.57 (m, 7H), 2.32 - 2.20 (m, 5H), 2.19 - 2.02 (m, 3H), 1.64 - 1.54 (m, 1H), 1.20 - 1.11 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). Example S106. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-(methylamino)ethyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (106) [00574] The product of Example S104 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 40.27 min. LCMS C34H39ClN10O3 requires 670.3, found 672.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.56 (s, 1H), 7.50 (dd, J = 1.7, 8.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.50 (dd, J = 1.5, 8.8 Hz, 1H), 6.44 (s, 1H), 5.68 (d, J = 9.1 Hz, 1H), 4.53 - 4.39 (m, 2H), 4.17 (dd, J = 5.1, 8.7 Hz, 1H), 3.81 (s, 3H), 3.70 (t, J = 6.5 Hz, 2H), 3.52 (s, 2H), 3.02 (br t, J = 11.7 Hz, 1H), 2.74 - 2.58 (m, 7H), 2.31 - 2.20 (m, 4H), 2.19 - 2.03 (m, 2H), 1.58 (br dd, J = 4.5, 5.8 Hz, 1H), 1.22 - 1.12 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). Example S107. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-fluoro-3-methylbutyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (107) [00575] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-fluoro-3-methylbutyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-1-(3-fluoro-3-methylbutyl)indolin-2-one and 3-(1-methyl-6- (((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. LCMS C36H41ClFN9O3 requires 701.3, found 702.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.62 (s, 1H), 8.15 (s, 1H), 7.51 (s, 1H), 7.46 (d, J = 8.40 Hz, 1H), 7.33 (d, J = 8.80 Hz, 1H), 6.97 (d, J = 8.40 Hz, 1H), 6.53 (d, J = 8.80 Hz, 1H), 6.47 (s, 1H), 4.27-4.25 (m, 2H), 4.19-4.16 (m, 1H), 3.81 (s, 3H), 3.54 (s, 2H), 3.36-3.31 (m, 1H), 3.18-3.12 (m, 1H), 2.88-2.82 (m, 1H), 2.63-2.58 (m, 2H), 2.26-2.23 (m, 1H), 2.16-2.09 (m, 2H), 1.92-1.83 (m, 2H), 1.65-1.63 (m, 1H), 1.36 (d, J = 21.60 Hz, 6H), 1.24-1.22 (m, 1H), 0.96 (d, J = 6.40 Hz, 3H). Example S108. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-fluoro-3-methylbutyl)- 2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (108) [00576] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-fluoro-3- methylbutyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione. The product of Example S107 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 7.46 min. LCMS C36H41ClFN9O3 requires 701.3, found 702.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.70 (br s, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.51 (dd, J = 1.8, 8.5 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.50 (dd, J = 1.4, 8.8 Hz, 1H), 6.43 (s, 1H), 5.68 (br d, J = 8.9 Hz, 1H), 4.52 - 4.39 (m, 2H), 4.17 (dd, J = 5.1, 8.7 Hz, 1H), 3.81 (s, 3H), 3.78 - 3.72 (m, 2H), 3.54 (s, 2H), 3.02 (br t, J = 12.2 Hz, 1H), 2.73 - 2.56 (m, 4H), 2.31 - 2.04 (m, 4H), 1.96 - 1.84 (m, 2H), 1.64 - 1.52 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 1.26 - 1.10 (m, 2H), 0.96 (d, J = 6.4 Hz, 3H). Example S109. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-fluoro-3-methylbutyl)- 2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (109) [00577] Step 1: Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-fluoro-3- methylbutyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione. The product of Example S107 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 10.56 min. LCMS C36H41ClFN9O3 requires 701.3, found 702.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.68 (br s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.51 (dd, J = 1.8, 8.5 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.51 (dd, J = 1.4, 8.8 Hz, 1H), 6.43 (s, 1H), 5.68 (br d, J = 9.1 Hz, 1H), 4.53 - 4.39 (m, 2H), 4.17 (dd, J = 5.2, 8.9 Hz, 1H), 3.81 (s, 3H), 3.77 - 3.70 (m, 2H), 3.53 (s, 2H), 3.02 (br t, J = 12.3 Hz, 1H), 2.72 - 2.58 (m, 4H), 2.30 - 2.03 (m, 4H), 1.94 - 1.83 (m, 2H), 1.63 - 1.53 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 1.28 - 1.12 (m, 2H), 0.96 (d, J = 6.4 Hz, 3H). Example S110. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2,2-difluoropropyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (110) [00578] The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-1-(2,2-difluoropropyl)indolin-2-one and 3-(1-methyl-6-(((3R,4R)-3- methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. LCMS C₃₄H₃₆ClF₂N₉O₃ requires 691.3, found 692.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.52 (dd, J = 2.00 Hz and 8.4 Hz, 1H), 7.31 (d, J = 8.80 Hz, 1H), 7.03 (d, J = 8.80 Hz, 1H), 6.51 (dd, J = 1.60 Hz and 8.8 Hz, 1H), 6.45 (s, 1H), 5.70 (d, J = 8.80 Hz, 1H), 4.54-4.46 (m, 2H), 4.19-4.10 (m, 3H), 3.82 (s, 3H), 3.65 (s, 2H), 3.02 (t, J = 12.80 Hz, 1H), 2.69-2.65 (m, 2H), 2.29-2.22 (m, 1H), 2.18-2.12 (m, 1H), 2.09-2.06 (m, 1H), 1.67 (t, J = 19.2 Hz, 3H), 1.62-1.58 (m, 2H), 1.18-1.13 (m, 1H), 0.97 (d, J = 6.80 Hz, 4H). Example S111. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2,2-difluoropropyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (111) [00579] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2,2-difluoropropyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The product of Example S110 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the first eluting peak, Rt = 6.18 min. LCMS C34H36ClF2N9O3 requires 691.3, found 692.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (s, 1H), 8.68 (s, 1H), 8.02 (s, 1H), 7.58 (s, 1H), 7.51 (dd, J = 1.9, 8.6 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.50 (dd, J = 1.6, 8.8 Hz, 1H), 6.44 (s, 1H), 5.68 (br d, J = 9.1 Hz, 1H), 4.54 - 4.39 (m, 2H), 4.26 - 4.06 (m, 3H), 3.81 (s, 3H), 3.64 (s, 2H), 3.02 (br t, J = 11.8 Hz, 1H), 2.74 - 2.56 (m, 4H), 2.38 - 2.34 (m, 1H), 2.30 - 2.03 (m, 4H), 1.66 (t, J = 19.1 Hz, 3H), 1.60 - 1.53 (m, 1H), 1.22 - 1.13 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H). Example S112. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2,2-difluoropropyl)-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (112) [00580] The product of Example S110 was then separated using preparatory HPLC with a Regis Whelk-O1 SS, 21x250mm, 5u column, 1 mL/min flow rate in 100% MeCN (no additives) isocratic elution at 22 °C. The title compound was isolated as the second eluting peak, Rt = 8.48 min. LCMS C34H36ClF2N9O3 requires 691.3, found 692.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO- d6): δ 10.80 (s, 1H), 8.66 (s, 1H), 8.02 (s, 1H), 7.58 (s, 1H), 7.54 - 7.48 (m, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.53 - 6.48 (m, 1H), 6.44 (s, 1H), 5.68 (d, J = 9.1 Hz, 1H), 4.52 - 4.40 (m, 2H), 4.20 - 4.08 (m, 3H), 3.81 (s, 3H), 3.64 (s, 2H), 3.07 - 2.96 (m, 1H), 2.73 - 2.58 (m, 6H), 2.38 - 2.34 (m, 1H), 2.31 - 2.03 (m, 3H), 1.66 (t, J = 19.1 Hz, 3H), 1.60 - 1.53 (m, 1H), 1.23 - 1.12 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H). [00581] Examples in Table 3 below have been made according to the general procedures outlined in the table beginning with their respective commercial starting materials and intermediates found within this document.

Example S124. Synthesis of 3-[6-[1-[5-chloro-4-[(2-oxoindolin-5-yl)amino]pyrimidin-2-yl]- 4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (124) [00582] Step 1: Synthesis of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]piperidine-1-carboxylate. To a reaction vial was added 3-[6-benzyloxy-2- (phenoxymethyl)-3-pyridyl]-6-bromo-1-methyl-indazole (300 mg, 0.60 mmol), tert-butyl 4- bromopiperidine-1-carboxylate (250 mg, 0.95 mmol), [4,4′-Bis(1,1-dimethylethyl)-2,2′- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (6.73 mg, 0.0100 mmol), tris(trimethylsilyl)silane (149.08 mg, 0.6000 mmol), and lithium hydroxide (28.72 mg, 1.2 mmol) to a vial equipped with a stir bar. Seal and purge with nitrogen before adding 1,4-dioxane (2 mL). A precatalyst solution was separately made. Add nickel(II) chloride ethylene glycol dimethyl ether complex (6.59 mg, 0.030 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridyl (8.05 mg, 0.030 mmol) to a vial equipped with a stir bar. Seal and purge with nitrogen. Add 1,4-dioxane (2 mL) and stir/sonicate for 10 min. Add 0.2 mL of the pre-catalyst solution to the intital reaction vial. After which, purge with argon and stir for 10 minutes. Seal with parafilm and irradiate with 34 W Blue LED light overnight at room temperature. LCMS indicated the reaction was complete. The mixture was concentrated and purified with silica gel chromatography using 0-40% EA/hexanes to give the title compound (208 mg, 0.336 mmol, 56.0% yield) as a pale yellow oil. [00583] Step 2: Synthesis of 3-[6-[1-[5-chloro-4-[(2-oxoindolin-5-yl)amino]pyrimidin-2- yl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione The title compound was synthesized according to General Procedures 4, 5, and 6 using tert-butyl 4-[3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate as the starting material. LCMS C30H29ClN8O3 requires 584.2, found 585.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ 10.84 (s, 1H), 10.30 (s, 1H), 8.59 (s, 1H), 8.01 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 4.72 – 4.62 (m, 2H), 4.32 (dd, J = 9.7, 5.1 Hz, 1H), 3.95 (s, 3H), 3.46 (s, 2H), 2.97 – 2.87 (m, 3H), 2.69 – 2.55 (m, 2H), 2.38 – 2.29 (m, 1H), 2.21 – 2.12 (m, 1H), 1.86 (d, J = 11.9 Hz, 2H), 1.70 – 1.58 (m, 2H). Example S125. Synthesis of 3-(6-(1-(5-Chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (125) [00584] Step 1: Synthesis of 3-(6-(1-(5-Chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized according to General Procedures 4, 5, and 6 using tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate as the starting material. LCMS C30H29ClN8O3 requires 598.2, found 599.3 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz) δ 10.8-10.9 (m, 1H), 8.6-8.7 (m, 1H), 8.03 (s, 1H), 7.6-7.6 (m, 1H), 7.5-7.6 (m, 2H), 7.4- 7.5 (m, 1H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 1H), 4.6-4.7 (m, 2H), 4.3-4.4 (m, 1H), 3.9-4.0 (m, 3H), 3.5-3.6 (m, 2H), 3.1-3.1 (m, 3H), 2.9-3.0 (m, 3H), 2.5-2.7 (m, 2H), 2.3-2.4 (m, 1H), 2.1-2.2 (m, 1H), 1.8-1.9 (m, 2H), 1.6-1.7 (m, 2H). Example S126. Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)amino)-2-oxopiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine- 2,6-dione (126) [00585] Step 1: Synthesis of tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]-2-oxo-4-piperidyl]carbamate. A mixture of tert-butyl N-(2-oxo-4- piperidyl)carbamate (1.3 g, 6.06 mmol), 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazole (3.33 g, 6.66 mmol), Pd2(dba)3 (277 mg, 0.30 mmol), Me4tBuXphos (291 mg, 0.61 mmol) and K3PO4 (3.21 g, 15.2 mmol) in tBuOH (60 mL) was heated to 100 °C for 24 h and then cooled to rt. The mixture was filtered on Celite and washed with DCM (15 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–10% MeOH in DCM. The fractions were concentrated and the residue was further purified by reverse phase chromatography (C18) using a gradient of 0–100% MeCN and 10 mM ammonium formate in water to afford title compound (2.64 g, 69%) as a solid. MS (ESI) [M+H]⁺ 634.7.¹H NMR (500 MHz, DMSO-d6) δ 7.91 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 1.1 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.44 – 7.25 (m, 8H), 7.18 (s, 1H), 6.97 (dd, J = 8.7, 1.7 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.48 (s, 2H), 5.43 (s, 2H), 4.05 (s, 3H), 3.91 (s, 1H), 3.77 – 3.57 (m, 2H), 2.78 – 2.60 (m, 1H), 2.40 – 2.30 (m, 1H), 2.09 (d, J = 6.0 Hz, 1H), 1.93 – 1.75 (m, 1H), 1.43 (s, 9H). [00586] Step 2: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)amino)-2-oxopiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine- 2,6-dione. The synthesis of the title compound was accomplished using General Procedures 4, 5, and 6 using tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-2-oxo-4- piperidyl]carbamate as the starting material. The crude residue was purified by reverse phase chromatography (C18) using a gradient of 0–100% MeCN and 10 mM ammonium formate in water. The fractions were concentrated under reduced pressure and the residue was further purified by preparative HPLC (BEH column, C18) using a gradient of 25–35% MeCN and 10 mM ammonium formate in water to afford title compound (8.6 mg, 5%) as a solid. LCMS C₃₁H₃₀ClN₉O₄ requires 627.2, found 628.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 10.91 (s, 1H), 8.60 (s, 1H), 7.98 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.55 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.20 (s, 1H), 7.03 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.38 (dd, J = 10.1, 5.0 Hz, 1H), 3.98 (s, 3H), 3.69 (s, 2H), 3.57 (s, 2H), 3.12 (s, 3H), 2.78 – 2.58 (m, 4H), 2.47 – 2.33 (m, 2H), 2.23 – 2.15 (m, 2H), 1.96 – 1.88 (m, 1H). Example S127. Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-2-oxopiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (127) [00587] Step 1: Synthesis of 4-[Benzyl(methyl)amino]piperidin-2-one To a solution of piperidine-2,4-dione (1.0 g, 8.8 mmol) in DCE (25 mL) were added sequentially N-methyl-1- phenyl-methanamine (1.1 mL, 8.8 mmol) and AcOH (0.5 mL, 8.8 mmol), and the mixture was stirred for 2 h at rt. At this time, NaBH3CN (833 mg, 13.3 mmol) was added to the reaction mixture and stirring was continued for 36 h. A saturated aqueous solution of NaHCO₃ (100 mL) and DCM (100 mL) were added, and the layers were separated. The organic layer was washed with water (100 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (790 mg, 41%) as a semi-solid. MS (ESI) [M+H]⁺ 219.2.¹H NMR (400 MHz, DMSO-d6) δ 7.45 (br s, 1H), 7.35 – 7.28 (m, 4H), 7.27 – 7.19 (m, 1H), 3.54 (q, J = 13.5 Hz, 2H), 3.22 – 3.16 (m, 1H), 3.08 – 2.99 (m, 1H), 2.89 – 2.80 (m, 1H), 2.31 – 2.20 (m, 2H), 2.09 (s, 3H), 1.97 – 1.87 (m, 1H), 1.68 – 1.54 (m, 1H). [00588] Step 2: Synthesis of 4-[Benzyl(methyl)amino]-1-[3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-indazol-6-yl]piperidin-2-one To a solution of 4-[benzyl(methyl)amino]piperidin-2- one (300 mg, 1.24 mmol), 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (681 mg, 1.36 mmol, intermediate provided by Celgene), Pd2(dba)3 (226 mg, 0.25 mmol) and XantPhos (358 mg, 0.62 mmol) in 1,4-dioxane (6.2 mL) was added Cs2CO3 (564 mg, 1.73 mmol) at rt. The reaction mixture was heated to 100 °C for 18 h and then cooled to rt. The mixture was diluted with DCM (100 mL), filtered over a pad of celite, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0– 20% MeOH in DCM to afford title compound (300 mg, 38%) as a solid. MS (ESI) [M+H]⁺ 639.3. [00589] Step 3: Synthesis of 3-[6-[4-[[5-Chloro-4-[(1-methyl-2-oxo-indolin-5- yl)amino]pyrimidin-2-yl]-methyl-amino]-2-oxo-1-piperidyl]-1-methyl-indazol-3- yl]piperidine-2,6-dione The synthesis of the title compound was accomplished using General Procedures 4 and 6 using 4-[Benzyl(methyl)amino]-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]piperidin-2-one as the starting material. The final reaction was heated to 100 °C for 18 h. before purification by preparative HPLC (BEH column, C18) using a gradient of 26–36% MeCN and 10 mM ammonium formate in water to afford title compound (13.6 mg, 12%) as a solid. LCMS C32H32ClN9O4 requires 641.1, found 642.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.90 (br s, 1H), 8.68 (s, 1H), 8.04 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.56 – 7.47 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 4.38 (dd, J = 10.1, 5.0 Hz, 1H), 3.98 (s, 3H), 3.83 – 3.72 (m, 1H), 3.71 – 3.59 (m, 1H), 3.54 (d, J = 4.9 Hz, 2H), 3.29 (s, 1H), 3.09 (s, 3H), 3.00 (s, 3H), 2.76 – 2.60 (m, 4H), 2.44 – 2.31 (m, 1H), 2.28 – 2.14 (m, 2H), 2.06 – 1.96 (m, 1H). Example S128. Synthesis of 3-(6-((S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-2-oxopiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (128) [00590] Step 1: Synthesis of 3-(6-((S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-2-oxopiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The title compound was synthesized using the product of Example S128 using chiral SFC and using the first eluting isomer in General Procedures 4, 5, and 6. Rt 6.63 min, SFC column: Lux C4; mobile phase: 55:45 (A: B), A = liquid CO2, B = 0.5% isopropyl amine in methanol; Flow Rate: 5.0 mL/min; MS (ESI) 642.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.71 (s, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.40 Hz, 1H), 7.64 (s, 1H), 7.54-7.52 (m, 2H), 6.99-6.94 (m, 2H), 4.94 (brs, 1H), 4.41-4.37 (m, 1H), 3.99 (s, 3H), 3.82- 3.75 (m, 1H), 3.67-3.62 (m, 1H), 3.55-3.54 (m, 2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.68-2.59 (m, 2H), 2.46-2.38 (m, 1H), 2.25-2.15 (m, 2H), 2.05-1.95 (m, 1H). Example S129. Synthesis of 3-(6-((R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-2-oxopiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (129) [00591] Step 1: Synthesis of 3-(6-((R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-2-oxopiperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The title compound was synthesized using the product of Example S128 using chiral SFC and using the second eluting isomer in General Procedures 4, 5, and 6. Rt 7.46 min, SFC column: Lux C4; mobile phase: 55:45 (A: B), A = liquid CO₂, B = 0.5% isopropyl amine in methanol; Flow Rate: 5.0 mL/min. MS (ESI) 642.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 8.70 (s, 1H), 8.05 (s, 1H), 7.70 (d, J = 8.40 Hz, 1H), 7.64 (s, 1H), 7.53-7.51 (m, 2H), 6.99-6.94 (m, 2H), 4.95 (brs, 1H), 4.41-4.37 (m, 1H), 3.99 (s, 3H), 3.81- 3.76 (m, 1H), 3.67-3.64 (m, 1H), 3.55-3.54 (m, 2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.72-2.64 (m, 2H), 2.46-2.39 (m, 1H), 2.23-2.18 (m, 2H), 2.03-1.98 (s, 1H). Example S130. Synthesis of 3-(6-((3R,4S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-3-methyl-2-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (130) [00592] Step 1: Synthesis of (S)-4-(benzyl(methyl)amino)-1-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-2-one (Isomer 2) A stirred solution of 4-[Benzyl(methyl)amino]piperidin-2-one (3.66 g, 16.8 mmol) and 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (7.0 g, 14.0 mmol) in 1,4-dioxane (150 mL) was degassed with nitrogen for 5 min. Then Pd₂(dba)₃ (1.28 g, 1.40 mmol), Xantphos (1.619 g, 2.80 mmol) and Cs2CO3 (6.84 g, 20.98 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was treated with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel with 10% methanol/dichloromethane to afford racemate (3.50 g) as an off-white solid. The racemate was separated by chiral preparative HPLC to afford isomer 1 (Rt 8.73 min) and the title compound as the second eluting isomer (Isomer-2, 1.55 g, 2.408 mmol, 17% yield) as off-white solids. Chiral-HPLC method: Column: Chiralpak IJ (250 x 4.6 mm), 5.0 µm; 0.2% ammonia in methanol/Isopropanol; Flow Rate: 3.0 mL/min: Rt 9.87 min. MS (ESI) [M+H]⁺ 638.3. [00593] Step 2: Synthesis of (3R,4S)-4-(benzyl(methyl)amino)-1-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3-methylpiperidin-2-one. To a stirred solution of compound (S)-4-(benzyl(methyl)amino)-1-(3-(2,6-bis(benzyloxy)pyridin-3- yl)-1-methyl-1H-indazol-6-yl)piperidin-2-one (250 mg, 0.392 mmol) in THF (8.0 mL) was added 1.0 M LHMDS in Hexane (0.784 mL, 0.784 mmol) dropwise at -78 °C under nitrogen and stirred for 45 min. Then methyl iodide (0.049 mL, 0.784 mmol) was added and slowly warmed to 25 °C, stirred for 1 h. The reaction mixture was treated with saturated NH₄Cl solution (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude product was purified by flash column chromatography on silica gel with 50-70% ethyl acetate/pet ether to afford the title compound (180 mg, 0.271 mmol, 69% yield) as an off-white solid. MS (ESI) [M+H]⁺ 652.3; ¹H NMR (400 MHz, DMSO-d6): δ 7.91 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.49-7.46 (m, 2H), 7.41-7.24 (m, 12 H), 6.93 (dd, J = 1.6 Hz and 8.8 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.47 (s, 2H), 5.42 (s, 2H), 4.04 (s, 3H), 3.78 (d, J = 13.6 Hz, 1H), 3.68-3.66 (m, 2H), 3.52 (d, J = 13.6 Hz, 1H), 2.80-2.76 (m, 1H), 2.68-2.63 (m, 1H), 2.19 (s, 3H), 2.18-2.13 (m, 1H), 1.96-1.91 (m, 1H), 1.28 (d, J = 6.8 Hz, 1H). [00594] Step 3: Synthesis of 3-(1-methyl-6-((3R,4S)-3-methyl-4-(methylamino)-2- oxopiperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. To a stirred solution of (3R,4S)-4- (benzyl(methyl)amino)-1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3- methylpiperidin-2-one (120 mg, 0.180 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was added TFA (0.014 L, 0.180 mmol) and 20% palladium hydroxide on carbon (60 mg) under nitrogen. The reaction mixture was stirred under hydrogenation pressure (5 atm) at 50 °C for 16 h. The reaction mixture was filtered through celite pad and the celite pad was washed with 1:1 mixture of THF and ethanol (30 mL). The filtrate was concentrated under reduced pressure to afford the title compound (70 mg, 0.172 mmol, 96%yield) as crude. The crude product was used for the next step without further purification. MS (ESI) 384.2 [M+H]⁺. [00595] Step 4: Synthesis of 3-(6-((3R,4S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl) amino)-3-methyl-2-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. To a stirred solution of compound 3-(1-methyl-6-((3R,4S)- 3-methyl-4-(methylamino)-2-oxopiperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (50 mg, 0.121 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (36.2 mg, 0.121 mmol) in DMSO (1.0 mL) was added DIPEA (0.064 mL, 0.364 mmol) at 25 ^oC. The reaction mixture was heated to 80 °C and stirred for 5 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (8 mg, 0.012 mmol, 10%yield) as an off-white solid. LCMS C33H34ClN9O4 requires 655.2, found 656.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.93 (brs, 1H), 8.07 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.63-7.48 (m, 3H), 6.99-6.96 (m, 2H), 4.81 (brs, 1H), 4.41-4.37 (m, 1H), 3.99 (s, 3H), 3.69-3.62 (m, 2H), 3.54 (s, 2H), 3.11 (s, 3H), 2.97 (s, 3H), 2.21 - 2.18 (m, 2H), 1.99- 1.90 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H). Example S131. Synthesis of 3-(6-((3S,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-3-methyl-2-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (131) [00596] Step 1: Synthesis of 3-(6-((3S,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-3-methyl-2-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione. The synthesis of the title compound was accomplished through the procedures outlined for Example S131 and using the first eluting isomer from Example S131, Step 1. LCMS C₃₃H₃₄ClN₉O₄ requires 655.2, found 656.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 10.62 - 10.53 (m, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.52 (br d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 6.97 (dd, J = 1.4, 8.6 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.87 - 4.77 (m, 1H), 4.36 (dd, J = 5.3, 9.3 Hz, 1H), 3.99 (s, 3H), 3.76 - 3.66 (m, 2H), 3.53 (s, 2H), 3.16 - 3.12 (m, 3H), 3.01 - 3.00 (m, 3H), 2.71 - 2.66 (m, 2H), 2.44 - 2.33 (m, 2H), 2.29 - 2.19 (m, 2H), 2.05 - 1.96 (m, 1H), 1.07 (d, J = 7.0 Hz, 3H). Example S132. Synthesis of 2-((3R,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl)amino)-3-methylpiperidin-1-yl)-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidine-5-carbonitrile (132) [00597] Step 1: Synthesis of 1-(1-methyl-6-nitro-indazol-3-yl) hexahydropyrimidine-2,4- dione. A mixture of 3-bromo-1-methyl-6-nitro-indazole (3.00 g, 11.7 mmol), hexahydropyrimidine-2,4-dione (1.60 g, 14.1 mmol), potassium phosphate tribasic (6.22 g, 29.3 mmol), tetramethyl tBuXPhos (281 mg, 0.58 mmol) and Pd₂(dba)₃ (268 mg, 0.29 mmol) in tert- butanol (125 mL) was degassed with nitrogen 3 times. The reaction mixture was heated to 100 °C for 24 h with stirring and then cooled to rt. Additional Pd2(dba)3 (268 mg, 0.29 mmol) and tetramethyl tBuXPhos (281 mg, 0.58 mmol) were added. The reaction mixture was heated to 100 °C for an additional 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure. Water (200 mL) was added and the resulting precipitate was collected by filtration on a Buchner funnel. The solid was then washed with water (3 x 50 mL) and dried under vacuum. The material was triturated in diethyl ether (100 mL) and collected by filtration to afford title compound (2.64 g, 78%) as a solid, which was used in next step without further purification. LCMS C12H11N5O4 requires 289.1, found 290.2 [M+H] +; ¹H NMR (500 MHz, DMSO) δ 10.67 (s, 1H), 8.70 (dd, J = 1.7, 0.7 Hz, 1H), 7.95 – 7.84 (m, 2H), 4.14 (s, 3H), 3.97 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H). [00598] Step 2: Synthesis of 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione. A mixture of 1-(1-methyl-6-nitro-indazol-3-yl)hexahydropyrimidine-2,4-dione (2.64 g, 9.13 mmol) and 10% Pd/C (0.97 g, 0.91 mmol) in methanol (250 mL) was hydrogenated under hydrogen atmosphere (1 atm) at rt for 6.5 h. The mixture was filtered through celite and washed with MeOH (5 x 45 mL). The filtrate was concentrated under reduced pressure, the material was triturated in diethyl ether and collected by filtration to afford title (1.92 g, 81%) as a solid. [00599] Step 3: Synthesis of 1-(6-Iodo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione. To a solution of 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (2.1 g, 8.1 mmol) in acetic acid (21 mL) cooled to 0 °C was added sequentially a solution of H₂SO₄ (1.11 mL, 20.3 mmol) in water (5 mL) followed by a solution of sodium nitrite (838 mg, 12.15 mmol) in water (5 mL). The reaction mixture was stirred at 0 °C for 2 h. At this time, a solution of KI (4.0 g, 24 mmol) in water (5 mL) was added and the mixture was stirred at 0 °C for 2 h then warmed to rt. A 50% aqueous solution of NaHSO₃ (50 mL) was added to the mixture and stirred for 18 h. The resulting precipitate was collected by filtration, washed with water (3 x 10 mL) and Et2O (3 x 10 mL) then dried under vacuum to afford title compound (1.98 g, 66%) as a solid, which was used in the next step without further purification. LCMS C₁₂H₁₁IN₄O₂ requires 370.0, found 371.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.12 (d, J = 0.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 8.6, 1.3 Hz, 1H), 3.97 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H). [00600] Step 4: Synthesis of 1-[1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-3-yl]hexahydropyrimidine-2,4-dione. A mixture of 1-(6-iodo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione (500 mg, 1.35 mmol), B2pin2 (412 mg, 1.62 mmol), Pd(OAc)₂ (30 mg, 0.14 mmol) and KOAc (398 mg, 4.05 mmol) in DMF (14 mL) was heated to 80 °C for 18 h and then cooled to rt. The mixture was filtered through celite and washed with EtOAc (5 x 15 mL). Water (50 mL) was added to the filtrate and the layers were separated. The organic layer was washed with water (5 x 25 mL), brine (25 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 50-100% EtOAc in hexanes to afford title compound (335 mg, 67%) as a solid. LCMS C18H23BN4O4 requires 372.2, found 371.2 [M+H]⁺. [00601] Step 5: Synthesis of [3-(2,4-Dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6- yl]boronic acid. To a solution of 1-[1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-3-yl]hexahydropyrimidine-2,4-dione (403 mg, 1.09 mmol) in THF (5 mL) and water (5 mL) were added sequentially NaIO₄ (698 mg, 3.27 mmol) and 1M aqueous HCl (2.2 mL, 2.2 mmol). The reaction mixture was stirred at rt for 18 h. The volatiles were evaporated under reduced pressure and the resulting precipitate was collected by filtration, washed with water (3 x 2 mL), and Et₂O (3 x 1 mL), then dried under vacuum to afford the title compound (240 mg, 76%) as a solid, which was used in the next step without further purification. LCMS C12H13BN4O4requires 288.1, found 289.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.16 (s, 2H), 8.01 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H). [00602] Step 6: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidin-1- yl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate. A mixture of [3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (200 mg, 0.69 mmol), tert- butyl (3R,4R)-4-amino-3-methyl-piperidine-1-carboxylate (228 mg, 1.04 mmol), Cu(OAc)₂ (152 mg, 0.76 mmol), Et3N (190 µL, 1.39 mmol) and 3Å MS (100 mg) in DCE (12.6 mL) under O2 (1 atm) was heated to 50 °C for 18 h. The mixture was filtered through celite and washed with a 1:1 mixture of MeCN and MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (BEH column, C18) using a gradient of 10–80% MeCN and 10 mM ammonium formate in water to afford the title compound (76 mg, 24%) as a solid. LCMS C₂₃H₃₂N₆O₄ requires 456.3, found 457.3 [M+H]⁺. [00603] Step 7: Synthesis of 2-Chloro-4-[(1-methyl-2-oxo-indolin-5- yl)amino]pyrimidine-5-carbonitrile. The title compound was synthesize according to General Procedure 1 using 2,4- dichloropyrimidine-5-carbonitrile as the starting material. [00604] Step 8: Synthesis of 2-((3R,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl)amino)-3-methylpiperidin-1-yl)-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidine-5-carbonitrile. The synthesis of the title compound was accomplished using General Procedures 4 and 5 using tert-butyl (3R,4R)-4-[[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1- carboxylate and 2-chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidine-5-carbonitrile as the starting materials. The crude residue was purified by preparative HPLC (BEH column, C18) using a gradient of 25–55% MeCN and 10 mM sodium bicarbonate in water to afford title compound (6.7 mg, 7%) as a solid. LCMS C32H33N11O3 requires 619.3, found 620.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.28 (s, 1H), 8.40 (s, 1H), 7.54 – 7.40 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 4.6 Hz, 1H), 6.51 (dd, J = 8.8, 1.9 Hz, 1H), 6.43 (s, 1H), 5.75 (d, J = 8.9 Hz, 1H), 4.66 (br s, 1H), 4.44 (s, 1H), 3.85 (t, J = 6.7 Hz, 2H), 3.81 (s, 3H), 3.53 (s, 2H), 3.18 – 3.03 (m, 3H), 2.85 – 2.75 (m, 1H), 2.72 (t, J = 6.7 Hz, 2H), 2.14 – 2.06 (m, 1H), 1.58 (s, 1H), 1.23 (s, 3H), 0.97 (d, J = 6.4 Hz, 3H). Example S133. Synthesis of 1-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (133) [00605] Step 1: Synthesis of 1-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione. The title compound was synthesized analogously to Example S133 using tert-butyl N-(4-piperidyl)carbamate as the reactant in Step 6. LCMS C₃₂H₃₃N₁₁O₃ requires 614.2, found 615.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.50 (br s, 1H), 8.53 (br s, 1H), 7.94 (s, 1H), 7.74 (br s, 1H), 7.56 (s, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.00 (br s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.83 (s, 1H), 3.92 – 3.88 (m, 2H), 3.88 (s, 3H), 3.82 (d, J = 12.7 Hz, 2H), 3.69 (br s, 1H), 3.55 (s, 2H), 3.10 (s, 3H), 2.82 (t, J = 11.8 Hz, 2H), 2.73 (t, J = 6.7 Hz, 2H), 1.95 (br d, J = 10.5 Hz, 2H), 1.59 (br dd, J = 21.8, 10.6 Hz, 2H). Example S134. Synthesis of 1-(6-(1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (134)

[00606] Step 1: Synthesis of tert-Butyl N-(6-bromo-1-methyl-indazol-3-yl)carbamate. To a solution of 6-bromo-1-methyl-indazol-3-amine (1.0 g, 4.42 mmol) in 1,4-dioxane (25 mL) was added Boc2O (1.16 g, 5.31 mmol), and the reaction mixture was heated to 100 °C for 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (1.18 g, 82%) as a solid. MS (ESI) [M–tBu]⁺ 271.0.¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 7.89 (s, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.20 (dd, J = 8.7, 1.6 Hz, 1H), 3.91 (s, 3H), 1.47 (s, 9H). [00607] Step 2: Synthesis of tert-Butyl N-(6-bromo-1-methyl-indazol-3-yl)-N-(2- cyanoethyl)carbamate. To a solution of tert-butyl N-(6-bromo-1-methyl-indazol-3- yl)carbamate (1.18 g, 3.61 mmol) in MeCN (15 mL) were added sequentially KF (429.4 mg, 7.39 mmol), acrylonitrile (0.83 mL, 12.6 mmol) and Al2O3 (1.29 g, 12.6 mmol), and the reaction mixture was heated to reflux for 18 h and then cooled to rt. The mixture was filtered on Celite and washed with MeCN (20 mL). The filtrate was concentrated under reduced pressure to afford the title compound (1.0 g, 73%) as an oil, which was used in the next step without further purification. MS (ESI) [M–tBu]⁺ 324.6. [00608] Step 3: Synthesis of tert-Butyl N-(3-amino-3-oxo-propyl)-N-(6-bromo-1-methyl- indazol-3-yl)carbamate. To a solution of tert-butyl N-(6-bromo-1-methyl-indazol-3-yl)-N-(2- cyanoethyl)carbamate (12 g, 31.6 mmol) in MeOH (90 mL) at 0 °C were added sequentially 30% H₂O₂ (128 mL, 1.23 mol) and NH₄OH (118 mL, 0.92 mol), and the reaction mixture was warmed to rt and stirred for 6 h. Water (500 mL) and DCM (500 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of Na2SO3 (200 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes followed by a second purification using and 0–20% MeOH in DCM to afford the title compound (10.6 g, 84%) as a solid. MS (ESI) [M+H]⁺ 397.1. [00609] Step 4: Synthesis of 1-(6-Bromo-1-methyl-indazol-3-yl)hexahydropyrimidine- 2,4-dione. To a solution of tert-butyl N-(3-amino-3-oxo-propyl)-N-(6-bromo-1-methyl-indazol- 3-yl)carbamate (10.6 g, 26.7 mmol) in THF (125 mL) was added KOtBu (6.0 g, 53.4 mmol), and the reaction mixture was stirred at 0 °C for 2 h. EtOAc (100 mL) and 1N HCl (40 mL) were added and the layers were separated. The organic layer was washed with brine (40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexane to afford the title compound (2.1 g, 24%) as a solid. MS (ESI) [M+H]⁺ 323.1. [00610] Step 5: Synthesis of tert-Butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. A mixture of 1-(6-bromo-1- methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (600 mg, 1.86 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (603 mg, 1.95 mmol), Pd(dppf)Cl2∙DCM (75.8 mg, 90 µmol) and K3PO4 (1.18 g, 5.57 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was heated to 90 °C for 4 h and then cooled to rt. Volatiles were removed and the residue was purified by reverse phase chromatography (C18) with a gradient of 20–100% MeCN and 10 mM ammonium formate in water to afford the title compound (200 mg, 25%) as a solid. MS (ESI) [M–H]^– 424.3.¹H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.62 – 7.57 (m, 2H), 7.26 (dd, J = 8.6, 1.4 Hz, 1H), 6.29 (s, 1H), 4.07 – 4.02 (m, 2H), 3.99 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 3.61 – 3.55 (m, 2H), 2.76 (t, J = 6.7 Hz, 2H), 2.61 – 2.55 (m, 2H), 1.44 (s, 9H). [00611] Step 6: Synthesis of 1-(6-(1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione. The title compound was synthesized according to General Procedures 4, 5, and 6 using tert-Butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6- dihydro-2H-pyridine-1-carboxylate as the starting material. LCMS C₃₀H₃₀ClN₉O₃ requires 599.2, found 600.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.64 (s, 1H), 8.02 (d, J = 3.7 Hz, 1H), 7.56 – 7.51 (m, 3H), 7.44 (s, 1H), 7.04 (dd, J = 8.6, 1.2 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.72 – 4.62 (m, 2H), 3.95 (s, 3H), 3.90 (t, J = 6.7 Hz, 2H), 3.53 (s, 2H), 3.10 (s, 3H), 2.98 – 2.88 (m, 3H), 2.74 (t, J = 6.7 Hz, 2H), 1.90 – 1.83 (m, 2H), 1.71 – 1.58 (m, 2H). Example S135. Synthesis of 1-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (135) [00612] Step 1: Synthesis of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]amino]piperidine-1-carboxylate. To a stirred solution of 1-(6-amino-1- methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (200 mg, 0.77mmol) and tert-butyl 4- oxopiperidine-1-carboxylate (307 mg, 1.54 mmol) in DCM (5 mL) were added acetic acid (10 mg, 0.77mmol) with the pH adjusted to 6 and added sodium triacetoxyborohydride (490 mg, 2.31 mmol) in portions at RT under nitrogen atmosphere. The resulting mixture was stirred for 2 h at RT under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was purified by flash to afford the title compound (240 mg, 70 %) as a yellow solid. [00613] Step 2: Synthesis of 1-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione The title compound was synthesized according to General Procedures 4, 5, and 6 using tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]amino]piperidine-1-carboxylate as starting material. LCMS C30H31ClN10O3 requires 614, found 615 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.01 (s, 1H), 7.57 – 7.47 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1H), 6.55 – 6.44 (m, 2H), 4.38 (d, J = 13.1 Hz, 2H), 3.83 (d, J = 11.9 Hz, 5H), 3.62 – 3.53 (m, 3H), 3.16 – 3.12 (m, 5H), 2.73 – 2.70 (m, 3H), 2.09 – 1.94 (m, 2H), 1.36 – 1.20 (m, 2H). Example S136. Synthesis of 1-(6-((1-(5-chloro-4-((2-oxo-1-(2,2,2-trifluoroethyl)indolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- [00614] Step 1: Synthesis of 1-(6-((1-(5-chloro-4-((2-oxo-1-(2,2,2-trifluoroethyl)indolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione. The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-1-(2,2,2-trifluoroethyl)indolin-2-one and 1-[1- Methyl-6-(4-piperidylamino) indazol-3-yl] hexahydropyrimidine-2,4-dione as starting materials. LCMS C₃₁H₃₀ClF₃N₁₀O₃ requires 682.2, found 683.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 8.6, 2.1 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.51 (dd, J = 8.9, 1.8 Hz, 1H), 6.44 (d, J = 1.4 Hz, 1H), 5.82 (d, J = 8.2 Hz, 1H), 4.58 (q, J = 9.4 Hz, 2H), 4.43 – 4.33 (m, 2H), 3.86 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.70 (s, 2H), 3.68 – 3.60 (m, 1H), 3.16 – 3.07 (m, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.03 – 1.96 (m, 2H), 1.38 – 1.27 (m, 2H). Example S137. Synthesis of 1-(6-((1-(5-chloro-4-((1-(2-hydroxyethyl)-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (137) [00615] Step 1: Synthesis of 1-(6-((1-(5-chloro-4-((1-(2-hydroxyethyl)-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione. The title compound was synthesized according to General Procedures 1 and 6 using 5-amino-1-(2-hydroxyethyl)indolin-2-one and 1-[1-methyl- 6-(4-piperidylamino) indazol-3-yl] hexahydropyrimidine-2,4-dione as starting materials. LCMS C31H33ClN10O4 requires 644.2, found 645.3 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 8.63 (s, 1H), 8.01 (s, 1H), 7.53 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.51 (dd, J = 8.9, 1.7 Hz, 1H), 6.44 (s, 1H), 5.82 (d, J = 8.3 Hz, 1H), 4.79 (bs, 1H), 4.44 – 4.32 (m, 2H), 3.86 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.70 (t, J = 5.9 Hz, 2H), 3.68 – 3.60 (m, 1H), 3.57 (t, J = 5.8 Hz, 2H), 3.53 (s, 2H), 3.16 – 3.07 (m, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.04 – 1.96 (m, 2H), 1.38 – 1.26 (m, 2H). Example S138. Synthesis of 2-(4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)amino)piperidin-1-yl)-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidine-5- carbonitrile (138)

[00616] Step 1: Synthesis of 2-(4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)amino)piperidin-1-yl)-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidine-5- carbonitrile. The title compound was synthesized according to General Procedures 1 and 6 using2,4-dichloropyrimidine-5-carbonitrile and 1-[1-methyl-6-(4-piperidylamino) indazol-3- yl]hexahydropyrimidine-2,4-dione;hydrochloride as starting materials. LCMS C₃₁H₃₁N₁₁O₃ requires 605.3, found 606.5 [M+H]⁺; ¹H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 9.28 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 7.52 – 7.40 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 6.98 – 6.81 (m, 1H), 6.51 (dd, J = 8.9, 1.7 Hz, 1H), 6.45 (s, 1H), 5.84 (d, J = 8.2 Hz, 1H), 4.67 – 4.50 (m, 1H), 4.41 – 4.27 (m, 1H), 3.86 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.72 – 3.62 (m, 1H), 3.54 (s, 2H), 3.26 – 3.15 (m, 2H), 3.10 (s, 3H), 2.72 (t, J = 6.7 Hz, 2H), 2.03 (d, J = 10.1 Hz, 2H), 1.32 (td, J= 13.6, 4.0 Hz, 2H). MS (ESI) [M+H]⁺. Example S139. Synthesis of 1-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)pyrimidine-2,4(1H,3H)-dione (139) [00617] Step 1: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl) urea. To a stirred a solution of 6-bromo-1-methyl-1H-indazol-3-amine (10 g, 44.2 mmol) in acetonitrile (100 mL) was added isocyanatotrimethylsilane (20.4 g, 177 mmol) in a sealed tube. The reaction mixture was heated to 65 °C and stirred for 16 h. The reaction mixture cooled to 25 °C and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel with 10% methanol/DCM to afford the title compound (4.0 g, 13.7 mmol, 30% yield) as a brown solid. [00618] Step 2: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl) pyrimidine- 2,4(1H,3H)-dione. To a stirred solution of 1-(6-bromo-1-methyl-1H-indazol-3-yl) urea (4.0 g, 13.67 mmol) in DMF (10 mL) at 0 °C was added methyl 3,3-dimethoxypropionate (2.431 g, 16.40 mmol) under nitrogen at 0 °C. The reaction mixture was heated to 90 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and treated with ice cold water to obtain solid. The solid was filtered and washed with water to afford the title compound (4.1 g, 4.63 mmol, 33% yield) as yellow solid. LCMS: 320.9 [M+H]⁺. [00619] Step 3: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl)-3-(4-methoxybenzyl) pyrimidine-2,4(1H,3H)-dione. To a stirred solution of 1-(6-bromo-1-methyl-1H-indazol-3-yl) pyrimidine-2,4(1H,3H)-dione (4.0 g, 12.46 mmol) in DMF (20 mL) was added cesium carbonate (6.09 g, 18.68 mmol) and 1-(bromomethyl)-4-methoxybenzene (3.76 g, 18.68 mmol). The reaction mixture was slowly heated to 80 °C and stirred for 3 h. The reaction mixture was poured in water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain crude. The crude product was purified by flash column chromatography on silica gel with 30% ethyl acetate/pet ether to afford the title compound (2.05 g, 3.58 mmol, 28% yield). [00620] Step 4: Synthesis of tert-butyl (3R,4R)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) amino)-3-methylpiperidine-1- carboxylate. To a stirred solution of 1-(6-bromo-1-methyl-1H-indazol-3-yl)-3-(4- methoxybenzyl) pyrimidine-2,4(1H,3H)-dione (500 mg, 0.872 mmol) in 1,4-dioxane (10 mL) was added cesium carbonate (710 mg, 2.181 mmol) and tert-butyl (3R,4R)-4-amino-3- methylpiperidine-1-carboxylate (280 mg 1.30 mmol) degassed with nitrogen for 10 min. Then CPhos-Pd-G3 (703 mg, 0.872 mmol) was added. The reaction mixture was heated to 90 ºC and stirred for 18 h. The reaction mixture was filtered through celite pad and the celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude. The crude product was purified by flash column chromatography on silica gel with 30% ethyl acetate/pet ether to afford the title compound (301 mg, 0.426 mmol, 48% yield) as a light- yellow solid. [00621] Step 5: Synthesis of 1-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl) amino)-1H- indazol-3-yl) pyrimidine-2,4(1H,3H)-dione. To a stirred solution of tert-butyl (3R,4R)-4-((3- (3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) amino)-3-methylpiperidine-1-carboxylate (300 mg, 0.42 mmol) in 1,4-dioxane (10 mL) was added TFA (5.0 mL). The reaction mixture heated to 80 °C and stirred for 48 h. The reaction mixture was concentrated under reduced pressure and triturated by diethyl ether to afford the title compound (301 mg, 0.426 mmol, 48% yield) as a brown gummy solid. The crude product was used for the next step without further purification. [00622] Step 6: Synthesis of 1-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl)-3-methylpiperidin-4-yl) amino)-1-methyl-1H-indazol-3-yl) pyrimidine-2,4(1H,3H)-dione. To a stirred solution of 1-(1-methyl-6-(((3R,4R)-3- methylpiperidin-4-yl) amino)-1H-indazol-3-yl) pyrimidine-2,4(1H,3H)-dione (100 mg, 0.172 mmol) in DMSO (2.0 mL) was added 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1- methylindolin-2-one (50.3 mg, 0.172 mmol) and DIPEA (0.15mL, 0.85 mmol) at 25 ºC. The reaction mixture was heated to 80 ºC and stirred for 6 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (7.0 mg, 0.01 mmol 5% yield) as an off-white solid. Prep method: Rt 10.5 min, Column: X-select C18 (150 x 19) mm, 5.0 µm, 0.1% formic acid in water/acetonitrile; Flow rate: 15.0 mL/min. LCMS C₃₁H₃₁N₁₀O₃ requires 626.2, found 627.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 11.55 (s, 1H), 8.68 (s, 1H), 8.03 (s, 1H), 7.74 (d, J = 7.60 Hz, 1H), 7.57-7.52 (m, 2H), 7.23 (d, J = 8.80 Hz, 1H), 6.95 (d, J = 8.00 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.5 (s, 1H), 5.90 (d, J = 8.80 Hz, 1H), 5.71 (d, J = 7.60 Hz, 1H), 4.52-4.46 (m, 2H), 3.88 (s, 3H), 3.54 (s, 2H), 3.11 (s, 3H), 3.06- 2.99 (m, 1H), 2.72-2.69 (m, 1H), 2.33-2.29 (m, 1H), 2.09-2.07 (m, 1H), 1.62-1.58 (m, 1H), 1.31- 1.17 (m, 2H), 0.98 (d, J = 5.60 Hz, 3H). Example S140. Synthesis of 1-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)-5- fluoropyrimidine-2,4(1H,3H)-dione (140) [00623] Step 1: Synthesis of 5-fluoro-3-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione. To a stirred solution of 5-fluoropyrimidine-2,4(1H,3H)-dione (5.0 g, 38.4 mmol) in DMF (100 mL) was added triethylamine (5.36 mL, 38.4 mmol) at 25 °C, under nitrogen. The reaction mixture was cooled to 0 °C and methyl chloroformate (2.98 mL, 38.4 mmol) was added dropwise and stirred for 3 h. Then Et3N (8.04 ml, 57.6 mmol) and 4-methoxybenzylchloride (7.82 mL, 57.7 mmol) were added at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 6 h. The reaction mixture was treated with ice cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude was dissolved in a 1:1 mixture of MeOH and DCM (50 mL) and added 30% H₂O₂ (4.32 mL, 42.3 mmol) followed by 6.0 N NaOH (0.1 mL) at 0 °C. The reaction mixture was stirred for 1 h and treated ice-cold water (100 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic layer was washed with water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography on silica gel with 50% ethyl acetate/pet ether to afford the title compound (5.10 g, 17.58 mmol, 46% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.16 (d, J = 5.6 Hz, 1H), 7.87 (t, J = 6.0 Hz, 1H), 7.26-7.23 (m, 2H), 6.88-6.86 (m, 2H), 4.88 (s, 2H), 3.72 (s, 3H). [00624] Step 2: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl)-5-fluoro-3-(4- methoxybenzyl) pyrimidine-2,4(1H,3H)-dione. To a stirred solution of 6-bromo-1-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (3.0 g, 8.90 mmol) and molecular sieves (0.5 g) in DCM (40 mL) was added compound 5-fluoro-3-(4-methoxybenzyl)pyrimidine- 2,4(1H,3H)-dione (5.06 g, 17.80 mmol), Et₃N (2.481 mL, 17.80 mmol) and copper (II) acetate (1.617 g, 8.90 mmol) at 25 °C. The reaction mixture was stirred for 16 h under oxygen. The reaction mixture was filtered through celite pad and the filtrate was concentrated under vacuum to afford crude compound. The crude product was purified by flash column chromatography on silica gel with 35-45% ethyl acetate/pet ether to afford the title compound (1.2 g, 2.61 mmol, 29% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.65 (dd, J = 0.4 Hz and 8.8 Hz, 1H), 7.37(dd, J = 1.2 Hz and 8.4 Hz, 1H), 7.33-7.30 (m, 2H), 6.91-6.88 (m, 2H), 5.00 (s, 2H), 4.07 (s, 3H), 3.73 (s, 3H). [00625] Step 3: Synthesis of tert-butyl (3R,4R)-4-((3-(5-fluoro-3-(4-methoxybenzyl)-2,4- dioxo-3,4-dihydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)amino)-3- methylpiperidine-1-carboxylate. A stirred solution of compound 1-(6-bromo-1-methyl-1H- indazol-3-yl)-5-fluoro-3-(4-methoxybenzyl) pyrimidine-2,4(1H,3H)-dione (1.10 g, 2.395 mmol) and tert-butyl (3R,4R)-4-amino-3-methylpiperidine-1-carboxylate (513 mg, 2.395 mmol) in 1,4- dioxane (30.0 mL) was degassed with nitrogen for 5 min. Then CPhos-Pd-G3 (97 mg, 0.120 mmol) and Cs₂CO₃ (1.171 g, 3.59 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 10 h. The reaction mixture was cooled to 25 °C, treated with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography on silica gel with 80-100% ethyl acetate/pet ether to afford the title compound (400 mg, 0.621 mmol, 26% yield) as an off white solid. LCMS: 593.2 (M+H), Rt 3.467 min [00626] Step 4: Synthesis of 5-fluoro-1-(1-methyl-6-(((3R,4R)-3-methyl-1-(2,2,2- trifluoroacetyl)-1l4-piperidin-4-yl)amino)-1H-indazol-3-yl)pyrimidine-2,4(1H,3H)-dione. To a stirred solution of compound 6 (500 mg, 0.844 mmol) in TFA (0.65 mL, 8.44 mmol) was added CF₃SO₃H (0.375 mL, 4.22 mmol) at 25 °C. The reaction mixture was heated to 50 °C and stirred for 8 h. The reaction mixture was concentrated under vacuum to afford the crude product. The crude compound was triturated with diethyl ether and dried under reduced pressure to afford the title compound (400 mg, 0.782 mmol, 93% yield) as a brown solid. The crude product was used for the next step without further purification. LCMS: 372.7 [M+H]⁺. [00627] Step 5: Synthesis of 1-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)-5- fluoropyrimidine-2,4 (1H,3H)-dione. To a stirred solution of 5-fluoro-1-(1-methyl-6- (((3R,4R)-3-methyl-1-(2,2,2-trifluoroacetyl)-1l4-piperidin-4-yl)amino)-1H-indazol-3- yl)pyrimidine-2,4(1H,3H)-dione (100 mg, 0.195 mmol) and 5-((5-chloro-2-fluoropyrimidin-4- yl)amino)-1-methylindolin-2-one (58.1 mg, 0.195 mmol) in DMSO (2.0 mL) was added DIPEA (0.102 mL, 0.586 mmol) in DMSO (2.0 mL) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the the title compound (30 mg, 0.045 mmol, 23% yield) as an off- white solid. LCMS C₃₁H₃₀ClFN₁₀O₃ requires 644.2, found 645.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.69 (s, 1H), 8.20 (d, J = 6.4 Hz, 1H), 8.03 (s, 1H), 7.58 (s, 1H), 7.52(dd, J = 1.6 Hz and 8.8 Hz, 1H), 7.27(d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.59 (dd, J = 1.6 Hz and 9.2 Hz, 1H), 6.51 (s, 1H), 5.90 (d, J = 9.2 Hz, 1H), 4.49-4.46 (m, 2H), 3.88 (s, 3H), 3.54 (s, 2H), 3.14 (s, 3H), 3.11-3.00 (m, 1H), 2.73-2.67 (m, 1H), 2.09-2.07 (m, 1H), 1.56- 1.63 (m, 1H), 1.24-1.15 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H). Examples S141-S144. Synthesis of Compounds 141-144 [00628] Examples in Table 4 below have been made according to the general procedures outlined in the table beginning with their respective commercial starting materials and intermediates found within this document. Table 4.

Example S145. Synthesis of 2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl) amino)-3-methoxypiperidin-1-yl)-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidine-5-carbonitrile (145) [00629] Step 1: Synthesis of tert-butyl (3R,4R)-4-(((benzyloxy) carbonyl) amino)-3- hydroxypiperidine-1-carboxylate. To a stirred solution of tert-butyl (3R,4R)-4-amino-3- hydroxypiperidine-1-carboxylate (2.5 g, 11.6 mmol) in DCM (10 mL) at 0 °C, Cbz-Cl (1.97 g, 11.6 mmol) and saturated aqueous sodium carbonate solution (10 mL) were added. The reaction mixture was warmed up to 25 °C and stirred for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 40% ethyl acetate/pet ether to afford the title compound (3.3 g, 9.42 mmol, 81% yield) as an off-white solid. [00630] Step 2: Synthesis of tert-butyl (3R,4R)-4-(((benzyloxy) carbonyl) amino)-3- methoxypiperidine-1-carboxylate. To a stirred solution of silver (I) oxide (10.9 g, 47.1 mmol) and tert-butyl (3R,4R)-4-(((benzyloxy) carbonyl) amino)-3-hydroxypiperidine-1-carboxylate (3.3 g, 9.42 mmol) in ACN (50 mL), methyl iodide (14.7 mL, 235 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered through a celite pad and the celite pad was washed with methanol (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 25% ethyl acetate/pet ether to afford the title compound (3.1 g, 8.45 mmol, 90% yield) as a colorless liquid. [00631] Step 3: Synthesis of tert-butyl (3R,4R)-4-amino-3-methoxypiperidine-1- carboxylate. To a stirred solution of tert-butyl (3R,4R)-4-(((benzyloxy) carbonyl) amino)-3- methoxypiperidine-1-carboxylate (3.0 g, 8.23 mmol) in methanol (20 mL) was added 10% palladium on carbon (1.0 g) under nitrogen. The reaction mixture was stirred under 1 atm of hydrogenation pressure at 25 °C for 3 h. The reaction mixture was filtered through a pad of celite and the celite pad was washed with methanol (200 mL). The filtrate was concentrated under reduced pressure to afford the title compound (1.7 g, 7.38 mmol, 90% yield) as crude product. The crude product was used in the next step without further purification. [00632] Step 4: Synthesis of tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl) amino)-3-methoxypiperidine-1-carboxylate. A stirred solution of tert-butyl (3R,4R)-4-amino-3-methoxypiperidine-1-carboxylate (200 mg, 0.87 mmol) and 3- (2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (435 mg, 0.87 mmol) in toluene (10 mL) was degassed for 10 min. Then NaO^tBu (167 mg, 1.74 mmol), Pd2dba3 (80 mg, 0.09 mmol) and CPhos (114 mg, 2.26 mmol) were added at 25 °C. The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was poured into water (150 mL) and diluted with ethyl acetate (150 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 25% ethyl acetate/pet ether to afford the title compound (485 mg, 0.66 mmol, 76% yield) as a light-brown solid. [00633] Step 5: Synthesis of tert-butyl (3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl) amino)-3-methoxypiperidine-1-carboxylate. To a stirred solution of tert- butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl) amino)-3- methoxypiperidine-1-carboxylate (485 mg, 0.66 mmol) and trifluoroacetic acid (0.05 mL, 0.66 mmol) in ethanol (4 mL) and THF (4 mL) was added 20% palladium hydroxide on carbon (150 mg) under nitrogen. The reaction mixture was stirred under 1 atm of hydrogenation pressure at 25 °C for 3 h. The reaction mixture was filtered through a pad of celite and the celite pad was washed with methanol (200 mL). The filtrate was concentrated under reduced pressure to afford the title compound (300 mg, 0.42 mmol, 64% yield) as crude product. The crude product was used in the next step without further purification. [00634] Step 6: Synthesis of 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl- 1H-indazol-3-yl) piperidine-2,6-dione. The title compound was synthesized according to General Procedure 5 using tert-butyl (3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl) amino)-3-methoxypiperidine-1-carboxylate (250 mg, 0.53 mmol) as the starting material. [00635] Step 7: Synthesis of 2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl) amino)-3-methoxypiperidin-1-yl)-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidine-5-carbonitrile. The synthesis of the title compound was accomplished using General Procedure 6 using 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione (200 mg, 0.38 mmol) and 4-((1-methyl-2-oxoindolin-5-yl) amino)-2-(methylsulfonyl) pyrimidine-5-carbonitrile (149 mg, 0.38 mmol). The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fractions containing clean product were combined and lyophilized to give the title compound as a white solid (7.7 mg, 0.012 mmol, 8.23% yield). MS (ESI) m/z 635.2 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 9.29 (s, 1H), 8.39 (d, J = 11.20 Hz, 1H), 7.50 (d, J = 11.20 Hz, 2H), 7.44 (d, J = 7.60 Hz, 1H), 6.93 (d, J = 8.40 Hz, 1H), 6.58 (d, J = 8.80 Hz, 1H), 6.47 (s, 1H), 5.90 (s, 1H), 4.21- 4.07 (m, 2H), 4.21- 4.07 (m, 3H), 3.92 - 3.83 (m, 1H), 3.82 (s, 3H), 3.81 - 3.60 (m, 2H), 3.54 (s, 3H), 3.53 - 3.48 (m, 1H), 3.10 (m, 3H), 2.62 (d, J = 8.40 Hz, 2H), 2.30 - 2.00 (m, 3H), 1.36 (brs, 1H). Example S146. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methoxypiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (146) [00636] Step 1: Synthesis of tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)amino)-3-methoxypiperidine-1-carboxylate. A dioxane (35 mL) solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (1750 mg, 3.50 mmol) tert-butyl (3R,4R)-4-amino-3-methoxypiperidine-1-carboxylate (1007 mg, 4.37 mmol) and sodium tert-butoxide (504 mg, 5.25 mmol) was degassed for 15 min with nitrogen before addition of Josiphos Pd G3 (323 mg, 0.350 mmol). The reaction mixture was then heated at 100 °C for 16 hr. The mixture was then cooled to RT and diluted with saturated sodium bicarbonate and extracted with EtOAc (3X). The combined organics were dried over magnesium sulfate and filtered through celite before being concentrated and purified with silica gel chromatography using 0 to 100% EtOAc in hexanes to provide the title compound (1.25g, 1.92 mmol).¹H NMR (500 MHz, CDCl3) δ ppm 7.92 (d, J = 7.99 Hz, 1H), 7.54 - 7.29 (m, 11H), 7.28 - 7.25 (m, 1H), 6.51 (d, J = 8.11 Hz, 1H), 6.47 - 6.41 (m, 2H), 5.49 (s, 2H), 5.41 (s, 2H), 4.00 (s, 4H), 3.96 - 3.73 (m, 2H), 3.49 (s, 4H), 3.22 (td, J = 7.60, 3.87 Hz, 2H), 2.30 - 2.19 (m, 1H), 1.51 (s, 9H). [00637] Step 2: Synthesis of 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl)amino)-1-methyl- 1H-indazol-3-yl)piperidine-2,6-dione hydrochloride. The synthesis of the title compound was accomplished using General Procedures 4 and 5 using tert-butyl (3R,4R)-4-((3-(2,6- bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)amino)-3-methoxypiperidine-1- carboxylate as the starting material. [00638] Step 3: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methoxypiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione. The synthesis of the title compound was accomplished using General Procedure 6 using 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione hydrochloride (65 mg, 0.159 mmol) and 5-((5-chloro-2-fluoropyrimidin- 4-yl)amino)-1-methylindolin-2-one (46 mg, 0.159 mmol). The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fractions containing clean product were combined and lyophilized to give the title compound as a white solid (7.7 mg, 0.012 mmol, 8.23% yield). MS (ESI) m/z 644.6 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.82 (s, 1H), 8.67 (s, 1H), 8.03 (s, 1H), 7.64 - 7.47 (m, 2H), 7.33 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.56 (dd, J = 1.7, 8.8 Hz, 1H), 6.46 (d, J = 1.2 Hz, 1H), 5.85 (d, J = 8.0 Hz, 1H), 4.29 (br d, J = 11.4 Hz, 1H), 4.18 (dd, J = 5.1, 8.8 Hz, 1H), 4.11 - 3.99 (m, 1H), 3.82 (s, 3H), 3.67 - 3.56 (m, 1H), 3.54 (s, 2H), 3.42 - 3.35 (m, 1H), 3.30 (s, 3H), 3.17 (dt, J = 3.9, 7.4 Hz, 1H), 3.10 (s, 3H), 2.66 - 2.57 (m, 2H), 2.32 - 2.21 (m, 1H), 2.19 - 2.11 (m, 1H), 2.07 - 1.99 (m, 1H), 1.42 - 1.31 (m, 1H). Example S147. Synthesis of rel-3-(6-(((3R,4S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-(trifluoromethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione, isomer 1 (147). [00639] Step 1: Synthesis of tert-butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl- 1H-indazol-6-yl)amino)-3-(trifluoromethyl)piperidine-1-carboxylate.3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (300 mg, 0.600 mmol), cesium carbonate (391 mg, 1.199 mmol), tert-butyl 4-amino-3-(trifluoromethyl)piperidine-1-carboxylate (241 mg, 0.899 mmol), and XPhos Pd G3 (50.7 mg, 0.060 mmol) were added to a 1 dram vial equipped with a stir bar and purged with nitrogen for 1 min. Next, dioxane (5995 µl) was added, and the reaction mixture was stirred at 70 °C overnight. LCMS indicated significant product formation. The reaction was cooled to RT and poured into a separatory funnel with water, sat. potassium carbonate, and dichloromethane. The aqueous layer was extracted with dichloromethane 3X. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The mixture was purified with 0-50% EA/hex and 1% MeOH. Fractions containing clean product were combined and lyophilized to give the title compound tert-butyl 4- ((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)amino)-3- (trifluoromethyl)piperidine-1-carboxylate (354 mg, 0.515 mmol, 86 % yield) as a yellow solid. The enantiomers were separated by chiral SFC using Method isocratic: 25B, where B is 0.1% FA in Methanol; Column: ChiralPack IC with a flow rate: 2ml/min. This afforded the relative enantiomers rel-tert-butyl (3R,4S)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)amino)-3-(trifluoromethyl)piperidine-1-carboxylate, isomer 1 (90.1 mg, 24.5% yield) and rel- tert-butyl (3R,4S)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)-3- (trifluoromethyl)piperidine-1-carboxylate, isomer 2 (87.4 mg, 24.5% yield). LC MS at t=3.89 (m+1 = 688.76) showed 688.311.¹H NMR (CHLOROFORM-d, 400 MHz) δ 7.8-8.0 (m, 1H), 7.3-7.5 (m, 8H), 6.4-6.6 (m, 1H), 6.3-6.4 (m, 2H), 5.3-5.5 (m, 4H), 4.0-4.1 (m, 3H), 4.0-4.0 (m, 3H), 3.5-3.7 (m, 2H), 2.17 (s, 3H), 2.0-2.1 (m, 1H), 1.6-1.8 (m, 2H), 1.5-1.5 (m, 9H). [00640] Step 2: Synthesis of rel-tert-butyl (3R,4S)-4-((3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)amino)-3-(trifluoromethyl)piperidine-1-carboxylate, isomer 1. tert- butyl 4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)amino)-3- (trifluoromethyl)piperidine-1-carboxylate, isomer 1 (90.1 mg, 0.131 mmol) and MeOH (1310 µl) were added to a 40 mL vial equipped with a stir bar. The reaction was purged with nitrogen and then palladium on carbon (27.9 mg, 0.013 mmol) was added. The vial was purged with nitrogen again and then a balloon of hydrogen was added. The vial was heated to 50 °C for 15 hours. The mixture was filtered over celite. The filtrate was concentrated to give the title compound (56 mg, 84% yield). LCMS at t=2.86 and 2.93 (m+1 = 510.2) showed 510.2.¹H NMR (CHLOROFORM-d, 500 MHz) δ 8.0-8.2 (m, 1H), 7.4-7.6 (m, 1H), 6.5-6.6 (m, 1H), 6.3- 6.4 (m, 1H), 4.2-4.3 (m, 1H), 4.0-4.2 (m, 2H), 3.9-4.0 (m, 4H), 3.8-3.8 (m, 1H), 3.4-3.5 (m, 1H), 2.9-3.1 (m, 1H), 2.6-2.8 (m, 2H), 2.4-2.6 (m, 1H), 2.3-2.4 (m, 1H), 2.0-2.1 (m, 1H), 1.9-1.9 (m, 1H), 1.7-1.9 (m, 1H), 1.50 (s, 10H). [00641] Step 3: Synthesis of 3-(1-methyl-6-(((3R,4S)-3-(trifluoromethyl)piperidin-4- yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione, isomer 1. A round bottom flask was charged with rel-tert-butyl (3R,4S)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)-3- (trifluoromethyl)piperidine-1-carboxylate (56.0 mg, 0.110 mmol) in DCM (1099 µL). Then HCl (55.0 µL, 0.220 mmol) was added and the solution stirred for 1 hour at room temperature. Next, the solution was concentrated to give the title compound as an HCl salt (49 mg, 0.110 mmol, 100 % yield) as a white solid, which was used without further purification in the next step. LCMS at t=141 and 1.53 (m+1=410.2) showed 410.2. [00642] Step 4: Synthesis of rel-3-(6-(((3R,4S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-(trifluoromethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione, isomer 1. To a stirred solution of 3-(1-methyl-6-(((3R,4S)-3- (trifluoromethyl)piperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione, Isomer 1 (28 mg, 0.075 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (28.6 mg, 0.075 mmol) in DMSO (1 mL) was added DIPEA (0.053 mL, 0.302 mmol). The reaction was stirred at 80 °C for 4 hours. The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fraction containing clean product were combined and lyophilized to give the title compound (3.2 mg, 4.69 µmol, 4.26 % yield).¹H NMR (CHLOROFORM-d, 400 MHz) δ 8.0- 8.1 (m, 1H), 7.8-7.9 (m, 1H), 7.4-7.6 (m, 3H), 6.9-7.0 (m, 1H), 6.7-6.8 (m, 1H), 6.5-6.7 (m, 1H), 6.2-6.4 (m, 1H), 4.5-4.6 (m, 1H), 4.1-4.3 (m, 4H), 3.91 (s, 3H), 3.6-3.7 (m, 1H), 3.52 (s, 3H), 3.22 (s, 3H), 2.9-3.1 (m, 1H), 2.6-2.8 (m, 2H), 2.3-2.6 (m, 2H), 2.0-2.2 (m, 1H), 2.0-2.0 (m, 1H), 1.7-1.8 (m, 1H). LC MS at t=2.49 (m+1 = 682.1) showed 682.3. Example S148. Synthesis of 3-(6-(((3S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-(trifluoromethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (148) [00643] Step 1: Synthesis of 3-(6-(((3S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-(trifluoromethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione, isomer 2. The title compound was synthesized analogously to Example S147 using the second eluting isomer from Example S147, Step 1.To a stirred solution of 3-(1-methyl-6-(((3S,4R)-3-(trifluoromethyl)piperidin-4-yl)amino)-1H-indazol-3- yl)piperidine-2,6-dione, Isomer 2 (56 mg, 0.137 mmol) and 5-((5-chloro-2-fluoropyrimidin-4- yl)amino)-1-methylindolin-2-one (40.0 mg, 0.137 mmol) in DMSO (1 mL) was added N-ethyl- N-isopropylpropan-2-amine (0.096 mL, 0.547 mmol). The reaction stirred at 80 °C for 4 hours. The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fractions containing clean product were combined and lyophilized to give the title compound (21.7 mg, 0.031 mmol, 23.03 % yield).¹H NMR (CDCl3, 400 MHz) δ 8.0-8.1 (m, 1H), 7.8-7.9 (m, 1H), 7.4-7.6 (m, 3H), 6.9-7.0 (m, 1H), 6.7-6.8 (m, 1H), 6.5-6.7 (m, 1H), 6.2-6.4 (m, 1H), 4.5-4.6 (m, 1H), 4.1-4.3 (m, 4H), 3.91 (s, 3H), 3.6-3.7 (m, 1H), 3.52 (s, 3H), 3.22 (s, 3H), 2.9-3.1 (m, 1H), 2.6-2.8 (m, 2H), 2.3-2.6 (m, 2H), 2.0-2.2 (m, 1H), 2.0-2.0 (m, 1H), 1.7-1.8 (m, 1H). LCMS [M+1 = 682.1] showed 682.3. Example S149. Synthesis of 3-(6-((4R,5S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)-5-methyl-2-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (149) [00644] Step 1: Synthesis of tert-butyl (S)-(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2- methyl-3-oxopropyl) carbamate. To a stirred solution of (S)-3-((tert-butoxycarbonyl) amino)- 2-methylpropanoic acid (10.00 g, 46.7 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (7.41 g, 51.4 mmol) in DCM (160 mL), EDC (13.44 g, 70.1 mmol) and DMAP (8.57 g, 70.1 mmol) were added. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with DCM (300 mL), washed with 10% aqueous sodium bisulfate solution (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude title compound (16.2 g, 27.5 mmol, 59% yield) as a yellow solid. The crude product was used in the next step without further purification. [00645] Step 2: Synthesis of tert-butyl (S)-5-methyl-2,4-dioxopiperidine-1-carboxylate. A solution of tert-butyl (S)-(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-3-oxopropyl) carbamate (16.2 g, 27.5 mmol) in ethyl acetate (150 mL) was refluxed at 80 °C and stirred for 8 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude compound. The crude material was purified by flash column chromatography on silica with 50% ethyl acetate/pet ether to afford the title compound (6.92 g, 27.4 mmol, quant. yield) as a white solid. [00646] Step 3: Synthesis of (S)-5-methylpiperidine-2,4-dione. Trifluoroacetic acid (21.1 mL, 274 mmol) was added dropwise at 0 °C to a stirred solution of tert-butyl (S)-5-methyl-2,4- dioxopiperidine-1-carboxylate (6.92 g, 27.4 mmol) in DCM (100 mL). The resulting solution was warmed up to 25 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, dissolved in acetonitrile (100 mL), and basified by solid sodium bicarbonate until the pH of the solution was greater than 8. The mixture was stirred for another hour, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude title compound (8.5 g, 26.9 mmol, 98% yield) as a yellow oil. The crude product was used in the next step without further purification. [00647] Step 4: Synthesis of (S)-4-(benzyl(methyl)amino)-5-methyl-5,6-dihydropyridin- 2(1H)-one. To a stirred solution of (S)-5-methylpiperidine-2,4-dione (8.5 g, 26.9 mmol) and N- methyl-1-phenylmethanamine (6.52 g, 53.8 mmol) in MeOH (150 mL), AcOH (2.3 mL, 40.4 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford the title compound, which was used without further purification (20 g, 26.4 mmol, 98% yield). [00648] Step 5: Synthesis of (4R,5S)-5-methyl-4-(methylamino) piperidin-2-one. To a solution of (S)-4-(benzyl(methyl)amino)-5-methyl-5,6-dihydropyridin-2(1H)-one (20 g, 26.4 mmol) in methanol (150 mL), platinum (IV) oxide (3.0 g) was added. The reaction mixture was stirred under 7 atm of hydrogenation pressure at 25 °C for 72 h. The reaction mixture was filtered through a pad of celite and the celite pad was washed with methanol (3 x 100 mL). The filtrate was concentrated under reduced pressure. This material was purified by preparative HPLC to afford the title compound (3.8 g, 26.3 mmol, 99% yield) as a white solid. Prep-HPLC method: Rt 5.4 min; Column: XSelect C18 (300 x 30) mm, 10.0 µm; 0.1% TFA in water/acetonitrile; Flow Rate: 20.0 mL/min. [00649] Step 6: Synthesis of tert-butyl methyl((4R,5S)-5-methyl-2-oxopiperidin-4-yl) carbamate. To a stirred solution of (4R,5S)-5-methyl-4-(methylamino) piperidin-2-one (3.8 g, 26.3 mmol) in THF (38 mL), Et₃N (9.2 mL, 65.8 mmol) and boc-anhydride (6.32 g, 28.9 mmol) were added sequentially. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with ethyl acetate (30 mL) and quenched with water (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (1.32 g, 4.15 mmol, 16% yield), which was used without further purification. [00650] Step 7: Synthesis of tert-butyl ((4R,5S)-1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)-5-methyl-2-oxopiperidin-4-yl) (methyl)carbamate. A stirred solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (1.32 g, 2.64 mmol) and tert-butyl methyl((4R,5S)-5-methyl-2-oxopiperidin-4-yl) carbamate (0.7 g, 2.20 mmol) in toluene (25 mL) was degassed with nitrogen for 5 min. Then cesium carbonate (2.87 g, 8.80 mmol), Pd2(dba)3 (0.20 g, 0.22 mmol) and xantphos (0.51 g, 0.88 mmol) were added. The reaction mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and quenched with water (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound which was purified by preparative HPLC to afford the title compound (0.86 g, 1.23 mmol, 56% yield) as a light-yellow solid. Prep-HPLC method: Rt 7.4 min; Column: XSelect C18 (300 x 30) mm, 10.0 µm; 0.1% TFA in water/acetonitrile; Flow Rate: 20.0 mL/min. [00651] Step 8: Synthesis of tert-butyl ((4R,5S)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl)-5-methyl-2-oxopiperidin-4-yl) (methyl)carbamate. To a stirred solution of tert-butyl ((4R,5S)-1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-5-methyl- 2-oxopiperidin-4-yl) (methyl)carbamate (860 mg, 1.23 mmol) and trifluoroacetic acid (0.10 mL, 1.23 mmol) in ethanol (7.5 mL) and THF (7.5 mL) was added 20% palladium hydroxide on carbon (400 mg) under nitrogen. The reaction mixture was stirred under 4 atm of hydrogenation pressure at 50 °C for 4 h. The reaction mixture was filtered through a pad of celite and the celite pad was washed with ethanol/THF (1:1, 200 mL). The filtrate was concentrated under reduced pressure to afford the title compound (510 mg, 0.70 mmol, 57% yield) as a crude product. The crude product was used in the next step without further purification. [00652] Step 9: Synthesis of 3-(6-((4R,5S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-5-methyl-2-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione. The title compound was synthesized according to General Procedures 5 and 6 using tert-butyl ((4R,5S)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)-5-methyl-2-oxopiperidin-4-yl) (methyl)carbamate (400 mg, 0.55 mmol) as the starting material. LCMS [M+H]⁺ found 656.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 8.67 (s, 1H), 8.05 (s, 1H), 7.70 (d, J = 8.40 Hz, 1H), 7.58-7.52 (m, 3H), 6.99-6.95 (m, 2H), 5.05 (brs, 1H), 4.41-4.37 (m, 1H), 3.99 (s, 3H), 3.70-3.65 (m, 1H), 3.57 (s, 3H), 3.33-3.25 (m, 3H), 3.08 (s, 3H), 2.83-2.63 (m, 5H), 2.40-2.34 (m, 1H), 2.21-2.17 (m, 1H), 0.99 (d, J = 6.80 Hz, 3H). Example S150. Synthesis of 3-(6-((2R,4S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-2-methyl-6-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione (150) [00653] Step 1: Synthesis of tert-butyl methyl((4R,5S)-5-methyl-2-oxopiperidin-4-yl) carbamate. The title compound was synthesized according to Steps 1-6, Example S149 using (R)-3-((tert-butoxycarbonyl) amino) butanoic acid as the original starting material. [00654] Step 2: Synthesis of tert-butyl ((2R,4S)-1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)-2-methyl-6-oxopiperidin-4-yl) (methyl)carbamate. To a stirred solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (4.13 g, 8.25 mmol) and tert-butyl methyl((4R,5S)-5-methyl-2-oxopiperidin-4-yl) carbamate (2.0 g, 8.25 mmol) in dioxane (40 mL), potassium phosphate (5.26 g, 49.5 mmol), CuI (4.72 g, 24.8 mmol) and DMEDA (4.37 g, 49.5 mmol) were added. The reaction mixture was heated to 120 ºC and stirred for 48 h. The reaction mixture was cooled down to room temperature, quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound which was purified by preparative HPLC to afford the title compound (0.41 g, 0.62 mmol, 8% yield, peak 1) as an off-white solid. Prep-HPLC method: Rt 15.0 min and 15.4 min; Column: YMC C18 Phenyl (250 x 21) mm, 5.0 µm; 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. [00655] Step 3: Synthesis of tert-butyl ((2R,4S)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl)-2-methyl-6-oxopiperidin-4-yl) (methyl)carbamate. To a stirred solution of tert-butyl ((2R,4S)-1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-2-methyl- 6-oxopiperidin-4-yl) (methyl)carbamate (410 mg, 0.62 mmol, peak 1) and trifluoroacetic acid (0.05 mL, 0.62 mmol) in ethanol (3 mL) and THF (3 mL) was added 20% palladium hydroxide on carbon (250 mg) under nitrogen. The reaction mixture was stirred under 4 atm of hydrogenation pressure at 50 °C for 4 h. The reaction mixture was filtered through a pad of celite and the celite pad was washed with ethanol/THF (1:1, 150 mL). The filtrate was concentrated under reduced pressure to afford the title compound (300 mg, 0.61 mmol, 99% yield) as a crude product. The crude product was used in the next step without further purification. [00656] Step 4: Synthesis of 3-(6-((2R,4S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-2-methyl-6-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione. The title compound was synthesized according to General Procedures 5 and 6 using tert-butyl ((2R,4S)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)-2-methyl-6-oxopiperidin-4-yl) (methyl)carbamate (300 mg, 0.61 mmol) as the starting material. LCMS [M+H]⁺ found 656.2; ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 7.70 (d, J = 8.80 Hz, 1H), 7.60 (s, 1H), 7.51 - 7.46 (m, 2H), 6.93 (d, J = 8.40 Hz, 1H), 6.85 (s, 1H), 5.00 (brs, 1H), 4.42 - 4.38 (m, 1H), 4.05 - 4.00 (m, 1H), 3.99 (s, 3H), 3.54 - 3.52 (m, 2H), 3.09 (s, 3H), 2.99 (s, 3H), 2.66 - 2.64 (m, 3H), 2.45 - 2.41 (m, 2H), 2.22 - 2.08 (m, 2H), 1.98 - 1.95 (m, 1H), 0.93 (d, J = 6.00 Hz, 3H). Example S151. Synthesis of 3-(6-((2R,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-2-methyl-6-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione (151) [00657] Step 1: Synthesis of tert-butyl ((2R,4R)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl)-2-methyl-6-oxopiperidin-4-yl) (methyl)carbamate. To a stirred solution of tert-butyl ((2R,4R)-1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-2-methyl- 6-oxopiperidin-4-yl) (methyl)carbamate (170 mg, 0.26 mmol, peak 2 from Example S150, Step 2) and trifluoroacetic acid (0.02 mL, 0.26 mmol) in ethanol (1 mL) and THF (1 mL) was added 20% palladium hydroxide on carbon (100 mg) under nitrogen. The reaction mixture was stirred under 4 atm of hydrogenation pressure at 50 °C for 4 h. The reaction mixture was filtered through a pad of celite and the celite pad was washed with ethanol/THF (1:1, 50 mL). The filtrate was concentrated under reduced pressure to afford the title compound (135 mg, 0.26 mmol, 99% yield) as a crude product. The crude product was used in the next step without further purification. [00658] Step 2: Synthesis of 3-(6-((2R,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-2-methyl-6-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione. The title compound was synthesized according to General Procedures 5 and 6 using tert-butyl ((2R,4R)-1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)-2-methyl-6-oxopiperidin-4-yl) (methyl)carbamate (135 mg, 0.26 mmol) as the starting material. LCMS [M+H]⁺ found 656.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 8.74 (s, 1H), 8.05 (s, 1H), 7.71 (d, J = 8.80 Hz, 1H), 7.56 (s, 1H), 7.46 (s, 2H), 6.97 (d, J = 8.40 Hz, 1H), 6.89 (d, J = 7.60 Hz, 1H), 5.14 (brs, 1H), 4.42 - 4.38 (m, 1H), 4.13 - 4.10 (m, 1H), 4.01 (s, 3H), 3.57 (s, 2H), 3.14 (s, 3H), 2.98 (s, 3H), 2.61 - 2.60 (m, 4H), 2.44 - 2.33 (m, 2H), 2.23 - 2.17 (m, 1H), 1.81 - 1.79 (m, 1H), 0.98 (s, 3H). Example S152. Synthesis of 3-(6-((2S,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-2-methyl-6-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione (152) [00659] Step 1: Synthesis of 3-(6-((2S,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-2-methyl-6-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione. The title compound was synthesized analogously to Example S150 using (R)-3-((tert-butoxycarbonyl) amino) butanoic acid (10.00 g, 49.2 mmol) as the original starting material. LCMS [M+H]⁺ found 656.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 8.67 (s, 1H), 8.05 (s, 1H), 7.71 - 7.69 (m, 1H), 7.61 (s, 1H), 7.51 - 7.47 (m, 2H), 6.95 - 6.86 (m, 2H), 5.11 - 5.10 (m, 1H), 4.41 - 4.38 (m, 1H), 3.99 (s, 3H), 3.55 - 3.52 (m, 2H), 3.13 (s, 3H), 3.03 (s, 3H), 2.80 - 2.60 (m, 3H), 2.49 - 2.38 (m, 3H), 2.32 - 2.10 (m, 2H), 2.02 – 1.92 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H). Example S153. Synthesis of 3-(6-((2S,4S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-2-methyl-6-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione (153) [00660] Step 1: Synthesis of 3-(6-((2S,4S)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl) (methyl)amino)-2-methyl-6-oxopiperidin-1-yl)-1-methyl-1H- indazol-3-yl) piperidine-2,6-dione. The title compound was synthesized analogously to Example S151. LCMS [M+H]⁺ found 656.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 8.72 - 8.68 (m, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 4.40, 8.60 Hz, 1H), 7.60 (s, 1H), 7.56 - 7.46 (m, 2H), 6.98 - 6.88 (m, 2H), 5.21 -5.10 (m, 1H), 4.39 - 4.35 (m, 1H), 4.19 - 4.11 (m, 1H), 4.00 (d, J = 4.80 Hz, 3H), 3.55 - 3.52 (m, 2H), 3.13 (d, J = 17.60 Hz, 3H), 3.03 (d, J = 4.00 Hz, 3H), 2.80 - 2.67 (m, 2H), 2.62 - 2.60 (m, 1H), 2.47 - 2.38 (m, 2H), 2.30 - 2.28 (m, 2H), 2.05 - 2.00 (m, 1H), 1.02 (d, J = 6.40 Hz, 3H). Example S154. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methoxypiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)-3- methylpiperidine-2,6-dione (154) [00661] Step 1: Synthesis of tert-butyl (3R,4R)-4-((3-(5-(tert-butoxy)-2-cyano-5- oxopentan-2-yl)-1-methyl-1H-indazol-6-yl) amino)-3-methoxypiperidine-1-carboxylate. A stirred solution of tert-butyl 4-(6-bromo-1-methyl-1H-indazol-3-yl)-4-cyanopentanoate (300 mg, 0.77 mmol) and tert-butyl (3R,4R)-4-amino-3-methoxypiperidine-1-carboxylate (176 mg, 0.77 mmol) in toluene (10 mL) was degassed for 5 min. Then NaO^tBu (110 mg, 1.15 mmol), Pd₂dba₃ (70.0 mg, 0.08 mmol) and BINAP (47.6 mg, 0.08 mmol) were added at 25 °C. The reaction mixture was heated to 100 °C and stirred for 6 h. The reaction mixture was quenched with water (20 mL) and diluted with ethyl acetate (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 100% ethyl acetate/pet ether to afford the title compound (300 mg, 0.41 mmol, 54% yield) as an off- white solid. [00662] Step 2: Synthesis of tert-butyl (3R,4R)-3-methoxy-4-((1-methyl-3-(3-methyl-2,6- dioxopiperidin-3-yl)-1H-indazol-6-yl) amino) piperidine-1-carboxylate. To a stirred solution of tert-butyl (3R,4R)-4-((3-(5-(tert-butoxy)-2-cyano-5-oxopentan-2-yl)-1-methyl-1H-indazol-6- yl) amino)-3-methoxypiperidine-1-carboxylate (300 mg, 0.55 mmol) in acetic acid (5 mL), sulfuric acid (0.03 mL, 0.55 mmol) was added. The reaction mixture was heated to 60 °C and stirred for 6 h. The reaction mixture was concentrated under reduced pressure and the resulting crude mixture was dissolved in acetonitrile (5 mL), followed by the addition of DIPEA (0.27 mL, 1.56 mmol) and BOC-anhydride (0.15 mL, 0.62 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (20 mL) and diluted with ethyl acetate (30 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 100% ethyl acetate/pet ether to afford the title compound (180 mg, 0.27 mmol, 49% yield over 2 steps) as an off-white solid. [00663] Step 3: Synthesis of 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl- 1H-indazol-3-yl)-3-methylpiperidine-2,6-dione. The title compound was synthesized according to General Procedure 5 using tert-butyl (3R,4R)-3-methoxy-4-((1-methyl-3-(3- methyl-2,6-dioxopiperidin-3-yl)-1H-indazol-6-yl) amino) piperidine-1-carboxylate (180 mg, 0.37 mmol) as the starting material. [00664] Step 4: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H-indazol-3-yl)-3- methylpiperidine-2,6-dione. The title compound was synthesized according to General Procedure 6 using 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H-indazol-3-yl)- 3-methylpiperidine-2,6-dione (100 mg, 0.20 mmol) and 5-((5-chloro-2-fluoropyrimidin-4- yl)amino)-1-methylindolin-2-one (59 mg, 0.20 mmol) as starting materials. LCMS [M+H]⁺ found 658.3; ¹H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 9.00 (s, 1H), 8.08 (s, 1H), 7.53 - 7.44 (m, 3H), 6.96 - 6.94 (m, 1H), 6.58 - 6.56 (m, 1H), 6.49 - 6.47 (m, 1H), 6.13 - 5.61 (m, 1H), 4.20 (br d, J = 12.5 Hz, 2H), 4.02 - 3.91 (m, 2H), 3.81 (s, 3H), 3.65 - 3.59 (m, 1H), 3.47 - 3.34 (m, 2H), 3.29 (s, 3H), 3.23 - 3.18 (m, 1H), 3.11 (s, 3H), 2.48 - 2.45 (m, 1H), 2.42 - 2.39 (m, 1H), 2.13 - 1.99 (m, 2H), 1.59 (s, 3H), 1.44 - 1.31 (m, 1H). Example S155. Synthesis of 2-((3R,4R)-3-methoxy-4-((1-methyl-3-(3-methyl-2,6- dioxopiperidin-3-yl)-1H-indazol-6-yl) amino) piperidin-1-yl)-4-((1-methyl-2-oxoindolin-5- yl) amino) pyrimidine-5-carbonitrile (155) [00665] Step 1: Synthesis of 2-((3R,4R)-3-methoxy-4-((1-methyl-3-(3-methyl-2,6- dioxopiperidin-3-yl)-1H-indazol-6-yl) amino) piperidin-1-yl)-4-((1-methyl-2-oxoindolin-5- yl) amino) pyrimidine-5-carbonitrile. The title compound was synthesized according to General Procedure 6 using 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H- indazol-3-yl)-3-methylpiperidine-2,6-dione (150 mg, 0.30 mmol) and 2-fluoro-4-((1-methyl-2- oxoindolin-5-yl)amino)pyrimidine-5-carbonitrile (103 mg, 0.30 mmol) as starting materials. LCMS [M+H]⁺ found 649.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 9.30 (s, 1H), 8.40 (br s, 1H), 7.48 - 7.42 (m, 3H), 6.96 - 6.91 (m, 1H), 6.58 (br d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 4.14 - 4.04 (m, 1H), 3.82 - 3.77 (m, 3H), 3.67 - 3.59 (m, 2H), 3.58 - 3.49 (m, 5H), 3.23 (br s, 2H), 3.10 (s, 3H), 2.58 - 2.53 (m, 2H), 2.48 - 2.45 (m, 1H), 2.43 - 2.37 (m, 1H), 2.13 - 1.98 (m, 2H), 1.59 (s, 3H), 1.45 - 1.37 (m, 1H). Example S156. Synthesis of 1-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H-indazol-3-yl) dihydropyrimidine-2,4(1H,3H)-dione (156) [00666] Step 1: Synthesis of tert-butyl (3R,4R)-3-methoxy-4-((3-(3-(4-methoxybenzyl)- 2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) amino) piperidine-1- carboxylate. A stirred solution of 1-(6-bromo-1-methyl-1H-indazol-3-yl)-3-(4-methoxybenzyl) dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 2.26 mmol) and tert-butyl (3R,4R)-4-amino-3- methoxypiperidine-1-carboxylate (0.52 g, 2.26 mmol) in toluene (3 mL) was degassed for 10 min. Then Cs₂CO₃ (1.47 g, 4.51 mmol) and Pd-Ruphos-G3 (0.19 g, 0.23 mmol) were added at 25 °C. The reaction mixture was heated to 120 °C and stirred for 12 h. The reaction mixture was poured into water (150 mL) and diluted with ethyl acetate (150 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 70% ethyl acetate/pet ether to afford the title compound (0.80 g, 1.27 mmol, 56% yield) as a pale-yellow solid. [00667] Step 2: Synthesis of 1-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl- 1H-indazol-3-yl) dihydropyrimidine-2,4(1H,3H)-dione. The title compound was synthesized according to General Procedure 5 using tert-butyl (3R,4R)-3-methoxy-4-((3-(3-(4- methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl) amino) piperidine-1-carboxylate (800 mg, 1.27 mmol) as the starting material. [00668] Step 3: Synthesis of 1-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidin-2-yl)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H-indazol-3-yl) dihydropyrimidine-2,4(1H,3H)-dione. The title compound was synthesized according to General Procedure 6 using 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H- indazol-3-yl)-3-methylpiperidine-2,6-dione (150 mg, 0.30 mmol) and 2-fluoro-4-((1-methyl-2- oxoindolin-5-yl)amino)pyrimidine-5-carbonitrile (103 mg, 0.30 mmol) as starting materials. LCMS [M+H]⁺ found 634.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.68 (s, 1H), 8.02 (s, 1H), 7.54 - 7.50 (m, 2H), 7.28 (d, J = 8.80 Hz, 1H), 6.93 (d, J = 8.40 Hz, 1H), 6.55 (dd, J = 1.60, 8.80 Hz, 1H), 6.45 (d, J = 1.20 Hz, 1H), 5.90 (d, J = 8.00 Hz, 1H), 4.32 (d, J = 10.80 Hz, 1H), 4.07 (brs, 1H), 3.86 (t, J = 6.80 Hz, 2H), 3.81 (s, 3H), 3.63 - 3.59 (m, 2H), 3.38 - 3.26 (m, 5H) 3.18 - 3.13 (m, 2H), 3.10 (s, 3H), 2.73 (t, J = 6.80 Hz, 2H), 2.07 - 2.02 (m, 1H), 1.35 (d, J = 9.60 Hz, 1H). Example S157. Synthesis of 2-((3R,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl) amino)-3-methoxypiperidin-1-yl)-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidine-5-carbonitrile (157) [00669] Step 1: Synthesis of 4-((1-methyl-2-oxoindolin-5-yl) amino)-2-(methylthio) pyrimidine-5-carbonitrile. To a stirred solution of 5-amino-1-methylindolin-2-one (1.0 g, 6.17 mmol) and 4-chloro-2-(methylthio) pyrimidine-5-carbonitrile (1.15 g, 6.17 mmol) in THF (10 mL), DIPEA (2.7 mL, 15.4 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the precipitated solids were washed with water (4 x 50 mL) to afford the title compound (1.77 g, 5.58 mmol, 91% yield) as a yellow solid. [00670] Step 2: Synthesis of 4-((1-methyl-2-oxoindolin-5-yl) amino)-2-(methylsulfonyl) pyrimidine-5-carbonitrile. To a stirred solution of 4-((1-methyl-2-oxoindolin-5-yl) amino)-2- (methylthio) pyrimidine-5-carbonitrile (750 mg, 2.41 mmol) in DCM (25 mL), mCPBA (1.25 g, 7.23 mmol) was added. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (25 mL) and diluted with ethyl acetate (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (715 mg, 1.57 mmol, 65% yield) as a yellow solid. [00671] Step 3: Synthesis of 2-((3R,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl) amino)-3-methoxypiperidin-1-yl)-4-((1-methyl-2-oxoindolin-5-yl) amino) pyrimidine-5-carbonitrile. The title compound was synthesized according to General Procedure 6 using 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H-indazol-3-yl)- 3-methylpiperidine-2,6-dione (100 mg, 0.26 mmol) and 4-((1-methyl-2-oxoindolin-5-yl) amino)-2-(methylsulfonyl) pyrimidine-5-carbonitrile (103 mg, 0.26 mmol) as starting materials. LCMS [M+H]⁺ found 636.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.29 (s, 1H), 8.40 (s, 1H), 7.48 - 7.43 (m, 2H), 7.30 (d, J = 8.80 Hz, 1H), 6.93 (d, J = 8.80 Hz, 1H), 6.57 (d, J = 8.80 Hz, 1H), 6.45 (s, 1H), 5.94 (s, 1H), 4.30 - 4.12 (m, 2H), 3.86 (t, J = 6.80 Hz, 2H), 3.81 (s, 3H), 3.65 (brs, 2H), 3.54 (s, 3H), 3.40 – 3.30 (m, 2H),3.25 – 3.12(m, 2H), 3.10 (s, 3H), 2.73 (t, J = 6.40 Hz, 2H), 2.08 (brs, 1H), 1.41 (brs, 1H). Example S158. Synthesis of 1-(6-(((3R,4R)-1-(5-chloro-4-fluoro-6-((1-methyl-2-oxoindolin- 5-yl) amino) pyrimidin-2-yl)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H-indazol-3-yl) dihydropyrimidine-2,4(1H,3H)-dione (158) [00672] Step 1: Synthesis of 5-((5-chloro-2,6-difluoropyrimidin-4-yl) amino)-1- methylindolin-2-one. To a stirred solution of 5-amino-1-methylindolin-2-one (500 mg, 3.08 mmol) and 5-chloro-2,4,6-trifluoropyrimidine (519 mg, 3.08 mmol) in ACN (25 mL), DIPEA (0.5 mL, 3.08 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (550 mg, 1.59 mmol, 52% yield) as an off- white solid. [00673] Step 2: Synthesis of 1-(6-(((3R,4R)-1-(5-chloro-4-fluoro-6-((1-methyl-2- oxoindolin-5-yl) amino) pyrimidin-2-yl)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H- indazol-3-yl) dihydropyrimidine-2,4(1H,3H)-dione. The title compound was synthesized according to General Procedure 6 using 1-(6-(((3R,4R)-3-methoxypiperidin-4-yl)amino)-1- methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, 0.39 mmol) and 5-((5- chloro-2,6-difluoropyrimidin-4-yl) amino)-1-methylindolin-2-one (148 mg, 0.43 mmol) as starting materials. LCMS [M+H]⁺ found 663.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.99 (s, 1H), 7.45 -7.49 (m, 2H), 7.29 (d, J = 8.80 Hz, 1H), 6.93 (d, J = 8.40 Hz, 1H), 6.56 (q, J = 1.60 Hz, 1H), 6.44 (d, J = 1.20 Hz, 1H), 5.91 (d, J = 8.00 Hz, 1H), 4.12 (d, J = 12.40 Hz, 1H), 3.86 (t, J = 6.80 Hz, 3H), 3.81 (s, 3H), 3.60 - 3.63 (m, 1H), 3.53 (s, 2H), 3.41 - 3.47 (m, 2H), 3.31 – 3.28 (m, 3H), 3.19 (s, 1H), 3.10 (s, 3H), 2.72 (t, J = 6.80 Hz, 2H), 2.01 - 2.07 (m, 1H), 1.50 - 1.60 (m, 1H). Example S159. Synthesis of Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-fluoro-6-((1-methyl- 2-oxoindolin-5-yl) amino) pyrimidin-2-yl)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H- indazol-3-yl)-3-methylpiperidine-2,6-dione (159) [00674] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-fluoro-6-((1-methyl-2- oxoindolin-5-yl) amino) pyrimidin-2-yl)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H- indazol-3-yl)-3-methylpiperidine-2,6-dione. The title compound was synthesized according to General Procedure 6 using 3-(6-(((3R,4R)-3-methoxypiperidin-4-yl) amino)-1-methyl-1H- indazol-3-yl)-3-methylpiperidine-2,6-dione (150 mg, 0.30 mmol) and 5-((5-chloro-2,6- difluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (93 mg, 0.30 mmol) as starting materials. LCMS [M+H]⁺ found 676.2; ¹H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 9.00 (s, 1H), 7.52 - 7.44 (m, 3H), 6.98 - 6.91 (m, 1H), 6.62 - 6.55 (m, 1H), 6.50 - 6.41 (m, 1H), 6.02 - 5.83 (m, 1H), 4.12 - 4.07 (m, 1H), 3.92 - 3.84 (m, 1H), 3.80 (s, 3H), 3.52 - 3.47 (m, 5H) 3.35 - 3.25 (m, 3H), 3.25 - 3.14 (m, 2H), 3.11 (s, 3H), 2.48 - 2.39 (m, 2H), 2.11 - 1.98 (m, 2H), 1.59 (s, 3H), 1.45 - 1.35 (m, 1H). Formulation Example Example F1. Formulation of Compound 70. [00675] Compound 70 was selected for dosage form development. Compound 70 is a mixture of two diastereomers, Compound 71 and Compound 72. [00676] Film-coated tablets of Compound 70 were developed into two dosage forms: 20 mg and 80 mg. The 20-mg and 80-mg strength tablets contain a spray dried dispersion (SDD) of Compound 70 and the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, sodium stearyl fumarate, and Opadry film coating. The SDD contains 35% weight/weight (w/w) of Compound 70, prepared by spray drying a solution of Compound 70 and Eudragit L100-55 in dichloromethane and methanol. The 20-mg tablets are pinkish gray, round, biconvex, film-coated tablets, and the 80-mg tablets are pinkish gray, oval biconvex, film-coated tablets. The tablets are supplied in a tightly closed, high density polyethylene (HDPE) bottle with desiccant and child-resistant closure. Biological Examples Example B1. BCL6_HiBiT degradation assay. [00677] A DHL-4 cell line with HiBiT-tag knocked into endogenous BCL6 locus using CRISPR was generated. The DHL-4_BCL6_HiBiT cells were dispensed into 384-well plates (Corning no.3570) that were pre-spotted with compounds. Compounds were dispensed by an acoustic despenser (ATS acoustic transfer system from EDC Biosystems) into a 384-well plate in a 10-point dose response curve using 3-fold dilutions starting at 1-10 μM and going down to 0.0015-0.00015 μM. 25 μL of media (RPMI-1640 + 10% heat inactivated FBS + 1×Pen/Strep) containing 2500 of DHL-4 was dispensed per well. Assay plates were incubated at 37 °C with 5% CO2 for 2 hours. After incubation, 25 μL of the Nano-Glo HiBiT lytic detection working solution (Promega, catalogue no. N3040, Madison, WI) was added to each well and incubated at room temperature for 15-30 min, protected from light. After 30 min, luminescence was read on an Envision or PHERAstar luminescence reader. To determine the EC50 value (the half- maximum effective concentration) and the level of the gradation (Yconstant) of a BCL6 degrader, luminescent signal normalized by DMSO control (Y) and compound concentration (x) was fitted using a four-parameter dose−response model (Y= (A+((B-A)/1+((C/x)^D) in Dotmatics. Fitted value C is the degradation EC50 and the minimum value A is the Y constant. [00678] The degradation of BCL6 at 2 h in DHL-4 results are shown in Table 5, where EC₅₀ is the half maximal effect and Ycon is the % remaining maximal effect. Table 5.

†Data from 24h degradation assay Example B2. Phase I Study of Compound 70 Alone and in Combination with Anti- Lymphoma Agents in Relapsed/Refractory Non-Hodgkin Lymphomas (R/R NHL). [00679] This study is a multi-center, open-label, dose-finding, Phase 1 study to determine the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of Compound 70 in participants with R/R NHL. The study will be carried out in two parts. Dose Escalation (Part A) will evaluate escalating oral doses of Compound 70 to evaluate the safety, tolerability, and PK, and to guide the determination of the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) of Compound 70, as a single agent (Part A1) or in combination with rituximab (Part A2), in participants with diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Dose expansion (Part B) will further evaluate the safety, preliminary efficacy, and PK of Compound 70 administered at or below the MTD/OBD in one or more expansion cohorts to determine the recommended Phase 2 dose (RP2D) at one or more doses, as a single agent (Part B1) or in combination with anti-lymphoma agents (Part B2). Additional expansion cohorts assessing other combinations (Part B2) or selected patient populations (Part B3) may be considered. [00680] Participants will complete up to three study periods: screening (up to 28 days [+ 3 days]), treatment (up to 104 weeks [approximately 2 years]) from the first dose of study intervention regardless of treatment delays, and follow-up. The follow-up period includes Safety Follow-up (28 days [± 3 days] after the last dose of study intervention), Survival Follow-up (up to 156 weeks [approximately 3 years] from the first dose of study intervention) and the efficacy follow-up (up to 52 weeks [approximately 1 year]). The maximum duration of study participation will be approximately 160 weeks (approximately 3 years) (up to 4 weeks of screening, treatment of up to 104 weeks, and follow-up of up to 52 weeks). Part A1 involves BID dosing of Compound 70. QD dosing exploratory cohorts may be opened based on emerging safety, PK, and PD data; the starting dose will not exceed the dose that has been shown tolerated in BID dosing. [00681] Approximately 273 participants may be enrolled in total, including 73 participants in Part A (41 in part A1 and 32 in Part A2), and 200 evaluable participants in Part B (approximately 20 in each cohort: up to 80 in Part B1 and Part B2, and up to 40 in Part B3). [00682] Inclusion criteria include: • Participants must be 18 years of age or legal adult age according to the local regulation with R/R NHL (including DLBCL [e.g., DLBCL not otherwise specified (NOS) and diffuse large B-Cell lymphoma/high-grade B-Cell lymphoma with MYC and BCL2 rearrangements] and FL) with relapsed or refractory disease according to one of the following requirements, as applicable to each indication: − For R/R DLBCL (de novo) and FL 3b: following at least two prior lines of therapy (e.g., have received first-line combination chemotherapy regimen containing rituximab, anthracycline, an alkylating agent, and steroids and have received at least one additional [second line/salvage] treatment). − For R/R DLBCL (transformed lymphoma): following at least two prior lines of therapy which must have been administered after transformation; therefore, at least two standard treatment regimens for DLBCL must have been received. − For R/R FL (except for FL 3b): following at least two prior lines of therapy and meet treatment criteria at the time of enrollment (e.g., according to, but not restricted, Group d’Etude des Lymphomes Folliculaires [GELF] criteria).− Participant must have measurable disease, defined by at least one fluorodoxyglucose (FDG)-avid lesion for FDG-avid disease and one bi-dimensionally measurable disease on cross sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) with at least one lesion > 1.5 cm in the transverse diameter, as defined by the Lugano classification of NHL. Measurable disease cannot be previously irradiated. • Participant should have the following laboratory values: − Absolute neutrophil count ≥ 1 x 10⁹/L without growth factor support for 7 days (14 days if pegfilgrastim) − Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN) or ≤ 5.0 x ULN if liver involvement − Total bilirubin ≤ 1.5 x ULN − Potassium, magnesium, and calcium (corrected Ca or free [ionized] Ca) concentrations within normal range, or correctable with supplements − Platelet count ≥ 75 x 10⁹/L − Hemoglobin count ≥ 9 g/dL − Estimated serum creatinine clearance of ≥ 50 mL/min, using the modification of diet in renal disease (MDRD) method • Participant must accept and follow pregnancy prevention plan. [00683] Exclusion criteria include: • Participant with Eastern Cooperative Oncology Group (ECOG) performance status ≥ 3. • Participant with non-hematologic toxicity related to prior or current anticancer therapy, which is not resolved, returned to baseline, or Grade ≤ 2, or deemed irreversible. • Participant with known dysphagia, short-gut syndrome, gastroparesis, or other conditions/surgery that limit the ingestion or gastrointestinal absorption of drugs administered orally. • Participant with uncontrolled hypertension (systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg) or hypotension (systolic BP < 90 mm Hg or diastolic BP < 60 mm Hg) at screening or within 1 month prior to C1D1. • Clinically significant cardiovascular or cerebrovascular diseases, including any of the following: (i) Complete left bundle branch or bifascicular block or other clinically significant abnormal ECG finding at screening; (ii) History of congenital long QT syndrome; (iii) Persistent or clinically meaningful ventricular arrhythmias at screening; (iv) QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥ 470 msec on screening ECG; (v) Unstable angina, myocardial infarction, or stroke ≤ 6 months prior to starting study intervention or history of clinically significant arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes); (vi) Cardiovascular disability status of New York Heart Association Class ≥ 3 at screening (Class 3 is defined as cardiac disease resulting in marked limitation of physical activity, and participants are comfortable at rest but less than ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain); (vii) LVEF < 45% as determined by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan at Screening. • Inability to comply with restrictions, precautions and prohibited treatments. • Any condition, including significant acute or chronic medical illness, active or uncontrolled infection, or the presence of laboratory abnormalities, that places participants at unacceptable risk if participating in this study. • Participant with known SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to Cycle 1 Day 1. • History of concurrent second cancers requiring active, ongoing systemic treatment. • Participant with known or suspected central nervous system involvement or history of primary CNS lymphoma (including those in remission). • The following prior concomitant therapies: (i) Prior live virus vaccines ≤ 4 weeks prior to starting intervention. (ii) Prior COVID-19 vaccine within 7 days prior to starting intervention (for vaccines requiring more than 1 dose, the full series (e.g., both doses of a 2-dose series) should be completed by at least 7 days prior to starting study intervention when feasible and when a delay in starting study intervention would not put the study participant at risk; (iii) Participant has received prior systemic anticancer treatment (approved or investigational) ≤ 5 half-lives or 4 weeks prior to starting study intervention, whichever is shorter; (iv) Participant has received prior CAR-T or other T-cell targeting treatment (approved or investigational) ≤ 4 weeks prior to starting study intervention; (v) Participant has received prior therapy with cereblon (CRBN)-modulating drug (e.g., lenalidomide, avadomide, pomalidomide, CC-99282) ≤ 4 weeks prior to starting study intervention; (vi) Participant is on chronic systemic immunosuppressive therapy or corticosteroids (e.g., prednisone or equivalent exceeding 10 mg per day within the last 14 days) or participants with clinically significant graft-versus-host disease (GVHD), except: (a) Stable use of inhaled corticosteroids is allowed; (b) Use of topical steroids for ongoing skin and ocular GVHD is permitted. • Participant had prior autologous SCT ≤ 3 months prior to starting study intervention. If participant had prior autologous SCT > 3 months prior to starting study intervention, any treatment-related toxicity is unresolved (Grade > 2). • Participant had prior allogeneic SCT with either standard or reduced intensity conditioning ≤ 6 months prior to starting study intervention. If participant had prior allogeneic SCT > 6 months prior to starting study intervention, any treatment-related toxicity is unresolved (Grade > 2). • Participant had major surgery ≤ 2 weeks prior to starting study intervention. Participants must have recovered from any clinically significant effects of recent surgery. • Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population. • Participants with known seropositive or active infection with HIV, or active infection with hepatitis B virus (HBV) or hepatitis C virus, demonstrated by positive blood screen for hepatitis C antibody; hepatitis B surface antigen, and anti-hepatitis B surface antibody, or HIV-1 and HIV-2 antibody. • History of allergy to rituximab or to any of the excipients. [00684] Compound 70 will be administered orally continuously from Cycle 1 Day 1 onwards twice daily (BID) in 28-day cycle until clinically significant disease progression, unacceptable toxicity, or participant/physician decision to withdraw, for up to 2 years of total treatment. Alternative schedules include 21/28-day schedule and 14/28-day schedule, or once daily (QD) in any of these schedules. Rituximab will be administered per package insert and institutional standard practice at the fixed dose of 375 mg/m² for a maximum of six infusions (Cycles 1-6, Day 1). Survival follow-up is for up to 3 years (156 weeks) from the first treatment. Participants may be enrolled in the study for up to approximately 160 weeks (inclusive of screening, treatment, and follow-up periods). [00685] For Part A1, a Bayesian optimal interval (BOIN) design in Stage 1 will be followed by the TITE-BOIN12 design in Stage 2 to guide dose escalation decision-making and determination of MTD and/or OBD(s). Dose escalation/de-escalation decision will be guided by BOIN for Part A2. For Part B, participants will be randomized to expansion cohorts of approximately 20 evaluable participants per dose level/schedule each to receive Compound 70, alone or in combination with anti-lymphoma agents. DLT rate by dose level and frequency distribution of participants with adverse events (AE) will be presented. Summary statistics for PK parameters will be provided. Point estimate of ORR with 95% confidence interval (CI) will be produced by Clopper-Pearson method. Median of time to event endpoints (e.g., progression- free survival (PFS)) and 95% CI will be estimated using KM method. [00686] Escalating doses of Compound 70 will be evaluated in Part A. Provisional dosing cohorts for Compound 70 dose escalation are summarized in Table 6. The starting dose of Compound 70 in Part A1 will be 40 mg given orally BID. If the starting dose of Compound 70 is not tolerated, a lower dose level may be explored (e.g., Cohort -1, 20 mg BID). The provisional dose increments will follow a modified Fibonacci design from 80 mg BID and above, wherein the doses in consecutive dose cohorts may increase by 100%, 62.5%, 53.8%, 33%, etc. of the dose in the previous cohort. Smaller increments for dose escalation may be recommended upon consideration of all the available clinical data. QD dosing exploratory cohorts may be opened based on emerging safety, PK, and pharmacodynamic data; the starting dose will not exceed the total daily dose that has been shown tolerated in BID dosing. Alternative dose, schedule, and frequency may be proposed. In all cases, the recommended dose for the next cohort will not exceed an approximately 100% increase from the previous total daily dose. Table 6. [00687] The starting dose and schedule of Compound 70 in Part A2 will be determined based on emerging safety, PK, and pharmacodynamic data from Parts A1 and B1, and will be at least one dose level below the maximum Compound 70 monotherapy dose explored in Part B1. Data of a minimum of 25 participants treated at the OBDs in monotherapy will be utilized to determine the starting dose of Compound 70 in Part A2. [00688] Following completion of Dose Escalation, expansion may occur at the Compound 70 OBDs, and/or alternative tolerable dosing schedule, in multiple cohorts assigned in a randomized manner. The decision to perform the Dose Expansion at established dose levels and schedules will be based on (but not limited to) overall safety profile, preliminary positive signals of efficacy, and available PK/pharmacodynamic data. Approximately 20 participants per dose level/schedule and with adequate follow-up will be enrolled in Parts B1 and B2 to further evaluate the safety and efficacy of Compound 70 administered at the OBDs and/or lower dose levels and/or alternative schedules alone or in combination with rituximab. Two dose schedules will be assessed for each indication (Part B1) or each combination (Part B2). Data of participants treated at the OBDs and/or lower dose levels and/or alternative schedules in Dose Expansion may be combined with those treated at the same dose level, schedule, and treatment arm in Dose Escalation, if from the same population. Additional expansion cohorts assessing other combinations or selected patient population may be considered and would be included in Part B2 or Part B3 via a protocol amendment. A Bayesian continuous monitoring will be utilized to monitor the toxicities in the monotherapy and combination Expansion cohorts. [00689] Compound 70 will be administered orally continuously from Cycle 1 Day 1 (C1D1) onwards BID in a 28-day cycle. Alternative schedules include 21/28-day schedule (21 days on/7 days off) and 14/28-day schedule (14 days on/14 days off) in a 28-day cycle, or once daily (QD) dosing in any of these schedules. Participants receiving BID dosing must take Compound 70 tablets in the morning and in the night at approximately the same time each day. The interval between the 2 doses should be approximately 12 hours ± 2 hours. Participants receiving QD dosing will take Compound 70 in the morning, one time per day at approximately the same time each day. [00690] Participants should refrain from consumption of Seville oranges, grapefruit, or grapefruit juice, [pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices] from 5 days before the start of study intervention until 24 hours after the final dose of Compound 70. [00691] Participants in all groups are required to fast (nothing to eat or drink except water) for approximately 2 hours prior until 1 hour after administration of Compound 70. Under certain circumstances, the restrictions for avoidance of food and drinking (except for water) for 2 hours before and 1 hour after administration of Compound 70 may be allowed for participants. If the participant misses a dose of Compound 70, the dose may still be taken up to 6 hours for BID dosing (or up to 12 hours for QD dosing), after the time they would normally take it. If more than 6 hours (or 12 hours for QD dosing) have elapsed, they should be instructed to skip the missed dose. At the next scheduled dose, they should take Compound 70 at the usual time. Participants should not take 2 doses to make up for the one that they missed. [00692] If the participant vomits within 30 minutes of Compound 70 ingestion, Compound 70 tablets may be ingested again. If emesis occurs after 30 minutes of Compound 70, participants must not ingest additional Compound 70 tablets unless there is visibility of intact medication in the vomitus. [00693] Compound 70 can be taken for up to 104 weeks (approximately 2 years) or until clinically significant disease progression, unacceptable toxicity, or withdrawal of consent. Retreatment with Compound 70 may be considered, if the following criteria are met: (i) The participant discontinued treatment for reasons other than an AE, progression, or start of a new anti-lymphoma therapy, (ii) The participant achieved demonstrated response with Compound 70 based on The International Workshop Criteria for Malignant Lymphoma, (iii) The participant has evidence of disease relapse based on The International Workshop Criteria for Malignant Lymphoma during survival follow-up period, (iv) Eligibility continues to be met. Participants who are retreated will follow the Schedule of Activities starting with Cycle 1 Day 1 but may continue at their most recent dose level and schedule or dose level shown to be adequately tolerated by at least one cohort of participants in this study. Participants may be retreated only once during the study. [00694] Rituximab will be administered as an IV infusion at a dose of 375 mg/m² on Day 1 of Cycle 1 to Cycle 6. No dose reductions of rituximab are permitted. Rituximab can be administered with or up to 2 hours after the morning dose of Compound 70. [00695] Suggested body surface area estimate methods include Mosteller and DuBois. BSA = √ ((height (cm) x weight (kg))/3600) BSA = 0.20247 x height (m)0.725 x weight (kg)0.425 [00696] Premedication consisting of acetaminophen and an antihistamine should be administered before each rituximab infusion (refer to the current local rituximab prescribing information). Steroids may also be administered before the start of the rituximab infusion according to institutional practice. Surveillance measures during and after infusion of rituximab should be applied as recommended by the manufacturer and current guidelines. [00697] Rituximab may be administered in either an inpatient or outpatient clinical setting. For dose modifications, it is recommended to follow the package insert and local practice. Dose reductions are not allowed for rituximab. [00698] Participants that do not require dose interruptions are allowed to proceed to the next treatment cycle (eg, hematologic toxicities must be resolved to Grade ≤ 2). If rituximab dose is interrupted due to a study intervention-related toxicity, rituximab may be restarted once the toxicity has resolved to Grade ≤ 2. In Cycle 1, skipped dose for toxicity will not be rescheduled. In Cycles ≥ 2, a missed dose of rituximab can be made up within 2 weeks (i.e., Days 1 to 14 of the Cycle). If toxicity resolves to Grade ≤ 2 during Days 15 to 28 of the cycle, the rituximab dose will be restarted on Day 1 of the next cycle. Participants will be monitored closely during the entire infusion and for at least 1 hour post infusion with serial vital signs obtained and pulse oximetry performed. Additional blood tests to evaluate for a severe allergic reaction may be obtained within 15 to 60 minutes of onset of symptoms in participants with a Grade 4 infusion reaction or recurrent Grade 3 infusion reactions necessitating permanent rituximab discontinuation. Laboratory tests could include Immunoglobulin E (IgE), total tryptase, and plasma histamine. [00699] In the phase 1 study evaluating Compound 70, a series of pharmacodynamic, predictive, and exploratory biomarkers will be collected to facilitate dose/schedule selection, and potentially identify biomarkers to predict response and inform potential combinations. [00700] The main pharmacodynamic biomarker for Compound 70 is expected to be degradation of BCL6 protein. For this purpose, changes from baseline in the expression of BCL6 levels will be measured in peripheral blood mononuclear cells (PBMCs). BCL6 and downstream markers will be measured to identify potential markers of target engagement and response to Compound 70 in tumor cells using flow cytometry-based assays from samples collected via fine needle aspirate (FNA) or tumor biopsy. Longitudinal quantitation of circulating tumor deoxyribonucleic acid (ctDNA) and apoptosis in lymph node (LN) tumor cells will be performed as means to assess early effects of study treatment on overall tumor burden. To explore evolving immune responses and dose schedule effects of Compound 70 as single agent and combination with anti-lymphoma agents, immune-related assessments will include immune profiling of subsets of T-, B-, and NK cells as well as cytokine secretion that will be evaluated before and during treatment with Compound 70. Predictive markers of response to single agent Compound 70 and its combination with other anti-lymphoma agents will be explored at baseline and on study treatment. These studies will include the collection of paired tumor biopsies, pre- and on-treatment. Assays based on RNA expression profiling, BCL6 protein expression levels, and characterization of immune cell infiltration (e.g., T-cells, B-cells, macrophages, and/or NK cells) will be explored as potential predictors of response. Diagnostic biopsies will be also analyzed for gene expression signatures that may be associated with enriched response to Compound 70 as single-agent or in combination with other anti-lymphoma agents including downstream markers (e.g., c-Myc, NCOR1/2, PELI1) and biomarkers associated with poor prognosis (e.g., COO, c-Myc, BCL2 or BCL6 genetic rearrangements, c- Myc, BCL2 or BCL6 protein expression, mutational status of lymphoma associated genes, etc.). The biomarker assessments will be conducted according to the laboratory manual. [00701] Table 7 lists sample type and planned analytical technique for the various biomarker assessments planned. Table 7. Example B3. [00702] This example incorporates herein by reference in its entirety the disclosure of the Investigator’s Brochure (Version number: 01; Version date: 21-June-2023). [00703] Reference in Example B3 to sections, tables, references, and/or appendices is to other sections, tables, references, and/or appendices in Example B3. [00704] List of Abbreviations ADME absorption, distribution, metabolism, and excretion AE adverse event ALT alanine aminotransferase ANOVA analysis of variance AUC area under the concentration-time curve AUC(INF) area under the concentration-time curve from 0 to infinity BCL 6 B-cell lymphoma 6 BCRP breast cancer resistance protein BID twice a day BLQ below limit of quantification BMS Bristol-Myers Squibb BSA body surface area BSEP bile salt export pump BUN blood urea nitrogen Caco-2 Caucasian colon adenocarcinoma cell line Cmax maximum observed concentration CDX cell line-derived xenograft CELMoD cereblon E3 ligase modulating drug CLTp plasma clearance COO cell of origin CV coefficient of variation CYP human cytochrome P450 DBP diasystolic blood pressure DC50 half-maximal degradation concentration that makes a protein for 50% degradation DCN document control number DDI drug-drug interactions DLBCL diffuse large B cell lymphoma DMAC dimethyl acetamide ECG electrocardiogram EMA European Medicines Agency F absolute oral bioavailability FDA Food and Drug Administration FIH first in human FL follicular lymphoma FOB fecal occult blood fu unbound fraction fu,p unbound fraction in plasma GALT gut-associated lymphoid tissue GC germinal center GLP Good Laboratory Practice HDPE high density polyethylene HEK human embryonic kidney hiPSC-CM human induced pluripotent stem cell-derived cardiomyocytes HPLC high-performance liquid chromatography HNSTD highest non-severely toxic dose HPMC-AS-HF hydroxypropyl methylcellulose acetate succinate _IC50 concentration at which 50% inhibition observed ICH International Conference on Harmonisation IFN interferon IL interleukin IV intravenous Ka absorption rate constant KI inhibition constant Kinact rate of enzyme inactivation KLH keyhole limpet hemocyanin LC-MS/MS liquid chromatography tandem mass spectrometry LC-UV/MS liquid chromatography-ultraviolet spectroscopy/mass spectrometry LDD ligand directed degrader LLOQ lower limit of quantitation MAP mean arterial pressure MATE multidrug and toxin extrusion protein MDCK Madin-Darby Canine Kidney epithelial cells MDR1 multi-drug resistance 1 gene mRNA messenger ribonucleic acid MRP multidrug resistance-associated protein MRSD maximum recommended start dose MRT mean resident time MTD maximum tolerated dose NA not available NADPH nicotinamide adenine dinucleotide phosphate NHL non-Hodgkin lymphoma NK natural killer NOAEL no-observed-adverse-effect level OATP organic anion transporting polypeptides OCT organic cationic transporter OECD Organization for Economic Cooperation and Development P-gp P-glycoprotein PD pharmacodynamic PDX patient-derived xenograft PEG-400 polyethylene glycol 400 PK pharmacokinetic PMBL primary mediastinal B cell lymphoma PO oral QC quality control RBC red blood cell R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone R/R relapsed/refractory SBP systolic blood pressure SDD spray dried dispersion Sf9 Spodoptera frugiperda 9 STD10 severely toxic dose in ≤10% in animals T-HALF apparent terminal half-life Tfh T-helper cells Tmax time of maximum observed concentration THL/TEL Triple-Hit or Triple Expressor Lymphoma TK toxicokinetic TNF tumor necrosis factor UDP uridine diphosphate ULOQ upper limit of quantitation UGT glucuronosyl transferase US United States UV ultraviolet Vss volume of distribution at steady-state WBC white blood cell [00705] 1 Summary. This Investigator’s Brochure contains information about BMS-986458, a small molecule bifunctional cereblon-dependent ligand directed degrader (LDD) of BCL6, initially being developed for the treatment of patients with relapsed and/or refractory diffuse large B cell lymphoma (R/R DLBCL) and follicular lymphoma (R/R FL). DLBCL is an aggressive subtype of non-Hodgkin lymphoma (NHL) that collectively accounts for approximately 4% of all cancers in the United States (US) with an estimated 29,108 new cases in the US in 2020¹, representing 26% of all cases of NHL neoplasms diagnosed. R/R FL is the second most common lymphoma diagnosed in the US and Western Europe, accounting for approximately 22% of cases of NHLs, and 70% of indolent lymphomas.² [00706] BMS-986458 is a mixture of two diastereomers. Two of the three stereogenic centers in each isomer are of the (R) configuration. The third stereogenic center is of the (R) configuration in BMT-648592 and (S) configuration in BMT-648599. The individual isomers were also tested in pharmacokinetic and pharmacodynamic studies. The individual diastereomers show equivalent activities in all in vitro pharmacological testing conducted.³ Similar extent of tumor BCL6 degradation was observed in an OCI-LY-1 xenograft model in vivo for BMS-986458 and its individual diastereomers at the same dose level.¹⁵ Additional chiral analysis indicate that significant epimerization occurs in vivo in the mouse. [00707] Pharmacology, safety pharmacology, and pharmacokinetics (PK) evaluations have been conducted with BMS-986458. Pivotal Good Laboratory Practice (GLP)-compliant toxicity studies were conducted in rats and dogs using the oral route (intended route of administration in clinical trials) to assess and characterize the potential toxicity of BMS-986458. [00708] 1.1 Background. The current standard of care in DLBCL is an intensive immuno- chemotherapy regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The addition of monoclonal anti-CD20 rituximab to CHOP therapy led to a 15% increase in overall survival, but despite this improvement, 40% of patients eventually experience relapsed or refractory disease and represent a large area of unmet medical need.^4,5,6,7,8,9 [00709] Clinical studies have demonstrated many cytogenetic and mutational profiles associated with high-risk NHL, the most damaging of which is defined by perturbations involving a triad of oncogenes, c-Myc, BCL2 and BCL6, called Triple-Hit or Triple Expressor Lymphoma (THL/TEL). In THL/TEL, these factors are either genetically translocated within the immunoglobulin locus resulting in exogenous upregulation or exhibit a mutational signature with regulatory factors that drive oncogene over-expression or protein stabilization. Collectively, these oncogenes result in aberrant proliferation of transformed B cell lymphoma and resistance to therapeutic agents. [00710] BCL6 is a master transcriptional regulator that controls the B cell differentiation and antibody affinity maturation program. BCL6 expression in activated B cells is elevated upon transition into the Germinal Center (GC) and facilitates tolerance of the genotoxic stress associated with somatichypermutation and class-switch recombination, a process required for differentiation into plasma or memory B cells that express or secrete high affinity antibody B cell receptors. In the 20% of newly diagnosed DLBCL patients that express exogenous levels of BCL6, cell cycle checkpoint and DNA damage response pathways are pleiotropically repressed resulting in unregulated cell proliferation and malignant transformation. Degradation and genetic perturbation of BCL6 in DLBCL cell lines models have shown that upon de-repression of the downstream program, the cell cycle is arrested or compromised, and DNA damage response is activated, eventually leading to apoptosis and cell death. [00711] BMS-986458 potently and selectively degrades BCL6 in both DLBCL cell lines and normal immune cells. In vitro, BMS-986458 induces an acute apoptotic response in a subset of DLBCL cell lines that express high levels of BCL6 protein prevalent in Germinal Centre B cell (GCB) cell of origin (COO) models. In all cases the both the apoptotic and anti-proliferative response to BMS-986458 was significantly more potent than the cereblon E3 ligase modulating drug (CELMoD) lenalidomide. Enhanced sensitivity to BMS-986458 is observed in models of R/R DLBCL relative to controls. In addition to in vitro activity, BMS-986458 exhibits strong anti- tumor activity in vivo in two DLBCL cell line-derived xenograft (CDX) models as well as an anti- proliferative response from ex vivo patient-derived xenograft (PDX) models. [00712] 1.2 Nonclinical Pharmacology. BMS-986458 was evaluated in several in vitro NHL models and showed rapid and potent anti-proliferative and pro-apoptotic tumor cell killing in a broad spectrum of GCB and primary mediastinal B cell lymphoma (PMBL) subtypes of DLBCL. The anti-tumor response was also assessed in several models of acquired resistance to standard of care agent, doxorubicin, which displayed significant sensitization to BMS-986458 and transition from anti-proliferative to apoptotic response relative to the doxorubicin sensitive control. [00713] Broadly, the anti-tumor response to BMS-986458 was correlative to BCL6 expression levels and consequentially GCB sub-type models which are enriched in perturbations leading to BCL6 upregulation or protein stabilization. The nature of the response from cell line models expressing BCL6 was sub-divided into two categories, either an acute apoptotic or delayed anti-proliferative response. Acutely responsive lines showed apoptotic signaling within 5 days of compound treatment, whereas delayed-sensitizers displayed either a negligible or mild impact on proliferation after 5 days, which was then potentiated upon an additional 5 days of BMS-986458 exposure. Cell line models that did not express BCL6 did not display any loss of proliferative capacity upon extended compound exposure. [00714] The mechanism of action of BMS-986458 entails interacting with the CRL4CRBN E3 ubiquitin ligase substrate receptor cereblon (CRBN) to induce the recruitment of target protein BCL6. The subsequent ubiquitination of BCL6 triggers proteasomal destruction of the target leading to growth inhibition and induction of apoptosis. Furthermore, proteomic and mechanistic investigations demonstrate that BCL6 is the only substrate degraded by BMS- 986458 and modulation of several downstream pathways mediates the antiproliferative activity of BMS-986458 in the models of DLBCL evaluated. Within 24 h of drug treatment, key regulatory factors and anti-proliferative proteins are de-repressed; these include the cell cycle checkpoint inhibitors p27/CDKN1, and PTEN/SHP1, a critical inhibitory phosphatase. [00715] In vivo, the antitumor activity of BMS-986458 was evaluated in OCI-LY-1 and WSU-DLCL2 DLBCL xenograft models with twice a day (BID) dosing regimen, representing acute and delayed sensitive pre-clinical models, respectively. Initial pharmacokinetic/pharmacodynamic (PK/PD) studies in tumor-bearing mice established a clear correlation between tumor concentration of BMS-986458 and depth/duration of BCL6 degradation in tumor tissue. BID dosing regimen PK/PD studies resulted in plasma and tumor concentrations suitable for inducing near complete degradation (95% to 100%) of BCL6 in tumors through 24 h. In two DLBCL xenograft models, BMS-986458 exhibited antitumor activity in vivo, achieving significant tumor volume reductions (TVRs) with a BID dosing paradigm. This TVR correlated with PK exposure and depth/duration of BCL6 degradation. PK and PD analysis of tumors collected at the end of these studies revealed substantial plasma and tumor concentrations of BMS-986458 and that a continuous degradation of ≥ 95% tumor BCL6 appears to be necessary to show a minimum of approximately 65% tumor volume reduction in the OCI-LY-1 xenograft model. This degree of tumor BCL6 degradation and the corresponding antitumor response could be achieved with repeat BID dosing of 15-30 mg/kg BMS-986458 in the OCI-LY-1 xenograft model. A similar extent of tumor BCL6 degradation was observed in an OCI-LY-1 xenograft model in vivo for BMS-986458 and its individual diastereomers at the same dose level. In addition, similar responses were observed in the WSU-DLCL-2 xenograft model in vivo at the same dose level. Additional chiral analysis indicates that significant epimerization occurs in vivo in the mouse. [00716] Within the GC, B cells circulate between dark and light zones as they undergo successive rounds of affinity maturation. In the light zone, B cells interact with follicular T- helper cells (Tfh) where through cell-cell interaction and cytokine signaling they facilitate selection and survival of high affinity clones. Tfh cells are also required to maintain the structure of the GC and are therefore essential for high affinity antibody generation upon immune challenge. Subtypes of NHL such as follicular lymphoma (FL) that proliferate within the lymph node depend on Tfh support for survival. BCL6 is a lineage defining factor of Tfh cells, required to maintain cell identity and function within the GC. The impact of BMS-986458 on the induced Tfh populations was evaluated in vitro, where it was shown that degradation of BCL6 results in penetrant loss of Tfh cellular identity through the expression of canonical markers CXCR5 and PD1. [00717] Although the molecular pathways downstream of BCL6 degradation are critical for lymphoid differentiation and function, there is potential for underlying biology in other immune populations. Neutropenia is a common grade II AE observed in many current hematological therapeutics; therefore, the impact of BMS-986458 treatment on neutrophil viability and maturation pathways was assessed in vitro. No loss of viability of CD34+CD33-CD11b- cell maturation up to the CD34-CD33-CD11b+ stage was observed at clinically relevant concentrations over vehicle control. [00718] 1.3 Nonclinical Pharmacokinetics. In vitro and in vivo studies have been conducted to characterize the absorption, PK, distribution, metabolism and drug interaction potential of BMS-986458. [00719] In mice, rats, dogs, and monkeys, BMS-986458 showed low to moderate systemic clearance (≤44% of liver blood flow), low to moderate volume of distribution at steady state (Vss; 0.4- to 3.5-fold of total body water volume), moderate oral bioavailability (22% to 37%) with corresponding apparent terminal half-life ranging from 0.9 to 5.5 hours. In addition, substantial interconversion (up to 41% based on AUC) between diastereomers of BMS-986458 (BMT-648592 or BMT-648599) was observed in rat, dog, and monkey following IV infusion or PO administration of individual diastereomers. [00720] BMS-986458 is highly bound to plasma proteins with unbound fraction (fu) <1% in mouse, rat, rabbit, dog, monkey, and human. Species differences (5.3×) in fu were observed between human and dog, whereas no substantial differences (≤ 2×) were observed between human vs rat or rabbit. Following 10 to 300 mg/kg single oral doses to Sprague-Dawley rats, brain BMS-986458 concentrations were < 0.22 µM (brain/plasma ratios were ≤ 0.10 at ≥ 100 mg/kg and could not be appropriately assessed at ≤ 30 mg/kg due to low or unmeasurable concentrations at 24 and 48 hours post dose in female and male rats, respectively, indicating minimum penetration across the blood-brain barrier. [00721] Metabolism of BMS-986458 was evaluated in human hepatocytes, as well as hepatocytes from preclinical species, and in plasma samples from rats and dogs following oral administration. The predominant metabolic pathways for BMS-986458 across the species tested included demethylation, oxidation followed by glucuronidation, and hydrolysis. BMS-986458 is the major drug-related circulating compound in rat and dog plasma. Although there were quantitative differences in the formation of metabolites across species, qualitatively all metabolites formed in human hepatocytes were also formed in hepatocytes from rat and/or dog, the two species used for preclinical safety testing, indicating that there were no unique human metabolites. [00722] Reaction phenotyping studies of human cytochrome P450 (CYP) isoforms and human liver microsomes showed that BMS-986458 is predominantly metabolized by CYP3A4/5 with minor participation from CYP1A2, CYP2C8, CYP2C9, and CYP2C19. In vitro, BMS- 986458 demonstrated time-dependent inhibition of CYP3A4 with the rate of enzyme inactivation (kinact) of 0.054/min and the inhibition constant (KI) of 28 μM. In human hepatocytes, BMS-986458 showed weak induction of CYP1A2 and no induction of CYP3A4 or CYP2B6, up to 20 µM. These data suggest that the potential for drug-drug interactions (DDI) exist if BMS-986458 is co-administered with strong inhibitors or inducers of CYP3A4, sensitive CYP3A substrates, or CYP3A substrates with a narrow therapeutic window. [00723] Additionally, BMS-986458 showed inhibition of uridine diphosphate (UDP)- glucuronosyl transferase (UGT) 1A1 with an IC50 of 0.15 µM. [00724] In vitro assays showed that BMS-986458 was a substrate of efflux transporter P- glycoprotein (P-gp) and likely a substrate of breast cancer resistance protein (BCRP). BMS- 986458 was also an inhibitor of P-gp and BCRP, with half maximal inhibitory concentration (IC50) values of 3.3 and 1.6 µM, respectively. These data suggest that there is the potential for BMS-986458 to cause inhibition of P-gp and/or BCRP in the gut, and absorption of BMS- 986458 may be increased in the presence of P-gp inhibitors. [00725] In addition, BMS-986458 showed inhibition of multiple hepatobiliary and renal transporters: organic anion transporting polypeptides (OATP) 1B1, OATP1B3, multidrug resistance-associated protein (MRP) 2, organic cationic transporter (OCT) 1, OCT2, bile salt export pump (BSEP), multidrug and toxin extrusion protein (MATE)1, and MATE2K, with IC50 values ranging from 0.29 to 9.5 µM. Overall, based on the expected clinical exposures, (within the projected efficacious dose range), the potential for systemic interactions with these drug transporters appears low. However, DDI potential will be continuously evaluated as clinical exposures are available. [00726] 1.4 Nonclinical Toxicology. The nonclinical toxicology of BMS-986458 (mixture of diastereomers BMT-648592 and BMT-648599) was evaluated in a comprehensive battery of nonclinical toxicity studies that included single-dose and repeat-dose toxicity studies of up to 28 days duration with BID dosing in rats and dogs, in vitro and in vivo genetic toxicity studies, an in vitro phototoxicity study, and in vitro and in vivo cardiovascular safety pharmacology studies. Exposure multiples shown below are calculated to the predicted exposures (AUC and Cmax) at the proposed 40 mg BID starting clinical dose. Cmax multiples have been corrected for free fraction using predicted species differences in protein binding using flux method and by assuming 99% protein binding for in vitro assays. [00727] The potential for BMS-986458 to affect the cardiovascular system has been characterized in vitro and in vivo. BMS-986458, BMT-648592 and BMT-648599 inhibited cardiac ion channels in vitro at generally comparable concentrations with hERG IC50s of 0.44, 0.52, and 0.16 µg/mL (0.7, 0.83, and 0.25 µM), respectively (519× for BMS-986458). BMT- 648592 and BMT-648599 inhibited cardiac L-type calcium channels by 9.4% and 7.4%, respectively, at the highest tested concentration of 0.628 µg/mL (1 µM). In a multi-electrode assay in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), BMS- 986458 increased field potential duration (FPDc), arrhythmic beats, and decreased conduction velocity at concentrations ≥ 0.19 µg/mL (0.3 µM; 224x) and increases in beat rate were observed at 1.9 µg/mL (3 µM; 2240×). In an exploratory rabbit electrophysiology study, increases in QTc interval (QT corrected for Fridericia [QTcF] = 51.2 ms; QT corrected for Van de Water’s [QTcV] = 24.4 ms) were noted at 12 mg/kg BMS-986458 (free plasma concentration = 1.16 µg/mL, 0.729 µM; 1365×) administered by IV infusion, but interpretation was confounded by increases in heart rate (34%) and decreases in mean blood pressure (-34%). In nonGLP studies in telemetered rats and dogs and in the 1-month GLP rat and dog studies, no BMS-986458-related cardiac, neurologic, and/or respiratory findings were noted at doses up to 500 mg/kg/BID in rats (free Cmax = 0.194 µg/mL; 228×) and 50 mg/kg BID in dogs (free Cmax = 0.866 µg/mL; 192×). [00728] In vitro, BMS-986458, BMT-648592 and BMT-648599 were negative for mutagenicity in Ames assays, but positive for clastogenicity and aneugenicity in the presence or absence of S9 fraction in exploratory in vitro assays in CHO and/or TK6 cells. In a nonGLP 2- week rat toxicity study and in a standalone GLP-compliant in vivo genetic toxicity study, no BMS-986458-related effects on peripheral micronucleus or COMET (duodenum and liver) assays were noted at daily doses up to 500 mg/kg BID, respectively, indicating that BMS- 986458 is not genotoxic in vivo. [00729] In a GLP-compliant neutral red uptake phototoxicity assay in Balb/c 3T3 mouse fibroblasts, BMS-986458 was positive for phototoxic potential. Follow up confirmation of phototoxic potential in an in vivo study will be carried out. [00730] Repeat-dose toxicity studies of up to 1 month in duration were conducted in rats and dogs. In the pivotal 1-month oral toxicity study in rats (doses of 50, 150, and 500 mg/kg BID), there were no adverse findings up to the high dose of 500 mg/kg BID (1000 mg/kg/day total). Therefore, 500 mg/kg BID was considered the no-observed-adverse-effect level (NOAEL). In the pivotal 1-month oral toxicity study in dogs, BMS-986458 was administered orally at doses of 0, 5, 15, and 50 mg/kg BID. At the dose of 50 mg/kg BID, decreases in food consumption were noted on Day 1 leading to body weight loss and decline in clinical condition requiring early euthanasia of 3 of 10 dogs on Day 7 without clear cause of the clinical decline. All other dogs at 50 mg/kg BID survived to scheduled necropsy without significant clinical signs. There were no other adverse findings and BMS-986458 was well tolerated at doses ≤ 15 mg/kg BID. Therefore, the NOAEL and highest non-severely toxic dose (HNSTD) were considered to be 15 mg/kg BID. [00731] In the repeat dose toxicity studies, several dose-responsive, non-adverse findings were observed in rats and dogs. Consistent with the role of BCL6 as a regulator of the immune system,^10,11 immunosuppressive and pro-inflammatory changes were observed in rats and dogs including increases in circulating WBC, neutrophils, lymphocytes, and T, B, and/or natural killer (NK) cells; decreases in anti-keyhole limpet hemocyanin (KLH) IgM and/or IgG antibody production; decreases in cytokines in rats only (interleukin [IL]-1β,IL-2, IL6, tumor necrosis factor [TNF]α, interferon [IFN]γ); decreases in lymphoid cellularity in thymus, gut-associated lymphoid tissue (GALT), and lymph nodes (dogs) or splenic marginal zone (rats); and mixed cell inflammation of the femorotibial joint in 4 dogs as well as minimal neutrophilic inflammation in the atrioventricular valve of 1 dog (both findings at high dose only). These findings are consistent with the published role of BCL6 as a master regulator of the immune system. Decreased red blood cell (RBC) parameters with regenerative response were observed in both species. In rats, increases in platelets were observed with no consistent change in coagulation parameters across studies. Increases in bilirubin were noted in dogs without microscopic correlates or increases in transaminases and was potentially mediated by UGT1A1 inhibition. Liver hypertrophy and increased weights were observed in both species with observed findings in rats correlating with enzyme induction and secondary thyroid epithelium hypertrophy. In dogs, inconsistent changes in fecal composition and positive fecal occult blood (FOB) tests were observed without correlating gastrointestinal pathology. Minor renal effects without pathologic correlates were noted in both species with increases in kidney weights in dogs and mild increases in blood urea nitrogen (BUN) in rats. Lastly, minimal hypertrophy in the zona fasciculata was observed in rats. [00732] BMS-986458 does not degrade classical CELMoD neosubstrates, such as Aiolos, CK1α, Ikaros, GSPT1, and SALL4. Therefore, the BMS-986458 toxicity profile is anticipated to be differentiated from CELMoDs, including potential reproductive toxicity. However, as reproductive toxicity assessments have not been conducted to date and the mechanism of BMS- 986458 is cereblon-dependent, BMS-986458 will be treated as a presumed selective developmental toxicant. [00733] Overall, the nonclinical toxicology assessment supports progression of BMS-986458 into clinical trials. [00734] 1.5 First-in-Human Clinical Study. Study CA123-1000 is a multi-center, open- label, dose-finding, Phase 1 study to determine the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of BMS-986458 in participants with R/R NHL. The study will be carried out in 2 parts. Dose Escalation (Part A) will evaluate escalating oral doses of BMS- 986458 to evaluate the safety, tolerability, and PK, and to guide the determination of the maximum tolerated dose (MTD) and/or OBD of BMS-986458, as a single agent or in combination with rituximab, in participants with DLBCL and FL. Dose expansion (Part B) will further evaluate the safety, preliminary efficacy, and PK of BMS-986458 administered at or below the MTD/OBD in one or more expansion cohorts to determine the RP2D at one or more doses, as a single agent or in combination with anti-lymphoma agents. [00735] 2 Introduction. BMS-986458 is under development for the treatment of R/R DLBCL and R/R FL. [00736] There are a few agents that have shown promise for the treatment of hematologic malignancies. Subjects with R/R NHL and FL represent a heterogeneous population with a poor life expectancy. In vitro, BMS-986458 has demonstrated multiple pharmacological activities including antiproliferative effects and potent induction of apoptosis in diffuse large B cell lymphoma (DLBCL) cell lines including cell lines that have acquired doxorubicin resistance. BMS-986458 has also demonstrated strong immunomodulatory activity in normal lymphocytes such as T-follicular helper populations. In vivo, BMS-986458 has demonstrated potent antitumor activity in multiple DLBCL xenograft models. [00737] 3 Physical/Chemical and Pharmaceutical Properties and Formulation [00738] 3.1 Physical/Chemical Properties. BMS-986458-01 was selected for dosage form development and is also referred to as BMS-986458. The drug substance is a mixture of 2 diastereomers, BMT-648592 and BMT-648599. Two of the three stereogenic centers in each isomer are of the (R) configuration. The third stereogenic center is of the (R) configuration in BMT-648592 and (S) configuration in BMT-648599. The physical and chemical properties of BMS-986458-01 drug substance are provided in Table 3.1-1.

Table B3-3.1-1: Physical and Chemical Properties

[00739] 3.2 Pharmaceutical Properties and Formulation

[00740] 3.2.1 Description of the Dosage Form

[00741] BMS-986458-01 Film Coated Tablets, 20 mg and 80 mg. BMS-986458-01 fdm coated tablets are used in clinical studies. The 20 mg and 80 mg fdm coated tablets are described in Table 3.2.1-1.

[00742] The 20-mg and 80-mg strength tablets contain BMS-986458-01 spray dried dispersion (SDD) and the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, sodium stearyl fumarate, and Opadry fdm coating. BMS- 986458-01 SDD contains 35% w/w of BMS-986458-01 drug substance, prepared by spray drying a solution of dmg substance and Eudragit L100-55 in dichloromethane and methanol. The tablets are supplied in a tightly closed, high density polyethylene (HDPE) bottle with desiccant and child-resistant closure.

Table B3.2.1-1: Descriptions for BMS-986458-01 Film Coated Tablets

[00743] 3.2.2 Drug Product Preparation

[00744] BMS-986458-01 Film Coated Tablets, 20 mg and 80 mg. No preparation is required for BMS-986458-01 fdm coated tablets.

[00745] 3.2.3 Recommended Storage and Use Conditions [00746] BMS-986458-01 Film Coated Tablets, 20 mg and 80 mg. BMS-986458-01 film coated tablets should be stored at 2°C to 8°C (36°F to 46°F) in a tightly closed HDPE container with protection from light. [00747] 4 Nonclinical Studies. A series of nonclinical primary and secondary pharmacology, safety pharmacology, PK, and toxicology studies have been conducted with BMS-986458. A summary of these studies is provided in the sections below. [00748] 4.1 Nonclinical Pharmacology [00749] 4.1.1 Primary Pharmacodynamics [00750] 4.1.1.1 In Vitro Pharmacology [00751] Endogenous degradation dynamics in OCI-LY-1 Model. BMS-986458 is a potent and highly selective CRBN-dependent LDD against the oncogenic target BCL6. Using MSD-ECL assay to measure BCL6 protein levels, following up to a 4 hr exposure in different in vitro models, the concentration at half maximal degradation (DC50) was determined as 0.12 nM ± 0.0018 (FIG.1; FIG.2A and 2B). The DC50 was independently assessed in individual distereoisomers BMT-648592 and BMT-648599. After a 2 hr incubation, the BCL6 degradation profile was similar, with BMT-648599 showing a 20-fold difference in potency vs BMT-648592 (DC50 = 1.6 ± 1.1 nM vs 0.08 ± 0.06 nM, respectively) (dose response from representative experiment shown in FIG.2C). The anti-proliferative response was assessed for both isomers and it was demonstrated that despite the shift in degradation potency at 2 h, the impact on proliferation over a 5-day period was not significantly different between isomers and the diastereomeric mixture, likely as a result of epimerization to equivalent ratio under the experimental conditions (FIG.2D). [00752] In the OCI-LY-1 model, which expresses a high level of BCL6 protein due to a THL classification, a single 10 nM dose of BMS-986458 degraded greater than 90% of BCL6 protein in less than 0.5 h, and maintained protein at maximally decreased levels for at least 5 days as assessed by western blot (FIG.2F and 2G). [00753] The anti-proliferative effect of BMS-986458 exposure was confirmed as CRBN- dependent as no loss of proliferative capacity from 5-day LDD treatment was observed in OCI- LY-1^CRBN-/- relative to vehicle as determined by CellTiter-Glo® luminescent cell viability assay (CTG) (FIG.2H). [00754] Proteomic Evaluation in OCI-LY-1 Model Following 4hr and 24hr Exposure. Selectivity of BMS-986458 was assessed in OCI-LY-1 cells using mass spectrometry whole proteome analysis. Following a 4 hr exposure using 100 nM BMS-986458, BCL6 was the only significantly degraded substrate. Historic neo-substrates impacted by CRBN-mediated degraders were not detected above statistical thresholds. Assessment of BMS-986458 under the same conditions at 24 h demonstrated significant alteration in the abundance of numerous proteins known to be directly regulated by BCL6 such as the de-repression of the cell cycle checkpoint ^{inhibitor p27/CDKN1B, and the regulatory phosphatase SHP-1/PTPN112,13 (FIG. 3).} [00755] Anti-Proliferative and Pro-Apoptotic Response in BMS-986458 DLBCL Cell Line Models. Twenty DLBCL cell line models were evaluated for anti-proliferative response following exposure to a BMS-986458 dose range spanning 0.015-100 nM and assessed using CTG, after which the Area Under the Curve (AUC) was used to quantify the depth of response. This evaluation was initially performed over 120 hr incubation with BMS-986458. Under these conditions, 3 out of 20 cell lines (15%) displayed greater than two-fold loss of proliferative capacity (AUC < 5 μM • h) and were classified as acutely sensitive. A milder response (AUC < 7 μM • h) was observed in an additional 15% of cell line models. This assessment was also performed following extended LDD exposure that incorporated a 5-day pre-incubation period with 10 nM BMS-986458, previously demonstrated to maintain 100% BCL6 loss for 120 h (FIG.4). The impact of the initial 5-day response was measured and incorporated in the T120/T0 DMSO CTG signal correction factor. After a total of 240 h exposure a further ten lines exhibited an AUC < 7 μM • h and were classified as delayed responsive. The total response rate to BMS- 986458 over 10 days, incorporating both acutely sensitive and delayed response was 65%. Ten of the responsive lines (acute and delayed) were further assessed for apoptotic response by AnnexinV+DRAQ+ staining. Following 5-day BMS-986458 treatment it was observed that only the acutely responsive lines induced apoptosis (FIG.5), indicating the delayed response was primarily cytostatic. [00756] The impact of baseline BCL6 substrate expression on the depth of BMS-986458 response was evaluated. Western blot protein analysis was performed on a large panel of cell line models and BCL6 expression was quantified. When compared with BMS-98645810-day response AUC this was found to be correlative, equating to a R² Pearson’s Correlation factor of 0.416. Of note, several cell line models displayed significantly more sensitivity than expected given a relatively low BCL6 baseline expression (FIG.6) [00757] In vitro response to BMS-986458 in Engineered Doxorubicin-resistant Models. The apoptotic response to BMS-986458 was evaluated in three paired DLBCL engineered cell line models that display acquired doxorubicin resistance, which was obtained following incubation with sub-lethal doses for several months¹⁴. Following a 5-day assay, the proliferation IC50 for doxorubicin was approximately 1 µM as expected. However, the response to BMS-986458 was significantly shifted (FIG.7). In SUDHL-4 and U2932, the AUC was decreased by at least 30%, indicating that these models displayed increased sensitivity to BCL6 degradation. In all doxorubicin resistant (DoxR) models (including WSU-DLCL-2-DoxR where the proliferative response to BMS-986458 was more resistant than the parent), there was a greater than two-fold increase in apoptotic induction as assessed by AUC. This indicates a significantly shifted dependency on BCL6 and the pathways activated upon its degradation within these models. Western blot protein analysis of a short exposure time course was used to confirm target degradation and evaluate key BCL6 downstream biomarkers (FIG.7). Analysis of baseline MDR1 expression demonstrated this membrane transporter as the primary driver of doxorubicin resistance, also leading to compromised BCL6 degradation. Despite this attenuated degradation response, several canonical BCL6 downstream biomarkers were still modulated in the DoxR lines, including p27/CDKN1B and SHP-1/PTPN6. However, major changes were observed in baseline expression and proliferative signaling activation including constitutively active [00758] AKT^ser473 in SUDHL-4^DoxR (present due to loss of PTEN expression) that was then down-regulated following BMS-986458 treatment. A common observation across all DoxR models were aberrations involving anti-apoptotic protein Bcl-2, either through loss of baseline expression or attenuated BMS-986458-dependent induction. Collectively, this partially explains the universal transition to apoptotic response following BMS-986458 treatment in the DoxR versus parental cell line models. [00759] 4.1.1.2 In Vivo Pharmacology. The objectives of the in vivo pharmacology studies were to determine the extent of BCL6 degradation activity and subsequent single agent antitumor activity of BMS-986458 in cell line derived DLBCL xenograft models. These studies included PK and PD studies to determine intratumoral degradation kinetics of BCL6 in correlation with plasma and tumor BMS-986458 concentrations, and single agent antitumor activity in OCI-LY-1 and WSU-DLCL-2 subcutaneous xenograft models. [00760] Pharmacokinetics, Pharmacodynamics and Antitumor Activities of BMS-986458 in OCI-LY-1 Xenograft Model. To evaluate the pharmacodynamic impact of BMS-986458 in vivo, intratumoral levels of BCL6 were determined and quantified using western blots in a short-term 3-day or 5-day PK/PD study with once a day (QD) or BID dosing in the OCI-LY-1 xenograft model. The PK/PD relationship established for BMS-986458 exposure in plasma and tumor and BCL6 degradation (PD marker). The PK/PD relationship was studied at 30 and 60 mg/kg. Dose- and time-dependent exposure of BMS-986458 and concomitant degradation of BCL6 was observed in OCI-LY-1 tumors. Some variability in PK was observed for the same doses, but PK and PD correlated with each other. [00761] Multiple PK/PD studies were designed to evaluate PK and PD parameters with BID dosing of BMS-986458 at 30 mg/kg for 5 consecutive (Study AP9506)¹⁵ or 3 consecutive days (Study AP9721)¹⁵ or QD dosing at 60 mg/kg for 3 consecutive days (Study 06E26-0023).¹⁵ Plasma and tumor BMS-986458 concentrations, along with degradation kinetics of BCL6 were evaluated. Significant degradation of intratumoral BCL6 following five consecutive days of twice daily dosing at 30 mg/kg (90% to 99%) was observed (FIG.8). During this time, the plasma BMS-986458 concentrations ranged between 0.00773 and 5.25 μM. The tumor BMS- 986458 concentrations ranged between 0.0354 and 0.873 μM (Table 4.1.1.2-1). Similarly, there was a significant degradation (97% to 98%) of intratumoral BCL6 following three consecutive days of twice daily dosing (FIG.8 and Table 4.1.1.2-1) when the plasma BMS-986458 concentrations ranged between 2.39 and 0.809 μM. The tumor BMS-986458 concentrations ranged between 1.26 and 0.202 μM (Table 4.1.1.2-1). With QD dosing, significant and sustained degradation of intratumoral BCL6 was observed through 24 h (91% to 98%) with plasma BMS- 986458 concentrations ranging between 11.360 and 0.223 μM. The tumor BMS-986458 concentrations ranged between 3.243 and 0.043 μM. Both the BID at 30 mg/kg (AP9721)¹⁵ and corresponding QD 60 mg/kg (06E26-0023)¹⁵ doses led to similar levels of BCL6 degradation. Table B3-4.1.1.2-1: Plasma/Tumor Exposures of BMS-986458 and Percent BCL6 Degradation in OCI-LY-1 Xenografts following BID × 5, BID × 3, or QD × 3 Dosing [00762] In summary, data from PK/PD studies in the OCI-LY-1 tumor model indicate that plasma and tumor BMS-986458 exposure was variable between studies, and this was possibly due to lot-to-lot variation and forms of the compound. Considering the variation, a plasma BMS- 986458 concentration of >2.4 μM at 10 h post-dose with BID dosing would result in a continuous tumor BMS-986458 concentration of > 0.04 μM. These exposures resulted in a > 90% BCL6 degradationin OCI-LY-1 tumors. Over 97% tumor BCL6 degradation could be achieved when the plasma and tumor concentrations were maintained > 0.8 μM and > 0.2 μM, respectively. [00763] The individual isomers were also tested in pharmacokinetic and pharmacodynamic studies. The individual diastereomers showed equivalent activities in all in vitro pharmacological testing conducted.³ Similar extents of tumor BCL6 degradation were observed in an OCI-LY-1 xenograft model in vivo for BMS-986458 and its individual diastereomers at the same dose level (OG00457).¹⁵ Additional chiral analysis of the exposure results also indicate that significant epimerization occurs in vivo in the mouse, with BMT-648599 being slightly more susceptible to epimerization in mouse than BMT-648592. [00764] The single-agent antitumor activity of BMS-986458 was tested in the OCI-LY-1 xenograft model with BID dosing at 15, 30 and 60 mg/kg (AP9553).¹⁵ A single cycle of CHOP therapy (combination of cyclophosphamide - single dose on day 1; doxorubicin - single dose on day 1; vincristine - single dose on day 1; and prednisone - QD dosing for 5 doses [QD × 5] on Days 1 to 5) was used as the positive control in this model. Significant (p < 0.0001) dose- dependent antitumor activity of BMS-986458 was observed with a tumor volume reduction of 53%, 62%, and 76% at 15, 30, and 60 mg/kg BID, respectively. Plasma and tumor samples collected at the termination of the response study showed a deep (95% to 99%) and statistically significant (p < 0.0001) BCL6 degradation at the 2 and 10 h time point post last dose with all doses of BMS- 986458 tested in this response study. Pharmacokinetic data from these samples indicate that continuous degradation of BCL6 ≥ 97%, which can be achieved with > 0.24 μM plasma and > 0.15 μM tumor BMS-986458 concentration at 10 h post-dose twice a day, confers to efficacy over 62% TVR in OCI-LY-1 xenograft model. Table B3-4.1.1.2-2: Percentage of Tumor Volume Reduction, Plasma/Tumor Exposures of BMS-986458 and Percent BCL6 Degradation in OCI-LY-1 Xenografts Following Twice Daily Dosing for 19 Consecutive Days (AP9553) [00765] In an additional study (AP9742),¹⁵ antitumor activities of BMS-986458 and its isomers, BMT-648592 and BMT-648599, were evaluated in the OCI-LY-1 xenograft model at 30 and 60 mg/kg with BID dosing. When compared with vehicle control, BMS-986458 and both isomers showed significant antitumor activity with a TVR of 60% and 64% for BMS-986458, 48% and 83% for BMT-648592 and 54% and 66% for BMT-648599 at 30 and 60 mg/kg, respectively (OG00457).¹⁵ In comparison with BMS-986458, no significant difference in the antitumor activity of BMT-648599 was observed at 30 mg/kg. The antitumor activity of BMT- 648592 at a higher dose (60 mg/kg) was significantly (p < 0.01) better than BMS-986458 at the corresponding dose level. The extent of BCL6 degradation was also assessed from the samples collected from the groups dosed with BMS-986458 and the isomers (BMT-964592 and BMT- 964599). Similar to BMT-986458, deep degradation of BCL6 was observed with isomers BMT- 648592 and BMT-648599 in OCI-LY-1 tumors. Similar depth of degradation (94% to 100%) was observed at the 6, 10, and 14 h timepoints for all three compounds. Additional chiral analysis of the exposure results also indicate that significant epimerization occurs in vivo in the mouse. Overall, the plasma and tumor BMS-986458 concentrations and antitumor activity in this OCI-LY-1 study appears moderately different than other OCI-LY-1 xenograft studies. The antitumor response with test compound or positive control (CHOP therapy) in the current study was lower than other studies at the corresponding dose level (OG00457).¹⁵ [00766] In a subsequent dose-response study (AP9776),¹⁵ BMS-986458 was tested in the OCI-LY-1 xenograft model at 15, 45, and 60 mg/kg BID. Significant (p < 0.0001) single-agent dose-dependent antitumor activity was observed at 15 mg/kg and 45 mg/kg with tumor volume reductions of 67% and 84%, respectively. Similar anti-tumor activity (84% TVR) was observed with BMS-986458 dosed at 45 and 60 mg/kg, BID (FIG.9 and Table 4.1.1.2-3). The minimum efficacious dose in this study (as defined by approximately 65% tumor volume reduction) was the 15 mg/kg BID dose level. [00767] Consistent with findings from AP9553 and AP9742,¹⁵ deep and statistically significant BCL6 degradation was observed in the OCI-LY-1 tumors collected at the termination of the study. At the 6 h time point, 98%, 99%, and 99% BCL6 degradation was achieved with the 15, 45, and 60 mg/kg BID doses of BMS-986458, respectively. Furthermore, 98%, 100%, and 99% BCL6 degradation was observed at the 10 h time point with the 15, 45, and 60 mg/kg BID doses, respectively (FIG.10). At the 14 h time point, 95%, 100%, and 100% BCL6 degradation was observed with the 15, 45, and 60 mg/kg BID doses of BMS-986458, respectively (Table 4.1.1.2-3). This pharmacodynamic data along with plasma and tumor BMS-986458 concentration analysis indicates that all three dose levels of BMS-986458 used in this study resulted in near complete BCL6 degradation (95% to 100%). The calculated plasma AUC_{(0-24 h)} values for each BMS-986458 dose group were 26.1, 137.2, and 256 at μM∙h/mL for 15, 45 and 60 mg/kg BID, respectively (Table 4.1.1.2-3). A sustained degradation of > 95% with plasma and tumor continuous concentrations of > 0.07 and > 0.04 μM BMS-986458, respectively was necessary to confer > 65% response. BMS-986458 was well-tolerated during treatment with no significant body weight loss at the dose levels tested. [00768] In this study antitumor activity of BMS-986458 was compared to individual isomer BMT-648592 with BID dosing at 15, 45 and 60 mg/kg. The tumor volume reduction with BMT- 648592 at 15, 45, and 60 mg/kg was 66%, 81%, and 81%, respectively. No significant difference in the antitumor activity of BMS-986458 and individual isomer BMT-648592 was observed (Table 4.1.1.2-3). Similar to BMT-986458, deep degradation of BCL6 was observed with individual isomer BMT--648592 in OCI-LY-1 tumors collected at the termination of the study. Similar depth of degradation (94% to 100%) was observed at the 6, 10, and 14 h timepoints for both the compounds (Table 4.1.1.2-3; OG00457¹⁵). [00769] In summary, data from studies using the OCI-LY-1 xenograft model in conjunction with PK and PD data obtained from the samples collected at the end of the study? indicate that plasma and tumor BMS-986458 exposure and antitumor activity for a given dose were variable between studies, and this was possibly due to lot-to-lot variation and forms of the compound. Considering the variations, a continuous degradation of > 95% tumor BCL6 degradation appears to be necessary to show a response of approximately 65% TVR (with the exception Study AP9742 in which TVR was lower in all study groups including positive control). This degree of tumor BCL6 degradation and corresponding antitumor response could be achieved with a plasma and tumor BMS-986458 concentration of > 0.24 and > 0.15 μM, respectively at 10 h post-dose with repeat BID dosing of 15-30 mg/kg. The calculated BMS-986458 efficacious plasma AUC(0-24) h derived from the study AP9776 was 26.1 μM•h/mL with 15 mg/kg BID (Table 4.1.1.2-3).

Table B3-4.1.1.2-3: Plasma Exposures and Percent BCL6 Degradation in OCI-LY-1 Xenografts Following Twice Daily Dosing for 21 Consecutive Days (AP9776) [00770] Anti-tumor Activity of BMS-986458 in WSU-DLCL-2 Xenograft Model with Twice Daily Dosing (AP9664). Single agent antitumor activity of BMS-986458 was tested in a WSU- DLCL-2 xenograft model with BID dosing at 30 and 60 mg/kg. A single cycle of CHOP therapy (combination of cyclophosphamide - single dose on day 1; doxorubicin - single dose on day 1; vincristine - single dose on day 1; and prednisone - QD dosing for 5 doses [QD x 5] on Days 1 to 5) was used as the positive control in this model. BMS-986458 significantly inhibited the growth of the WSU-DLCL-2 xenograft tumors with 69% and 74% TVR at 30 and 60 mg/kg BID, respectively (Table 4.1.1.2-4). No significant (p > 0.05) body weight loss was observed in the groups treated BMS-986458 at 30 mg/kg. Marginal (3.6 - 5.1%) but statistically significant body weight loss was observed in the animals treated with 60 mg/kg BMS-986458 on day 29 (p < 0.01), 33 (p < 0.05), 36 (p < 0.05) and 39 (p < 0.01). [00771] Similar to data from the studies in the OCI-LY-1 xenograft model (Studies AP9553, AP9742, and AP9776) in the samples collected at the study termination, deep and statistically significant BCL6 degradation was observed in the WSU-DLCL-2 tumor lysates from groups treated with BMS-986458 compared to the vehicle group. There was a 98%, 97%, and 86% BCL6 degradation at 6, 10, and 14 h at 30 mg/kg. At 60 mg/kg, the BCL6 degradation was 99%, 99%, and 98% at 6, 10 and 14 h (Table 4.1.1.2-4). This pharmacodynamic data along plasma and tumor BMS-986458 concentration analysis indicates that 30 and 60 mg/kg with BID dosing resulted in near complete BCL6 degradation (97% to 99% with exception of 14 h at 30 mg/kg that showed 86% degradation). Continuous plasma and tumor BMS-986458 concentrations of > 0.1 and > 0.07 μM, respectively, were necessary to confer > 65% antitumor response. Table B3-4.1.1.2-4: Plasma/Tumor Exposures of BMS-986458 and Percent BCL6 Degradation in WSU-DLCL-2 Xenografts Following Twice Daily Dosing for 14 Consecutive Days (AP9664) [00772] In summary, data from the study using the WSU-DLCL-2 xenograft model in conjunction with PK and PD data obtained from the samples collected at the end of the study indicate that > 95% tumor BCL6 degradation could be achieved with a plasma and tumor BMS- 986458 concentrations of > 0.7 and > 0.5 μM, respectively and the minimum efficacious dose to attain > 65% TVR was 30 mg/kg, BID. [00773] 4.1.2 Secondary Pharmacodynamics. The impact of BCL6 degradation by BMS- 986458 treatment was evaluated in normal immune populations associated with BCL6 functional dependencies or commonly observed therapeutic sensitivities. [00774] 4.1.2.1 BMS-986458 Impact on T-Follicular Helper Cells. The impact of BMS- 986458 was assessed in T-follicular helper cells in vitro. These populations generally do not exist outside the germinal center; therefore, evaluations require differentiation from naive T- cells isolated from healthy donor PBMCs. Under the conditions of these studies, a maximal induction of CXCR5+PD1+ICOS+BTLA+ from sorted CD4+ cells were observed at 4 days post stimulation using anti-CD3/CD28 beads, activin A and IL-12, where differentiation rate was consistently between 20% to 30%. Further characterization of differentiated Tfh cells at day 4 showed strong induction of canonical Tfh cytokine, IL-21, and induced expression of BCL6 (FIG.11C). When 10 nM BMS-986458 was included with stimulation, the day 4 differentiation rate of CXCR5+PD1+ICOS+BTLA+ IL-21 secreting cells was not impacted over vehicle, despite full degradation of BCL6, and was consistent across donors. However, the IL-10 secretion was significantly increased (FIG.11F). When cell phenotype was profiled at day 8 and day 12, there was a BMS-985458 dose-dependent loss of CXCR5+PD1+ iTfh cells, and concomitant loss of IL-21 secretion across donors, without a significant loss in viability. The phenotypic identification of these cells following BMS-986458 treatment is ongoing. [00775] 4.1.2.2 BMS-986458 Impact on Neutrophil Maturation. Cell viability and proliferation of CD34+ derived cells were not affected under BMS-986458 exposure. A slight reduction in neutrophils, reflective of maturation Stage II, was observed at doses beyond clinically relevant concentrations. This mild effect was reversible as complete recovery was observed upon compound washout.

Table B3-4.1.2.2-1: In Vitro Nonclinical Pharmacology Studies

[00776] 4.2 Nonclinical Pharmacokinetics and Metabolism. In vitro and in vivo studies were conducted to characterize the absorption, PK, distribution, metabolism, and drug- interaction potential of BMS-986458. Robust and reproducible bioanalytical methods for the determination of BMS-986458 concentrations were developed and used in PK and toxicokinetic (TK) studies. Pharmacokinetics and oral bioavailability of BMS-986458 were evaluated in mice (IV PK only), rats, dogs, and monkeys. In vitro studies were conducted to assess BMS-986458 metabolism, permeability, plasma protein binding, blood-to-plasma distribution, the inhibition and induction potential of cytochrome P450 (CYP) enzymes, intestinal efflux transporter substrate and inhibition potential, hepatic and renal transporter inhibition potential, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) inhibition potential. Additionally, plasma samples from multiple-dose exploratory toxicity studies in rats and dogs were evaluated for circulating metabolites. Table 4.2-1 lists the analytical method validation, absorption, distribution, metabolism, PK, and drug-interaction studies conducted with BMS-986458 to date. Table B3-42-1: Nonclinical Pharmacokinetic Studies

[00777] 4.2.1 Bioanalytical Methods. Robust and reproducible bioanalytical methods for the determination of BMS-986458 plasma concentrations were developed and used in PK and TK studies. In the non-clinical GLP-compliant toxicology studies, the liquid chromatography with tandem mass spectrometry (LC-MS/MS) bioanalytical assays used for quantification of BMT- 648592 and BMT 648599 (the diastereomers of BMS-986458) were fully validated as per Health Authority Guidance^33,34. Details of the validated methods are summarized in Table 4.2.1-1. Other PK and drug metabolism studies used fit-for-purpose bioanalytical methods to quantitate BMS-986458.

Table B3-4.2.1-1: Bioanalytical Method Validations for the Measurement of Plasma Concentrations of BMS-986458 [00778] 4.2.2 Absorption and Pharmacokinetics. The PK of BMS-986458 was evaluated in male CD-1 mice (IV only), male Sprague Dawley rats, male beagle dogs, and male cynomolgus monkeys following intravenous (IV) infusion and oral administration. The mean PK parameters are summarized in Table 4.2.2-1 for IV and oral administration. [00779] Following single IV infusion, BMS-986458 systemic plasma clearance (CLTp) was low (≤ 11% of hepatic blood flow) in mouse and dog, and moderate (≤ 44% of hepatic blood flow) in rat and monkey.³⁵,36 The volume of distribution at steady state (Vss) ranged from 0.217 to 2.45 L/kg and was low (0.4- to 0.7-fold of total body water volume) in mouse and dog, low to moderate (0.4- to 3.0-fold of total body water volume) in rat, and moderate (2.4- to 3.5-fold of total body water volume) in monkey, indicating some extravascular distribution of BMS- 986458. The apparent terminal half-life (T-HALF) of BMS-986458 was moderate in all nonclinical species tested and ranged from 0.9 to 5.5 hours.²⁰,21,22,23 [00780] Following a single oral dose, BMS-986458 was absorbed, with mean Tmax values ranging from 2.67 to 4.0 hours in rat, dog, and monkey. In all 3 nonclinical species tested, BMS- 986458 had moderate oral bioavailability (22% to 37%).²⁰,21,22,23 [00781] In addition, following a single IV infusion or oral dose of the individual diastereomers (BMT-648592 or BMT-648599) of BMS-986458, substantial interconversion (up to 41% based on AUC) between diastereomers was observed in rat, dog, and monkey.²⁰ [00782] Toxicokinetics of BMS-986458 following multiple oral doses were examined in toxicology studies.^45,47 In general, large inter-individual variability in exposures were observed in both rats and dogs. After repeated dosing of BMS-986458, mean BMS-986458 systemic exposures (AUC[0-24h]) in rats generally increased less than dose proportionally across the dose range of 50 to 500 mg/kg BID with no substantial sex differences, in consideration of large inter-individual variability. In rats, mean AUC(0-24h) values on Day 28 were slightly less (0.4 to 0.8×) than those on Day 1. In dogs, mean AUC(0-24h) values after repeated dosing generally increased greater than dose proportionally from 5 to 15 mg/kg BID and approximately dose proportionately from 15 to 50 mg/kg BID with no substantial sex differences and no accumulation or loss of exposure noted, in consideration of large inter-individual variability. [00783] Overall, BMS-98458 exhibits low to moderate systemic clearance across preclinical species, with low to moderate steady state volume of distribution, and acceptable oral bioavailability in mouse (no bioavailability data available), rat, dog, and monkey. Substantial interconversion (up to 41% based on AUC) between diastereomers was observed in rat, dog, and monkey following IV infusion or PO administration of individual diastereomers.

[00784] 4.2.3 Distribution. The in vitro plasma protein binding of BMS-986458 was evaluated in CD-1 mouse, Sprague-Dawley rat, New Zealand White rabbit (female), beagle dog, cynomolgus monkey, and human (pooled male and female) plasma. Plasma protein binding was assessed at 0.1, 1, and 10 µg/mL in plasma for each species with an ultracentrifugation method. In addition, in vitro blood-to-plasma partitioning of BMS-986458 was evaluated at 1 µg/mL in mouse, rat, rabbit, dog, monkey, and human whole blood. [00785] Binding of BMS-986458 to plasma protein was high at 99.95%, 99.84%, 99.78%, 99.99%, 99.68% and 99.06% in mouse, rat, rabbit, dog, monkey, and human plasma, respectively, with corresponding unbound fraction (fu) <1%. This result is consistent with earlier exploratory results obtained from a modified rapid equilibrium dialysis (with 10-fold plasma dilution) coupled with an exploratory bioanalytical method. No notable differences in plasma protein binding were observed over the concentration ranges tested in all species, suggesting there was no saturation of binding to the plasma proteins in all species. Considering the uncertainties in plasma protein binding measurements (ie, unmeasurable concentration in multiple protein-free supernatant samples), an orthogonal assay (ie, flux dialysis method) was conducted and plasma fu of BMS-986458 was confirmed to be < 1% in all species tested. In addition, species differences (5.3×) in fu were observed between human and dog, whereas no substantial differences (≤ 2×) were observed between human vs rat or rabbit.²⁰,25 [00786] The blood-to-plasma concentration ratios of BMS-986458 were 0.68, 0.68, 0.87, 0.62, 0.74 and 0.76 in mouse, rat, rabbit, dog, monkey, and human, respectively, indicating limited partitioning of BMS-986458 into blood cells.²⁵ [00787] The distribution of BMS-986458 into brain was determined in rat following single oral doses ranging from 10 to 300 mg/kg. Following 10 to 300 mg/kg single oral doses to Sprague Dawley rats, the brain BMS-986458 concentrations were ≤ 0.22 µM (brain/plasma ratios were ≤ 0.10 at ≥ 100 mg/kg and could not be appropriately assessed at ≤ 30 mg/kg due to low or unmeasurable [i.e., < LLOQ of 0.0029 µM] concentrations) at 24 hours post dose in female rats and unmeasurable at 48 hours post dose in male rats, indicating minimum penetration across the blood brain barrier. In addition, BMS-986458 also distributed into liver, spleen, lymph nodes, ileum, heart, and lung with tissue/plasma ratios ranging from 0.6 to 42 (see details in Section 4.3.1.1 Nonclinical Toxicology).²⁶ [00788] Distribution of BMS-986458 into other tissues and the transport of BMS-986458 across the placental barrier have not been evaluated. [00789] 4.2.4 Metabolism [00790] 4.2.4.1 Metabolism Stability. Metabolic stability of BMS-986458 was evaluated with NADPH-fortified liver microsomes and hepatocytes of human, rat, mouse (microsomes only), dog, and monkey.^20,24 BMS-986458 (0.5 µM) was incubated with NADPH-fortified liver microsomes (1 mg/mL) at 37°C for up to 45 minutes to determine in vitro half-life and the rate of CYP-mediated metabolism. After the incubation period, the mixtures were precipitated with acetonitrile, and centrifuged. The supernatants were analyzed by LC-MS/MS for the relative amount of the BMS-986458 remaining in the reaction mixtures. In addition, BMS-986458 (1.0^µM) was incubated with pooled cryopreserved hepatocyte suspensions (1×10⁶^cell/mL) of rat, dog, monkey, and human at 37°C for up to 120 minutes to determine in vitro half-life. The reaction was stopped by addition of acetonitrile containing an internal standard (ie, terfenadine) and centrifuged. The supernatant was analyzed by LC- UV [ultraviolet] /MS and the remaining amount of the BMS-986458 in the reaction mixtures was quantified against a standard curve. [00791] A variable rate (0.0070 to 0.0189 nmol/min•mg protein) of CYP-mediated metabolism of BMS-986458 was observed with liver microsome incubation. The highest rate of metabolism was observed in monkey and rat, followed by human and mouse, and the lowest in dog. The in vitro half-life of BMS-986458 in hepatocytes ranged from 53 to 114 minutes with the longest value observed in human hepatocytes. [00792] 4.2.4.2 Metabolite Profiling. Metabolism of BMS-986458 was evaluated in mouse, rat, dog, monkey, and human hepatocytes, and in plasma samples from rats and dogs following oral administration. BMS-986458 (2 µM) was incubated with cryopreserved hepatocytes from animals (pooled male) and human (individual male) at 37 C up to 4 hours. After the incubation period, the mixtures were precipitated with acetonitrile, and centrifuged. The supernatants were analyzed by LC-MS/MS with in-line UV for metabolite identification. [00793] In human hepatocytes, BMS-986458 was mainly metabolized by demethylation with hydrolysis and oxidation followed by subsequent glucuronidation playing a lesser role. Additional minor metabolic pathways in human hepatocytes included mono-oxidation, dehydrogenation, and cleavage of the linker between the piperidine and indazole moiety. The most prominent metabolites in human hepatocytes (detectable by UV) were M11 (demethylation); M6 and M8 (hydrolysis); M9, M10, M13, M13a, and M13b (mono-oxidation); M21 (oxidation followed by glucuronidation); M20 (cleavage of the linker between the piperidine and indazole moiety), M12a and M12b (dehydrogenation). Of these metabolites, all were detected by UV in hepatocytes of mouse, rat, dog, and money, except that M9, M13, and M13b were only detected by MS in dog hepatocytes, as was M13b in monkey hepatocytes. Although there were quantitative differences in the formation of metabolites across species, qualitatively all metabolites formed in human hepatocytes were also formed in hepatocytes from rat and/or dog, the two species used for preclinical safety testing, indicating that there were no unique human metabolites.³⁷ [00794] In plasma from rat and dog following multiple oral administrations, BMS-986458 was the major (76% to 90%) drug-related circulating species and the metabolites observed were similar to those observed in hepatocytes suggesting good in vitro to in vivo correlation. Metabolites detected by UV in rat plasma were M9, M9a, M10, M11, M13a, and M20; and in dog plasma, M6, M9, M9a, M10, M11, M12, M12a, M12b, M13, M13a, M13b, M16, and M20 were detectable by UV.^28,29 [00795] 4.2.4.2 Reaction Phenotyping. Reaction phenotyping studies of human CYP isoforms and human liver microsomes with isozyme specific inhibitors showed that BMS- 986458 is predominantly metabolized by CYP3A4/5 with minor participation from CYP1A2, CYP2C8, CYP2C9, and CYP2C19.²⁷ [00796] 4.2.5 Excretion. Studies to investigate the excretion of BMS-986458 have not been performed. The excretion of BMS-986458 or its related components into breast milk has not been evaluated. [00797] 4.2.6 Pharmacokinetic Drug Interactions [00798] 4.2.6.1 Evaluation of Metabolism-based Drug Interactions. An in vitro study was conducted to evaluate the potential for drug-drug interactions (DDI) due to inhibition of CYP isozymes by BMS-986458. Under the experimental conditions used to examine direct inhibition, BMS-986458 had no inhibitory effect (IC50 > 20 µM) on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In vitro, BMS-986458 demonstrated time- dependent inhibition of CYP3A4 with >16.3- or >18.1-fold IC50 shift (without vs with preincubation with BMS-986458) when midazolam or testosterone was used as substrate, respectively. Using midazolam as a substrate, the rate of enzyme inactivation (kinact) and inhibition constant (KI) were determined to be 0.054/min and 28 μM, respectively. In addition, weak time-dependent inhibition of CYP1A2 by BMS-986458 was also observed with >2.5-fold shift IC50. Based on the expected clinical doses and exposures and interpreting in vitro CYP inhibition data in accordance with the FDA and EMA guidance documents³⁸,39, potential clinically relevant systemic DDI may exist if BMS-986458 is co-administered with strong inhibitors or inducers of CYP3A4, sensitive CYP3A substrates, or CYP3A substrates with a narrow therapeutic window. The potential for DDI will be evaluated throughout the development of BMS-986458. Additionally, BMS-986458 showed inhibition of uridine diphosphate (UDP)-glucuronosyl transferase (UGT) 1A1 with an IC50 of 0.15 µM.²⁴ [00799] An in vitro study was conducted to determine the potential for BMS-986458 to induce expression of CYP1A2, CYP2B6, and CYP3A4 mRNA in cultures of cryopreserved human hepatocytes. Treatment of cultured human hepatocytes with BMS-986458 (0.1 to 20 μM) caused ≤4-fold increase in CYP1A2 mRNA over vehicle controls. The mRNA increases were ≤ 9.86% of the positive control inducer. These results indicate that BMS-986458 may be a weak inducer of CYP1A2. In contrast, BMS-986458 (0.1 to 20 μM) treatment caused <2-fold increase in CYP2B6 and CYP3A4 mRNA over vehicle controls and the mRNA increases were ≤ 4.94% of positive control inducers, indicating that BMS-986458 is not an inducer for CYP3A4 or CYP2B6.³⁰ [00800] 4.2.6.2 Evaluation of Transporter-based Drug Interactions. To assess passive permeability, BMS-986458 was tested in Madin-Darby canine kidney cells strain II (MDCK II), in which endogenous canine multi-drug resistance 1 gene (cMDR1) was knocked out. BMS- 986458 A-to-B permeability was approximately 151 nm/sec with concentrations at 3 µM in the assay buffer containing 0.5% bovine serum albumin. However, the A-to-B permeability was likely underestimated due to the poor recovery (64%) noted. The passive permeability value observed in MDCKII-mdr1-Knockout cell assay was consistent with the moderate oral bioavailability of BMS-986458.²⁴ [00801] BMS-986458 at 3 µM was tested in the Caco-2 (with or without efflux transporter inhibitors) and MDR1-expressing MDCKII cells to assess intestinal efflux transporter substrate potential. In Caco-2 cells, BMS-986458 recovery was 60%, and efflux ratios were >4.4. Moreover, BMS-986458 at 3 µM was incubated with a breast cancer resistance protein (BCRP) inhibitor (KO143 at 1 µM) or a P-glycoprotein (P-gp) inhibitor (Zosuquidar at 5 µM) in Caco-2 cells. The efflux ratio was only slightly reduced with the addition of BCRP and P-gp inhibitors and remained >3.1 or >2.5, respectively. BMS-986458 recovery of this assay was relatively low (54% to 63%), indicating that the permeability was likely underestimated. In MDR1-expressing MDCK cells, the efflux ratio was 111 with BMS-986458 recovery ranging from 58% to 110%.²⁴ Taken together, in vitro assays showed that BMS-986458 was a substrate of P-gp and likely a substrate of BCRP. [00802] An in vitro assay was conducted in Caco-2 to assess the potential for BMS-986458 to inhibit intestinal efflux transporters. BMS-986458 was determined to be an inhibitor of P-gp and BCRP, with half maximal inhibitory concentration (IC50) values of 3.3 and 1.6 µM, respectively. These data suggest that there is the potential for BMS-986458 to cause inhibition of P-gp and/or BCRP in the gut, and absorption of BMS-986458 may be increased in the presence of P-gp inhibitors.²⁴ [00803] The potential for BMS-986458 (up to 50 µM) to inhibit a panel of hepatobiliary and renal transporters was assessed in uptake transporter-expressing HEK293 cells and inside-out plasma membranes (vesicles) from baculovirus-infected insect cells expressing either human bile salt export pump (BSEP) or human multidrug resistance-associated protein (MRP) 2. BMS- 986458 showed inhibition of multiple transporters: organic anion transporting polypeptides (OATP) 1B1, OATP1B3, MRP2, organic cationic transporter (OCT) 1, OCT2, BSEP, multidrug and toxin extrusion protein (MATE)1, and MATE2K, with IC50 values ranging from 0.29 to 9.5 µM. Overall, based on the expected starting clinical exposures (within the projected efficacious dose range), the potential for systemic interactions with drug transporters appears low. However, DDI potential will be continuously evaluated as clinical exposures are available. [00804] 4.2.7 Other Pharmacokinetic Studies. Based on PK properties in nonclinical species and using allometric scaling corrected for unbound total clearance in mouse, rat, dog, and monkey, human clearance was predicted to be low (3.6 mL/min/kg). The human steady- state volume of distribution (Vss) was predicted using Øie-Tozer model⁴⁰ with Vss and plasma protein binding data from rat, dog, and monkey. BMS-986458 is predicted to have a moderate Vss of 2.08 L/kg in humans. The predicted human T-HALF is approximately 10.6 hours. Because BMS-986458 is highly bound (unbound fraction in plasma [fu,p] < 1%) in all species tested, the accuracy of human CL and Vss estimation could be affected by the protein binding measurements. The human absorption rate constant (ka) and oral bioavailability (F) were predicted to be 0.32 h^-1 and 26%, respectively; both are the geometric means derived from rat, dog, and monkey.³² [00805] At the expected clinical starting dose of 40 mg BID in the multiple ascending dose study and assuming a 70-kg human, these PK parameters result in a projected steady state Cmax of 85 ng/mL and AUC(0-12h) of 754 ng•h/mL. At the highest proposed dose of 640 mg BID, these PK parameters result in Cmax of 1354 ng/mL and AUC(0-12h) of 12,064 ng•h/mL, at steady state.³² [00806] 4.2 Nonclinical Toxicology. A battery of nonclinical studies, including single-dose toxicity, repeat-dose toxicity, genotoxicity, safety pharmacology, and phototoxicity have been completed to assess the potential toxicologic profile of BMS-986458. Rat and dogs were selected for toxicity studies as BMS-986458 is pharmacologically active in both species. The scope of the toxicologic evaluation for BMS-986458, as outlined in Table 4.3-1, supports its proposed clinical testing in a Phase 1 study in humans. Pivotal studies were conducted in countries that are members of the Organization for Economic Cooperation and Development (OECD) Mutual Acceptance of Data program and in accordance with the OECD Test Guidelines and Principles of GLP or GLP regulations of the United States Food and Drug Administration (FDA) Code of Federal Regulations (CFR), Title 21, Part 58 (21CFR58). Table B3-4.3-1: Toxicology Studies

[00807] 4.3.1 Single-dose Toxicity [00808] 4.3.1.1 Single-dose Study in Rat. In a single-dose toxicokinetic and tolerability study in rats,²⁶ BMS-986458 was administered by oral gavage as a single dose of 0 (vehicle), 10, 30, 100, or 300 mg/kg to groups of 6 rats (3M/3F). All doses were administered at 10 mL/kg in a vehicle/carrier consisting of 10% Captisol in 25 mM citrate buffer (pH = 3). Criteria for evaluation included pharmacokinetics, biodistribution, BCL6 expression, survival, body weights, clinical observations, clinical pathology, and cytokine evaluations. These evaluations occurred at designated times during the dosing course of the study. The toxicokinetic summary for BMS-986458 are presented in the following table. Table B3-4.3.1.1-1: Toxicokinetic Summary – BMS-986458 Mean Values in Male and Female Rats [00809] At 24- or 48-hours post dose, tissues were collected for bioanalysis to measure the amount of BMS-986458 in plasma and tissues and determine the respective tissue/plasma ratios. Plasma and tissues were collected from female rats at 24-hours post dose, and from males at 48- hours post dose, for bioanalysis. In female rats, the highest drug concentration and tissue/plasma ratios were found in the ileum at all doses. In male rats, the highest drug concentration and tissue/plasma ratios were found in the liver following a dose of 10 mg/kg, and in the ileum, following doses of ≥ 30 mg/kg. The tissue bioanalytical data are summarized in the following tables. Table B3-4.3.1.1-2: BMS-986458 concentrations in plasma and tissues in female rats at 24 hours post dose [00810] Samples of spleen, liver, and heart were collected from females at 24 hours and males at 48 hours post dose and evaluated for BCL6 expression using western blot and normalized for beta-actin protein expression. At both 24- or 48-hours post treatment, rats showed decreased BCL6 protein in the spleen and lung. There was no significant decrease in BCL6 protein in the heart. [00811] BMS-986458 was well tolerated at all doses with no adverse effects on body weight or clinical signs, significant changes in serum chemistry or hematology, or macroscopic findings at necropsy. Serum cytokine analysis showed BMS-986458-related decreases in CX3CL1, IL- 12(p70) and IL-5, which are involved in T and B cell differentiation and/or cell adhesion/migration activity and may be related to BCL6 pharmacology. Additional compound- related changes in IL-12(p70), CXCL10, Leptin and VEGF-A, may indicate homeostatic changes in angiogenic activities. [00812] In conclusion, BMS-986458 administered as a single dose up to 300 mg/kg in rats was well tolerated. Evidence of statistically significant decreases in BCL6 protein levels were detected at 24- and 48-hours post dose in the spleen and lung indicating pharmacological activity in these tissues. [00813] 4.3.1.2 Maximum Tolerated Dose and Toxicokinetic Assessment of Dogs Administered a Single Oral Dose. In a single-dose maximum tolerated dose study,⁴¹ BMS- 986458 was administered by oral gavage at doses of 0 (vehicle), 15, 45, or 90 mg/kg to groups of 2 dogs (1 male and 1 female/group). Criteria for evaluation included pharmacokinetics, proteomics, survival, body weights, clinical observations, food consumption, and clinical pathology evaluations. Food consumption was evaluated on Days 1 to 3. Clinical pathology evaluations were conducted pretest, and on Days 3 and 6. Pharmacokinetics were evaluated 0.5, 1, 4, 5, 7, 24 and 48 hours after dosing. [00814] Dose proportionality was not observed between doses of 15 mg/kg to 90 mg/kg. BMS-986458 individual diastereomers (BMT-648592 and BMT-648599) had a significant trend favoring BMT-648592 in plasma concentrations at a 2:1 ratio. There was a large individual variability between the 2 dogs dosed with 45 mg/kg or 90 mg/kg. The individual toxicokinetic data for BMS-986458, BMT-648592, and BMT-648599 is summarized below. Table B3-4.3.1.2-1: Toxicokinetic Summary - Maximum Tolerated Dose and Toxicokinetic Assessment of Dogs Administered a Single Oral Dose [00815] Proteomic evaluation of leukocytes collected from peripheral blood showed 85 to 90% BCL6 degradation in all dose groups 4 hours post dosing. At all doses, there was a partial rebound in BCL6 levels at 24 hours post dose, with 70 to 80% degradation sustained at 90 mg/kg. BCL6 was selectively degraded by BMS-986458 at 4 hours post dosing in all dose groups to compared to vehicle. No additional proteins displayed statistically significant modulation in this comparison, including canonical CELMoD substrates (e.g., IKZF1, IKZF3, GSPT1, CK1α). No other proteins were significantly modulated at 24 hours post dosing indicating BCL6 degradation may not have been sustained for sufficient time to see secondary effects of its degradation in leukocytes. [00816] Dogs in all dose groups appeared normal (alert and active) when observed prior to and for up to 6 days after BMS-986458 administration. There were no clinical signs, effects on body weight or food consumption. At all doses, increases in WBC and neutrophils compared to pretest were observed. In the female dog at 90 mg/kg, increases in alanine aminotransferase (ALT) levels compared to pretest were noted and persisted until Day 10 post dose (up to 2.02- fold at Day 10). [00817] In conclusion, BMS-986458 administered as single oral doses of 15, 45, or 90 mg/kg did not achieve dose proportional exposure with a plasma concentration ratio of the 2 diastereomers, BMT-648592 and BMT-648599, at a ratio of 2:1, respectively. BCL6 degradation was 85 to 90% at 4 hours post dosing while by 24 hours, there was a dose related BCL6 rebound, with only the 90 mg/kg dose maintaining at least 70% BCL6 degradation. BMS- 986458 dose administration showed good selectivity in BCL6 degradation without notable off- target activity. BMS-986458 was well tolerated with only a high-dose female (4201) presenting elevated ALT levels persisting for at least 10 days post dosing (AUC[INF] = 1512 µg•h/mL). [00818] 4.3.2 Repeat-dose Toxicity [00819] 4.3.2.15-day NonGLP Study in Rat. In an exploratory 5-day toxicity study,⁴² BMS- 986458 was administered by oral gavage BID (8 ± 0.5 hours apart) at doses of 0 (control article), 50, 150, or 500 mg/kg (total daily doses of 0, 100, 300, and 1000 mg/kg/day) to groups of 6 male rats (except for Day 5 when rats received only a single dose in the morning). All doses were administered at 10 mL/kg BID in a vehicle consisting of 0.25% Methocel E4M in water. Endpoints included survival, toxicokinetics, metabolite profiling, clinical observations, body weights, food consumption, clinical pathology (hematology, coagulation, clinical chemistry, and urinalysis) evaluations, pharmacodynamic (BCL6 expression) evaluation, organ weights, and gross and microscopic pathology analyses. Scheduled necropsies were conducted at the end of a 5-day dosing period (6/group). [00820] After repeated dosing on Day 4, mean systemic exposures (AUC[0-24h]) of BMS- 986458 and its diastereomers, BMT-648592 and BMT-648599, generally increased dose proportionally from 50 to 150 mg/kg BID and less than dose proportionately from 150 to 500 mg/kg BID. The toxicokinetic summary for BMS-986458 and diastereomers BMT-648592 and BMT-648599 are presented in the following table. Table B3-4.3.2.1-1: Toxicokinetic Summary - Mean Values - Five-day Oral Exploratory Toxicity Study in Male Rats [00821] Metabolite profiles of rat plasma samples indicated unchanged BMS-986458 as the predominant drug species in circulation, which was about 76% of total circulating species in rat plasma after a multiple daily dose of 500 mg/kg BID. The most abundant metabolites in rat plasma were formed via mono-oxidation (M9 and M10) of parent, representing 10.9% and 6.9% of the total circulating species. A low level of oxidation and N-dealkylation metabolites were also detected (≤ 2.5%). A similar metabolite profile was also found for the dose group of 150 mg/kg BID. [00822] At 4 hours after dosing on Day 4, group mean percentages of BCL6 levels in WBCs relative to vehicle group mean were 102.6%, 90.8%, and 91.3% at 50, 150, and 500 mg/kg BID BMS-986458, respectively, indicating BCL6 was not significantly decreased at ≤ 500 mg/kg BID. Basal BCL6 expression in circulating WBCs is low and may have confounded the ability to detect decreases in BMS-986458-dosed rats. [00823] There were no BMS-986458-related moribundity or mortality or effects on clinical observations, body weights, food consumption, organ weights, gross pathology, or histopathology. [00824] At ^ 50 mg/kg BID, BMS-986458-related findings included: • Minimal decreases in mature red cell mass parameters (RBC, hematocrit [HCT], hemoglobin [HGB]) correlated with minimal to mild, dose-related decreases in reticulocyte counts at doses ≥ 150 mg/kg BID with no microscopic correlates • Minimal, generally dose-related, increases in total WBC lymphocyte, monocyte (at ≥ 150 mg/kg BID), basophil, and/or large unstained cell counts with no histologic correlates Minimal decreases in triglyceride, minimal to mild decreases in total bile acid concentrations, and minimal dose-related increases in cholesterol concentrations o Triglyceride and cholesterol findings were considered potentially pharmacologically mediated given reports describing an emerging role of BCL6 in lipid metabolism (knock-out mouse studies)^65,66 and/or also potentially due to decreased bile acid synthesis⁶⁷ [00825] At the high dose of 500 mg/kg BID, BMS-986458-related mild prolongations in prothrombin time (PT) and activated partial thromboplastin time (APTT) were observed with no clinical observation correlates. [00826] In conclusion, BMS-986458 was clinically well tolerated by male rats for 5 days at oral doses ^ 500 mg/kg BID. Based on the absence of dose-limiting toxicity, the MTD was considered to be 500 mg/kg BID (BMS-986458 mean AUC[0-24h] of 149 µg•h/mL). [00827] 4.3.3.2 Exploratory Toxicokinetic and Tolerability Study in Female Rats Orally Administered BMS-986458 (CC-2021676) Twice Daily for 10 Consecutive Days. In an exploratory toxicokinetic and tolerablity study,⁴³ female rats (6 per treatment group) were administered BMS-986458 at doses of 0, 50, 150 and 300 mg/kg BID (dosed 6 hours apart) for 10 days. Criteria for evaluation included toxicokinetics, BCL6 protein measurement, survival, body weights, food consumption, clinical observations, clinical pathology, histopathology, and hepatic CYP transcriptional profiles. [00828] Less than dose-proportional exposures were observed for the total drug concentration of BMS-986458 or each individual diastereomer concentration. There was a 60:40 ratio of individual isomers (BMT-648592:BMT-648599) detected in plasma, favoring BMT- 648592. The toxicokinetic data are summarized below. Table B3-4.3.2.2-1: Toxicokinetic Summary - Mean Values - Exploratory Toxicokinetic and Tolerability Study in Female Rats Orally Administered BMS-986458 (CC-2021676) Twice Daily for 10 Consecutive Days

[00829] BCL6 protein was measured in the spleen, ileum, and liver at ~18 hours post final dose. At the high dose, there was a potential rebound of BCL6 protein expression ranging from ~1.3 to 1.7× in the spleen, ileum, and liver (p ≤ 0.06). [00830] At all doses, BMS-986458 was well tolerated, with no changes in body weight, clinical observations, or serum chemistry. There was a dose-related increase in WBCs with fold changes of 1.54, 1.85, and 2.95 at 50, 150, and 300 mg/kg BID, respectively. In all dose groups, there were no adverse histopathological findings in the liver, spleen, mesenteric lymph nodes, and ileum. [00831] At 150 and 300 mg/kg BID, there was a non-statistically significant (to 13%) group mean increase in absolute liver weights compared to vehicle controls, without histopathological correlates. [00832] At 300 mg/kg BID, lymphocytes were increased 3-fold and monocytes 3.7-fold, compared to controls. Also at this dose level, all animals showed minimal myeloid hyperplasia and/or marginal zone depletion in the spleen, considered pharmacologically related. [00833] Transcriptional expression of CYP2B2, CYP3A23, and CYP4A2, as well as Ehhadh (enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase), which encodes a bifunctional enzyme important in the peroxisomal beta-oxidation pathway, were measured in liver samples. There was a statistically significant decrease in CYP2B2 (~0.5×, 0.2×, and 0.25×) and increase in CYP3A23 (~3.5×, 7×, and 14×) transcriptional expression at 50, 150, and 300 mg/kg BID, respectively. [00834] Based upon the findings in this study, the MTD of BMS-986458 is greater than or equal to 300 mg/kg BID. [00835] 4.3.2.3 Two-week Oral BID Exploratory Study in Female Rats. In an exploratory two-week toxicity study,⁴⁴ BMS-986458 was administered by oral gavage to groups of 6 female rats BID (6 ± 0.5 hours apart) for 13 days for a total daily dose of 0, 100, 300, or 600 mg/kg/day (0, 50, 150, or 300 mg/kg BID). On Day 14, a single dose of 0, 50, 150, or 300 mg/kg was administered prior to necropsy for the timed collection of genetic toxicology samples. All BMS-986458 doses were administered BID at 10 mL/kg (20 mL/kg total daily) or once on the last day at 10 mL/kg in a vehicle consisting of 10% Captisol (beta-cyclodextrin sulfobutylether sodium) and 90% 25 mM citrate buffer pH 3 ±0.1. For genotoxicity evaluations, a positive control group of 6 female rats was administered by oral gavage with 10 mg/kg/day cyclophosphamide (CP) on Days 11 and 12, and 200 mg/kg/day of ethyl methanesulfonate (EMS) on Day 14, both administered at 10 mL/kg. Endpoints included survival, toxicokinetics, clinical observations, body weights, clinical pathology (hematology, coagulation, and serum chemistry evaluations), immunological (plasma cell phenotyping and peripheral blood lymphocyte phenotyping) evaluations, organ weights, gross and microscopic pathology analyses, BCL6 protein evaluation in spleen and ileum, micronucleus assessment, and comet assay evaluation. Scheduled necropsies were conducted following 2 weeks of BID dosing. [00836] The evaluation of BMS-986458 and its diastereomers BMT-648592 and BMT- 648599 demonstrated dose proportional increases in the 4-hour post dose concentrations of BMT-648592, BMT-648599, and therefore BMS-986458 on Day 1. On Day 13, BMT-648592 and BMT-648599 concentrations at 4 hours post dose were 2- to 4-fold lower than those on Day 1. After repeat dosing, exposures (AUC[0-24h] and Cmax) of BMT-648592 and BMT-648599, and therefore BMS-986458, were less than dose proportional. Day 13 exposures (AUC) and Day 14-hour post dose concentrations of BMT-648592 and BMT-648599 were approximately at a ratio of 2:1 favoring BMT-648592. [00837] The toxicokinetic summary for BMS-986458, BMT-648592, and BMT-648599 is presented in following Table 4.3.2.3-1. Table B3-4.3.2.3-1: Toxicokinetic Summary - Mean Values - Two-week Oral BID Exploratory Toxicity Study in Female Rats

[00838] At all doses, BMS-986458 was well tolerated without effects on survival, clinical observations, body weights, coagulation, micronucleus assessment, and comet assay. [00839] Pharmacodynamic changes of reduced BCL6 protein (27% to 44% BCL6 protein degradation) were demonstrated in the spleen at ≥ 50 mg/kg BID. [00840] BMS-986458-related findings were generally dose related and included: At ≥ 50 mg/kg BID: • Minimal increases in reticulocyte counts and corresponding increases in red cell distribution width values denoting an appropriate bone marrow response to the minimal non-dose-related decreases in mature RBC parameters (RBCs, HGB, and HCT)

• Minimal to mild increases in total WBC and constituent lymphocyte, monocyte, basophil counts, and/or large unstained cell counts • Increases in peripheral blood plasma cells (to 4× compared to control) • Minimal to mild, non-dose-related increases in total bilirubin concentrations with no histologic correlates • Minimal to mild, non-dose-related increases in phosphorus concentrations • Minimal to mild increases in cholesterol • Increases in liver (absolute and/or relative to body weight) weights correlated with increased liver size in 1 rat each at 300 and 600 mg/kg/day, minimally increased hepatocellular mitoses in 1 rat at 300 mg/kg/day, and minimal hepatocellular hypertrophy at all dose levels At ≥ 150 mg/kg BID: • Minimal increases in platelet counts • Minimal increases in globulin concentrations which, along with increases in leukocyte counts seen at ≥ 100 mg/kg/day, denote a possible immune/inflammatory response with no histologic correlates • Compared to controls, increases in T, helper T, cytotoxic T, B, and NK cells (up to 2×) At 300 mg/kg BID: • Minimal increase in glucose concentration which, in conjunction with minimal increases in cholesterol at doses ≥ 100 mg/kg/day, suggest a slight effect on metabolic parameters [00841] In conclusion, BMS-986458 was clinically well tolerated by female rats for 13 days when administered by oral gavage at total daily doses ≤ 150 mg/kg BID (a single dose of 150 mg/kg on the day of necropsy). The primary target organ at doses ≥ 50 mg/kg BID (mean Day 13 AUC ≥ 216 μg•h /mL) was the liver (minimal hepatocellular hypertrophy and increased mitoses). Based on the minimal severity of findings, the MTD was determined to be ^ 300 mg/kg BID (mean Day 13 AUC ≤ 335 μg•h/mL). [00842] 4.3.2.4 A One-month Oral Toxicity Study in Rats with a 2-week Recovery Period. In a pivotal one-month toxicity study,⁴⁵ BMS-986458 was administered at doses of 0 (reference item), 50, 150, or 500 mg/kg BID (8 ± 0.5 hours apart; total daily doses of 0, 100, 300, or 1000 mg/kg/day) to groups of 15 rats per sex. The control group was administered hydroxypropyl methylcellulose acetate succinate high-grade fine (HPMC-AS-HF) at a concentration (149.04 mg/mL) equivalent to the HPMC-AS-HF concentration in the BMS-986458 high-dose (Group 4) formulation. All doses were administered at 10 mL/kg in a vehicle/carrier consisting of 0.25% w/w Methocel E4M in ultra-pure water. [00843] Criteria for evaluation included survival; TK parameters; clinical observations; physical examinations; body weights; food consumption; ophthalmologic examinations; clinical pathology evaluations (hematology, coagulation, clinical chemistry, and urinalysis); cytokine evaluations; BCL6 protein levels in circulating WBCs analyzed by LC-MS, peripheral blood immunophenotyping (total, helper, and cytotoxic T lymphocytes, B lymphocytes, NK cells); T- cell-dependent antibody response (TDAR) analyses; organ weights; and gross and microscopic pathology. Scheduled necropsies were conducted after 1 month of dosing (10/sex/group, all groups) and following a 2-week recovery period (5/sex/group, all groups). [00844] After repeated dosing on Day 28, mean systemic exposures (AUC[0-24h]) of BMS- 986458 and its diastereomers, BMT-648592 and BMT-648599, generally increased less than dose proportionally across the dose range of 50 to 500 mg/kg BID (100 to 1000 mg/kg/day) with no substantial sex differences, in consideration of large inter-individual variability. Mean AUC(0-24h) values on Day 28 were slightly less (0.4 to 0.8×) than those on Day 1 for all analytes. On Days 1 and 28, mean systemic exposures (AUC[0-24h]) to BMT-648592 were approximately 2.5 to 3.3× those of the other diastereomer, BMT-648599. Diastereomer ratios were generally similar across all doses with no substantial change after repeated dosing. [00845] The toxicokinetic summary for BMS-986458 and its diastereomers is presented in the following table. Table B3-4.3.2.4.-1: Toxicokinetic Summary - Mean Sex-combined Values - A One-month Oral Toxicity Study in Rats with a 2-week Recovery Period

[00846] BCL6 protein was quantified across all tested leukocyte samples. BCL6 levels were not significantly modulated in circulating WBCs at any dose level relative to controls. Basal BCL6 expression in circulating WBCs is low and may have confounded the ability to detect decreases in BMS-986458-dosed rats. BCL6 is a regulator of immune function and the immune findings described in the sections below, including changes in immune cell counts, cytokine levels, and antibody response to KLH, are consistent with pharmacologic activity downstream of BCL6 degradation.¹⁰’¹¹ [00847] BMS-986458 was clinically well tolerated at all doses with no BMS-986458-related mortalities or effects on body weights, food consumption, clinical observations, physical examinations, ophthalmology, urinalysis, or immunophenotyping endpoints. No BMS-986458- related adverse findings were noted at any dose level. Although BMS-986458-related, the following changes were considered not adverse because they were of minimal severity and/or lacked toxicologic significance. [00848] At doses ^ 50 mg/kg BID, BMS-986458-related findings included: • Mild increases in globulin and at ≥ 150 mg/kg BID, mild decreases in albumin to globulin ratio (A/G) • Non-dose-dependent mild increases in mean urea nitrogen in males and in individual females at ≥ 150 mg/kg BID, with no microscopic correlates • Mild decreases in total bile acids in females and at 500 mg/kg BID in males, and minimal increases in cholesterol at ≥ 150 mg/kg in females only. These changes were potentially pharmacologically mediated given reports describing an emerging role of BCL6 in lipid metabolism and/or due to decreased bile acid synthesis^65,66,67 • Mild increases in mean monocyte, lymphocyte (≥ 150 mg/kg BID), WBC (≥ 150 mg/kg BID), large unstained cell (males at 500 mg/kg BID), and platelet counts (≥ 150 mg/kg BID) • Mild or moderate increases in splenic extramedullary hematopoiesis in males and at ≥ 150 mg/kg in females, correlating with increased spleen weights (mean absolute and relative [to body and brain]; up to 31%) at ≥ 150 mg/kg BID, minimal to mild increases in red cell distribution width and reticulocyte counts at 50 mg/kg BID only and minimal decreases in mean red cell parameters (RBC, HGB, and/or HCT) at ≥ 150 mg/kg BID • Increased liver weights (mean absolute and relative [to body and brain]; up to 31%) in males and at ≥ 150 mg/kg BID in females, correlating with minimal hypertrophy of centrilobular hepatocytes in the liver at 500 mg/kg BID • Minimal hypertrophy of the thyroid gland follicular epithelium, correlating with increased thyroid weights (mean absolute and relative [to body and brain]; up to 30%) and considered secondary to the findings in the liver • Mild or moderate decreases in splenic marginal zone lymphoid cells • Decreases in serum TNFα (to 0.2×), IL-6 (to 0.1×), IFNγ (to 0.1×), and IL-2 (to 0.3×) levels on Day 28 in females and at 150 mg/kg BID in males, and decreases in serum IL- 1β (to 0.6×) on Day 28 in males at 500 mg/kg BID [00849] At ≥ 150 mg/kg BID, BMS-986458-related findings included: • Minimal decreases (shortening) in PT in females, and at 500 mg/kg BID in males • Increased adrenal gland weights (mean absolute and relative [to body and brain]; up to 38%) in females and at 500 mg/kg BID in males, correlating with minimal hypertrophy of the zona fasciculata of the adrenal cortex in females only at 500 mg/kg BID [00850] At 500 mg/kg BID, additional BMS-986458-related findings included: • Minimal increase in phosphorus in females • Minimal increase in potassium in males • Decreases in anti-KLH IgM (Day 8) and anti-KLH IgG (Day 15 and 29) levels after KLH immunization in females only (down to 0.4× across all time points and Ig isotypes) [00851] All BMS-986458-related findings were fully reversible by the end of the 2-week recovery period, except for mild non-dose-related increases in urea nitrogen in females at ≥ 50 mg/kg BID and in males at ≥ 150 mg/kg BID. [00852] In conclusion, BMS-986458 was well tolerated by rats for 1 month at BID oral doses of ≤ 500 mg/kg BID. There were no BMS-986458-related adverse findings at any dose. BMS-986458-related nonadverse findings included changes in serum chemistry parameters (potassium, phosphorus, BUN), decreases in RBC parameters with regenerative response, decreases in platelets, changes in immune parameters (cell counts, cytokines, antibody response to KLH), and microscopic findings in the adrenal gland, thyroid gland, liver, and spleen at the end of dosing. All BMS-986458-related changes were fully reversible, with the exception of mild, non-dose-related increases in urea nitrogen. The no-observed-adverse-effect level (NOAEL) was considered to be ≥ 500 mg/kg BID (mean sex-combined Day 28 AUC[0-24h] = 229 µg•h/mL for BMS-986458). Severe toxicity was not observed, and therefore the STD10 was considered to be > 500 mg/kg BID, the highest dose tested. [00853] 4.3.2.5 Tolerability and Toxicokinetic Study in Dogs Dosed Twice Daily for 5 Consecutive Days. In a five-day toxicokinetic and tolerability study,⁴⁶ BMS-986458 was administered by oral gavage at doses of 0 (vehicle), 7.5, 15, or 30 mg/kg BID (separated by 6 hours; 15, 30, or 60 mg/kg/day total) to groups of 3 dogs (mixed sex per group). All doses were administered at 3 mL/kg in a vehicle/carrier consisting of 10% Captisol in 25 mM citrate buffer (pH 3). Criteria for evaluation included toxicokinetics, BCL6 protein assessment in leukocytes by proteomics, potential changes in off-target protein levels in leukocytes by proteomics, survival, body weights, food consumption, clinical observations, FOB evaluation, and clinical pathology (serum chemistry and hematology) evaluations. [00854] Dose proportionality was observed between dose groups from 7.5 mg/kg BID to 30 mg/kg BID on Day 5, and for Day 1 between the 15 mg/kg BID and 30 mg/kg BID for the individual diastereomer concentrations. Individual isomers of BMS-986458 (BMT-648592 and BMT-648599) had a trend favoring BMT-648592 in plasma concentrations at a 2:1 ratio. The toxicokinetic summary for BMS-986458 and the 2 isomers are presented in the following table. Table B3-4.3.2.5-1: Toxicokinetic Summary - Mean Values - Tolerability and Toxicokinetic Study in Dogs Dosed Twice Daily for 5 Consecutive Days

[00855] Non-dose-dependent, BMS-986458-related BCL6 degradation in peripheral blood leukocytes was noted approximately 4- and 24-hours post-morning dose on Day 1 and 4, indicating sustained BCL6 degradation (> 80% decrease compared to controls) throughout the dosing period. Canonical CELMoD molecular glue substrates (e.g., IKZF1/3, GSPT1, CK1α, HBS1L) were unaffected. BCL6 was selectively downregulated at the early collection points. Modest changes to the leukocyte proteome were observed in the later samples collected after Day 4 dosing. [00856] No BMS-986458-related body weight or clinical chemistry changes were noted at any dose level. [00857] At doses ≥ 7.5 mg/kg BID, BMS-986458 caused sporadic fecal changes including unformed or liquid feces or no fecal output starting on Day 1 and becoming most prevalent by Day 5, with some dogs presenting fecal changes during post-dose period until Day 8. All dogs treated with BMS-986458 were positive for blood in stool samples on Day 4 and/or 5. Decreases in food consumption (up to 50% decreases) were observed starting on Day 3. In addition, all dogs treated with BMS-986458 presented WBC and neutrophil elevations by Day 5 and sustained through Day 15. [00858] In conclusion, BMS-986458 administered for 5 days orally in dogs at 7.5, 15, and 30 mg/kg BID, achieved dose-proportional exposures and sustained BCL6 degradation > 80% in leukocytes throughout the course of the study. At all doses, BMS-986458 caused fecal changes including blood in the stool with evidence of recovery during the post-dosing period. [00859] 4.3.2.6 Five-day Oral Exploratory Study in Female Dogs. In a 5-day exploratory toxicity study in groups of 2 female dogs,²⁸ control article at a dose volume of 5 mL/kg BID (8 ± 0.5 hours apart) was administered orally for 5 days (only 1 administration on Day 5) as a lead in period to assess tolerability of the control article. Following a 9-day no-dose period (Days 6 to 14), BMS-986458 was administered orally at doses of 5, 15, or 50 mg/kg BID (8 ± 0.5 hours apart; total daily dose of 10, 30, or 100 mg/kg/day) to the dogs daily for 5 days (Days 15-19), except on Day 19, when the dogs received only 1 dose. All doses were administered at 5 mL/kg BID in a vehicle/carrier consisting of 0.25% Methocel E4M in water. Endpoints included survival, toxicokinetics, metabolite profiling, clinical observations, body weights, food consumption, clinical pathology and exploratory FOB testing evaluations, targeted protein (BCL6) expression in leukocytes, organ weights, and gross and microscopic pathology analyses. Scheduled necropsies were conducted post dose at the end of a 5-day dosing period. [00860] There we no control article-related findings noted during the 5-day control article lead-in period. [00861] After repeated dosing, mean systemic exposures (AUC[0-24h]) of BMS-986458 and its diastereomers, BMT-648592 and BMT-648599, generally increased greater than dose proportionally from 5 to 15 mg/kg BID and approximately dose proportionately from 15 to 50 mg/kg BID. The toxicokinetic summary for BMS-986458, BMT-648599, and BMT-648592 are presented in the following table. Table B3-4.3.2.6-1: Toxicokinetic Summary - Mean Values - Five-day Oral Exploratory Study in Female Dogs [00862] Metabolite profiles of dog plasma samples indicated unchanged BMS-986458 as the predominant drug species in circulation, which was about 90% of total circulating species in dog plasma after doses of 15 or 50 mg/kg BID. The most abundant metabolites in dog plasma were formed via demethylation (M11) and oxidation (M9) of parent, representing 1.6% to 3.3% of the total circulating species. A low level of oxidation, dehydrogenation, dealkylation, and hydrolysis metabolites were also detected (< 0.4%). [00863] At 4 hours post first dose on the fourth dosing day of BMS-986458, the concentrations of BCL6 in leukocyte samples were below the limit of quantification (LOQ) in 5 of the 6 dogs, with the exception being slightly above the LOQ at the low dose of 5 mg/kg BID. This finding is indicative of BCL6 degradation at all dose levels as samples from untreated dogs in another study were all above the LOQ.⁴⁷ [00864] There was no BMS-986458-related moribundity/mortality, or effects on feeding behavior, organ weights, or gross pathology. [00865] At ≥ 15 mg/kg BID, BMS-986458-related findings included: • Minimal decrease in body weight compared to beginning of dosing period (-0.15 kg compared to beginning of dosing period) • Positive FOB results in 4/4 dogs at doses ≥ 15 mg/kg BID with no clinical observations or microscopic correlates; FOB+ pretest incidence was 1/5 (1 sample not submitted) [00866] At the high dose of 50 mg/kg BID, BMS-986458-related findings included: • Clinical observations of liquid feces starting dosing day 3 and thin for 1 dog on dosing day 4 • Minimal increase in monocyte counts and fibrinogen concentrations, suggestive of an inflammatory response, with no histopathologic correlates • Minimal increase in cholesterol concentrations • Minimal to moderate decrease in lymphoid cellularity observed in the thymus, mandibular lymph node, and GALT of stomach and colon in 1 female dog [00867] In conclusion, BMS-986458 was clinically well-tolerated by female dogs for 5 days at oral doses ≤ 50 mg/kg BID. Based on the absence of dose-limiting toxicity, the MTD was considered to be 50 mg/kg BID (mean AUC[0-24h] of 2,120 µg•h/mL for BMS-986458). [00868] 4.3.2.7 A One-month Oral Toxicity Study in Dogs with a 2-week Recovery Period. In a pivotal one-month toxicity study,⁴⁷ BMS-986458 was administered by BID oral gavage at doses of 0 (vehicle), 5, 15, or 50 mg/kg BID (8 ± 0.5 hours apart; total daily doses of 0, 10, 30, or 100 mg/kg/day) to groups of 5 dogs per sex in Groups 1, 3, and 4; and 3 dogs/sex in Group 2. All doses were administered at 5 mL/kg in a vehicle/carrier consisting of 0.25% w/w Methocel E4M in ultra-pure water. The control group were administered HPMC-AS-HF at a concentration (29.81 mg/mL) equivalent to the HPMC-AS-HF concentration in the BMS- 986458 high-dose (Group 4) formulation. Endpoints included survival, toxicokinetics, clinical observations, body weights, food consumption, physical (including respiratory and neurologic) and ophthalmologic examinations, electrocardiology, clinical pathology evaluations (hematology, coagulation, clinical chemistry, urinalysis, and FOB), cytokine evaluation, BCL6 protein expression in circulating WBCs using LC-MS and lymphoid tissues by immunohistochemistry, immunophenotyping (total T, helper T, cytotoxic T, and B cells), TDAR analysis, organ weights, and gross and microscopic pathology analyses. Scheduled necropsies were conducted after 28 days of dosing (3/sex/group) and following a 2-week recovery period (2/sex/group in Groups 1, 3, and 4). [00869] After repeated dosing, mean systemic exposures (AUC[0-24h]) for BMS-986458 as well as the diastereomers, BMT-648592 and BMT-648599, generally increased greater than dose proportionally from 5 to 15 mg/kg BID and approximately dose proportionately from 15 to 50 mg/kg BID with no substantial sex differences and no accumulation or loss of exposure noted, in consideration of large inter-individual variability. On Days 1 and 28, mean systemic exposures (AUC[0-24h]) to BMT-648592 were approximately 2.7 to 3.7× those of the other diastereomer, BMT-648599. Diastereomer ratios were generally similar across all doses with no substantial change after repeated dosing. Table B3-4.3.2.7-1: Toxicokinetic Summary - Mean Sex-combined Values - A One- month Oral (Gavage) Toxicity Study in Dogs with a 2-week Recovery Period (Source: Study DN22136⁴⁷)

[00870] Degradation of BCL6 was assessed by immunohistochemistry of lymph nodes and LC-MS analysis of circulating leukocytes. Immunohistochemical analysis of lymph nodes from control dogs showed robust staining for BCL6 in germinal centers. In all dose groups, BCL6 staining was negative and germinal centers were reduced or absent. After the 2-week recovery period, BCL6 staining recovered at 15 mg/kg BID, but 2 of 4 dogs were still negative for BCL6 at 50 mg/kg BID. Consistent with the immunohistochemistry findings, at all dose levels, significantly lower BCL6 levels were measured in circulating leukocytes compared to control on Days 1 and 28. [00871] BMS-986458-related mortality was noted at 50 mg/kg BID. Starting Day 1, marked decreases in food consumption were noted at 50 mg/kg BID which led to deteriorating clinical condition (body weight loss, decreased activity, thin conditions, and/or localized tremors). Nutritional enrichment was provided to all 50 mg/kg BID dogs and improved the condition of all but 3 dogs, which were euthanized on Day 7 or 8. In 1 early decedent, minimal neutrophilic inflammation of the atrioventricular valve and right atrium of the heart was observed but was not considered a direct test item-related effect though may have been secondary to the lymphoid changes. The cause of the clinical signs necessitating euthanasia of these 3 dogs could not be determined from the macroscopic or microscopic examinations, but the deaths were considered BMS-986458 related. [00872] There were no BMS-986458-related effects on ophthalmology, electrocardiology, neurological endpoints, respiratory rate, urinalysis, or cytokine endpoints at any dose. The following BMS-986458-related changes were considered not adverse because they were of minimal severity and/or lacked toxicologic significance. [00873] At ^ 5 mg/kg BID, BMS-986458-related findings included: [00874] Dose-dependent minimal to mild increases in mean WBC count, neutrophil count and lymphocyte counts [00875] Presence of 2+ or 3+ band neutrophils and 1+ cytoplasmic vacuolation indicative of an inflammatory response; increased total lymphocyte counts correlated with increases in the absolute counts of total T cells, helper T, and B cells [00876] Minimal to mild decreases in mean RBC count, HGB, and HCT which correlated with mild decreases in mean reticulocyte counts, increases in red cell distribution width at 50 mg/kg BID, and microscopic observations of decreased bone marrow erythroid cellularity at 15 and 50 mg/kg BID for females, and 15 mg/kg BID only for males [00877] Minimal to mild increases in cholesterol [00878] Increased mean liver weights (mean absolute and relative [to body and brain]; up to 47%) correlating with microscopic hepatocellular hypertrophy and hepatocellular rarefaction in males at ≥ 15 mg/kg BID [00879] Decreased KLH-specific IgG responses compared to vehicle on Days 15, 22, and 29 [00880] At ^ 15 mg/kg BID, BMS-986458-related findings included: • Lower mean body weights/body weight loss noted throughout the dosing period compared to their respective pretest values on Day -1 (-4.7% for males at 15 mg/kg BID and -11% and -8% for males and females, respectively, at 50 mg/kg/dose BID)

• Lower mean food consumption noted during Week 1 for males at ≥ 15 mg/kg/dose BID and females at 50 mg/kg/dose BID, which was mitigated by the provision of extra dietary supplementation in the form of canned food to the 50 mg/kg BID group starting Day 7/6 until the end of dosing • Minimal to mild increases in total bilirubin and minimal decrease in glucose [00881] At the high dose of 50 mg/kg BID, BMS-986458-related findings included: • Clinical observations of decreased activity, prominent backbone, and/or thin condition noted in most of the surviving males and females which correlated with mean body weight loss • Minimal to mild increases in fibrinogen • Minimal increases in mean triglycerides • Decreases in mean albumin with correlating decreases in A/G ratio in males • Increased mean kidney weights (mean absolute and relative [to body and brain]; up to 18%) with no microscopic correlates • Small thymus in 1 male and 1 female correlating with minimal to moderate (females) and moderate or severe (males) decreased lymphocyte cellularity • Minimal mixed cell inflammation of the femorotibial joint observed in 1 female and all 3 early decedents [00882] All BMS-986458-related findings were fully reversible by the end of the 1-month recovery period, except: • Minimal decreases in RBC count, HGB, and HCT; however a regenerative response was observed consisting of minimal to mild increases in red cell distribution widths and reticulocyte counts at ≥ 15 mg/kg BID along with rebound effects of increased cellularity of the bone marrow and extramedullary hematopoiesis in the spleen at ≥ 15 mg/kg BID • Decreased lymphocyte cellularity in the GALT in females at ≥15 mg/kg BID [00883] In conclusion, administration of BMS-986458 resulted in the early euthanasia of 2 males (Day 8) and 1 female (Day 7) in the 50 mg/kg BID group due to clinical signs associated with body weight loss and decreased food consumption. The cause of the clinical signs necessitating euthanasia of these 3 dogs was not determined from the macroscopic or microscopic examinations but was considered to be BMS-986458 related. As no adverse findings or morbidity was observed at 15 mg/kg BID, the NOAEL and HNSTD was considered to be 15 mg/kg BID (mean sex combined BMS-986458 AUC[0-24h] = 400 µg•h/mL on Day 28). [00884] 4.3.3 Gentoxicity [00885] 4.3.3.1 In Vitro. In exploratory bacterial reverse-mutation assays in S. typhimurium (TA98, TA100, and TA1537), BMS-986458 and its individual diastereomers, BMT-648592 and BMT-648599,^48,49,50 were not mutagenic without metabolic activation at ≤ 400, 481, and 481 μg/plate, respectively, or with S9 metabolic activation at ≤ 800, 1050, and 1050 µg/plate, respectively. Similarly, in a definitive GLP-compliant bacterial reverse-mutation assay in S typhimurium (TA98, TA100, TA1535, TA1537) and E. coli (WP2 uvrA),⁵¹ BMS- 986458 was not mutagenic at up to 313 μg/plate without or with metabolic activation (activated liver S9), respectively. [00886] In exploratory micronucleus assays,^68,69,70,71 BMS-986458 and individual diastereomers BMT-648592 and BMT-648599 were positive for micronuclei formation in CHO and/or TK6 cells without S9 metabolic activation at ≥ 1.7, 9, and 1.5 μg/mL, respectively, and with S9 activation at ≥ 1.7, 59, and 4.5 μg/mL, respectively. In a multiflow assay in TK6 cells,⁷¹ BMS-986458-related increases in H2AX and p53 protein were observed at ≥ 3.87 ug/mL and increases in polyploidy were observed at ≥ 88 ug/mL. These findings indicate that in vitro BMS- 986458 is clastogenic at low concentrations and aneugenic at high concentrations. [00887] 4.3.3.2 In Vivo [00888] In Vivo Micronucleus and Comet NonGLP Study in Rat. As part of an exploratory toxicity study,⁴⁴ BMS-986458 was administered by oral gavage to groups of 6 female rats BID (6 ±0.5 hours apart) for 13 days for a total daily dose of 0, 100, 300, or 600 mg/kg/day (0, 50, 150, or 300 mg/kg BID). On Day 14, a single dose of 0, 50, 150, or 300 mg/kg was administered prior to necropsy for the timed collection of genetic toxicology samples. A positive control group of 6 female rats was administered by oral gavage with 10 mg/kg/day CP on Days 11 and 12, and 200 mg/kg/day of EMS on Day 14. Criteria for evaluation included peripheral micronucleus assessment and comet assay in the liver and duodenum. At all doses, BMS-986458 was well tolerated without effects on micronucleus assessment and comet assay (300 mg/kg BID AUC[0-24h] = 335 μg•h/mL and Cmax = 32 µg/mL). [00889] In Vivo Micronucleus and Comet GLP Study in Rat. BMS-986458 was administered twice daily (BID, 3 hours apart) by oral gavage at doses of 0 (negative control), 50, 150, or 500 mg/kg BID (100, 300, or 1000 mg/kg/day) to male rats (6/group) for 4 days.⁵³ All doses were administered at 10 mL/kg in a vehicle consisting of 0.25% w/w Methocel E4M in ultra pure water. Criteria for evaluation included survival, toxicokinetics, clinical observations, body weights, percentage of reticulocytes and frequency of micronucleated reticulocytes in the peripheral blood, and comet tail intensity (% tail DNA) in liver and duodenum. Scheduled necropsies were conducted 2 hours (± 30 minutes) post last dose on Day 4. [00890] Following repeated dosing, as measured after the first daily dose on Day 3, mean systemic exposures (AUC[0-21h]) of BMS-986458 and its diastereomers, BMT-648592 and BMT-648599, generally increased less than dose proportionally across the dose range of 50 to 500 mg/kg BID. These toxicokinetic results are summarized in the following table. Table B3-4.3.3.2-1: Toxicokinetic Summary of BMS-986458 - Day 3 in Male Rats [00891] BMS-986458 was well tolerated up to 500 mg/kg BID when dosed for 4 days, with no effects on clinical observations, body weight, and percentage of reticulocytes (indicating a lack of hematopoietic system cytotoxicity). No statistically significant increases compared to the negative control in percentage of micronucleated reticulocytes, or percentage of comet tail intensity in the liver and duodenum were observed at any dose level. The positive controls, cyclophosphamide, and ethyl methanesulfonate, performed as expected, demonstrating the study capable of detecting genotoxic substances. [00892] In conclusion, BMS-986458 did not induce damage to the chromosome or mitotic spindle apparatus as assessed in the micronucleus test and did not show evidence of DNA damage in the liver or duodenum in the in vivo comet assay, when administered twice daily via oral gavage for four consecutive days to male Sprague Dawley rats at doses up to 500 mg/kg BID (mean Day 3 AUC(0-21h) = 254 µg•h/mL for BMS-986458), the maximum feasible dose. [00893] 4.3.4 Carcinogenicity. No carcinogenicity studies have been performed with BMS- 986458. [00894] 4.3.5 Reproductive and Developmental Toxicity. No reproductive or developmental toxicity studies have been performed with BMS-986458. [00895] 4.3.6 Local Tolerance. No local tolerance studies have been performed with BMS- 986458. [00896] 4.3.7 Other Toxicity Studies [00897] 4.3.7.1 Phototoxicity Assay in Balb/C 373 Mouse Fibroblasts (DN22066). Because BMS-986458 absorbs light between 290 and 700 nm, in vitro testing of BMS-986458 was performed in the neutral red uptake assay in Balb/c 3T3 mouse fibroblasts.⁵⁴ When tested up to its limit of solubility in 1% dimethyl sulfoxide/Dulbecco’s phosphate buffered saline, 17.8 µg/mL, BMS-986458 demonstrated phototoxic potential. [00898] 4.4 Safety Pharmacology. BMS-986458 and its individual diastereomers, BMT- 648592 and BMT-648599, were evaluated for potential off-target pharmacology (binding and/or functional activity) against a broad panel ofreceptors, ion channels, transporters, and enzymes, including assessments of hERG (potassium), cardiac calcium, and cardiac sodium ion channel function. Additional in vitro assessment of BMS-986458, BMT-648592, and BMT-648599 was conducted in hiPSC-CM. In vivo safety pharmacology assessments of BMS-986458 included exploratory cardiovascular telemetry studies in conscious rats and dogs, and anesthetized rabbits, and cardiovascular, respiratory, and/or neurologic endpoints assessed as part of the pivotal 1- month oral toxicity studies in rats and dogs. [00899] 4.4.1 In Vitro Off-Target Interaction Assessment. BMS-986458 and/or BMT- 648592 and BMT-648599 were tested in vitro for activity against a broad spectrum of pharmacologic receptors, transporters, ion channels, nuclear hormones, and enzymes at maximum concentrations ≤ 62.8 μg/mL.^55,56,57 BMT-648592 and BMT-648599 inhibited phosphodiesterase (PDE) 3 and PDE4 at generally comparable concentrations with an IC50 for PDE3 of 3.7 and 1.9 µg/mL, respectively, and PDE4 of 1.8 and 2.7 µg/mL, respectively. When tested as the mixture, BMS-986458, no inhibition of PDE3 or PDE4 was observed. When screened against a panel of hepatobiliary transporters and enzymes, BMS-986458 inhibited BSEP, MRP2, and UGT1A1 with respective IC50 values of 2.4, 4.6, and 0.094 µg/mL. [00900] 4.4.2 Cardiovascular Assessments [00901] 4.4.2.1 In Vitro Cardiac Ion Channel Assays. In patch clamp assays,^58,59,60 BMS- 986458, BMT-648592, and BMT-648599 inhibited cardiac ion channels in vitro at generally comparable concentrations with hERG IC50s of 0.44, 0.52, and 0.16 µg/mL, respectively. BMT-648592 and BMT-648599 inhibited cardiac L-type calcium channels by 9.4% and 7.4%, respectively, at the highest tested concentration of 0.628 µg/mL. [00902] 4.4.2.3 Cardiovascular Study in Telemetered Rats. In a single day cardiovascular study in telemetered rats,⁶² BMS-986458 was evaluated to investigate the potential to induce changes in arterial blood pressure and heart rate after oral dosing. BMS-986458 was administered by oral gavage at doses of 0, 50, 150, or 300 mg/kg BID (6 hours between doses; total daily doses of 0, 100, 300, or 600 mg/kg/day) to 5 to 6 male rats per group; each rat was instrumented with telemetry implants. Vehicle control group animals (0 mg/kg) received the test article carrier (10% Captisol in 25mM citrate buffer pH 3) at the same volume. Parameters for evaluation were systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), heart rate (HR), core body temperature (CBT), and locomotor activity, which were monitored continuously for 24 hours prior to dose and for 24 hours after dose. Non-instrumented male satellite rats (n = 3) received 0, 50, 150, or 300 mg/kg BID BMS-986458 to investigate plasma concentrations of BMS-986458 and its diastereomers BMT-648592 and BMT-648599. [00903] Exposures from 50 mg/kg BID to 300 mg/kg BID were less than dose proportional. Exposures of BMT-648592 and BMT-648599 had an estimated 1:1 ratio, with a slight non- significant trend favoring BMT-648592 in plasma concentrations. The toxicokinetic data are summarized in Table 4.4.2.3-1. Table B3-4.4.2.3-1: Toxicokinetic Summary - Mean Values - Oral Single Day BID-dose Investigative Cardiovascular Study in Telemeterized Male Rats [00904] There were no BMS-986458-related changes in blood pressure (MAP, SBP, DBP), heart rate, or core body temperature up to 300 mg/kg BID. The locomotor activity was reduced by BMS-986458 in the animal’s most active period at doses of 150 and 300 mg/kg BID. [00905] 4.4.2.4 Electrophysiology Study in Anesthetized Rabbits. In an electrophysiological study in anesthetized rabbits,⁶³ BMS-986458 was given intravenously over 30 minutes using incremental doses of 0.33, 2, or 12 mg/kg (12 mg/mL) to 3 anesthetized male rabbits. An additional 3 anesthetized male rabbits were given infusions of vehicle as controls. Intracardiac His-bundle electrograms and surface electrocardiograms (ECG) were recorded continuously before, during, and after incremental dosing. BMS-986458 concentration was determined in plasma collected at the end of each infusion and 10, 20, and 30 minutes after completion of infusion of the highest dose. [00906] Plasma concentrations of BMS-986458 increased dose-dependently, averaging 1.6, 12.2, 45.8 µg/mL (2.6, 19.5 and 72.9 µM) after intravenous infusion at doses of 0.33, 2, and 12 mg/kg, respectively. [00907] At the high dose of 12 mg/kg, BMS-986458 caused an increase in heart rate- corrected QT interval of 51.2 ms (QTcF) and 24.4 ms (QTcV). At 2 and 12 mg/kg, BMS- 986458 caused decreases in blood pressure of -11.6% and -34.4% as well as increases in heart rate of 10.8% and 34.1% which confounded interpretation of the QT interval findings. The compound had no significant effect on PR, QRS, AH, or HV intervals at any dose tested. [00908] In conclusion, BMS-986458 administered intravenously to anesthetized rabbits caused an increase in QTc at the high dose of 12 mg/kg (plasma concentration of 45.8 µg/mL). Decreases in blood pressure and increases in heart rate were observed at doses of 2 and 12 mg/kg and confounded interpretation of QT interval. [00909] 4.4.2.5 Single Day (BID) Oral Exploratory Cardiovascular Telemetry Study in Dogs. In an exploratory cardiovascular study in telemetered dogs,⁶⁴ BMS-986458 was administered as BID oral doses of 30 mg/kg (60 mg/kg/day) to 6 female beagle dogs instrumented with telemetry devices at a dose volume of 6 mL/kg. The dogs, serving as their own control, were administered vehicle (10 % Captisol / 90 % 25 mM citrate buffer pH 3 ± 0) the day prior to BMS-986458 administration. Criteria for evaluation, including heart rate, systemic arterial blood pressure (systolic, diastolic, and mean), left ventricular pressure (systolic and end diastolic), left ventricular pressure derived parameters (+dP/dt, -dP/dt), ECG parameters (P wave duration, PR, RR, QRS, and QT intervals), physical activity, and core body temperature, were monitored telemetrically and evaluated for a 1-hour period prior to treatment and approximately 21 hours after treatment with either vehicle or BMS-986458. Clinical observations and rate-corrected QT interval (QTcA, QT interval normalized to a heart rate of 80 beats per minute) were also evaluated. ECG waveforms were analyzed for noteworthy changes in rate, rhythm, or morphology at approximately 4 and 10 hours after dosing, and plasma samples were taken for analyses of BMT-648592 and BMT-648599, the 2 diastereomers of BMS-986458, 6 and 24 hours after dosing. [00910] Plasma concentrations of BMT-648592 and BMT-648599 determined from samples taken 6 and 24 hours after BMS-986458 administration were generally similar between animals and ranged in individual animals from 1.26 to 24.5 µg/mL. Mean BMT-648592 and BMT- 648599 plasma concentration results are summarized in the following table. Table B3-4.4.2.5-1: Mean BMT-648592 and BMT-648599 Plasma Levels - Single Day (BID) Oral Exploratory Cardiovascular Telemetry Study in Dogs [00911] Drug- or vehicle-related clinical signs of toxicity observed following treatment included unformed stool after BMS-986458 administration, which resolved within 48 hours. [00912] Transient, minimal decreases in systolic blood pressure (~11%) were observed from 6 to 12 hours after the second BID dose. Transient, minimal decreases in left ventricular systolic blood pressure (~7%) were noted from approximately 10 to 12 hours after the second BID dose. Left ventricular negative dP/dt was decreased (~10%) overnight following the second BID dose. There were no noteworthy changes to heart rate, other hemodynamic endpoints, ECG endpoints, physical activity, or core body temperature following BMS-986458 administration. There were no BMS-986458-related changes in ECG waveform morphology. [00913] In conclusion, BMS-986458 produced transient, minimal decreases in arterial systolic and left ventricular systolic blood pressure and negative dP/dt overnight following the second oral BID dose of 30 mg/kg in dogs (60 mg/kg/day), which resulted in mean BMS- 986458, BMT-648592, and BMT-648599 plasma concentrations of 16.21, 11.46 and 4.75 µg/mL, respectively, 6 hours after the first dose and 58.4, 39.5, and 18.9 µg/mL, respectively, 24 hours after the first dose. [00914] 4.4.2.6 Cardiovascular Assessments in the 1-Month GLP Toxicity Study in Dogs. In the 1-month GLP toxicity study in dogs,⁴⁷ ECG recordings were taken during Week 4 approximately 2 hours after the first daily dose. No BMS-986458-related ECG findings were observed at any dose level (≤ 50 mg/kg BID; Cmax = 86.6 µg/mL). [00915] 4.4.2.7 Respiratory and Neurologic Assessments in the 1-Month Toxicity Study Dogs. In the 1-month toxicity study in dogs,⁴⁷ respiratory and neurologic assessments were conducted 2 hours post first daily dose during Week 4. No BMS-986458-related findings were noted for any parameter at any dose level (≤ 50 mg/kg BID; Cmax = 86.6 µg/mL). [00916] 7. Summary of Data [00917] 7.1 Summary of Safety. As there is no clinical experience with BMS-986458, the precautions and safety monitoring plans for the initial clinical trials are based on the findings in the nonclinical toxicology studies (Sections 4.3 and 4.4). A summary of these findings, their potential clinical safety significance, and requirements for safety monitoring by organ system, are outlined below. Exposure multiples shown below in this section are calculated to the predicted exposures (AUC and Cmax) at the 40 mg BID starting clinical dose. Cmax multiples have been corrected for free fraction using predicted species differences in protein binding using flux method and by assuming 99% protein binding for in vitro assays. [00918] As BMS-986458 is an experimental agent, it is possible that unforeseen, unknown, or unanticipated adverse events may occur. The investigator should review all the pertinent information in the IB as well as the specific protocol under consideration (including inclusion/exclusion criteria) to determine suitability of subjects for enrollment and appropriate evaluations of subjects once randomized into the study. [00919] 7.1.1 Immune Modulation. In repeat-dose toxicity studies in rats and dogs, immune findings consistent with immune suppression and pro-inflammation were observed. Pertaining to potential immune suppression, in the 1-month toxicity studies, decreases in IgG and/or IgM antibody responses to KLH were observed at doses ≥ 500 mg/kg BID (AUC[0-24h] = 229 µg•h/mL; 152×) in rats and ≥ 5 mg/kg BID (AUC[0-24h] = 47.5 µg•h/mL; 31×) in dogs. Minimal to severe decreases in lymphoid cellularity in thymus, GALT, and lymph nodes characterized by decreased size and number of germinal centers were also noted in dogs at ≥ 5 mg/kg BID. The effects on IgM and IgG production and lymph node germinal center pathology is consistent with the published role of BCL6 as a master regulator of antibody affinity maturation in germinal centers.^10,11 In the 1-month rat toxicity study only,⁴⁵ other findings included mild to moderate decreases in splenic marginal zone lymphoid cells and decreases in cytokines IL-2, IL-6, TNFα, and IFNγ on Day 28 at ≥ 50 mg/kg BID (AUC[0-24h] = 129 µg•h/mL; 86×) and IL-1β at 500 mg/kg BID. [00920] Pro-inflammatory findings were noted in rats and dogs. In the 1-month rat toxicity study,⁴⁵ mild increases in monocytes and globulin were noted at doses ≥ 50 mg/kg BID and increases in total WBC count, large unstained cells and lymphocytes were noted at ≥ 150 mg/kg BID (AUC[0-24h] = 179 µg•h/mL; 119×). In the 2-week nonGLP rat toxicity study,⁴⁴ minimal increases in total T, cytotoxic T, B, and NK cells were noted at ≥ 150 mg/kg BID (AUC[0-24h] = 282 µg•h/mL; 187×), but there were no similar changes in the GLP-compliant 1-month rat study at similar exposures. Similarly, in the 1-month dog toxicity study,⁴⁷ minimal to mild increases in WBC counts, neutrophils, lymphocytes, total T cells, helper T cells, and B cells were observed at ≥ 5 mg/kg BID. BMS-986458-related minimal to moderate mixed cell inflammation of the femorotibial joint was noted in 4 dogs as well as minimal neutrophilic inflammation in the atrioventricular valve of 1 dog at 50 mg/kg BID (AUC[0-24h] = 1,290 µg•h/mL; 855×). [00921] Based on the preclinical findings, monitoring of appropriate hematology parameters (WBC counts with differential, immunophenotyping), antibody levels (IgA, IgG, and IgM), cytokines, and physical exam is included in the clinical protocol as well as guidance on management of potential adverse events. [00922] 7.1.2 Hematology – Red Blook Cells and Platelets. BMS-986458-related decreases in RBC parameters (RBC count, HGB, HCT) were noted in repeat-dose toxicity studies in rats and dogs. In the 1-month rat and dog GLP toxicity studies,^45,47 decreased RBC parameters were observed at doses ≥ 150 mg/kg BID (AUC[0-24h] = 179 µg•h/mL; 119×) and ≥ 5 mg/kg BID (AUC[0-24h] = 47.5 µg•h/mL; 31×), respectively. In both species, decreases in RBC parameters were correlated with a regenerative increase in reticulocytes, increased red cell distribution widths, extramedullary hematopoiesis, and/or rebound cellularity in bone marrow with partial to full recovery of RBC parameters during the 2-week recovery period. [00923] Minimal BMS-986458-related increases in platelets were observed in the 1-month rat toxicity study at doses ≥ 150 mg/kg BID. Minimal increases in platelet counts and/or changes in coagulation times were noted in the nonGLP repeat-dose toxicity studies in rats with no consistent change (both prolongation and shortening observed) in coagulation times across studies.⁴⁴ No changes in platelet counts or coagulation times were noted in the dog repeat-dose toxicity studies. [00924] Based on the preclinical findings, appropriate monitoring of hematology parameters (red blood cell count with indices, hemoglobin, hematocrit, and platelet count) and coagulation parameters (PT, APTT, and fibrinogen) has been included in the clinical protocol as well as guidance on management of potential hematology adverse events. [00925] 7.1.3 Pro-Arrhythmic Potential. BMS-986458, BMT-648592, and BMT-648599 inhibit cardiac ion channels in vitro at comparable concentrations with a BMS-986458 hERG IC50 of 0.44 µg/mL, equating to free Cmax multiples of 518× over the clinical starting dose of 40 mg BID.⁵⁸ In an in vitro study in hiPSC-CM,⁶¹ BMS-986458 increased FPDc, arrhythmic signals, and decreased conduction velocity were noted at concentrations ≥ 0.19 µg/mL (224×) and increased beat rate was noted at 1.9 µg/mL (2240×). [00926] BMS-98458 showed pro-arrhythmic potential in anesthetized rabbits, but not conscious dogs when tested at comparable exposures. In an exploratory rabbit electrophysiology study,⁶³ BMS-986458-related increases in QTc interval (QTcF = 51.2 ms; QTcV = 24.4 ms) were noted at 12 mg/kg (plasma concentration = 45.8 µg/mL; 539×) administered by IV infusion, but interpretation was confounded by increases in heart rate (34%) and decreases in mean blood pressure (-34%). No ECG findings were noted in dogs in a nonGLP telemetry study at 30 mg/kg BID or in the 1-month GLP toxicity study (Cmax ≤ 86.6 µg/mL; 192×). [00927] Based on pre-clinical data, QT prolongation is not expected to occur at the doses to be tested in the first-in-human (FIH) trial. However, to identify any pro-arrhythmic effect, ECG monitoring will be implemented in the FIH trial. [00928] 7.1.4 Gastrointestinal Toxicity. In the 5-day dog exploratory toxicity studies but not in the 1-month GLP compliant toxicity study at comparable exposures,^28,46,47 BMS-986458- related changes in fecal composition (unformed or liquid feces) were noted at doses ≥ 7.5 mg/kg BID (AUC[0-24h] = 366 µg•h/mL; 243×) and correlated with positive FOB tests. No macroscopic or microscopic pathology correlates in the gastrointestinal tract were noted and findings recovered upon cessation of dosing. FOB tests could not be interpreted in the 1-month study due to confounding high positive rates in pre-test and controls. There were no fecal findings or gastrointestinal pathology findings observed in the 1-month rat toxicity study at any dose up to the high dose of 500 mg/kg BID. [00929] Based on the preclinical data, appropriate monitoring and management for gastrointestinal toxicity has been included in the clinical protocol. [00930] 7.1.5 Reproductive Risk Assessment. BMS-986458 does not degrade selected, classical CELMoD neosubstrates such as Aiolos, CK1α, Ikaros, GSPT1, and SALL4. Therefore, the BMS-986458 toxicity profile is anticipated to be differentiated from CELMoDs, including potential reproductive toxicity. However, the molecular basis of CELMoD-mediated reproductive toxicity is not fully elucidated. Since reproductive toxicity assessments have not been conducted to date and the mechanism of BMS-986458 is cereblon-dependent, BMS- 986458 will be treated as a presumed selective developmental toxicant. In the 1-month GLP toxicity studies in rats and dogs, no pathology findings were observed in males or female reproductive tissues at any dose. [00931] Based on this, an appropriate pregnancy prevention plan, which includes counseling, pregnancy testing and pregnancy prevention measures, is mandated for clinical trials. [00932] 7.1.6 Liver Risk Assessment. BMS-986458 was determined to be an inhibitor of BSEP, MRP2, and UGT1A1 with respective IC50s of 2.4, 4.6, and 0.094 µg/mL. However, the risk for inhibition at the FIH clinical dose range is low with free Cmax margins to these IC50s of more than 100× for the 40 mg BID starting dose. In the 1-month dog toxicity study, minimal to mild increases in total bilirubin were noted at doses ≥ 15 mg/kg BID (Cmax = 25.1 µg/mL; 56×) without changes in other liver enzymes. Increased bilirubin may have been secondary to inhibition of UGT1A1 as the free Cmax at 15 mg/kg BID (0.251 µg/mL assuming 1% unbound) was higher than the in vitro UGT1A1 IC50. Contrasting to the potential effects of BSEP, MRP2, and UGT1A1 inhibition, decreases in circulating bile acids were noted in the 1-month rat study at ≥ 50 mg/kg BID (Cmax = 11 µg/mL; 129×). [00933] In both the 1-month rat and dog toxicity studies,^45,47 liver findings were limited to increases in liver weights correlated with minimal to mild hepatocellular hypertrophy, which is a finding consistent with BMS-986458 as a CYP inducer. Considered secondary to the hepatic changes and unlikely to be human-relevant, BMS-986458-related minimal hypertrophy of the thyroid gland follicular epithelium was noted in rats only at doses ≥ 50 mg/kg BID (AUC[0-24h] = 129 µg•h/mL; 86×). [00934] In the GLP-compliant 1-month rat and dog toxicity studies, minimal to mild BMS- 986458-related increases in cholesterol were noted at doses ≥ 150 mg/kg BID (AUC[0-24h] = 179 µg•h/mL; 119×) and 5 mg/kg BID (AUC[0-24h] = 47.5 µg•h/mL; 31×), respectively. These findings correspond to the growing literature that demonstrates the role of BCL6 in the regulation of liver lipid metabolism.^65,66 [00935] Based on the preclinical data, drug-induced liver injury is not anticipated at doses in the FIH clinical dose range. Appropriate monitoring of liver function will be conducted at an appropriate frequency for all participants in the FIH study, including assessments of transaminases, bilirubin, and alkaline phosphatase. Though the secondary thyroid findings were considered unlikely to be human relevant, clinical safety laboratory assessments will be performed monitoring TSH and free T4, if TSH is abnormal. Based on the preclinical lipid profile changes, clinical safety laboratory assessments will be performed to monitor total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein. [00936] 7.1.7 Phototoxicity. BMS-986308 absorbs light between 290 and 700 nm. In a GLP- compliant neutral red uptake phototoxicity assay in Balb/c 3T3 mouse fibroblasts,⁵⁴ BMS- 986458 was determined to be positive for phototoxic potential. Follow up confirmation of phototoxic potential in an in vivo study has not yet been completed. [00937] Based on the current preclinical data, patients should be counseled to minimize exposure to ultraviolet light, wear protective clothing and sunglasses when out in the sun, and use a broad- spectrum ultraviolet (UV)A/UVB sunscreen. [00938] 7.2 Human Dosing Range and Safety Margins. The clinical starting dose was selected based on findings from the 1-month toxicity studies in rats and dogs, and PD studies in the OCI-LY1 xenograft mouse model. In the pivotal 28-day toxicity study in rats, there were no adverse findings, and the NOAEL was ≥ 500 mg/kg BID. Therefore, the STD10 was considered > 500 mg/kg BID. In the pivotal 28-day dog toxicity study, decreases in food consumption were noted at the high dose of 50 mg/kg BID that led to decreases in body weight and poor clinical condition, resulting in subsequent early humane euthanasia of 3 dogs on Day 7, without clear cause of clinical decline. There were no adverse effects at the mid dose of 15 mg/kg BID and this dose was considered the NOAEL and HNSTD. Taking the dog as the most sensitive species, a maximum recommended start dose (MRSD) of 83 mg BID was calculated using the approach described in ICH S9 (body surface area [BSA] conversions and allometric scaling) after applying a 6× safety factor. [00939] The pharmacokinetic/pharmacodynamic and efficacy study in an OCI-LY1 xenograft mouse model suggested that full BCL6 suppression is required for 24 hours to achieve maximum tumor growth inhibition. In humans, BMS-986458 is predicted to have low clearance (3.6 mL/min/kg) and a moderate Vss (2.08 L/kg) with a corresponding terminal half-life of approximately 10.6 hours. Based on the predicted terminal half-life humans, BID dosing is projected to achieve full BCL6 suppression for 24 hours. The current projected efficacious dose range based on tumor growth inhibition in this xenograft model is 10 to 80 mg BID. [00940] The starting dose in CA1231000 was selected to be 40 mg BID. Since this dose is in the middle of the projected efficacious dose range and is less than the MRSD of 83 mg BID, it is anticipated to be both efficacious and safe. The highest clinical dose will be determined based upon human tolerability. The predicted AUC and Cmax at the proposed highest clinical dose of 640 mg BID are at least 9.5× and 3.5×, respectively, lower than those at the NOAEL in the pivotal 1-month rat and dog studies. [00941] Exposure multiples presented in Table 7.2-1 were calculated using comparisons of systemic exposure (Cmax and AUC) and BSA.

Table B3-7.2-1: Exposure Multiples Relative to Noteworth Drug-related Effects

[00942] 7.3.1 Pregnancy. BMS-986458 does not degrade classical CELMoD neosubstrates, such as Aiolos, CK1α, Ikaros, GSPT1, and SALL4. Therefore, the BMS-986458 toxicity profile is anticipated to be differentiated from CELMoDs and IMID drugs (including thalidomide), including potential reproductive toxicity. However, as reproductive toxicity assessments have not been conducted to date and the mechanism of BMS-986458 is cereblon-dependent, BMS- 986458 will be treated as a presumed selective developmental toxicant. Therefore, a pregnancy prevention program must be followed in the clinical program. [00943] There are no data on administration of BMS-986458 in pregnant women or animals and therefore it should not be administered to pregnant subjects. Requirements for contraception and pregnancy screening are fully detailed for male and female participants in the respective clinical protocol. [00944] 7.3.2 Drug-Drug Interaction Potential. Drug-drug interactions (DDI) have not been investigated in clinical studies of BMS-986458. [00945] Reaction phenotyping studies of human cytochrome P450 (CYP) isoforms and human liver microsomes showed that BMS-986458 is predominantly metabolized by CYP3A4/5 with minor participation from CYP1A2, CYP2C8, CYP2C9, and CYP2C19. In addition, BMS- 986458 is an inhibitor of CYP3A4. These data suggest that potential DDI exists if BMS-986458 is co-administered with strong inhibitors or inducers of CYP3A4, sensitive CYP3A substrates, or CYP3A substrates with a narrow therapeutic window. If use of strong CYP inhibitors or inducers is necessary, the risks and benefits should be discussed with the Sponsor’s Medical Monitor prior to its concomitant use with study intervention. [00946] Examples of strong CYP3A inhibitors or inducers include (but are not limited to): • CYP3A inhibitors: clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, grapefruit, and grapefruit juice • CYP3A inducers: carbamazepine, phenytoin, rifampin, and St. John’s Wart • A detailed list of strong CYP3A inhibitors or inducers, sensitive CYP3A substrates, or CYP3A substrates with a narrow therapeutic window is available on the FDA website. [00947] Based on in vitro data, BMS-986458 may cause inhibition of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the gut, thereby enhancing oral absorption and plasma exposure of substrates of P-gp and BCRP. BMS-986458 may also have the potential to inhibit hepatic uptake transporters (OATP1B1 and OATP1B3) and Phase II drug metabolizing enzyme (UGT1A1) at higher doses. Subjects receiving P-gp substrates (eg, dabigatran, digoxin), BCRP substrates (eg, rosuvastatin, sulfasalazine), P-gp or BCRP inhibitors (eg, erythromycin, cyclosporine A) or OATP1B1 and OATP1B3 substrates (eg, statins), or UGT1A1 substrates (eg, valproic acid, levothyroxine, or phenytoin) should be closely monitored for signs of toxicity given the potential for this interaction. [00948] References ¹ Kanas G, Ge W, Quek RGW, et al. Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020-2025. Leuk Lymphoma.2022;63:54-63. ² WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2017. ³ Preclinical Investigation of In Vitro and Ex Vivo Response to BCL6 Degrader BMS-986458 in Models of Diffuse Large B-Cell Lymphoma (OG00458). Bristol-Myers Squibb, 2023. DCN 930205191. ⁴ Crump M, Neelapu SS, Farooq U, et al, Outcomes in refractory diffuse large B cell lymphoma: results from the international SCHOLAR-1 study [published erratum appears in: Blood 2018;131(5):587-8]. Blood 2017;130:1800-8. ⁵ Purdum A, Tieu R, Reddy SR, Broder MS. Direct Costs Associated with Relapsed Diffuse Large B cell Lymphoma Therapies. Oncologist.2019;24:1229-36. ⁶ Vaidya R, Witzig TE. Prognostic factors for diffuse large B cell lymphoma in the R(X)CHOP era. Ann Oncol 2014;25:2124-33. ⁷ Nagle SJ, Woo K, Schuster SJ, et al. Outcomes of patients with relapsed/refractory diffuse large B cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol 2013;88:890-4. ⁸ Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B cell lymphoma in the rituximab era. J Clin Oncol 2010;28:4184-90. ⁹ Epperla N, Badar T, Szabo A, et al. 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J Pharm Sci 1979; 68(9): 1203-1205. ⁴¹ BMS-986458: Maximum tolerated dose and toxicokinetic assessment of dogs administered a single oral dose of BMS-986458 (CEL-009463, CC2021676) (Study DT21066); Report and Amendment 1. Bristol-Myers Squibb Company; 2022. Document Control No.930187418. ⁴² BMS-986458: Five-day oral exploratory toxicity study in male rats (Study DN22115). Bristol-Myers Squibb Company; 2023. Document Control No.930205113. ⁴³ Exploratory toxicokinetic and tolerability study in female rats orally administered BMS- 986458 (CC2021676) twice daily for 10 consecutive days (Study DT22011); Report and Amendment 1. Bristol-Myers Squibb Company; 2023. Document Control No.930199752. ⁴⁴ CC2021676: Two-week oral BID exploratory toxicity study in female rats (Study DN21129); Report and Amendment 1. Bristol-Myers Squibb Company; 2023. Document Control No. 930203162. ⁴⁵ BMS-986458: A one-month oral toxicity study in rats with a 2-week recovery period (Study DN22135). Bristol-Myers Squibb Company; 2023. Document Control No.930204855. ⁴⁶ BMS-986458 (CC2021676): Tolerability and toxicokinetic study in dogs dosed twice daily for 5 consecutive days (Study DT21078); Report, Amendment 1, and Amendment 2. Bristol- Myers Squibb Company; 2023. Document Control No.930186855. ⁴⁷ BMS-986458: A 1-month oral (gavage) toxicity study in dogs with a 2-week recovery (Study DN22136). Bristol-Myers Squibb Company; 2023. Document Control No.930204949. ⁴⁸ CEL-009463: Exploratory Ames reverse-mutation study in Salmonella typhimurium (Study DN21064); Report and Amendment 01. Bristol-Myers Squibb Company; 2021. Document Control No.930175635. ⁴⁹ BMT-648592: Exploratory Ames reverse-mutation study in Salmonella typhimurium (Study DN21135). Bristol-Myers Squibb Company; 2022. Document Control No.930183007. ⁵⁰ BMT-648599: Exploratory Ames reverse-mutation study in Salmonella typhimurium (Study DN21133). Bristol-Myers Squibb Company; 2022. Document Control No.930183026. ⁵¹ BMS-986458: Ames reverse-mutation study in Salmonella typhimurium and Escherichia coli (Study DN22069). Bristol-Myers Squibb Company; 2023. Document Control No. 930204435. ⁵² CEL-009463: Exploratory genotoxic mode of action using the multiflow assay in TK6 Cells (Study DN21111). Bristol-Myers Squibb Company; study on-going. ⁵³ BMS-986458: Four-day oral micronucleus study with comet evaluation in male rats (Study DN22070). Bristol-Myers Squibb Company; 2023. Document Control No.930204851. ⁵⁴ BMS-986458: Neutral red uptake phototoxicity assay in Balb/c 3T3 mouse fibroblasts (Study DN22066). Bristol-Myers Squibb Company; 2023. Document Control No.930201045. ⁵⁵ BMS-986458/CEL-009463: In vitro assessment of receptors, ion channels, monoamine transporters, and enzymes (Study LDO00020). Bristol-Myers Squibb Company; 2023. Document Control No.930201989. ⁵⁶ BMS-986458 isomer BMT-648592: In vitro assessment of interactions with receptors, ion channels, and enzymes (Study LDO00021). Bristol-Myers Squibb Company; 2023. Document Control No.930201984. ⁵⁷ BMS-986458 isomer BMT-648599: In Vitro assessment of interactions with receptors, ion channels, and enzymes (Study LDO00022). Bristol-Myers Squibb Company; 2023. Document Control No.930201983. ⁵⁸ BMS-986458: Effects on cardiac hERG channels (Study DT23033). Bristol-Myers Squibb Company; 2023. Document Control No.930202916. ⁵⁹ BMT-648592: Effects on cardiac hERG channels (Study DT23035). Bristol-Myers Squibb Company; 2023. Document Control No.930202931. ⁶⁰ BMT-648599: Effects on cardiac ion channels (Study DT23034). Bristol-Myers Squibb Company; 2023. Document Control No.930202919. ⁶¹ BMS-986458 (CEL-009463), BMT-648592 and BMT-648599: Exploratory in vitro multi- electrode array (MEA) study in human induced pluripotent stem cell-derived cardiomyocytes (Study DT23044); Report and Amendment 1. Bristol-Myers Squibb Company; 2023. Document Control No.930204098. ⁶² BMS-986458 (CC2021676): Oral single day BID-dose investigative cardiovascular study in telemeterized male rats (Study DT21068); Report and Amendment 1. Bristol-Myers Squibb Company; 2022. Document Control No.930186261. ⁶³ BMS-986458: Electrophysiological effects in anesthethized rabbits (Study DT21051). Bristol-Myers Squibb Company; 2022. Document Control No.930183352. ⁶⁴ BMS-986458: Single day (BID) oral exploratory cardiovascular telemetry study in dogs (Study DT21079); Report and Amendment 1. Bristol-Myers Squibb Company; 2021. Document Control No.930179833. ⁶⁵ LaPensee CR, Lin G, Dent AL, et al. Deficiency of the transcriptional repressor B cell lymphoma 6 (Bcl6) is accompanied by dysregulated lipid metabolism. PLos One 2014;Jun 3;9(6):e97090. ⁶⁶ Chikada H, Ida K, Nishikawa Y, et al. Liver-specific knockout of B cell lymphoma 6 suppresses progression of non-alcoholic steatohepatitis in mice. Sci Rep 2020 Jun 16;10(1):9704. ⁶⁷ Chiang JYL. Bile acid metabolism and signaling. Compr Physiol 2013;Jul 3(3): 1191-212. ⁶⁸ CEL-009463: Exploratory in vitro micronucleus study in Chinese hamster ovary cells (Study DN21094). Bristol-Myers Squibb Company; study on-going. ⁶⁹ BMT-648592: Exploratory in vitro micronucleus study in TK6 cells (Study DN21136). Bristol-Myers Squibb Company; study on-going. ⁷⁰ BMT-648599: Exploratory in vitro micronucleus study in TK6 cells (Study DN21134). Bristol-Myers Squibb Company; study on-going. ⁷¹ BMT-648592, BMT-648599: Exploratory in vitro micronucleus study in TK6 cells (Study DN22072). Bristol-Myers Squibb Company; 2023. Document Control No.930205597. Example B4. Clinical Protocol CA 1231000 [00949] This example provides additional details of the Phase I study described in Example B2 and incorporates herein by reference in its entirety the disclosure of Clinical Protocol CA 1231000 (Protocol Amendment 01; Date: 15-Jun-2023; Revised Date: 23-Aug-2023). [00950] Reference in Example B4 to sections, tables, references, and/or appendices is to other sections, tables, references, and/or appendices in Example B4. [00951] 1 Protocol Summary p g g

saety an pre mnary e cacy ata at tose ose(s) or etermnaton.

me o . Abbreviations: AE, adverse events; BOIN, Bayesian Optimal Interval; CAR, chimeric antigen receptor; D, day; DLBCL, diffuse large B-Cell lymphoma; DLT, dose limiting toxicity; ECOG, Eastern Cooperative Oncology Group; FDG, fluorodeoxyglucose; FL, follicular lymphoma; MTD, maximum tolerated dose; NHL, non- Hodgkin lymphomas; OBD, optimal biological dose; ORR, Overall response rate; PK, pharmacokinetic; R/R, Relapsed/Refractory; RP2D, recommended Phase 2 dosing; SAE, serious adverse events; SCT, stem- cell transplantation. a Sensitivity estimators of the main estimands and supplemental estimands will be defined in the statistical analysis plan, where applicable. [00952] 2 Schedule of Activities

Table B4-2-1: Screening and On-treatment Procedural Outline

Table B4-2-2: Long-term Follow-up Procedural Outline

Table B4-2-5: Biomarker Sampling Schedule

[00953] In the event that multiple procedures are required at a single time point, the ECG may be obtained up to 15 minutes earlier, vital signs may be obtained up to 10 minutes earlier or later, and clinical laboratory samples may be obtained up to 5 minutes earlier than the nominal timepoint, ensuring that the PK samples can be collected on time. [00954] 3 Introduction [00955] 3.1 Study Rationale. BMS-986458 is a small molecule, bifunctional cereblon- dependent ligand-directed degrader (LDD) that will be investigated for the treatment of patients with relapsed and/or refractory (R/R) non-Hodgkin Lymphoma (NHL). This Phase 1, first-in- human (FIH), clinical study of BMS-986458 will explore the safety, tolerability, PK, pharmacodynamics, and preliminary biological and clinical activity of BMS- 986458 as a single agent and in combination with anti-lymphoma agents in the setting of R/R NHL. [00956] 3.2 Background [00957] 3.2.1. Disease Background. NHL, the most common hematological malignancy worldwide, is a heterogeneous group of B-cell and T-cell lymphomas that collectively accounts for approximately 4% of all cancers in the US. While there are over 40 major subtypes, the most common ones include indolent follicular lymphoma (FL) and aggressive DLBCL. [00958] 3.2.1.1 Diffuse Large B-Cell Lymphoma. DLBCL is the most common subtype of NHL representing 26% of all cases of NHL neoplasms diagnosed and with an estimated incidence of 29,105 new cases in the US in 2020.¹ The current standard of care (SOC) for these patients is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in combination with rituximab (R-CHOP); however, approximately 10% to 15% of the patients have primary refractory disease and 20% to 25% will eventually relapse after achieving a complete remission (CR), typically within the first 2 years.² Outcomes remain poor for these patients, especially if refractory disease with a median overall survival (OS) of approximately 6 months.³ [00959] For many years, SOC for second-line R/R DLBCL has been high-dose chemotherapy followed by autologous stem cell transplantation (SCT). In the last years, CAR-T cell therapies have shown to cure a significant portion of patients with R/R DLBCL with CR rates ranging between 40% to58% and have been approved for refractory disease or relapse within 12 months of first-line chemoimmunotherapy.^4,5,6 In relapsed or refractory patients who have received 2 or more lines of therapy (including SCT or CAR-T cell therapies) or are not candidates for or do not have access to potentially curative therapies due to advanced age or poor perfo1mance status, DLBCL remains an incurable disease for which clinical trials are indicated. [00960] 3.2.1.2 Follicular Lymphoma. Follicular lymphoma (FL) is the most common indolent lymphoma originating from ge1minal center B cells. [00961] When therapy is indicated, anti-CD20 immunotherapy with or without chemotherapy are standard first or subsequent line options for advanced FL. Approximately 20% of patients have early relapse and progression of disease within 24 months (POD24), and these patients have poor outcomes.⁷ Upfront identification of these patients is not possible, and more effective treatments for these patients are needed. [00962] There is no standard treatment or sequence of treatments for R/R FL; multiple approaches include cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants. A chemoimmunotherapy regimen (bendamustine and rituximab [BR], R-CHOP, or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) different from the first-line therapy is an option in the relapse setting. Additional agents for multiply relapsed patients include lenalidoinide, PBK inhibitors, tazemetostat, bispecific T cell engagers (mosunetuzumab) and CAR- T cell therapy. Beyond the commercially approved targeted therapies in FL, there are multiple emerging agents that target the biology of FL, including antibody-mug conjugate (ADC), monoclonal or bispecific antibodies, checkpoint-based therapies, and novel combination strategies. [00963] There is a high unmet medical need to develop novel treatments for FL patients who fail to respond to standard therapy and whose treatment options for disease remission have been exhausted. [00964] 3.2.2. BMS-986458. BMS-986458 is a small molecule, mixture of diastereomers BMT-648592 and BMT-648599, bifunctional cereblon-dependent LDD. LDDs induce target protein degradation through the recruitment of the Cereblon (CRBN) E3 Ubiquitin ligase, ubiquitination, and subsequent proteolytic processing by the 26S proteasome. Downstream effects of degradation include cell cycle arrest and apoptosis in tumor B-cells and immunomodulation of T-cells. [00965] In vitro sensitivity of tumor B-cells to LDD is closely related to expression level. Post-treatment transcriptomic response and baseline genomics were used to define a sensitivity signature that incorporated expression with LDD induced post-translational modulators and mechanistic drivers. High-risk patient segmentation clusters identified by the Lymphoma Genome Project showed significant enrichment of the LDD sensitivity signature. [00966] BMS-986458 was evaluated in several in vitro NHL models and showed rapid and potent anti-proliferative and pro-apoptotic tumor cell killing. [00967] BMS-986458 demonstrates potent and selective degradation, in vitro/in vivo efficacy across multiple cell line-derived xenograft (CDX) models, favorable PK/pharmacodynamic and toxicologic profile in nonclinical safety assessments to enable trials in humans. A detailed description of the chemistry, pharmacology, efficacy, and safety of BMS-986458 is provided in the investigator brochure.¹⁸ [00968] 3.2.2.1 Nonclinical Pharmacology. BMS-986458 In Vivo Pharmacology. BMS986458 was evaluated as a single agent in 2 DLBCL CDX models where treatment exhibited tumor volume reductions between 74% and 84% following oral administration at the highest dose. In all studies this anti-tumor effect was achieved following greater than 98% degradation within tumor tissue that was maintained throughout the dosing period. [00969] 3.2.2. Nonclinical Pharmacokinetics. In vitro and in vivo studies have been conducted to characterize the absorption, pharmacokinetics, distribution, metabolis, and drug interaction potential of BMS-986458. [00970] Metabolism of BMS-986458 was evaluated in human hepatocytes, as well as hepatocytes from preclinical species, and in plasma samples from rats and dogs following oral administration. The predominant metabolic pathways for BMS-986458 across the species tested included demethylation, oxidation followed by glucuronidation, and hydrolysis. [00971] 3.2.2.3 Nonclinical Toxicology. The nonclinical toxicology of BMS-986458 (mixture of diastereomers BMT-648592 and BMT‑648599) was evaluated in a comprehensive battery of nonclinical toxicity studies that included single-dose and repeat-dose toxicity studies of up to 28 days duration with twice daily dosing (BID) in rats and dogs, in vitro and in vivo genetic toxicity studies, an in vitro phototoxicity study, and in vitro and in vivo cardiovascular safety pharmacology studies. Exposure multiples shown below are calculated to the predicted exposures (AUC and Cmax) at thestarting clinical dose. Cmax multiples have been corrected for free fraction using predicted species differences in protein binding using flux method and by assuming 99% protein binding for in vitro assays. [00972] The potential for BMS-986458 to affect the cardiovascular system has been characterized in vitro and in vivo. BMS-986458, BMT-648592, and BMT-648599 inhibited cardiac ion channels in vitro at generally comparable concentrations with hERG IC50s of 0.44, 0.52, and 0.16 μg/mL (0.7, 0.83, and 0.25 μM), respectively (518× for BMS-986458). BMT- 648592 and BMT-648599 inhibited cardiac L-type calcium channels by 9.4% and 7.4%, respectively, at the highest tested concentration of 0.628 μg/mL (1 μM). In a multi-electrode assay in human induced pluripotent stem cell -derived cardiomyocytes (hiPSC-CM), BMS- 986458 increased field potential duration (FPDc), arrhythmic beats, and decreased conduction velocity at concentrations ≥ 0.19 μg/mL (0.3 μM; 224×) and increases in beat rate observed at 1.9 μg/mL (3 μM; 2240×). In an exploratory rabbit electrophysiology study, increases in QTc interval (QT corrected for Fridericia [QTcF] = 51.2 ms; QT corrected for Van de Water’s [QTcV] = 24.4 ms) were noted at 12 mg/kg BMS-986458 (free plasma concentration = 1.16 μg/mL, 0.729 μM; 1365×) administered by intravenous (IV) infusion, but interpretation was confounded by increases in heart rate (34%) and decreases in mean blood pressure (-34%). In nonGLP studies in telemetered rats and dogs and in the 1-month GLP rat and dog studies, no BMS-986458-related cardiac, neurologic, and/or respiratory findings were noted at doses up to 500 mg/kg BID in rats (free Cmax = 0.194 μg/mL; 228×) and 50 mg/kg BID in dogs (free Cmax = 0.866 μg/mL; 192×). [00973] In vitro, BMS-986458, BMT-648592, and BMT-648599 were negative for mutagenicity in Ames assays, but positive for clastogenicity and aneugenicity in the presence or absence of S9 fraction in exploratory in vitro assays in CHO and/or TK6 cells. In a non-GLP 2- week rat toxicity study and in a standalone GLP-compliant in vivo genetic toxicity study, no BMS-986458-related effects on peripheral micronucleus or COMET (duodenum and liver) assays were noted at daily doses up to 500 mg/kg BID, respectively, indicating that BMS- 986458 is not genotoxic in vivo. [00974] In a GLP-compliant neutral red uptake phototoxicity assay in Balb/c 3T3 mouse fibroblasts, BMS‑986458 was positive for phototoxic potential. Follow up confirmation of phototoxic potential in an in vivo study will be carried out. [00975] Repeat-dose toxicity studies of up to 1 month in duration were conducted in rats and dogs. In the pivotal 1-month oral toxicity study in rats (doses of 50, 150, and 500 mg/kg BID), there were no adverse findings up to the high dose of 500 mg/kg BID (1000 mg/kg/day total). Therefore, 500 mg/kg BID was considered the no-observed-adverse-effect level (NOAEL). In the pivotal 1‑month oral toxicity study in dogs, BMS‑986458 was administered orally at doses of 0, 5, 15, and 50 mg/kg BID. At the dose of 50 mg/kg BID, decreases in food consumption were noted on Day 1 leading to body weight loss and decline in clinical condition requiring early euthanasia of 3 dogs on Day 7 without clear cause of the clinical decline. All other dogs at 50 mg/kg BID survived to scheduled necropsy without significant clinical signs. There were no other adverse findings and BMS-986458 was well tolerated at doses ≤ 15 mg/kg BID. Therefore, the NOAEL and highest non-severely toxic dose (HNSTD) were considered to be 15 mg/kg BID. [00976] In the repeat-dose toxicity studies, several dose-responsive, non-adverse findings were observed in rats and dogs. Immunosuppressive and pro-inflammatory changes were observed in rats and dogs including increases in circulating white blood cells (WBCs), neutrophils, lymphocytes, T, B, and/or natural killer (NK) cells; decreases in anti-keyhole limpet hemocyanin (KLH) IgM and/or IgG antibody production; decreases in cytokines in rats only (interleukin [IL]-1β, IL-2, IL-6, tumor necrosis factor [TNF]α, interferon [IFN]γ); decreases in lymphoid cellularity in thymus, gut-associated lymphoid tissue (GALT), and lymph nodes (dogs) or splenic marginal zone (rats); and mixed cell inflammation of the femorotibial joint in 4 dogs as well as minimal neutrophilic inflammation in the atrioventricular valve of 1 dog (both findings at high dose only). Decreased red blood cell (RBC) parameters with regenerative response were observed in both species. In rats, increases in platelets were observed with no consistent change in coagulation parameters across studies. Increases in bilirubin were noted in dogs without microscopic correlates or increases in transaminases and was potentially mediated by UGT1A1 inhibition. Liver hypertrophy and increased weights were observed in both species with observed findings in rats correlating with enzyme induction and secondary thyroid epithelium hypertrophy. In dogs, inconsistent changes in fecal composition and positive fecal occult blood (FOB) tests were observed without correlating gastrointestinal pathology. Minor renal effects without pathologic correlates were noted in both species with increases in kidney weights in dogs and mild increases in blood urea nitrogen (BUN) in rats. Lastly, minimal hypertrophy in the zona fasciculata was observed in rats. [00977] BMS-986458 does not degrade of classical CELMoD neosubstrates, such as Aiolos, CK1α, Ikaros, GSPT1, and SALL4. Therefore, the BMS-986458 toxicity profile is anticipated to be differentiated from CELMoDs, including potential reproductive toxicity. However, as reproductive toxicity assessments have not been conducted to date and the mechanism of BMS- 986458 is cereblon-dependent, BMS-986458 will be treated as a presumed selective developmental toxicant. [00978] Overall, the nonclinical toxicology assessment supports progression of BMS-986458 into Phase 1 clinical trials. [00979] 3.2.3. Rituximab. Rituximab is a recombinant chimeric murine/human antibody directed against the CD20 antigen, a hydrophobic transmembrane protein located on normal pre- B and mature B lymphocytes. Following binding, rituximab triggers a cytotoxic immune response against CD20-positive cells. [00980] Rituximab is indicated for several oncologic and non-oncologic treatments. The approved indications for lymphoma in the US and European Union (EU) are as follows: • US: Rituximab is indicated for the treatment of patients with: − previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or other anthracycline based chemotherapy regimens − previously untreated follicular, CD20-positive B-cell NHL in combination with CVP (cyclophosphamide, vincristine, prednisolone) chemotherapy − relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent • EU: MabThera is indicated for the treatment of patients with: − CD20 positive diffuse large B-cell non-Hodgkin lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy − previously untreated patients with stage III-IV FL in combination with chemotherapy − stage III-IV FL who are chemo resistant or are in their second or subsequent relapse after chemotherapy as a monotherapy − adult patients with FL responding to induction therapy, as maintenance therapy [00981] While rituximab is not FDA approved for treatment of R/R lymphoma other than FL, rituximab is a component of most salvage chemoimmunotherapy regimens (e.g., R-ICE, R- DHAP, R-ESHAP, R-gemcitabine/oxaliplatin), is listed as a treatment option for second (and subsequent) line treatment of B-cell lymphoma in the NCCN and European Society of Medical Oncology (ESMO) guidelines, and is routinely used in standard practice in this setting. In addition, in the US and EU, rituximab is approved in combination with lenalidomide in the treatment of patients with R/R FL. [00982] 3.3 Benefit/Risk Assessment [00983] 3.3.1 Risk Assessment Table B4-3.3.1-1: Risk Assessment n ng agents.

ontorng an management

y [00984] Standard eligibility criteria are included to ensure acceptable baseline organ function (including hematopoietic function) and lack of clinically significant comorbid diseases. [00985] As this is a FIH study, there is currently no human experience with BMS-986458. Thus, the analysis of potential risks is based on nonclinical toxicology studies and the review of the safety profiles of available compounds with similar mechanism of action. [00986] BMS-986458 degradation is cereblon-dependent, but does not lead to the off-target degradation of classical CELMoD neosubstrates, such as Aiolos, CK1α, Ikaros, GSPT1, and SALL4. Therefore, the BMS-986458 toxicity profile is anticipated to be differentiated from CELMoDs, including potential reproductive toxicity. However, as reproductive toxicity studies have not been conducted to date and the mechanism of BMS-986458 is cereblon-dependent, BMS-986458 will be treated as a presumed selective developmental toxicant and participants will be required to follow BMS-986458 Pregnancy Prevention Plan (PPP) for BMS Clinical trials. [00987] BMS-986458 will be administered in combination with rituximab in Part A2 and Part B2. The most common adverse reactions (> 25%) observed in patients with NHL are infusion reactions, fever, lymphopenia, chills, infection, and asthenia. Fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and PML have been reported. Participants also will be monitored for infections and reactivation of infections (including hepatitis B reactivation), neurologic function (PML), cardiac arrhythmias, and other AEs as per the rituximab prescribing information. [00988] Infusion of a biologic product may cause severe and life-threatening infusion reactions. Fatal infusion reactions within 24 hours of rituximab infusion occur; approximately 80% of fatal reactions occurred with first infusion (refer to USPI and EU SmPC). Premedication requirements and participant monitoring are included. [00989] Potential BMS-986458 and rituximab overlapping toxicities include cytopenias, infections, and TLS. Participants are being monitored throughout the study by physical exam, AE collection, standard and specialized laboratory tests as described in this study protocol. Dose modification guidelines, participants monitoring, and AE management guidance are included in this protocol. [00990] The global coronavirus disease 2019 (COVID-19) pandemic has been identified as a potential risk to clinical trial participants in general. Whether BMS-986458 administration increases the risk for contracting severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection or increases the severity or duration of symptoms is currently unknown. This unknown risk must be considered when enrolling a participant. [00991] No additional safety monitoring or routine screening tests will be required due to the SARS-CoV-2 pandemic. Participants with recent or acute infections will be excluded or delay start of study intervention. If a participant has a confirmed SARS-CoV-2 infection while on study intervention, dose delay or interruption of study intervention is required. [00992] The study has been designed with study visits that allow for close monitoring of participant’s safety throughout the clinical trial, and participants are encouraged to contact the investigator if an intercurrent illness develops between study visits. Testing for COVID-19 to inform decisions about clinical care during the study should follow local standard practice. [00993] Non-live COVID-19 vaccination is considered a simple concomitant medication within the study. [00994] 3.3.2 Benefit Assessment. Participants who have R/R NHL have a poor prognosis and few curative options. CA1231000 is a FIH study to evaluate BMS-986458 in this patient population. Therefore, although benefits might be hypothesized based on mechanisms of action and/or nonclinical observations, actual clinical benefits to participants with advanced cancer have not been established yet. The information collected during this study may help the Sponsor gain information about BMS-986458 that could benefit patients with R/R NHL. [00995] 3.3.3 Overall Benefit/Risk Conclusion. The Sponsor will evaluate the benefit/risk profile of the study on an ongoing basis. This evaluation will be based on all available data, with particular attention to (i) AEs or other safety trends in this or any other clinical study of BMS- 986458 whose character, severity, and/or frequency suggest that participants would be exposed to an unreasonable and significant risk of illness or injury; (ii) new non-clinical data suggesting unreasonable and significant risk of illness or injury. [00996] If such evaluation suggests that the benefit/risk profile of the study has become unfavorable to participants, the Sponsor will pause enrollment and/or treatment until further evaluation of data, and interaction with the appropriate Health Authority(ies) can take place on potential actions. Such actions may include (but are not limited to) study continuation, substantial amendment, or termination of the study. [00997] 4 Objective and Endpoints Table B4-4-1: Objective and Endpoints [Estimands] . , an us ng a ro, )

Abbreviations: AE, adverse event; AUC(0-T), area under the plasma concentration-time curve; Cmax, maximum concentration; CRBN, cereblon; DLT, dose-limiting toxicity; DOR, duration of response; lgG, immunoglobulin G; NHL, non-Hodgkin lymphoma; ORR, overall response rate; OS, overall survival; PFS; progression-free survival; PK, pharmacokinetic; RP2D, recommended phase 2 dose; R/R, relapsed/refractory; SAE, serious adverse event; Tmax, time of maximum concentration; TTR, time to response. ^a Sensitivity estimators of the main estimand and supplemental estimands will be defined in the statistical analysis plan, where applicable. [00998] 5 Study Design [00999] 5.1 Overall Design. This is a FIH, phase 1, multi-center, open-label, dose-finding study to determine the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of BMS-986458 in participants with R/R NHL. The study will be carried out in 2 parts. Dose Escalation (Part A) will evaluate escalating oral doses of BMS-986458 to evaluate the safety, tolerability, and to guide the determination of the MTD and/or optimal biological dose (OBD) of BMS-986458, as a single agent or in combination with anti-lymphoma agents, in participants with DLBCL and FL. Dose expansion (Part B) will further evaluate the safety and preliminary efficacy of BMS-986458 administered at the MTD/OBD in one or more expansion cohorts assigned in a randomized manner to determine the RP2D. [001000] All participants will complete up to 3 study periods: screening (up to 28 days [+ 3 days]), treatment (up to 104 weeks [approximately 2 years]) from the first dose of study intervention regardless of treatment delays, and follow-up. The follow-up period includes Safety Follow-up (28 days [± 3 days] after the last dose of study intervention), Survival Follow-up (up to 156 weeks [approximately 3 years] from the first dose of study intervention) and the efficacy follow-up (up to 52 weeks [approximately 1 year]). The maximum duration of study participation will be approximately 160 weeks (approximately 3 years) (up to 4 weeks of screening, treatment of up to 104 weeks, and follow-up of up to 52 weeks). [001001] 5.1.1. Screening Phase. The Screening Phase starts 28 days (+ 3 days flexibility window, up to 31 days) prior to first dose of study intervention. Informed consent must be obtained prior to any study-specific procedures and its completion documented in source documents and in the electronic Case Report Form (eCRF). All screening tests and procedures must be completed within 28 days (+ 3 days) prior to the start of study treatments. [001002] All participants being screened will be evaluated based on inclusion and exclusion criteria and will be enrolled using an Interactive Response Technology (IRT) system. All screening tests and procedures must be completed and the results received and assessed within 28 days (+ 3 days) prior to the first dose of study intervention, unless otherwise noted. Participants may be rescreened. [001003] If a participant exceeds the screening period due to a study-related procedure (e.g., scheduling of a tumor biopsy or waiting for a study-related laboratory value), the participant must be re-consented, but a new participant identification number is not required. In this situation, the fewest number of procedures from the initial screening period should be repeated to qualify the participant, while maintaining participant safety and eligibility. Screening laboratory tests that are out of window should be repeated. [001004] 5.1.2 Treatment Phase. Upon confirmation of eligibility, participants will be enrolled and begin study intervention in the appropriate part of the study and dose cohort. [001005] The treatment period for BMS-986458 will last for up to 104 weeks (approximately 2 years) from the first dose of study intervention. Details for oral administration of BMS-986458 can be found below. [001006] For participants receiving rituximab in combination with BMS-986458, rituximab will be administered (per package insert and institutional standard practice) on planned dosing days at the fixed dose of 375 mg/m² for a maximum of 6 infusions. Rituximab will be given on Day 1 from Cycles 1 to 6. Details for rituximab infusion can be found below. [001007] Any sampling or assessments should be performed prior to dosing on the visit day, unless otherwise specified. [001008] 5.1.2.1 Dose Escalation (Part A). Escalating doses of BMS-986458 will be evaluated in Part A. Provisional dosing cohorts for BMS-986458 dose escalation are summarized herein. [001009] If the starting dose of BMS-986458 is not tolerated, a lower dose level may be explored (i.e., Cohort -1). The provisional dose increments will follow a modified Fibonacci design from 80 mg and above, wherein the doses in consecutive dose cohorts may increase by 100%, 62.5%, 53.8%, 33%, etc. of the dose in the previous cohort. Smaller increments for dose escalation may be recommended by the safety review committee (SRC) upon consideration of all the available clinical data. Exploratory cohorts may be opened by the SRC based on emerging safety, PK, and pharmacodynamic data; the starting dose will not exceed the total daily dose that has been shown tolerated. The SRC may propose alternative dose, schedule, and frequency. In all cases, the recommended dose for the next cohort will not exceed an approximately 100% increase from the previous total daily dose. [001010] The starting dose and schedule of BMS-986458 in Part A2 will be determined by the SRC based on emerging safety, PK, and pharmacodynamic data from Parts A1 and B1 and will be at least one dose level below the maximum BMS-986458 monotherapy dose explored in Part B1. Data of a minimum of 25 participants treated at the OBDs in monotherapy will be utilized to determine the starting dose of BMS-986458 in Part A2. [001011] Dose Escalation Decisions. A 2-stage design will be utilized in Part A1 to find the MTD and/or OBD. In Stage 1, dose escalation/de-escalation decisions of BMS-986458 as single agent will be guided by a Bayesian Optimal Interval (BOIN) Design. TITE-BOIN12 design will be used in Stage 2 to find OBD. BOIN design will be utilized in Part A2 to guide dose escalation/de-escalation decision of BMS-986458 with rituximab. [001012] For Part A1 (single agent dose escalation), a minimum of 3 and up to 9 participants per dose level may be enrolled in cohorts to assess safety in Stage 1. With a target DLT rate of 30%, a dose with an observed DLT rate within (23.6%, 35.9%) will be considered acceptable, based on this design principle. Dose escalation/de-escalation in this stage will be based on the standard BOIN design method using the above toxicity boundaries and setting the maximum number of participants by 9 at each dose level. Stage 1 will move to Stage 2 when the escalation/de-escalation under Stage 1 either reaches the highest dose level within the acceptable toxicity limit or the MTD is determined. In Stage 2, the dose escalation/de-escalation will be guided by the TITE-BOIN12 design to assess preliminary efficacy as well as fuller tolerability of each dose level for determining optimal biological doses (OBDs) by enrolling more participants at the tolerable dose levels determined under Stage 1. [001013] For Part A2 (rituximab combination dose escalation), 2 consecutive monotherapy OBDs will be selected from Part A1. Up to 16 participants (including back-fill participants) will be treated at the selected OBDs, for a total of up to 32 response-evaluable participants. Combination dose escalation will be performed based on the BOIN criteria same as those for Stage 1 in Part A1. [001014] The final recommendation to dose escalation/de-escalation, evaluate additional participants within a dose cohort, a higher dose level, the use of smaller dose increments, intermediate dose levels, an alternate dosing schedule or frequency, or declare an MTD and/or OBD will be made by the SRC according to an integrated assessment of the safety, and available PK, pharmacodynamic and efficacy data. All recommendations made at the SRC meetings will be formally documented (via meeting minutes and memos) and distributed to study Investigators. [001015] The administration of the IMP(s) will start on C1D1; after the first dose is administered in any dose level/cohort during Dose Escalation, participants in each cohort are observed over the defined DLT assessment period before the next higher dose level can begin. [001016] Following completion of the DLT assessment period for the first 3 DLT-evaluable participants treated in a dose cohort in Dose Escalation, the tolerability of the administered dose will be established as guided by the BOIN design and confirmed by the SRC. The dose level of the next enrolled participants will be determined based on the number of observed DLTs that describe the optimal Dose Escalation decisions by the BOIN design with target DLT rate of 30% (23.6%, 35.9%) under Stage 1 and the TITE-BOIN12 design with the same target DLT rate and the utility matrix for finding OBDs under Stage 2. [001017] For a dose level to be selected for Dose Expansion, at least 6 DLT-evaluable participants will be evaluated for DLTs in Dose Escalation with the dose level determined as tolerable. The decision to declare a tolerable dose level based on review of additional safety, and any available PK, pharmacodynamic, and efficacy data will be confirmed by the SRC. [001018] All participants will be monitored for AEs during the study. Adverse events will be graded in severity according to the guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, except for selected AEs (e.g., TLS and TFR). DLTs during Dose Escalation will be based on AEs that occur during the DLT assessment period from C1D1 to C1D28. Any toxicities that occur beyond the DLT assessment period will be considered in making dose level decisions and/or dose level modifications, as well as defining the OBD(s) upon agreement between the Sponsor and Investigators. [001019] Staggered Dosing in Part A. During the dose-escalation phase (Part A), a staggered dosing approach will be used. The first participant enrolled in each dose level enrolling more than1 participant will be observed for at least 1 day before additional participants in that dose level can be treated. [001020] 5.1.2.2 Dose Expansion (Part B). Following completion of Dose Escalation, expansion may occur at the BMS-986458 OBDs, and/or alternative tolerable dosing schedule, in multiple cohorts assigned in a randomized manner. The SRC will select the dose, schedule, and treatment regimen for expansion cohorts. The decision to perform the Dose Expansion at established dose levels and schedules will be based on (but not limited to) overall safety profile, preliminary positive signals of efficacy, and available PK/pharmacodynamic data. [001021] Approximately 20 participants per dose level/schedule and with adequate follow-up will be enrolled in Parts B1 and B2 to further evaluate the safety and efficacy of BMS-986458 administered at the OBDs and/or lower dose levels and/or alternative schedules alone or in combination with rituximab. Two dose schedules will be assessed for each indication (Part B1) or each combination (Part B2). Data of participants treated at the OBDs and/or lower dose levels and/or alternative schedules in Dose Expansion may be combined with those treated at the same dose level, schedule, and treatment arm in Dose Escalation, if from the same population. A Bayesian continuous monitoring will be utilized to monitor the toxicities in the monotherapy and combination Expansion cohorts. The SRC will continue to monitor the overall safety/tolerability data. A multi-layered process is established to guarantee adequate participant safety monitoring throughout the study. [001022] 5.1.2.3 Definition of Stopping Criteria. During Part A, the dose escalation will stop when either MTD or OBDs are declared by the Investigators and the Sponsor/Medical Monitor, based on the number of participants experiencing DLT events during the DLT assessment period, and cumulative review of the available safety, tolerability, PK, PD, and preliminary efficacy data. [001023] During Part B, a Bayesian method will be utilized to monitor for excess toxicities defined as the occurrence of AEs, at any time during treatment, that would fulfill the DLT criteria specified in Dose Escalation (except for dose reductions due to AEs not meeting the DLT criteria; Section 10.3). This safety monitoring rule and operating characteristics are described in Section 10.2. When the stopping boundaries are met, further enrollment at that expansion dose level will be temporarily halted. [001024] Recommendations from interim calculations and the totality of the data will be reviewed by the SRC. Based on the SRC’s review, the current dose level may be permanently discontinued, and a lower dose level will be evaluated in the remaining study part. Similar continuous safety monitoring will be applied to the new dose level being evaluated. [001025] In both Parts A and B, additional ad-hoc SRC meetings will be held to conduct this review if any participant experiences any of the following serious adverse events (SAEs): • Life-threatening (Grade 4) events that are unmanageable (i.e., does not resolve to Grade 3 or lower with study intervention interruption and medical management) unless clearly related to disease or an extraneous cause. • Grade 5 events (death) unless clearly related to disease or an extraneous cause. Review of these SAEs, and any decision to pause enrollment or terminate the study, will be determined by the SRC. [001026] 5.1.3 Follow-up Periods. All participants who discontinue treatment will continue to be followed according to Table B4-2-2. [001027] 5.1.3.1 Safety Follow-up. All participants will be followed for 28 days (± 3 days) after the last dose of study intervention, for AE reporting and concomitant medication information as well as new anticancer therapies, as well as for SAEs made known to the Investigator at any time thereafter (see Section 9.2.1) until recovered (returned to baseline), recovered with sequelae, or death (due to SAE). The safety follow-up contact may be by telephone. Pregnancy test(s) will be required for WOCBP participants (see Section 9.4.7). [001028] All safety follow-up period lasts 28 days after the last dose of study intervention (see Section 9.2.5). [001029] 5.1.3.2 Survival Follow-up. After the last dose of study intervention, participants will be followed by phone contact or clinic. Survival Follow-up will be performed along with the Safety Follow-up visit 28 days after the last dose of BMS-986458 and then will occur every 12 weeks (± 14 days) for up to 156 weeks (approximately 3 years) from the first dose of BMS- 986458 or until death, lost to follow-up, withdrawal of consent or end of the study, whichever occurs first. In addition, information about anticancer therapies after discontinuation of the study intervention will be collected. [001030] Survival follow-up may be conducted by record review (including public records) and/or telephone contact with the participant, family, or the participant’s treating physician. [001031] 5.1.3.3 Efficacy Follow-up. Participants who have discontinued study intervention for reasons other than clinically significant disease progression should continue response assessments every 26 weeks (± 14 days) from the last dose of BMS-986458 and up to 52 weeks (approximately 1 year), until progression of disease, death, initiation of new anticancer therapy, lost to follow-up, withdrawal of consent from the study, or end of the study, whichever occurs first. [001032] 5.1.4.1 Safety Review Committee. Safety considerations, including recommendations to open a new dose level cohort will be made by the SRC. The SRC will include investigators (and/or designated representatives), the Sponsor’s clinical trial physician, safety physician, chair of the SMT, study statistician, and clinical scientist along with ad hoc attendees that may include the study pharmacokinetic scientist, translational scientist, and global trial manager. Other internal and external experts may be consulted by the SRC, as necessary. [001033] The SRC will be responsible for reviewing the safety data including DLTs and assessing if a dose level or schedule is tolerable or non-tolerable and making a recommendation on escalation/de- escalation to subsequent dose level, alternative dose/schedule/frequency, intermediate doses, the use of smaller dose increments for dose escalation, continuation, delay or termination of dosing, repetition of a cohort, enrollment of additional participants in a cohort. The SRC will select the dose, schedule, and treatment regimen for expansion cohorts and will continue to monitor the overall safety/tolerability data. All decisions made by the SRC will be formally documented and circulated to all sites in writing. The dose escalation, de-escalation, change to dosing schedule, or expansion of existing dose cohorts will not commence until a written notification of the respective SRC decision is sent to all participating sites, and protocol amendment implemented when applicable. The final determination of MTD and/or OBD(s) will be determined by the SRC. Recommended Phase 2 dose(s) (RP2D[s]) will also be determined by the SRC, based on their integrated review of clinical and laboratory safety data, efficacy, and PK/pharmacodynamic/biomarker data (as available). Prior to declaring the RP2D(s), and in consultation with investigators, the Sponsor has the option to expand any dose level previously established to be tolerable (during the DLT evaluation) in order to obtain additional experience. [001034] 5.2 Number of Participants. The approximate total number of participants will be 273, as shown below: • Dose Escalation Part A: approximately 73 participants may be treated, including: o monotherapy cohort (Part A1): approximately 41 participants o rituximab combination cohort (Part A2): approximately 32 participants. • Dose expansion Part B: approximately 200 efficacy-evaluable participants may be treated, including: o monotherapy cohort(s) (Part B1): approximately 80 participants o combination cohort(s) (Part B2): approximately 80 participants o patient selection cohort(s) (Part B3): approximately 40 participants. [001035] 5.3 End of Study Definition. The start of the study is defined as the first participant’s first visit. [001036] The primary completion date is defined as the date on which the last data point is collected for the study’s primary endpoint. If the study has multiple primary endpoints, the primary completion date is the date on which the last data point is collected for the last primary endpoint. [001037] End of study is defined as the last participant’s last visit. [001038] Participants are considered to have completed the study if they have completed all periods of the study, including the last procedure shown in the schedule of activities. [001039] 5.4 Scientific Rationale for Study Design. There is a strong biological rationale for evaluating BMS-986458, a new investigation product (IP), as treatment for participants with R/R NHL. This Phase 1, FIH, clinical study of BMS-986458 will explore the safety, tolerability, PK, and preliminary biological and clinical activity of BMS-986458 as a single agent or in combination with anti-lymphoma agents in the setting of relapse or refractory disease. [001040] 5.5 Justification for Dose. Doses were selected based on findings from the pivotal 28-day toxicity studies in rats and dogs and efficacy studies in the OCI-LY1 xenograft mouse model. In the pivotal 28-day toxicity study in rats, at doses up to the high dose, all rats survived to their scheduled necropsy and no adverse effects were noted. In the pivotal 28-day dog toxicity study, BMS-986458-related decreases in food consumption were noted at the high dose starting on Day 1 that led to decreases in body weight, clinical observations of decreased activity, weak, thin, dehydration, and partially closed eyes, and subsequent early euthanasia of 3 dogs on Day 7. During necropsy of the 3 early decedents, there were no pathologic findings indicative of the cause of clinical decline. No morbidity or adverse effects were noted at the mid dose and this dose was considered the NOAEL and Highest Non- Severely Toxic Dose (HNSTD). The calculations for human equivalent dose (HED) below are based on body surface area and interspecies allometric scaling. The STD10 in the pivotal 28-day rat study supports a maximum recommended starting dose (MRSD) after applying a 10x safety factor. The HNSTD in the pivotal 28-day dog study supports a MRSD after applying a 6x safety factor. [001041] The PK/pharmacodynamic and efficacy studyin an OCI-LY1 xenograft mouse model suggested that full suppression is required to achieve maximum tumor growth inhibition. Based on the predicted terminal half-life in human, dosing is selected to be evaluated in this study. The starting dose in CA1231000 was selected. Since this dose is in the middle of the projected efficacious dose range and is less than the MRSD, it is anticipated to be both efficacious and safe. Using predicted PK parameters and an assumption of % oral bioavailability, the projected steady state maximum plasma concentration (Cmax) and area under the concentration curve following oral doses to a 70-kg human are estimated. [001042] The highest clinical dose will be determined based upon tolerability. At the proposed highest clinical dose the smallest predicted AUC and Cmax safety margins are 15.2x and 5.6x, respectively, lower than the NoAEL in either rat or dog pivotal 1-month GLP toxicity studies. [001043] 5.6 Rationale for Exploratory Biomarker Research. In the phase 1 study evaluating BMS-986458, a series of pharmacodynamic, predictive, and exploratory biomarkers will be collected to facilitate dose/schedule selection, and potentially identify biomarkers to predict response and inform potential combinations. [001044] Digital imaging samples including CT/MRI scans will be used for research related to treatment efficacy using more advanced image analysis techniques. [001045] Genetic variation may impact a participant’s response to study intervention, susceptibility to disease, and severity and progression of disease. Variable response to study intervention may be due to genetic determinants that impact intervention absorption, distribution, metabolism, and excretion; mechanism of action of the intervention; disease etiology; and/or molecular subtype of the disease being treated. [001046] DNA samples will be used for research related to the study intervention(s) and/or disease/condition under study and related conditions. The samples may also be used to develop tests/assays, including diagnostic tests related to the study intervention(s) and/or the disease/condition under study and related conditions. Genetic research may consist of the analysis of 1 or more candidate genes or the analysis of genetic markers throughout the genome or analysis of the entire genome. [001047] All subjects participating in this study will consent to biomarker sampling procedures, as described via the ICF. [001048] 5.7 Rationale for Optional Future Research. Future research may be performed using residual samples originally collected for another test required in this study from consented participants only. Future research is intended to allow for research aimed at emergent or future questions that are not addressed elsewhere in the protocol and may include research that is unrelated to the study intervention(s) and/or disease under study. The research may involve genetic tests using deoxyribonucleic acid (DNA) or ribonucleic acid (RNA); this may consist of the analysis of 1 or more candidate genes, analysis of genetic markers throughout the genome or analysis of the entire genome. Analysis of samples for future research may also involve the use of other clinical data collected as part of this study. Such future research may also lead to the development of new diagnostic tests. The participant’s decision to consent to this optional future research will not affect his/her ability to participate in the main study. Consent for optional future research can be collected at a later visit if needed. In some countries, according to local regulations, it may require approval from local Health Authority. [001049] 6 Study Population. Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted. [001050] 6.1 Inclusion Criteria. Participants are eligible to be included in the study only if all of the following criteria apply: 1) Signed Written Informed Consent a) Participant must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form (ICF) in accordance with regulatory, local, and institutional guidelines. This ICF must be obtained before performing any protocol-related procedures that are not part of normal patient care. 2) Age of Participant a) Participant must be 18 years of age or legal adult age according to the local regulation, inclusive, at the time of signing the ICF. 3) Type of Participant and Target Disease Characteristics a) Participant with a history of NHL (including DLBCL [ie, DLBCL NOS and diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements with DLBCL morphology], and FL) with relapsed or refractory disease according to one of the following requirements below, as applicable to each indication. In addition, all potentially efficacious therapies that are available and accessible to the participant should have been discussed as options by the treating physician, in the best interest of the participant, prior to enrollment: i) For R/R DLBCL (de novo) and FL 3b: following at least 2 prior lines of therapy (eg, have received first-line combination chemotherapy regimen containing rituximab, anthracycline, an alkylating agent, and steroids and have received at least one additional [second line/salvage] treatment). ii) For R/R DLBCL (transformed lymphoma): following at least 2 prior lines of therapy which must have been administered after transformation; therefore, at least 2 standard treatment regimens for DLBCL must have been received. iii) For R/R FL (except for FL 3b): following at least 2 prior lines of therapy and meet treatment criteria at the time of enrollment based on investigator’s assessment (eg, according to, but not restricted, Groupe d’Etude des Lymphomes Folliculaires [GELF] criteria).²¹ iv) Participants must have measurable disease, defined by at least one fluorodeoxyglucose (FDG)-avid lesion for FDG-avid disease and one bi-dimensionally measurable disease on cross sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) with at least one lesion > 1.5 cm in the transverse diameter, as defined by the Lugano classification of NHL.²⁰ Measurable disease cannot be previously irradiated. v) For Part A, participant must consent to and have tumor accessible for tumor biopsy and FNA during Screening and for FNA in Cycle 1. vi) For Part B, participant must consent to and have tumor accessible for paired tumor biopsies during Screening and Cycle 1. 4) Physical and Laboratory Findings a) Must have the following laboratory values (eligibility should be confirmed prior to the first dose of study intervention): i) Absolute neutrophil count ≥ 1 x 109/L without growth factor support for 7 days (14 days if pegfilgrastim) ii) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN) or ≤ 5.0 x ULN if liver involvement iii) Total bilirubin ≤ 1.5 x ULN iv) Potassium, magnesium, and calcium (corrected Ca or free [ionized] Ca) concentrations within normal range, or correctable with supplements. v) Platelet count ≥ 75 x 109/L vi) Hemoglobin ≥ 9 g/dL vii) Estimated serum creatinine clearance of ≥ 50 mL/min, using the modification of diet in renal disease (MDRD) method 5) Reproductive Status • Investigators shall counsel women of childbearing potential (WOCBP) participants (as defined in PPP for BMS-986458), and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention, present in seminal fluid, to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant. • The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. • Local laws and regulations may require the use of alternative and/or additional contraceptive methods. • Participant must adhere to the Pregnancy Prevention Plan. a) Female Participants: i) Female participant who are not of childbearing potential must have documented proof. Note: Documentation can be obtained from the site personnel’s review of the participant’s medical records or medical examination of medical history interview. (1) Women who are not of childbearing potential (as defined in PPP for BMS-986458) are exempt from contraceptive requirements. ii) WOCBP must have a negative highly sensitive serum pregnancy test (minimum sensitivity 25 mIU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of BMS-986458. (1) Additional requirements for pregnancy testing before, during and after study intervention are in Section 2: Schedule of Activities. (2) The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of a woman with an undetected pregnancy. iii) WOCBP and male participants who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF. (1) WOCBP are not permitted to use hormonal contraceptive methods alone as a highly effective method (as described in PPP for BMS-986458). iv) A female is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies: (1) Is not a WOCBP OR (2) Is a WOCBP and using 2 reliable forms of contraception simultaneously, one that is highly effective (with a failure rate of < 1% per year), with user independent methods, and one additional effective (barrier) method, as described in PPP for BMS-986458, for at least 28 days prior to starting BMS-986458, during the intervention period and for at least 28 days after the last dose of BMS-986458, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period, or up to 1 year after the last dose of rituximab. b) Male Participants: − Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF. i) Azoospermic males are not exempt from contraceptive requirements and will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant. ii) Male participants are required to use a condom during the intervention period and for at least 28 days after the last dose of BMS-986458. iii) Female partners of male participants should be advised to use a highly effective method of contraception during the study intervention period and for at least 28 days after the last dose of BMS-986458 for the male participant. iv) Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral) during the intervention period and for at least 28 days after the last dose of BMS- 986458. v) Male participants must refrain from donating sperm during the intervention period and for at least 28 days after the last dose of BMS-986458. vi) Breastfeeding partners of male participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms. [001051] 6.2 Exclusion Criteria. Participants are excluded from the study enrollment if any of the following criteria apply: 1) Medical Conditions a) Participant with Eastern Cooperative Oncology Group (ECOG)²² performance status ≥ 3. b) Participant with non-hematologic toxicity related to prior or current anticancer therapy, which is not resolved, returned to baseline or Grade ≤ 2, or deemed irreversible. i) These participants are potentially eligible after consultation with the Sponsor Medical Monitor, if meeting all other inclusion/exclusion criteria. c) Participant with known dysphagia, short-gut syndrome, gastroparesis, or other conditions/surgery that limit the ingestion or gastrointestinal absorption of drugs administered orally. d) Participant with uncontrolled hypertension (systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg) or hypotension (systolic BP < 90 mm Hg or diastolic BP < 60 mm Hg) at screening or within 1 month prior to C1D1. e) Clinically significant cardiovascular or cerebrovascular diseases, including any of the following: i) Complete left bundle branch or bifascicular block or other clinically significant abnormal ECG finding at screening. ii) History of congenital long QT syndrome. iii) Persistent or clinically meaningful ventricular arrhythmias at screening. iv) QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥ 470 msec on screening ECG. v) Unstable angina, myocardial infarction, or stroke ≤ 6 months prior to starting study intervention or history of clinically significant arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes). vi) Cardiovascular disability status of New York Heart Association Class ≥ 3 at screening.²³ Class 3 is defined as cardiac disease resulting in marked limitation of physical activity, and participants are comfortable at rest but less than ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain. vii) LVEF < 45% as determined by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan at Screening. f) Participant with any condition that confounds the ability to interpret data from the study. g) Participant with any condition, including significant acute or chronic medical illness, active or uncontrolled infection, or the presence of laboratory abnormalities, that places participants at unacceptable risk if participating in this study. h) Participant with known SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to Cycle 1 Day 1. Acute symptoms must have resolved and based on investigator´s assessment in consultation with the Sponsor Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving study intervention. i) Inability to be venipunctured and/or tolerate venous access. j) Any other sound medical, psychiatric, and/or social reason as determined by the investigator. k) History of concurrent second cancers requiring active, ongoing systemic treatment. l) Participant with known or suspected central nervous system (CNS) involvement or history of primary CNS lymphoma (including those in remission). A brain/spine scan (CT or MRI) is only required for participants with suspected cerebral involvement during screening. 2) Reproductive Status a) Women who are pregnant or breastfeeding. 3) Prior/Concomitant Therapy a) Inability to comply with restrictions, precautions and prohibited treatments as listed in Section 7.7: Concomitant Therapy. b) Prior live virus vaccines ≤ 4 weeks prior to starting intervention. c) Prior COVID-19 vaccine within 7 days prior to starting intervention. For vaccines requiring more than 1 dose, the full series (eg, both doses of a 2-dose series) should be completed by at least 7 days prior to starting study intervention when feasible and when a delay in starting study intervention would not put the study participant at risk. d) Participant has received prior systemic anticancer treatment (approved or investigational) ≤ 5 half-lives or 4 weeks prior to starting study intervention, whichever is shorter. e) Participant has received prior CAR-T or other T-cell targeting treatment (approved or investigational) ≤ 4 weeks prior to starting study intervention. f) Participant has received prior therapy with CRBN-modulating drug (e.g., lenalidomide, avadomide, pomalidomide, CC-99282) ≤ 4 weeks prior to starting study intervention. g) Participant is on chronic systemic immunosuppressive therapy or corticosteroids (eg, prednisone or equivalent exceeding 10 mg per day within the last 14 days) or participants with clinically significant graft-versus-host disease (GVHD). i) Stable use of inhaled corticosteroids is allowed. ii) The use of topical steroids for ongoing skin or ocular GVHD is permitted. h) Participant had prior autologous SCT ≤ 3 months prior to starting study intervention. If participant had prior autologous SCT > 3 months prior to starting study intervention, any treatment-related toxicity is unresolved (Grade > 2). i) Participant had prior allogeneic SCT with either standard or reduced intensity conditioning ≤ 6 months prior to starting study intervention. If participant had prior allogeneic SCT > 6 months prior to starting study intervention, any treatment-related toxicity is unresolved (Grade > 2). j) Participant had major surgery ≤ 2 weeks prior to starting study intervention. Participants must have recovered from any clinically significant effects of recent surgery. k) Prior radiotherapy within ≤ 4 weeks prior to starting study intervention. 4) Physical and Laboratory Test Findings a) Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population in the judgment of the investigator. b) Participants with known seropositive or active infection with HIV, or active infection with hepatitis B virus (HBV) or hepatitis C virus, demonstrated by positive blood screen for hepatitis C antibody; hepatitis B surface antigen, and anti-hepatitis B surface antibody, or HIV-1 and HIV-2 antibody. 5) Allergies and Adverse Drug Reactions a) History of allergy to rituximab or to any of the excipients. 6) Other Exclusion Criteria a) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply, and Sponsor approval is required.) b) Participation in another clinical trial concurrent with this study. c) Donation of blood to a blood bank or in a clinical study (except at a screening visit) within 4 weeks prior to starting study intervention (within 2 weeks for plasma only). [001052] 6.4 Screen Failures. Screen failures are defined as participants who consent to participate in the clinical study but who are not subsequently enrolled in the study/included in the analysis population. [001053] A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, as applicable, and to respond to queries from regulatory authorities. Minimal information includes date of consent, demography, screen failure details, eligibility criteria, and any serious adverse events (SAEs) that occurred following consent. [001054] 6.4.1 Re-testing During Screening. This study permits the re-enrollment of a participant who has discontinued the study as a screen failure (i.e., participant has not been randomized/has not been treated). If re-enrolled, the participant must be re-consented. [001055] Re-testing of laboratory parameters and/or other assessments in any single screening will be permitted (in addition to any parameters that require a confirmatory value). [001056] The most current result prior to the first dose of study intervention is the value by which study inclusion will be assessed because it represents the participant’s most current clinical state. [001057] Laboratory parameters and/or assessments that are included in Screening Procedural Outline may be repeated in an effort to find all possible well-qualified participants. Consultation with the Medical Monitor may be needed to identify whether repeat testing of any particular parameter is clinically relevant. [001058] 7 Study Intervention(s) and Concomitant Therapy. Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, procedure(s), or medical device intended to be administered to a study participant according to the study protocol. [001059] Study intervention includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational/Auxiliary [Medicinal] Product (Non-IP/Non-IMP/AxMP). [001060] An Investigational Product (IP), also known as an Investigational Medicinal Product (IMP) in some regions, is defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical study, including products already with a marketing authorization but used or assembled (formulated or packaged) differently from the authorized form, used for an unauthorized indication, or when used to gain further information about the authorized form. [001061] Other medications used as support or escape medication for preventative, diagnostic, or therapeutic reasons, as components of the standard of care for a given diagnosis may be considered Non- IMPs/AxMPs. [001062] 7.1 Study Interventions Administered. Treatment cycle duration is 28 days. Study visits will occur as detailed in the Schedule of Activities table. BMS-986458 will be administered according to the specified schedule for up to 104 weeks (approximatively 2 years) from C1D1, regardless of dose delays, or until progression, unacceptable toxicity, or decision to withdraw by the participant or physician. Rituximab will be administered IV on Day 1 of Cycle 1 to Cycle 6. [001063] See information regarding dose modifications, treatment discontinuation, and safety management, respectively. Table B4-7.1-1: Study Interventions

accordance with the package insert or SmPC. [001064] 7.1.1. BMS-986458 Dosing. BMS-986458 will be administered orally continuously from Cycle 1 Day 1 (C1D1) onwards. The protocol will be amended prior to the introduction of any other alternative schedules. [001065] On study days were PK samples will be collected, BMS-986458 will be administered in the clinic. [001066] Participants will be requested to record the date and time of each self-administered study intervention. Participants in all groups are required to fast (nothing to eat or drink except water) for approximately 2 hours prior until 1 hour after administration of BMS-968458. Under certain circumstances, the restrictions for avoidance of food and drinking (except for water) for 2 hours before and 1 hour after administration of BMS-968458 may be allowed for participants after discussion with the Medical Monitor. [001067] If the participant vomits within 30 minutes of BMS-986458 ingestion, BMS-986458 tablets may be ingested again. If emesis occurs after 30 minutes of BMS-986458, participants must not ingest additional BMS-986458 tablets unless there is visibility of intact medication in the vomitus. [001068] BMS-986458 can be taken for up to 104 weeks (approximately 2 years) or until clinically significant disease progression, unacceptable toxicity, or withdrawal of consent. [001069] Retreatment with BMS-968458 may be considered, at the investigator’s discretion and after discussion with the Medical Monitor, if all the following criteria are met: • The participant discontinued treatment for reasons other than an AE, progression, or start of a new anti-lymphoma therapy • The participant achieved demonstrated response with BMS-986458 based on The International Workshop Criteria for Malignant Lymphoma • The participant has evidence of disease relapse based on The International Workshop Criteria for Malignant Lymphoma during survival follow-up period • Eligibility continues to be met [001070] Participants who are retreated will follow the Schedule of Activities starting with Cycle 1 Day 1 but may continue at their most recent dose level and schedule or dose level shown to be adequately tolerated by at least one cohort of participants in this study. Participants may be retreated only once during the study. [001071] Please refer to the current Investigator Brochure and/or Pharmacy Manual for further details regarding storage, preparation, and administration of BMS-986458. [001072] 7.1.2 Rituximab Dosing. Rituximab will be administered as an IV infusion at a dose of 375 mg/m² on Day 1 of Cycle 1 to Cycle 6. No dose reductions of rituximab are permitted. [001073] Rituximab can be administered with or up to 2 hours after the morning dose of BMS- 986458. Suggested body surface area estimate methods include Mosteller²⁴ and DuBois²⁵. • BSA = √ ((height (cm) x weight (kg))/3600) • BSA = 0.20247 x height (m)0.725 x weight (kg)0.425 [001074] Preparation, infusion rate, and guidance on pregnancy prevention should be performed according to the locally approved rituximab prescribing information or local institutional practice (rituximab PI). BSA calculation methods and timing will be performed per institutional guidance Premedication consisting of acetaminophen and an antihistamine should be administered before each rituximab infusion (refer to the current local rituximab prescribing information). Steroids may also be administered before the start of the rituximab infusion according to institutional practice. Surveillance measures during and after infusion of rituximab should be applied as recommended by the manufacturer and current guidelines. [001075] Rituximab may be administered in either an inpatient or outpatient clinical setting. For dose modifications, it is recommended to follow the package insert and local practice. Dose reductions are not allowed for rituximab. [001076] Participants that do not require dose interruptions are allowed to proceed to the next treatment cycle (e.g., hematologic toxicities must be resolved to Grade ≤ 2). If rituximab dose is interrupted due to a study intervention-related toxicity, rituximab may be restarted once the toxicity has resolved to Grade ≤ 2. In Cycle 1, skipped dose for toxicity will not be rescheduled. In Cycles ≥ 2, a missed dose of rituximab can be made up within 2 weeks (i.e., Days 1 to 14 of the Cycle). If toxicity resolves to Grade ≤ 2 during Days 15 to 28 of the cycle, the rituximab dose will be restarted on Day 1 of the next cycle. [001077] Participants will be monitored closely during the entire infusion and for at least 1 hour post infusion with serial vital signs obtained and pulse oximetry performed. Full emergency resuscitation facilities should be immediately available, and participants should be under close supervision of the Investigator or appropriately trained staff at all times. [001078] Additional blood tests to evaluate for a severe allergic reaction may be obtained within 15 to 60 minutes of onset of symptoms in participants with a Grade 4 infusion reaction or recurrent Grade 3 infusion reactions necessitating permanent rituximab discontinuation. Laboratory tests could include Immunoglobulin E (IgE), total tryptase, and plasma histamine. [001079] The Medical Monitor should be notified of any Grade 4 or recurrent Grade 3 infusion reactions within 24 hours of the event. [001080] Refer to the locally approved rituximab label or Pharmacy Manual for additional details around dosing and storage information. [001081] 7.2 Assignment to Study Intervention. All participants will be centrally using IRT. Before the study is initiated, each user will receive log-in information and directions on how to access the IRT. The site will record the treatment assignment on the applicable electronic Case Report Form (eCRF), if required. During the screening visit, the investigative site will utilize IRT for assignment of a 5-digit participant number that will be unique across all sites. Enrolled participants, including those not dosed, will be assigned sequential participant numbers. Enrolled participants meeting inclusion and exclusion criteria will be eligible to be dosed. Sequential numbering may restart for each participating site because the distinct patient identification number will ultimately comprise the site number and participant number. After completing all screening procedures, sites will utilize IRT to either screen fail or obtain treatment assignment information, including randomization for the Expansion cohorts, as applicable. Subsequent visits will be registered into the IRT system for drug supply. If the IRT system is not available, participants will be enrolled manually. [001082] Study intervention will be dispensed at the study visits listed in the Schedule of Activities. [001083] 7.3 Blinding. This is an open-label study (open to sponsor and site/participant; not treated as sponsor-blind). It has been determined that blinding is not required to meet study objectives. Blinding procedures are not applicable and access to treatment assignment information is unrestricted to any Bristol- Myers Squibb Company (BMS) team, site, or participant. The specific treatment to be taken by a participant will be assigned using IRT. The site will contact the Interactive Response System prior to the start of study intervention administration for each participant. The site will record the treatment assignment on the applicable electronic Case Report Form (eCRF), if required. [001084] 7.4 Dosage Modification [001085] 7.4.1 Dosage Modifications. The guidelines for dose modifications for BMS-986458 are presented Table 7.4.1-1 and Table 7.4.1-2 for study intervention-related AEs. These cases should be discussed with the Medical Monitor before dosing changes are made. Only 2 dose reductions are allowed before discontinuation is required or 1 dose reduction if at the starting dose. If BMS-986458 is permanfor study intervention-related AEs. These cases should be discussed with the Medical Monitor before dosing changes are made. Only 2 dose reductions are allowed before discontinuation is required or 1 dose reduction if at the starting dose. If BMS- 986458 is permanently discontinued in any combination cohort, the combining anti-lymphoma agent should also be discontinued. [001086] For rituximab-related toxicities, it is recommended to follow the package insert and local practice. Dose reductions are not allowed for rituximab. [001087] For AEs not outlined in Table 7.4.1-1 and Table 7.4.1-2, discuss with the Medical Monitor. Table B4-7.4.1-1: Dose Modification Guidelines for Hematologic Toxicities at t e same ose eve . factor. Table B4-7.4.1-2: Dose Modification Guidelines for Non-hematologic Toxicities .

ose euc o interval by Fredericia. [001088] 7.4.2 Mangagement of Select Adverse Events [001089] 7.4.2.1 Infection. Vigilance for the signs and symptoms of infection should be practiced and managed according to institutional standard medical practice. Routine infectious disease prophylaxis is not recommended; however, antibiotic, antiviral, antipneumocystis, antifungal, or other prophylaxis may be implemented during the study at the discretion of the Investigator and/or SRC. Refer to Table 7.4.1-2 for guidelines on dose modifications. [001090] 7.4.2.2 SARS-CoV-2 Infection. Participants with confirmed SARS-CoV-2 infection should interrupt study intervention(s) and may resume when there is no sign of active disease and confirmed by investigator´s assessment. Treatment of active SARS-CoV-2 infections or high- risk exposures, including use of investigational therapies and taking into consideration the risk of DDI (e.g., Paxlovid), is allowed and should be discussed with the Medical Monitor. [001091] 7.4.2.3 Management of Tumor Lysis Syndrome (TLS). Participants who are considered to be at risk of TLS (e.g., subjects with a high tumor burden or a high circulating lymphocyte count [> 25 x 10⁹/L]) must receive adequate tumor lysis prophylaxis with uricostatics (eg, allopurinol) and hydration starting 12 to 24 hours prior to the start of BMS- 986458. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. Investigators are to exercise clinical judgment as to whether more frequent serum chemistry monitoring may be appropriate. [001092] Refer to Tumor Lysis Syndrome (TLS) Prophylaxis Recommendations Based on TLS Risk,²⁶ Cairo-Bishop definition of laboratory TLS, and Cairo-Bishop grading system for TLS²⁷ for TLS definitions. [001093] 7.4.2.4 Tumor Flare Reaction (TFR). Participants in this study should be monitored for tumor flare. Tumor flare reaction (TFR) is defined as a sudden and tender increase in the size of the disease-bearing sites, including the lymph nodes, spleen and/or the liver often accompanied by low-grade fever, non-pruritic diffuse rash, and in some cases increase in the peripheral blood lymphocyte counts. Tumor flare usually occurs within the first cycle of treatment. Tumor flare reaction may mimic progression of disease; however, TFR will generally subside over time. Therefore, careful monitoring and evaluation is important prior to discontinuing a participant for disease progression in the initial cycles of BMS-986458. [001094] There are currently no laboratory or radiological tests that distinguish TFR from disease progression. The distinction should be made on clinical grounds, incorporating observations such as associated physical findings, laboratory findings, and pace of disease before and after institution of treatment. Tumor flare will be recorded as an AE and graded using the NCI CTCAE 3.0 criteria. [001095] Treatment of TFR is up to the discretion of the Investigator depending on the severity and clinical situation. In mild to moderate cases (Grade 1 to 2), it is suggested that BMS-986458 be continued along with symptomatic treatment such as NSAIDs and/or narcotics. Corticosteroids can be administered at the Investigator’s discretion. In more severe cases (Grade 3 to 4), BMS-986458 should be interrupted and therapy with corticosteroids should be initiated. NSAIDs and/or narcotics may also be used at the Investigator’s discretion. When symptoms resolve to Grade ≤ 1, BMS-986458 can be restarted at the same dose level. For instances of possible TFR, Investigators are encouraged to discuss with the Sponsor Medical Monitor. [001096] 7.4.2.6 Infusion-related Reactions. Administration of rituximab can result in serious, including fatal, infusion-related reactions. Fatal infusion reactions within 24 hours of rituximab infusion have occurred; approximately 80% of fatal infusion reactions occurred in association with the first infusion. Symptoms may include fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticarial, rash, vomiting, myalgia, dizziness, or hypertension. Infusion-related reactions typically occurred within 30 to 120 minutes of beginning the first infusion of rituximab and resolved with slowing or interruption of the infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline) (refer to US PI and/or SmPC). [001097] Premedication requirements and subject monitoring are included. Full emergency resuscitation facilities should be immediately available in the event of a severe and life- threatening infusion reaction and subjects should be under close supervision of the investigator or appropriately trained staff during the infusions. Medical management of infusion reactions should be instituted according to standard medical practice using glucocorticoids, epinephrine, oxygen, intravenous fluids, and other medications as medically indicated. [001098] The Medical Monitor should be notified of any Grade 4 or recurrent Grade 3 infusion reactions within 24 hours of the event. [001099] 7.4.2.7 Progressive Multifocal Leukoencephalopathy. John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, has been observed in participants treated with rituximab. Participants with new-onset or changes to pre-existing neurologic manifestations should be evaluated for PML. [001100] The symptoms of PML are unspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (eg, muscular weakness, paralysis, and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptoms regarded as “cortical” (eg, aphasia or visual- spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture (cerebrospinal fluid testing for John Cunningham viral DNA). Rituximab and BMS-986458 should be discontinued in participants who develop PML. Participants should be referred to a neurologist for the evaluation and treatment of PML. [001101] 7.4.3 Dose Interruption Criteria for BMS-986458 and Rituximab. Participants who experience the following should have the study intervention interrupted, unless otherwise specified in Table 7.4.1-1 and Table 7.4.1-2. • Any study intervention-related AE meeting the definition of DLT will require dose interruption. If the AE does not improve to Grade ≤ 2 or baseline, this may require subsequent dose reduction. Such cases should be discussed with the Sponsor´s Medical Monitor to determine the optimal duration of the dosing delay or reduction. • Study intervention-related Grade ≥ 3 toxicity, chronic Grade 2 toxicity, or significant missed doses due to tolerability may warrant dose reduction of BMS-986458. Such cases should be discussed with the Medical Monitor before dosing changes are made. • Confirmed SARS-CoV-2 infection (refer to Section 7.4.2.2). [001102] Treatment with study intervention(s) may be interrupted for up to 4 weeks, until toxicity reaches either Grade ≤ 2 or baseline levels. On rare occasions, participants may derive benefit from resumption of BMS-986458 after an interruption of longer than 4 weeks. All decisions regarding resumption of dosing after > 4 weeks interruption must be discussed with the Medical Monitor. BMS-986458 may restart either at the same or a reduced dose as described in Section 7.4.3.1. [001103] In Part A during Cycle 1, a study intervention interruption of > 7 days for reasons other than DLT will make a participant non-evaluable for DLT and necessitate replacement of that participant in the dosing cohort. Any such interruptions must be discussed with the Sponsor’s Medical Monitor. [001104] Continue assessments per protocol even if dosing is delayed. [001105] 7.4.3.1 Criteria to Resume Treatment. Participants experiencing AEs not meeting criteria for permanent discontinuation may resume treatment with study intervention(s) once study intervention-related non-DLT AEs resolve to ≤ Grade 1 or baseline, unless otherwise specified in Table 7.4.1-1 and Table 7.4.1-2. Prior to re-initiating study intervention in a participant with a dosing interruption lasting > 4 weeks, the Medical Monitor/designee must be consulted. [001106] 7.4.3.2 Criteria for Dose Reduction. Dose reductions of BMS-986458 are permitted in any cycle, including Cycle 1 after consultation with the Sponsor’s Medical Monitor. Dose reductions of BMS-986458 due to AEs that occur in Cycle 1 during dose escalation will constitute a DLT (refer to Section 7.4.1), but participants will be allowed to continue on BMS- 986458 at the reduced dose. [001107] When a dose reduction of BMS-986458 is indicated, the next lower dose level that was deemed safe and tolerable will be selected. If a participant is on a dose schedule, the participant can dose reduce to the total daily dose equivalent of the next lower dose level administered in a schedule. For Part B, this means the participant can dose reduce to the total daily dose equivalent of the next lower dose level that was deemed safe and tolerable in Part A, administered in the same schedule to which the participant was assigned. Once the dose has been reduced, it can be escalated when toxicity reaches Grade ≤ 1. If toxicity recurs at the higher dose, the dose will be reduced a second time, but no re-escalation is then permitted. Two dose reductions are allowed (one for starting dose). If any participant continues to experience unacceptable toxicity after 2 dose reductions (one reduction for the starting dose), BMS-986458 will be discontinued permanently. [001108] Chronic Grade 2 toxicity may warrant dose reduction of study intervention. Such cases should be discussed with the Medical Monitor before changes are made. [001109] No dose reductions are permitted for rituximab. [001110] 7.4.3.3 Criteria for Dose Increase. Intra-participant dose escalation beyond the dose initially assigned to a participant is not permitted during Cycle 1. Those in Part A continuing to take BMS-986458 beginning with Cycle 2 may, at the Investigator’s discretion following approval by the SRC, have the dose level increased provided that the alternative dose level has been shown to be well tolerated by at least 1 cohort of other participants in this study. To be considered for intra-participant dose escalation, participants must be shown to be adequately tolerating their current dose level (e.g., not have experienced a BMS-986458-related Grade ≥ 3 toxicity at their assigned dose level). In Part B, no dose escalation beyond the MTD is allowed. [001111] 7.4.4 Definition of Dose-limiting Toxicities. Toxicity severity will be graded according to NCI CTCAE Version 5.0 except for TLS and TFR, which will be graded according to Cairo-Bishop TLS grading system²⁶ and NCI CTCAE Version 3.0, respectively. [001112] The DLT assessment period is defined as Cycle 1 Day 1 to Cycle 1 Day 28, including the predose assignments specified for Day 1 of Cycle 2. Any of the following events will be considered a DLT, unless the event can be attributed by the investigator to a clearly identifiable cause, such as underlying illness or disease progression, other concurrent illness, or concomitant medication. [001113] Dose-limiting toxicities are described below: • Hematological toxicities as follows: o Febrile neutropenia of any duration o Grade 4 neutropenia lasting > 7 days o Grade 4 thrombocytopenia lasting > 24 hours or Grade ≥ 3 thrombocytopenia with clinically significant bleeding o Grade 4 anemia lasting > 24 hours • Any non-hematologic toxicity Grade ≥ 3, EXCEPT for: o Grade 3 nausea, vomiting, dehydration, or diarrhea that resolves within 72 hours (with optimal medical management) and does not require tube feeding, total parenteral nutrition, or prolonging hospitalization. o Grade 3 IRR controlled by study intervention interruption and medical management that resolves to Grade ≤ 1 within 48 hours. o Grade 3 fatigue that resolves to Grade ≤ 2 within 7 days of study intervention interruption and does not recur at the same level with resumption of study intervention at the same dose (with optimal medical management). o Grade 3 TLS, if it is not clinically complicated and resolves within 7 days with conventional medical management and with no end organ damage. o Grade 3 electrolyte abnormalities (ie, those occurring without clinical consequence) that resolve, with therapy or without intervention, to Grade ≤ 2 levels within 72 hours. o Grade 3 AST or ALT elevation that resolves to Grade ≤ 2 within 72 hours and do not meet the criteria for Hy´s law. o Grade 3 rash of the acneiform, pustular, or maculopapular type that resolves to Grade ≤ 2 within 7 days of study intervention interruption (with optimal medical management). Topical steroid treatment is allowed for symptom control. • Any confirmed Hy’s law case. Note: A Hy’s law case is one in which liver aminotransferase levels ≥ 3× ULN are accompanied by an elevation of total bilirubin to > 2× ULN without initial findings of cholestasis (eg, elevated serum ALP), for which no other reason can be found to explain the combination of increased aminotransferase and total bilirubin. • Any AE, unless clearly determined to be unrelated to the study intervention(s), and necessitating dose-level reduction during Cycle 1. • Any death during Cycle 1. • Isolated laboratory changes without associated clinical signs or symptoms and/or ECG changes (eg, hypomagnesemia, hypermagnesemia, hypoalbuminemia, hypophosphatemia, lymphocyte count increased or decreased) may not be included in this definition. These findings will be discussed and reviewed by the SRC. Any toxicities that occur beyond the DLT period will be considered in making final dose level decisions. [001114] See the Dose Modification Guidance (see Table 7.4.1-1 and Table 7.4.1-2) for actions to be taken on BMS-986458, and rituximab in relation to DLTs or other AEs. [001115] 7.4.5 Definition of DLT-evaluable Participant. All participants who receive at least 1 dose of BMS-986458 will be evaluable for safety. After the first dose is administered in any cohort of participants during Dose Escalation, participants in each cohort will be observed for 28 days (DLT assessment period) before the next higher, protocol- specified dose-schedule cohort can begin. • A participant evaluable for a DLT is defined as one who received at least 75% of the total planned Cycle 1 dose intensity of IMP(s) without experiencing a DLT during the DLT assessment period. OR • A participant experienced a DLT after receiving at least one dose or fraction thereof of IMP(s) during the DLT assessment period. Participants non-evaluable for DLT may be replaced. Additional participants within any tolerated dose cohort may be enrolled at the discretion of the investigators and upon agreement with the Sponsor’s Medical Monitor. [001116] 7.4.6 Determination of the MTD, OBD(s), and RP2D(s). The MTD is defined as the dose level that can be given such that the estimated DLT probability is closest to approximately 30%. Preliminary estimation of the MTD will be based on the estimation of the incidence rate of DLTs across doses with all treated safety-evaluable participants in Stage 1 and Stage 2 and OBDs will be estimated based on the TITE-BOIN12 (Stage 2) algorithm. The final determination of MTD and OBDs will be decided by the SRC. [001117] Based on the cumulative safety, PK/pharmacodynamics (as available) and efficacy data from participants treated in Part A, 1 or more dose level(s) may be selected for further evaluation in Part B. RP2D(s) will be recommended by the SRC after review of data from Part A and Part B of the study. [001118] 7.5 Preparation/Handling/Storage/Accountability. The IP/IMP/Non-IMP/AxMP must be stored in a secure area according to local regulations. It is the responsibility of the investigator, or designee where permitted, to ensure that IP/IMP/Non- IMP/AxMP is only dispensed to study participants. The IP/IMP/Non-IMP/AxMP must be dispensed only from official study sites by authorized personnel according to local regulations. [001119] The product storage manager should ensure that the study intervention is stored in accordance with the environmental conditions (temperature, light, and humidity) as determined by the Sponsor. If concerns regarding the quality or appearance of the study intervention arise, the study intervention should not be dispensed, and the Sponsor should be contacted immediately. [001120] Study intervention not supplied by the Sponsor will be stored in accordance with the package insert. [001121] IP/IMP/Non-IMP/AxMP documentation (whether supplied by the Sponsor or not) must be maintained and must include all processes required to ensure the drug is accurately administered. This includes documentation of drug storage, administration and, as applicable, storage temperatures, reconstitution, and use of required processes (eg, required diluents, administration sets). • The investigator or designee must confirm that appropriate temperature conditions have been maintained during transit for all study intervention received and any discrepancies are reported and resolved before use of the study intervention. • Only participants enrolled in the study may receive study intervention, and only authorized site staff may supply, prepare, or administer study intervention. • All study intervention must be stored in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the investigator and authorized site staff. • The investigator, institution, head of the medical institution (where applicable), or authorized site staff is responsible for study intervention accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition of records). • Further guidance and information for the final disposition of unused study interventions are provided in the Pharmacy Manual. For study interventions not provided by the Sponsor and obtained commercially by the site, storage should be in accordance with the product label. [001122] 7.6 Study Intervention Compliance. Participants will be asked to record their daily self-administration of BMS-986458 at home in the dosing diary. Study intervention compliance will be monitored periodically by drug accountability (review of dosing diary). Drug accountability should be reviewed by the study site staff at each visit to confirm treatment compliance. Study site staff should discuss discrepancies with the participant at each on- treatment study visit. Compliance will be assessed by direct questioning and counting returned tablets during the site visits and documented in the source documents and relevant form. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. [001123] Study intervention start and stop dates, including dates for intervention delays and/or dose reductions, will be recorded in the eCRF. A record of the number of tablets of BMS- 986458 dispensed to and taken by each participant must be maintained and reconciled with study intervention and compliance records. [001124] 7.7 Concomitant Therapy [001125] 7.7.1 Prohibited and/or Restricted Treatments. Prohibited and/or restricted medications taken prior to study intervention administration in the study are described below: • Prior exposure to BMS-986458 • Exposure to any investigational drug or placebo within 4 weeks of study intervention initiation and during the study • Anticancer therapy (chemotherapy, biologic or investigational therapy, and surge1y) other than the study intervention during the study. Focal palliative radiotherapy for treatment of cancer­ related symptoms may be pennitted during study treatment at the discretion of the Investigator after discussion with the Sponsor Medical Monitor. The Medical Monitor will have the opportunity to advise the site investigator on drng washout prior to radiation therapy and allow treatment to be resumed based on possible radiation toxicity. Maintenance honnonal therapies are allowed in subjects with a histo1y of breas t or prostatecancer. • Complementa1y medications (eg, herbal supplements or traditional Chinese medicines) should be used with caution. Use of St. John's woli is not pennitted, see list of prohibited CYP3A inducers and inhibitors below. • Any live/attenuated vaccine (eg varicella, zoster, yellow fever, rotavirns, oral polio and measles, mumps, rnbella [MMR]) during the study and until 28 days post last dose of study intervention. o Killed or inactivatedor component vaccines, such as an injectable annual influenza vaccine, are pennitted. o Live COVID-19 vaccines should not be administered to a paiiicipant during the study, including during the treatment, and within the 28-day follow-up period following the last dose of study intervention. In addition, the administration of a live COVID-19 vaccine is prohibited up to 28 days prior to the initiation of study intervention. • Other investigational therapies during the study, except for therapies used to treat active SARS-CoV-2 infections or high-risk exposures, which are allowed and should be discussed with the Medical Monitor. Administration of investigational SARS-CoV-2 vaccines is not allowed. • Strong CYP3A4 inhibitors and inducers, sensitive CYP3A substrates, or CYP3A substrates with a naiTow therapeutic window. [001126] Examples of strong CYP3A inhibitors, inducers, and substrates include (but are not limited to): o Atazanavir, Seville oranges o alfentanil, avanafil, buspirone, conivaptan, darifenacin, darnnavir, ebastine, everolimus, ibrntinib, lornitapide, lovas tatin, rnidazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, ta.crolimus, tipranavir, triazolam, vardenafil, budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, indinavir, lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan • In vitro solubility data indicate that BMS-986458 has decreased solubility with increasing pH. Until further data are available, concomitant use of proton pump inhibitors and H2 antagonists is prohibited. If while on study, it becomes medically necessary (e.g., peptic ulcer disease, gastroesophageal reflux disease, erosive esophagitis), they may be given with caution after the discussion with Medical Monitor. Short-acting antacid agents, such as Maalox® or TUMS®, may be taken, but it is recommended that these not be taken 2 hours before or 2 hours after dosing of BMS-986458. • Consumption of Seville oranges, grapefruit or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 5 days before the start of study intervention until 24 hours after the final dose of BMS-968458. Medications taken within 4 weeks prior to study intervention administration and up to 28 days after the last dose of study intervention must be recorded on the eCRF. [001127] 7.7.2 Permitted Therapy. Participants are permitted the use of the following treatments while receiving study intervention: • Granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) for therapeutic intent at investigator discretion • Parenteral flu vaccination • Any antibiotic, antiviral, antipneumocystis, antifungal, or other prophylaxis at the discretion of the investigator • Medications to prevent and treat IRRs, including antihistamines, antipyretics, corticosteroids, bronchodilators, and other medications, as medically indicated • Medications to prevent and treat TLS, including hypouricemic agents (eg, allopurinol, rasburicase), diuretics, and phosphate and potassium binders. Rasburicase is contraindicated in participants with baseline G6PD deficiency (refer to the package insert or SmPC for further information on rasburicase) • Authorized or approved non-live SARS-CoV-2 vaccines at the discretion of the Investigator • Treatment of active SARS-CoV-2 infections or high-risk exposures, including use of investigational therapies and taking into consideration the risk of DDI (eg, Paxlovid), is allowed and should be discussed with the Medical Monitor. • Prophylactic measures with anti-coagulation or anti-platelet agents is allowed at the investigator´s discretion. It is recommended that the Investigator carefully assess an individual participant’s underlying risk for thromboembolism and bleeding. • Any complementary medications such as vitamin and mineral supplements are allowed. Subject to the precautions described in Section 7.7.1, the use of any concomitant medication or therapies deemed necessary for the care of the participant should be used. Repeat PK evaluations may be conducted if changes are made to concomitant medications suspected of affecting drug absorption or metabolism. [001128] 7.7.3 Other Restrictions and Precautions. The ability of the study intervention to induce photosensitivity has not been yet fully assessed. Participants receiving study intervention must be counseled to minimize exposure to ultraviolet light, wear protective clothing and sunglasses when out in the sun, and use a broad-spectrum ultraviolet (UV)A/UVB sunscreen with a sun protection factor of at least 25 on their exposed skin until at least 2 days after permanent discontinuation of study intervention. [001129] If use of antiarrhythmic drugs known to prolong the QT interval and/or other drugs known to prolong the QT interval is necessary, the risks and benefits should be discussed with the Sponsor’s Medical Monitor prior to its concomitant use with study intervention. [001130] 7.7.3.1 Imaging Restrictions and Precautions. It is the local imaging facility’s responsibility to determine, based on participant attributes (e.g., allergy history, diabetic history, renal status), the appropriate imaging modality and contrast regimen per imaging study. Imaging contraindications and contrast risks are to be considered in this assessment. Participants with renal insufficiency are to be assessed as to whether they should receive contrast and if so, which contrast agent and dose are appropriate. Specific to magnetic resonance imaging (MRI), participants with severe renal insufficiency (i.e., estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²) are at increased risk of nephrogenic systemic fibrosis; therefore, MRI contrast is contraindicated. In addition, participants may be excluded from MRI if they have tattoos, metallic implants, pacemakers, etc. These restrictions will be outlined in the Imaging Manual. [001131] Gentle hydration before and after IV contrast should follow local standard of care. The ultimate decision to perform MRI in an individual participant enrolled in this study rests with the site radiologist, the investigator, and standards set by the local Ethics Committee. [001132] 7.8 Continued Access to Study Intervention After the End of the Study. At the conclusion of the study, if the study intervention is not available as an approved treatment in the local country, participants who continue to demonstrate clinical benefit will be eligible to receive Sponsor-supplied study intervention for a maximum treatment duration as specified in Section 7.1. If the study intervention is not available as an approved and available treatment, study intervention will be provided via an extension of the study, a rollover study requiring approval by the responsible Health Authority and Ethics Committee, or through another mechanism at the discretion of the Sponsor. [001133] The Sponsor reserves the right to terminate access to Sponsor-supplied study intervention if any of the following occur: a) the study is terminated due to safety concerns; b) the development of BMS-986458 is terminated for other reasons, including, but not limited to, lack of efficacy and/or not meeting the study objectives; or c) the participant can obtain medication from a government- sponsored or other health program. In all cases, the Sponsor will follow local regulations. [001134] 8 Discontinuation Criteria. Discontinuation of the study at specific sites or of the entire study is detailed. [001135] 8.1 Discontinuation of Study Intervention. Participants MUST discontinue IP/IMP (and Non-IMP/AxMP at the discretion of the investigator) for any of the following reasons: • Participant’s request to stop study intervention. Participants who request to discontinue study intervention will remain in the study and should continue to be followed for protocol-specified follow-up procedures. The only exception to this is when a participant specifically withdraws consent for any further contact with him/her or persons previously authorized by the participant to provide this information. • Any clinical AE, laboratory test result abnormality, or intercurrent illness that, in the opinion of the investigator, indicates that continued participation in the study is not in the best interest of the participant. • Termination of the study by the Sponsor. • Loss of ability to freely provide consent through imprisonment or involuntary incarceration for treatment of either a psychiatric or physical illness (eg, infectious disease). (Note: Under specific circumstances and only in countries where local regulations permit, a participant who has been imprisoned may be permitted to continue as a participant. Strict conditions apply, and Sponsor approval is required.) • Any event that leads to delay in dosing lasting > 4 weeks as described in Section 7.4.1. o On rare occasions, participants may derive benefit from resumption of BMS- 986458 after an interruption of longer than 4 weeks. All decisions regarding resumption of dosing after > 4 weeks interruption must be discussed with the Medical Monitor. • Evidence of clinically significant disease progression based on the judgement of the Investigator. • Pregnancy (refer to Section 9.2.5). • Significant noncompliance with protocol (eg, procedures, assessments, medications, etc). The investigator should discuss such issues with the Medical Monitor. [001136] Refer to Section 2: Schedule of Activities for data to be collected at the time of treatment discontinuation and follow-up and for any further evaluations that can be completed. [001137] All participants who discontinue study intervention should comply with protocol- specified follow- up procedures as outlined in Section 2: Schedule of Activities. The only exception to this requirement is when a participant withdraws consent for all study procedures, including post- treatment study follow-up, or loses the ability to consent freely (eg, is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical illness). [001138] If study intervention is discontinued prior to the participant’s completion of the study, the reason for the discontinuation must be documented in the participant’s medical records per local regulatory requirements in each region/country and entered on the appropriate eCRF page. [001139] 8.1.1 Post-study Intervention Study Follow-up. Participants who discontinue study intervention may continue to be followed. BMS may request that survival data be collected on all treated participants outside of the protocol defined window. At the time of this request, each participant will be contacted to determine their survival status unless the participant has withdrawn consent for all contact or is lost to follow-up. [001140] 8.2 Discontinuation From the Study • Participants should notify the investigator of the decision to withdraw consent from future follow-up. • The withdrawal of consent should be explained in detail in the medical records by the investigator as to whether the withdrawal is from further treatment with study intervention only or also from study procedures and/or post-treatment study follow-up, and entered on the appropriate eCRF page. • In the event that vital status (whether the participant is alive or dead) is being measured, publicly available information should be used to determine vital status only as appropriately directed in accordance with local law. • If the participant withdraws consent for disclosure of future information, the Sponsor may retain and continue to use any data collected before such a withdrawal of consent. [001141] 8.2.1 Individual Discontinuation Criteria • A participant may withdraw completely from the study at any time at his/her own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or administrative reasons. This is expected to be uncommon. Stopping study intervention is not considered withdrawal from the study. • At the time of discontinuing from the study, if possible, an early termination visit should be conducted, as shown in Section 2: Schedule of Activities. See the Schedule of Activities for data to be collected at the time of study discontinuation and follow-up and for any further evaluations that need to be completed. • The participant will be permanently discontinued from both the study intervention and the study at that time. • If the participant withdraws consent for disclosure of future information, the Sponsor may retain and continue to use any data collected before such a withdrawal of consent. [001142] 8.3 Lost to Follow-up. The following actions must be taken if a participant fails to return to the clinic for a required study visit: • All reasonable efforts must be made to locate participants to determine and report their ongoing status. This includes follow-up with persons authorized by the participant. • Lost to follow-up is defined by the inability to reach the participant after a minimum of 3 documented phone calls, faxes, or emails, as well as lack of response by participant to 1 registered mail letter. All attempts should be documented in the participant’s medical records. • If the investigator’s use of a third-party representative to assist in the follow-up portion of the study has been included in the participant’s informed consent, then the investigator may use a Sponsor-retained third-party representative to assist site staff with obtaining the participant’s contact information or other public vital status data, such as public health registries and databases, necessary to complete the follow-up portion of the study. • The site staff and representative will consult publicly available sources, such as public health registries and databases, to obtain updated contact information. • If, after all attempts, the participant remains lost to follow-up, then the last known alive date as determined by the investigator should be reported and documented in the participant’s medical records. • If it is determined that the participant has died, the site will use permissible local methods to obtain date and cause of death. [001143] 9 Study Assessments and Procedures • Study procedures and timing are summarized in Section 2: Schedule of Activities. • Protocol waivers or exemptions are not allowed. • All immediate safety concerns must be discussed with the Sponsor immediately upon occurrence or awareness to determine whether the participant should continue or discontinue treatment. • Adherence to the study design requirements, including those specified in the Schedule of Activities, is essential and required for study conduct. • All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria before enrollment. The investigator will maintain a screening log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, as applicable. • Procedures conducted as part of the participant’s routine clinical management (eg, complete blood count) and obtained before signing of informed consent may be utilized for screening or baseline purposes provided the procedure meets the protocol-defined criteria and has been performed within the time frame defined in the Schedule of Activities. • The maximum amount of blood collected from each participant over the duration of the study, including any extra assessments that may be required, will not exceed 920 mL. • Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples. Perform additional measures, including non-study required laboratory tests, as clinically indicated or to comply with local regulations. • Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations. [001144] 9.1 Efficacy Assessments [001145] 9.1.1 Efficacy Assessment for the Study. Assessments for the anti-tumor activity of BMS-986458 will be determined by the Investigator. The International Workshop Criteria for Malignant Lymphoma²⁰ and the Deauville Criteria for fluorodeoxyglucose-positron emission tomography (FDG-PET) scan interpretation^29,30 will be used for efficacy assessment (“Lugano criteria”). [001146] Efficacy assessments include the following: • Clinical findings (eg, physical examination, constitutional symptoms) • Contrast-enhanced computed tomography (CT) scans and FDG-PET, or FDG-PET-CT where appropriate • Bone marrow examination (bone marrow biopsy [BMB] and bone marrow aspiration [BMA]) where appropriate • Magnetic resonance imaging (MRI) where appropriate [001147] Screening tumor assessments will include the following: • CT of the chest, abdomen and pelvis: CT scan with contrast is the recommended imaging modality. Contrast-enhanced MRI of abdomen and pelvis is also permitted. Standard of care CT scans or MRI performed up to 56 days prior to Cycle 1 Day 1 may be acceptable for Screening, even if performed prior to signing the ICF. • A baseline FDG-PET or FDG-PET/CT scan will be performed for all participants except those with known FDG-PET negative tumors. • A bone marrow aspirate and biopsy will be performed only for participants with known/suspected bone marrow involvement. • A brain/spine scan (contrast-enhanced MRI preferred, while CT can be performed if MRI is contraindicated) will be performed only for participants with suspected cerebral involvement (if clinically indicated). [001148] On-treatment tumor assessments will be performed as follows: • Radiologic assessments will be performed as noted in the Schedule of Activities (Section 2) until investigator-assessed progression, withdrawal of consent, death, or maximum study duration, using the same scanning modalities used at Screening. An EOT scan does not need to be obtained if the prior scan was within 28 days. If study intervention is discontinued for other reasons than disease progression, imaging should be continued every 26 weeks from the last dose up to 52 weeks or until progression of disease, death, initiation of new anticancer therapy, loss to follow-up, withdrawal of consent from the study, or end of the study, whichever occurs first. • For participants with bone marrow involvement at Screening, a bone marrow evaluation with flow immunophenotyping will be performed to confirm a complete response (CR). All participants who discontinue treatment for reasons other than disease progression or relapse, start of a new anticancer therapy, or withdrawal of consent from the entire study will be followed every 6 months (± 14 days) until progression, initiation of new systemic anticancer therapies including SCT, or withdrawal, up to 1 year after the end of treatment. After progression, CT scans are no longer required per protocol; however, assessments may be continued according to local clinical practice. • Tumor response at each post-screening assessment will be determined by the Investigator- based Revised Response Criteria for Malignant Lymphoma. Treatment decisions will be based on Investigator’s assessment.²⁰ [001149] Survival status will be determined following disease progression, approximately every 12 weeks for up to 1 year. Anticancer therapies including systemic treatment, cellular therapy, SCT, surgery, and radiation will be collected after disease progression. [001150] 9.1.2 Imaging Assessment for the Study. Images for tumor assessment will be submitted to a central imaging vendor for collection in a central repository and may undergo blinded independent central review (BICR) at any time during and/or after the study. Prior to scanning first participant, sites should be qualified and understand the image acquisition guidelines and submission process as outlined in the Imaging Manual provided by the central imaging vendor. Any additional imaging that may demonstrate tumor response or progression (including scans performed at unscheduled timepoints and/or at an outside institution) for response assessment by Lugano criteria²⁰ must be collected and submitted to the central imaging vendor. Refer to Section 2 for further details. Clinical data may be provided to the imaging vendor, if applicable. [001151] Images should be acquired with slice thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should be made to image each participant using an identical acquisition protocol on the same scanner for all imaging timepoints. Tumor measurements should be made by the same investigator or radiologist for each assessment, whenever possible. [001152] In case of a contraindication for either contrast agent or MRI (e.g., incompatible pacemaker), it is strongly recommended to use the following guidance: • If a participant has a contraindication for CT intravenous contrast, then a non- contrast CT of the chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of disease should be obtained. • If a participant has a contraindication for both MRI and CT intravenous contrasts, then a non-contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other known/suspected sites of disease should be obtained. • If a participant has a contraindication for MRI in addition to contraindication to CT intravenous contrast, then a non-contrast CT of the chest, abdomen, pelvis, and other known/suspected sites of disease is acceptable. [001153] Low dose or attenuation correction CT portions of a combined PET-CT are of limited use in efficacy assessments and it is therefore suggested that they should not be substituted for dedicated diagnostic contrast-enhanced CT scans for Lugano measurements. However, if a site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for Lugano measurements. [001154] 9.2 Adverse Events. The definitions of an AE or SAE can be found in Appendix 3. [001155] AEs will be reported by the participant (or, when appropriate, by a caregiver or a surrogate). [001156] The investigator and any qualified designees are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE and remain responsible for following up on AEs that are serious, considered related to the study intervention or the study, or that caused the participant to discontinue before completing the study.Refer to Appendix 3 for SAE reporting. [001157] CTCAE v5.0 definitions and grading will be used for safety reporting of all AE and SAEs on the eCRF, except for tumor flare reaction (NCI CTCAE v3.0) and tumor lysis syndrome.²⁶ [001158] 9.2.1 Period and Frequency for Collecting AE and SAE Information. All AEs and SAEs must be collected from the time of signing the informed consent form, including those thought to be associated with protocol-specified procedures and until 28 days following discontinuation of dosing or the last scheduled visit as noted in the Schedule of Activities (Section 2). [001159] The investigator must report any SAE that occurs after these periods and that is believed to be related to a study intervention or protocol-specified procedure (eg, a follow-up skin biopsy). • All SAEs will be recorded and reported to the Sponsor or designee, promptly and not to exceed 24 hours of awareness of the event as indicated in Appendix 3. • The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours of updated information being available. [001160] Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the investigator learns of any SAE, including a death, at any time after a participant has been discharged from the study, and he/she considers the event reasonably related to the study intervention or study participation, the investigator must promptly notify the Sponsor. [001161] The method of evaluating and assessing causality of AEs and SAEs and the procedures for completing and reporting/transmitting SAE reports are provided in Appendix 3. [001162] 9.2.2 Method of Detecting AEs and SAEs. AEs can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a participant. Care should be taken not to introduce bias when collecting AEs and/or SAEs. Inquiry about specific AEs should be guided by clinical judgment in the context of known AEs, when appropriate for the program or protocol. [001163] 9.2.3 Follow-up of AEs and SAEs • All SAEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3: Lost to Follow-up). • Non-serious AEs should be followed to resolution or stabilization or reported as SAEs if they become serious (see Appendix 3). • Follow-up is also required for non-serious AEs that cause interruption or discontinuation of study intervention and for those present at the end of study intervention as appropriate. • All identified non-serious AEs must be recorded and described on the non-serious AE page of the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs and/or laboratory test result abnormalities that are reported/identified during the study. [001164] Further information on follow-up procedures is given in Appendix 3. [001165] 9.2.5 Pregnancy. If, following initiation of the study intervention, it is discovered that a participant is pregnant or may have been pregnant at the time of study intervention exposure, including at least 28 days after study intervention administration, the investigator must immediately notify the Sponsor Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to the Sponsor designee within 24 hours of awareness of the event. Pregnancy reporting must follow the same transmission timing and processes to BMS as those used for SAEs, in accordance with reporting procedures described in Appendix 3. [001166] In all cases, the study intervention will be discontinued in an appropriate manner (e.g., dose tapering if necessary for participant safety). [001167] Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where applicable, offspring information, must be reported on the Pregnancy Surveillance Form. Protocol-required procedures for study discontinuation and follow-up must be performed. [001168] Any pregnancy that occurs in a female partner of a male participant at the time of study intervention exposure, including at least 28 days after study intervention administration, should be reported to the Sponsor or designee. For the Sponsor or designee to collect any pregnancy surveillance information from the female partner, the female partner must sign an ICF for disclosure of this information. Information on this pregnancy will be collected and recorded on the Pregnancy Surveillance Form. [001169] The exposure of any pregnant individual (e.g., caregiver, pharmacist, study coordinator, monitor) to BMS-986458 must follow the same reporting transmission timing and processes to BMS as those used for SAEs, in accordance with reporting procedures described in Appendix 3. [001170] If any sexual activity involving penile intercourse (e.g., vaginal, anal, oral) has occurred between a male participant and a pregnant partner(s) without the use of a condom during and for at least 28 days after study intervention administration, the information should be reported to the Sponsor or designee, even if the male participant has undergone a successful vasectomy. [001171] 9.2.6 Laboratory Test Result Abnormalities. The following laboratory test result abnormalities should be captured on the Adverse Events – Non-serious and Serious Events eCRF page. Paper forms are only intended as a back-up option when the electronic system is not functioning. • Any laboratory test result that is clinically significant or meets the definition of an SAE • Any laboratory test result abnormality that requires the participant to have study intervention discontinued or interrupted • Any laboratory test result abnormality that requires the participant to receive specific corrective therapy It is expected that, wherever possible, the clinical rather than the laboratory term will be used by the reporting investigator (e.g., anemia vs low hemoglobin value). [001172] 9.2.7 Potential Drug-induced Liver Injury. Specific criteria for identifying a potential drug-induced liver injury (DILI) have not been identified for this protocol. Standard medical practice in identifying and monitoring hepatic issues should be followed. [001173] 9.2.8 Other Safety Considerations. Any significant worsening of conditions noted during interim or final physical examinations, ECG, radiographic imaging, or any other potential safety assessment required or not required by the protocol should also be recorded as a non- serious AE or SAE, as appropriate, and reported accordingly. [001174] 9.3 Overdose. An overdose is defined as the accidental or intentional administration of any dose of a product that is considered both excessive and medically important. Overdoses that meet the regulatory definition of an SAE will be reported as SAEs (see Appendix 3), [001175] In the event of an overdose, the investigator/treating physician should: • Contact the Medical Monitor immediately. • Closely monitor the participant for AEs/SAEs and laboratory test result abnormalities, • Document the quantity of the excess dose as well as the duration of the overdosing in the eCRF. [001176] 9.4 Safety. Planned timepoints for all safety assessments are listed in Section 2: Schedule of Activities. Starting after Cycle 6, clinic visits and assessments on Day 1 may be performed on a less frequent schedule at the discretion of the Investigator in the absence of any ≥ Grade 2 toxicity related to study intervention. [001177] 9.4.1 Physical Examinations and ECOG Performance Status. Physical examination including height (Screening and EoT only), weight, BMI, and BSA when applicable, and ECOG Performance Status will be performed. If the screening PE is performed within 24 hours prior to dosing on Day 1, then a single examination may count as both the screening and pre-dose evaluation. Any findings during the PE will be recorded as medical history in the participant’s medical records and on the appropriate eCRF. [001178] 9.4.2 Vital Signs. Vital signs include body temperature, blood pressure, heart rate, and pulse oximetry. Blood pressure and heart rate should be measured after the participant has been resting quietly for at least 5 minutes. Additional vital signs should be obtained as clinically indicated per the Investigator’s assessment. Recorded measurements will be captured in the participant’s medical records and on the appropriate eCRF. [001179] 9.4.3 Electrocardiograms. Triplicate ECG collection timepoints for Part A and Part B, respectively. The 12-lead ECGs (12-lead at 25 mm/sec reporting rhythm, heartrate/ventricular rate, PR interval, QRS complex, QT interval, and QT interval corrected using Fridericia's formula [QTcF]) will be performed after the participant has been in the supine or semi- recumbent position for at least 10 minutes. Triplicate 12-lead ECGs (3 recordings collected at 2 ± 1-minute intervals) should be collected at each timepoint using the Sponsor's provided machine and will be sent to the central ECG laboratory for processing by third-party evaluation. Triplicate ECG outputs will be uploaded to the central ECG laboratory at the end of each visit for definitive analysis and interpretation. Investigators will make immediate clinical decisions based on their interpretation of the safety ECG results. [001180] During the treatment period, specific triplicate ECGs will be collected within approximately 15 minutes before time-matched PK samples. [001181] Thereafter single ECGs will be performed if clinically indicated after Cycle 4. Only a single ECG is required for the EOT visit if after Cycle 4. The ECGs starting at Cycle 5 will be single ECGs and will not be sent to the central ECG laboratory. Clinically significant changes for these ECGs will be documented on the AE section of the eCRF. [001182] 9.4.4 ECHO or MUGA Scan. LVEF will be determined at Screening and EOT by multiple gated acquisition scan or echocardiogram. Follow-up assessments should be performed as clinically indicated. Follow-up assessments should use the same procedure used at the Screening assessment. A clinically significant reduction is defined as either a ≥ 20% absolute reduction in LVEF or drop to below 45% from baseline. [001183] 9.4.5 Clinical Safety Laboratory Assessments. Investigators must document their review of each laboratory safety report. The clinical safety laboratory tests will be performed at local laboratories, which will provide reference ranges for these tests. Results of safety clinical laboratory tests performed during Screening and at dosing visits must be available and reviewed prior to dosing. Table B4-9.4.5-1: Clinical Laboratory Assessments deydogease; , pot o b t e; WOC , wo e o c dbea g poteta. [001184] 9.4.6 Other Safety Assessment. Any incidental findings of potential clinical relevance that are not directly associated with the objectives of the protocol should be evaluated and handled by the study investigator per standard medical/clinical judgment. [001185] 9.4.7 Pregnancy Test. A woman of childbearing potential (WOCBP) is defined as a sexually mature female who has: • Not undergone a hysterectomy or bilateral oophorectomy or bilateral salpingectomy. • Not been naturally postmenopausal (amenorrhea following anticancer therapy does not rule out childbearing potential) for at least 12 consecutive months (eg, has had menses at any time in the preceding 12 consecutive months). [001186] The Investigator will classify a female participant as a WOCBP according to this definition. Pregnancy testing is not required for WNOCBP participants, but justification must be recorded in the eCRF and the source document. Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for WOCBP. Pregnancy testing will be conducted by the local laboratory. • For a WOCBP, pregnancy testing will be conducted at the visits listed below and detailed in the PPP. A serum pregnancy test is to be obtained at Screening (within 10 to 14 days prior to Cycle 1 Day 1) and another pregnancy test (serum or urine) must be performed within 24 hours prior to Cycle 1 Day 1 of study treatment. The participant may not receive BMS-986458 until the Investigator has verified the 2 screening pregnancy tests to be negative. • A serum or urine pregnancy test should be done within 24 hours prior to Day 1 of every following cycle and at the end of treatment (EOT) visit. The participant may not receive BMS-986458 until the Investigator has verified the pregnancy test to be negative. • A WOCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while taking BMS-986458, at study discontinuation, and monthly for at least 28 days after the last dose of BMS-986458. • A WOCBP with irregular menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 14 days while taking BMS- 986458, at study discontinuation, every 14 days for at least 28 days after the last dose of BMS-986458. • A WOCBP or a male participant whose partner is a WOCBP must avoid activities that could lead to conception for at least 28 days after the last dose of BMS-986458. [001187] Results for pregnancy tests will be recorded in the source document and eCRF. [001188] 9.5 Pharmacokinetics. Pharmacokinetics of BMS-986458 and its diastereomers will be derived from plasma concentration versus time data, during monotherapy and in combination, as shown below as data permits. [001189] The PK parameters to be assessed, as appropriate if data permit, include but are not limited to the following: _ [001190] Individual participant PK parameter values will be derived by non-compartmental methods by a validated PK analysis program. Actual times will be used for the analyses. [001191] PK data from this study may be combined with PK data from other studies to characterize the PK using population PK analysis. Results of this analysis will be reported separately (see Section 10.4: Statistical Analyses for additional details). [001192] 9.5.1 Pharmacokinetics Sampling Instructions and Collection Windows. Blood samples will be collected at selected visits from all participants. [001193] It is expected that every effort be made to collect PK samples at the times indicated in the PK sampling schedule table. The exact sampling date and time should always be recorded accurately. Instructions for PK sample collection are provided below: • Predose samples will be taken within minutes prior to oral dose. All On-Treatment timepoints are intended to align with days on which study intervention is administered. If it is known that a dose is going to be delayed, then the predose sample should be collected just prior to the delayed dose. However, if a predose sample is collected but the dose is delayed, an additional predose sample should not be collected. [001194] 9.5.2 Pharmacokinetic Sample Analyses. Plasma will be used to determine the concentration of BMS-986458 diastereomers (BMT-648592 and BMT-648599) using a validated liquid chromatography-tandem mass spectrometry (LC- MS/MS) method. Plasma BMS-986458 concentrations will be derived from BMT-648592 and BMT-648599 concentrations. An exploratory analysis of BMS-986458 metabolites in plasma may be performed utilizing the blood samples collected for PK evaluation, using exploratory LC-MS/MS methods, as appropriate. [001195] Treatment assignments will be released to the bioanalytical laboratory to minimize unnecessary analysis and/or re-analysis of PK study samples. [001196] Bioanalytical samples designated for assessment (e.g., PK, biomarker) from the same collection timepoint may be used interchangeably for analyses, if required. [001197] Additionally, residual bioanalytical samples will be archived for up to 20 years after the end of the study or the maximum period allowed by applicable law and may be used for potential exploratory bioanalysis (including, but not limited to, metabolite analyses, etc.) and/or for additional method purposes (including, but not limited to, cross-validation, PK selectivity, cut-point, etc.). [001198] 9.7 Biomarkers [001199] 9.7.1 Germline Genetics. Blood samples for DNA isolation will be collected from all participants unless prohibited by local law/regulation or if not approved by the IRB/IEC. In these cases, the DNA collection may be presented to participants as an optional collection. Refer to Table 2-5 in Section 2: Schedule of Activities for the biomarker sampling schedule. [001200] Collection and shipment information for these samples is in the laboratory/procedure manual. The Sponsor will store the DNA samples in a secure storage space with adequate measures to protect confidentiality. The samples may be retained for up to 20 years beyond the end of the study, unless prohibited by local law/regulation or IRB/IEC, to understand genetic mechanisms of response and/or the disease/condition under study and related conditions. [001201] 9.7.3 Tumor Biopsies. Tumor biopsies are mandatory for all participants in both Part A and Part B except for when the tumor is inaccessible (or in a location that would put the paiiicipant at risk), the investigator will discuss the possibility of omitting the on- treatment biopsy with the Medical Monitor. [001202] The biopsy is collected by tumor excision or core needle (4 passages recommended) at the following timepoints: • Screening biopsy o Performed only after eligibility by all other criteria has been established: • Excision or core needle fresh biopsy from one or more sites no sooner than 2 weeks after discontinuing prior anticancer therapy. o Participants with no sites of disease that can, in the investigator's opinion, be safely biopsied percutaneously or through other minimally invasive techniques may still be emolled only after a discussion with the Sponsor Medical Monitor: - Diagnostic archival FFPE (either in tumor blocks or sectioned/mounted specimens) may be submitted in lieu of a Screening fresh biopsy if meets the following criteria: • If it has been obtained no more than 1 yeai· prior to emollment, collected after the last intervene therapy and only after discussion with the Sponsor Medical Monitor. • If enough material is available for Pharmacodynamic assessments. Refer to lab manual for detailed infonnation. • On-treatment biopsies o For participants in Part B only, there is one mandatory on-treatment tumor biopsy on Cycle 1 on either Day 13, 14 or 15. o On-treatment (optional). An optional sample with paired blood sample may be collected for research purposes from an on-treatment biopsy if one is collected during clinical cai·e in Part A or Part B. • End of Treatment biopsy (optional) [001203] Optimally, the tumor tissue samples will be obtained from the same tumor site. [001204] Biopsies should be processed as detailed in the lab manual. Fine needle aspiration is not sufficient as a source of tumor biopsy material. Anatomic pathology reports should be sent along with the biopsy material. [001205] 9.7.4 Fine Needle Aspiration (Part A only). All participants in Part A will require collection of an FNA sample for Pharmacodynamic biomarker studies. This sample will be collected at Screening (only if an Archival sample is submitted in place of a Screening tumor biopsy) and in Cycle 1 on Day 13, 14, or 15. If a fresh tumor biopsy is collected at screening, part of the sample will be submitted for pharmacodynamic assessments by flow cytometry in lieu of the FNA. [001206] If the tumor is inaccessible (or in a location that would put the participant at risk), the investigator will discuss with the Medical Monitor the possibility of omitting the FNA or substituting the on- treatment FNA with a core biopsy. [001207] 9.8 Optional Future Research. This protocol will include residual sample storage for optional future research. Samples kept for future research will be stored at the Sponsor- designated storage facility. The manager of these samples will ensure that they are properly used throughout their usable life and will destroy the samples at the end of the scheduled storage period, no longer than 20 years after the end of the study or the maximum period allowed by applicable law. Samples will be stored in a coded fashion, and no researcher will have access to the key. The key will be securely held by the investigator at the clinical site, so there is no direct ability for a researcher to connect a sample to a specific individual. [001208] 10 Statistical Considerations [001209] 10.1 Statistical Hypotheses. It is anticipated that BMS-986458, administered as a single agent or in combination with anti-lymphoma agents will demonstrate adequate safety and tolerability, as well as a favorable benefit/risk profile, to support further clinical testing. No prospective hypotheses are being formally evaluated. [001210] 10.2 Sample Size Determination. Sample size considerations are as follows: • For Monotherapy Dose Escalation in Part A1, no formal statistical power calculations to determine sample size will be performed. The actual number depends on the number of DLTs observed, number of efficacious responses, and number of dose levels required to determine the OBD(s) (optimal biological dose) for the selection of the RP2D based on a 2-stage Phase I design (Stage 1: BOIN, Stage 2: TITE-BOIN12). We employ this 2-stage design to fully evaluate toxicity yet assess early efficacy without delaying participant enrollment and treatment during our dose escalation/de-escalation. If we encounter an unexpected high toxicity at the first dose level), we will deescalate to dose level -1); otherwise, dose escalation will be considered for dose levels 2 to 5. The anticipated number of toxicity and preliminary efficacy evaluable participants in Stage 1 and 2 is between 3 and 16 per dose level; approximately 41 participants from both Stage 1 and Stage 2 in Part A1 (Appendix 8 and Appendix 9; FIG.13A and 13B). The BOIN design guides the escalation/de-escalation decisions in Stage 1 based only on toxicity. Stage 1 (BOIN) will move to Stage 2 (TITE-BOIN12) if the BOIN-guided dose escalation either i) reaches and confirms the highest dose level within the acceptable toxicity or ii) find the MTD based on the prespecified toxicity range. The additional participants in Stage 2 will then be assigned based on the TITE-BOIN12 design among the admissible doses defined in Section 10.4.2.1. Up to 16 participants will be treated at each dose level (together with the participants from Stage 1) to select the OBDs in Stage 2. • For the combination with rituximab in Part A2, the starting dose of BMS-986458 will be determined by the SRC based on emerging safety, PK, and pharmacodynamic data from Parts A1 and B1, as defined in Section 5.1.2.1. Up to 16 participants will be treated per dose level, with a total of up to 32 response-evaluable participants. Dose escalation will be performed from the lower to the higher combination dose based on the same BOIN criteria as for Stage 1 in Part A1. [001211] In Part B1 and Part B2, 2 OBDs will be investigated per indication to further confirm the tolerability and early efficacy for the selected OBDs of single agent (Part A1) and combination (Part A2). A sample size of approximately 20 response-evaluable participants will be enrolled per indication and dose level for monotherapy and combination to further evaluate the safety and estimate the preliminary efficacy in Part B1 and Part B2. A 55% observed CRR or 11 participants with CRR in the 20 participants will have the two-sided 95% Clopper--Pearson confidence interval (CI; 31.5%, 76.9%) in DLBCL, whose lower bound will be above CRR 28% as reported from the RE-MIND2 study³¹. A 85% observed CRR or 17 participants with CR in the 20 participants will have the two--sided 95% Clopper-Pearson confidence interval (CI; 62.1%, 96.8%) in FL, whose lower bound will be above CRR 60% as reported from Bartlett et.al. (2022).³² These Expansion cohorts will also allow to further observe preliminary efficacy signals at the OBDs, which will guide the selection of the RP2D. [001212] For these expansion cohorts and participants treated at the same dose levels in dose escalation, we will use a Bayesian continuous monitoring to determine an early stopping rule - either pausing or discontinuing treatment at a potential toxic dose level that may not be fully observed during the dose escalation study in Part A1 and Part A2. Safety information from all subjects treated at these dose levels (including both dose escalation and dose expansion cohorts) collected up to end of Cycle 4 will be included in the continuous toxicity monitoring. For participants that would fulfill DLT criteria (except for dose reductions due to AEs not meeting the DLT criteria), excess toxicity rate (based on DLT definition) will be monitored. We will use the statistical criterion based on the posterior probability less than a 60% chance to exceed the upper toxicity limit: posterior prob (excess toxicity based on DLT > 0.3 |data, a, b) > = 0.6 as the early stopping rule, where a and b are parameters of the beta (a, b) prior distribution assumed for the DLT rate: a = 0.3, b = 0.7 for the target toxicity rate 0.30 (see Appendix 10 for its operating characteristics and continuous toxicity monitoring boundary); the prior will be updated to derive the posterior, taking into account the number of observed DLTs at the selected dose level (eg, if 0 DLT are observed in 6 participants at a dose level, the updated posterior will be beta [0.3, 6.7]). [001213] 10.3 Analysis Sets. For the purposes of analysis, the following populations are defined: ) eat pr or to t e rst on-treatment tumor eva uaton p [001214] 10.4 Statistical Analyses [001215] 10.4.1 General Considerations. The statistical analysis plan (SAP) will be developed and finalized before database lock and will describe the selection of participants to be included in the analyses and procedures for accounting for missing, unused, and spurious data. Below is a summary of planned statistical analyses of the primary and secondary endpoints. [001216] 10.4.2 Primary Endpoint(s) Table B4-10.4.2-1: Primary Endpoints an eat . up per o . Abbreviations: AE, adverse event; CTC, Common Terminology Criteria; DLT, dose-limiting toxicity; PT, preferred term; SAE, serious adverse event. Table B4-10.4.2.-2: Summary of the attributes of the Main Estimand for the Primary Objective p [001217] 10.4.2.1 Dose Escalation/De-escalation Rules. A 2-stage dose escalation design will be employed in Part A1. The first stage is based on the Bayesian Optimal Interval (BOIN) design^33,34 to find the MTD. In Stage 1, the BOIN design (see Appendix 8) is implemented. The target toxicity rate is ^q> = 0.30. Participants will be enrolled and treated in cohorts of size 3. DLTs are defined in Section 7.4.4 and only those DLTs that occur within the first cycle will be used for dose finding. [001218] Stage 1 (BOIN) will move to Stage 2 (TITE-BOIN12) if the BOIN-guided dose escalation either i) reaches and confirms the highest dose level within the acceptable toxicity or ii) finds the MTD based on the prespecified toxicity range. In Stage 2, dose escalation/de-escalation will follow the TITE-BOIN12 trial design^35•36 with a 30% target tolerated toxicity rate (DLT rate), a minimum baseline acceptable efficacy rate (ORR) 30% for DLBCL and FL, and the utility scores reflecting clinical desirability (i.e., the risk-benefit trade-off) of the toxicity and efficacy outcomes. TITE-BOIN12 is an extension of BOIN12 to mitigate late onset toxicity and efficacy data. The TITE feature is utilized only for imputing less than 50% efficacy data based on efficacy posterior distributions while fully (100%) requiring toxicity data availability, which is identical to BOIN12 for toxicity evaluation. By the time when the study moves from Stage 1 (BOIN) to Stage 2 (TITE- BOIN12), it is expected that at least 50% or a higher proportion of efficacy data of participants will likely be available, so the study can be continued without much delay. However, if at least 50% of efficacy data has not been collected for a certain dose level by the end of Stage 1, a moderate pausing of study is expected to define next dose level for OBD finding under the TITE-BOIN12 design. Table 10.4.2.1-1 shows the utility ascribed to each possible efficacy­toxicity outcome. To safeguard participants from toxic and/or futile doses, two-dose acceptability criteria are used. A dose is deemed as admissible and eligible for treating pa1iicipants if it sat isfies the following safety and efficacy criteria based on the TITE-BOIN12 guideline. (Safety) Pr (DLT rate > 0.3 _I data) < 0.8, (Efficacy) Pr (ORR < 0.30 _I data) < 0.75 Doses that are not admissible will be eliminated from the trial. If a dose is eliminated due to toxicity, all doses higher than that dose will also be eliminated. Table B4-10.4.2.1-1: Utility Table of the Utility Scores in for TITE-BOIN12 Design u_{. . . y} [001219] 10.4.3 Secondary Endpoint(s). A summary of planned statistical analyses for the secondary endpoints are described in Table 10.4.3-1. Table B4-10.4.3-1: Secondary Endpoints ; , p Table 10.4.3-2: Summary of the Attributes of the Main Estimand for the Key Secondary Objective ea e : - o a e a e os g sc e u e o eque cy, [001220] References 1 Kanas G, Ge W, Quek RGW, et al. Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020-2025. Leuk Lymphoma.2022 Jan;63(1):54-63. 2 Maurer MJ, Ghesquieres H, Jais J-P, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma ti·eated with immunochemotherapy. J Clin Oncol.2014 Apr 1;32(10):1066-73. 3 Crump M, Neelapu SS, Farooq U, et al. Outcomes in refracto1y diffuse large B-cell lymphoma: results from the international SCHOLAR-I study. Blood.2017 Oct 19;130(16):1800-1808. 4 Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refracto1y large B-cell lymphomas (TRANSCEND NHL 001): a multicenu-e seamless design study. Lancet 2020;396:839-52. ⁵ Neelapu SS, Locke FL, Baiilett NL, et al. Axicabtagene Ciloleucel CART-Cell Therapy in Refracto1yLarge B-Cell Lymphoma. N Engl J Med 2017;377:2531- 44. ⁶ Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsedor refracto1y diffuse large B-cell lymphoma. N Engl J Med 2019;380:45-56. ⁷ Casulo C, Le-RademacherJ, Dixon J, et al. Validation of POD24 as a robust eai·ly clini cal endpoint of poor survival in follicular lymphoma: results from the Folliculai· Lymphoma Analysis of SmTogacy H ypothesis (FLASH) investigation using individual data from 5,453 patients on 13 clinical ti·ials [abstract]. Blood. 2017;130(suppl 1). Absu-act 412. ¹⁰ Fratoni S, Zanelli M, Zizzo M, Sanguedolce F, Aimola V, Cen one G, Ricci L, Filosa A, Maiiino G, Fai·a AM, Annessi V, Soriano A, Ascani S. The broad landscape of folliculai· lymphoma: Pa.ii II. Pathologica.2020 Jun;l 12(2):79-92. ¹¹ Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulato1y T Cells and Human Disease. Annu Rev Immunol.2020 Apr 26;38:541-566. doi: 10.1146/annurev­ immunol-042718-041717. Epub 2020 Feb 4. PMID: 32017635. ¹² Whibley N, Tucci A, Powrie F. Regulato1y T cell adaptation in the intestine and skin. Nat lmmunol.2019 Apr;20(4):386-396. doi: 10.1038/s41590-019-0351-z. Epub 2019 Mai· 19. PMID: 30890797. ¹³ Plitas G, Rudensky AY. Regulato1y T cells in cancer. Annu Rev Cancer Biol.2020 March 4:459-77. doi: 10.1146/annurev-cancerbio-03041933428. ¹⁴ Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity.2013 Jul 25;39(1):1-10. doi: 10.1016/j.immuni.2013.07.012. PMID: 23890059. ¹⁵ Tanaka A, Sakaguchi S. Targeting Treg cells in cancer immunotherapy. Eur J Immunol. 2019 Aug;49(8):1140-1146. doi: 10.1002/eji.201847659. Epub 2019 Jul 5. PMID: 31257581. ¹⁶ Kotlov N, Bagaev A, Revuelta MV, Phillip JM, Cacciapuoti MT, Antysheva Z, Svekolkin V, Tikhonova E, Miheecheva N, Kuzkina N, Nos G, Tabbo F, Frenkel F, Ghione P, Tsiper M, Almog N, Fowler N, Melnick AM, Leonard JP, Inghirami G, Cerchietti L. Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures. Cancer Discov.2021 Jun;11(6):1468-1489. doi: 10.1158/2159-8290.CD-20-0839. Epub 2021 Feb 4. PMID: 33541860; PMCID: PMC8178179. ¹⁷ Bunse M, Pfeilschifter J, Bluhm J, Zschummel M, Joedicke JJ, Wirges A, Stark H, Kretschmer V, Chmielewski M, Uckert W, Abken H, Westermann J, Rehm A, Höpken UE. CXCR5 CAR- T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells. Nat Commun.2021 Jan 11;12(1):240. doi: 10.1038/s41467-020-20488-3. PMID: 33431832; PMCID: PMC7801647. ¹⁸ BMS-986458 Investigator Brochure, version 1.02023. Bristol-Myers Squibb Company; Document Control Number 930206195. ¹⁹ Davies, B., & Morris, T. Physiological parameters in laboratory animals and humans. Pharm Res, 1993; 10(7), 1093-1095. ²⁰ Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol.2014 Sep 20;32(27):3059-68. ²¹ National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Bcell Lymphomas; V.4.2023. National Comprehensive Cancer Network [Internet]. June 2, 2023 V.4. Available from: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. ²² Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982 Dec;5(6):649-55. ²³ Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels.9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994. ²⁴ Mosteller RD. Simplified Calculation of Body Surface Area. N Engl J Med.1987 Oct 22;317(17):1098. ²⁵ DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Int Med 191617:863-71. ²⁶ Cairo MS, Coiffier B, Rieter A, Younes A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Brit J Haematol.2010; 149:578-586. ²⁷ Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Brit J Haematol.2004; 127:3-11. ²⁸ https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and- drug- interactions-table-substrates-inhibitors-and-inducers. ²⁹ Itti E, Meignan M, Berriolo-Riedinger A, Biggi A, Cashen AF, Véra P, Tilly H, Siegel BA, Gallamini A, Casasnovas RO, Haioun C. An international confirmatory study of the prognostic value of early PET/CT in diffuse large B-cell lymphoma: comparison between Deauville criteria and ΔSUVmax. Eur J Nucl Med Mol Imaging.2013 Sep;40(9):1312-20. doi: 10.1007/s00259-013-2435-6. Epub 2013 May 7. PMID: 23649463. ³⁰ Meignan M, Barrington S, Itti E, Gallamini A, Haioun C, Polliack A. Report on the 4th International Workshop on Positron Emission Tomography in Lymphoma held in Menton, France, 3-5 October 2012. Leuk Lymphoma.2014 Jan;55(1):31-7. doi: 10.3109/10428194.2013.802784. Epub 2013 Jun 14. PMID: 23763460. ³¹ Grzegorz S Nowakowski, Dok Hyun Yoon, Anthea Peters, Patrizia Mondello, Erel Joffe, Isabelle Fleury, et. al. (2022) Improved Efficacy of Tafasitamab plus Lenalidomide versus Systemic Therapies for Relapsed/Refractory DLBCL: RE-MIND2, an Observational Retrospective Matched Cohort Study. Clin Cancer Res 28(18):4003-4017. ³² Nancy L. Bartlett, Sarit Assouline, Pratyush Giri, et. al. Mosunetuzumab monotherapy is active and tolerable in patients with relapsed/refractory diffuse large B-cell lymphoma Clinical Trials & Observations. American Society of Hematology (ASH) Annual Meeting 2022. ³³ Liu S. and Yuan, Y. (2015). Bayesian optimal interval designs for phase I clinical trials. Journal of the Royal Statistical Society: Series C, 64, 507-523. ³⁴ Yuan Y., Hess K.R., Hilsenbeck S.G. and Gilbert M.R. (2016) Bayesian optimal interval design: a simple and well-performing design for phase I oncology trials, Clinical Cancer Research, 22(17), 4291-4301. ³⁵ Lin R, Zhou Y, Yan F, et al. BOIN12: Bayesian Optimal Interval Phase I/II Trial Design for Utility-Based Dose Finding in Immunotherapy and Targeted Therapies. JCO Precision Oncology 2020; 4; 1393-1402. ³⁶ Zhou Y, Lin R, Lee J, et al. TITE-BOIN12: A Bayesian Phase I/II Trial Design to Find the Optimal Biological Dose with Late-onset Toxicity and Efficacy. Stat. Med.2022; 41; 1918- 1931. [001221] Appendix B4-1: Abbreviations [001222] Appendix B4-3: Adverse Events and Serious Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting [001223] Adverse Events [001224] Definition of SAE. If an event is not an AE per the definition above, then it cannot be an SAE, even if serious conditions are met. [001225] Serious Adverse Events

[001226] Pregnancy and DILI must follow the same transmission timing and process to the Sponsor as those used for SAEs. (See Section 9.2.5: Pregnancy of the protocol for reporting pregnancies.) [001227] Evaluating AEs and SAEs

e e o o a , we s ae as sevee.

[001228] Reporting of SAEs to Sponsor or Designee • SAEs, whether related or not related to study intervention, and pregnancies must be reported to the Sponsor (or the designee) promptly and not to exceed 24 hours of awareness of the event. • SAEs must be recorded on the SAE Report Form. • The required method for SAE data reporting is through the electronic Case Report Form (eCRF). o The paper SAE Report Form is intended only as a back-up option when the electronic data capture system is unavailable/not functioning for transmission of the eCRF to the Sponsor (or the designee). ▪ In this case, the paper form is transmitted via email or confirmed fax transmission. ▪ When paper forms are used, the original paper forms are to remain on site. • Pregnancies must be recorded on paper Pregnancy Surveillance Forms and transmitted via email or confirmed fax transmission. [001229] Appendix B4-8: Flow and Operating Characteristics of the BOIN Design in Stage 1 Under Part A1 and Part A2 ^{. . . . .} _.

. . . . . . [001230] For the purpose of overdose control, doses j and higher levels will be eliminated from further examination if Pr (pj > 0.30 | data) >0.95 and at least 3 evaluable participants have been treated at dose level j, where pj is the true DLT rate of dose level j, j = 1,…, 5. This posterior probability is evaluated based on the beta-binomial model yj I pj ~ binomial (pj) with ρj ~ uniform (0,1), where yj is the number of participants experienced DLT at dose level j . When the lowest dose is eliminated, stop the trial for safety. The probability cutoff 0.95 is chosen to be consistent with the common practice that when the target DLT rate ≤ 1/3, a dose with 2/3 participants experienced DLT is eliminated. Simulation studies were conducted with 5000 simulated trials, cohort size of 3 and up to 10 cohorts. The target toxicity is set as 0.3 and stop the trial if number of patients assigned to each dose reaches 9. The Operating Characteristics of this Dose Escalation/de- escalation rule is presented in the table above. [001231] Appendix B4-9: Flow and Operating Characteristics of the TITE-BOIN12 Design in Stage 2 Under Part A1 [001232] As the stage 2 design in Part A1, this design will start from the most selected dose in stage 1. _. . . . . . .

. . , . . . [001233] The planned TITE-BOIN12 design will utilize Bayesian imputation to augment missing or unobserved missing efficacy data (if missing less than 50%). Bayesian imputation is one of the most rigorous statistical approaches to deal with late-onset efficacy data. Thus, Bayesian data augmentation will be performed for missing efficacy data based on its posterior distribution as follows. Assuming that the joint outcome Y follows a Dirichlet-multinomial model, when YT is observed and YE is missing, we draw missing values of YE from its conditional posterior. Prespecified prior specification will be used for (YT, YE) = (01, 00, 11, 10), (a01= 4/8, a00= 1/8, a11= 2/8, a10= 1/8), which will favor a higher dose a prior (like a traditional RP2D finding based on MTD) but whose impact will rapidly dimmish once >50% (n>=2) of efficacy data are available. After the imputation, BOIN12 algorithm can be directly applied to guide dose transition and identification of OBD. Simulation studies were conducted with 5000 simulated trials, cohort size of 3 and up to 10 cohorts. The target toxicity is set as 0.3 and stop the trial if number of patients assigned to each dose reaches 10. DLT assessment window is 1 month, efficacy assessment window is 2 months, accrual rate is 3 patients per month, we would suspend the accrual if 50% or more efficacy data is pending, and the safety and efficacy criteria and utility table is set as described in Section 10.4.2.1. The starting dose in the 2^nd stage in simulations is set with the most selected dose in stage 1, specifically, doses 2, 3, 5, 5, 1 for scenarios 1-5. The operating characteristics of the TITE-BOIN12 design are provided in the table above. [001234] Appendix B4-10: Continuous Toxicity Monitoring Plan In the Expansion Cohorts [001235] Continuous toxicity monitoring will be conducted for subjects in dose expansion and dose- escalation phase who were treated with the doses that are selected for the dose expansion cohorts. During the dose expansion (Parts B), a non-binding Bayesian safety monitoring method will be utilized to continuously monitor for excessive toxicities defined as the occurrence of AEs that would fulfill the DLT criteria defined in dose escalation. Weakly informative priors, e.g., beta (0.3, 0.7), will be constructed for estimating the stopping boundaries. After a minimum of 6 subjects have enrolled and completed at least one cycle of study treatment, the following non- binding Bayesian stopping criterion to pause the trial based on the posterior distribution of excessive toxicity will be calculated. Probability of (excessive toxicity > 0.3|data, a = 0.3, b = 0.7) >= 0.60, where a = 0.3, b = 0.7 are parameters of Beta prior distribution. This criterion implies that the study may pause when there is a greater than 0.60 chance that toxicity rate is over 0.3. The excessive toxicity rate of 0.3 is established to be consistent with the target toxicity rate specified in dose escalation. The operating characteristics of the proposed Bayesian safety monitoring plan (Parts B) at the specified interims are detailed in the tables below based on the Bayesian toxicity monitoring analysis tool at Trialdesign.org. max . . . . . . [001236] Although the present invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein in their entirety by reference.

Claims

CLAIMS 1. A method of treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of an anti-CD20 antibody and a compound of Formula (IA): ( ) or a pharmaceutically acceptable salt thereof, wherein: X¹ and X² are each independently N or CH, provided that at least one of X¹ and X² is N; R^1a and R^1b are each independently H, halo, or C1-C6 alkyl; R^2a and R^2b are each independently H, C₁-C₆ alkyl, -O(C₁-C₆ alkyl), -OH, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl-OH, or R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₅ cycloalkyl, or R^2a and R^2b are taken together to form oxo; or R^1a and R^2a are taken together to form a bridging C2-C3 alkylene; R^3a and R^3b are each independently H, halo, or C1-C6 alkyl; R^4a and R^4b are each independently H, halo, or C₁-C₆ alkyl, or R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl; R^5a and R^5b are each independently H, halo, or C₁-C₆ alkyl; w is 0 or 1; R⁶ is H or C1-C6 alkyl; R⁷ is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R⁸ is Cl or -CN; R⁹ is F; X³ is N or CH; z is 0 or 1; R^10a and R^10b are each independently H or halo; R¹¹ is H, C₁-C₆ alkyl, -(C₁-C₆ alkylene)-(5- to 6-membered heterocyclyl), -(C₁-C₆ alkylene)- O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R¹² is H, halo, or C₁-C₆ alkyl; R¹³ is H or halo; R¹⁴ is H or C1-C6 alkyl; X⁴ is N or CR¹⁵; R¹⁵ is H or C1-C6 alkyl; X⁵ and X⁶ are each independently N or CH; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

2. A method of treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA): ( ) or a pharmaceutically acceptable salt thereof, wherein: X¹ and X² are each independently N or CH, provided that at least one of X¹ and X² is N; R^1a and R^1b are each independently H, halo, or C₁-C₆ alkyl; R^2a and R^2b are each independently H, C₁-C₆ alkyl, -O(C₁-C₆ alkyl), -OH, halo, C₁-C₆ haloalkyl, or C1-C6 alkyl-OH, or R^2a and R^2b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₅ cycloalkyl, or R^2a and R^2b are taken together to form oxo; or R^1a and R^2a are taken together to form a bridging C2-C3 alkylene; R^3a and R^3b are each independently H, halo, or C₁-C₆ alkyl; R^4a and R^4b are each independently H, halo, or C1-C6 alkyl, or R^4a and R^4b are taken together with the carbon atom to which they are attached to form a spiro C₃-C₅ cycloalkyl; R^5a and R^5b are each independently H, halo, or C1-C6 alkyl; w is 0 or 1; R⁶ is H or C₁-C₆ alkyl; R⁷ is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R⁸ is Cl or -CN; R⁹ is F; X³ is N or CH; z is 0 or 1; R^10a and R^10b are each independently H or halo; R¹¹ is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)- O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R¹² is H, halo, or C1-C6 alkyl; R¹³ is H or halo; R¹⁴ is H or C₁-C₆ alkyl; X⁴ is N or CR¹⁵; R¹⁵ is H or C1-C6 alkyl; X⁵ and X⁶ are each independently N or CH; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium, wherein the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is administered: (i) daily on each day of a 28-day cycle; or (ii) on days 1-14 of a 28-day cycle and is not administered on days 15-28 of the 28-day cycle: or (iii) on days 1-21 of a 28-day cycle and is not administered on days 22-28 of the 28-day cycle; or wherein the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is administered to the subject once daily or twice daily at a dose of about 20 mg/day, about 40 mg/day, about 80 mg/day, about 160 mg/day, about 260 mg/day, about 400 mg/day, or about 640 mg/day.

3. The method of claim 1 or 2, wherein the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is administered to the subject once daily or twice daily at a dose of about 20 mg/day, about 40 mg/day, about 80 mg/day, about 160 mg/day, about 260 mg/day, about 400 mg/day, or about 640 mg/day.

4. The method of any one of claims 1-3, wherein the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is administered: (i) daily on each day of a 28-day cycle; or (ii) on days 1-14 of a 28-day cycle and is not administered on days 15-28 of the 28-day cycle: or (iii) on days 1-21 of a 28-day cycle and is not administered on days 22-28 of the 28- day cycle.

5. The method of any one of claims 2-4, further comprising administering to the subject an anti-CD20 antibody.

6. The method of claim 1 or 5, wherein the anti-CD20 antibody is rituximab.

7. The method of claim 6, wherein rituximab is administered intravenously.

8. The method of claim 6 or 7, wherein about 375 mg/m² rituximab is administered once every 28 days.

9. The method of any one of claims 6-8, wherein rituximab is administered on day 1 of a 28-day treatment cycle and the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is administered: (i) daily on each day of the 28-day treatment cycle; or (ii) on days 1-14 of the 28-day treatment cycle and is not administered on days 15-28 of the 28-day treatment cycle: or (iii) on days 1-21 of the 28-day treatment cycle and is not administered on days 22-28 of the 28-day treatment cycle.

10. The method of any one of claims 1-9, wherein the method is a method of treating a cancer.

11. The method of claim 10, wherein the cancer is a lymphoma.

12. The method of claim 11, wherein the lymphoma is a B cell lymphoma.

13. The method of claim 11 or 12, wherein the lymphoma is a non-Hodgkin lymphoma.

14. The method of any one of claims 11-13, wherein the lymphoma is diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, or lymphoplasmacytic lymphoma.

15. The method of claim 14, wherein the lymphoma is diffuse large B cell lymphoma or follicular lymphoma.

16. The method of any one of claims 10-15, wherein the cancer is relapsed or refractory.

17. The method of any one of claims 1-16, wherein the compound is of the following formula: ( ), or an isomer thereof, or a pharmaceutically acceptable salt of the foregoing.

18. The method of claim 17, wherein the compound is of the following formula: ( ), or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound of the following formula: (70), or an isomer thereof, or a pharmaceutically acceptable salt of the foregoing, and two or more of: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate.

20. A unit dosage formulation comprising a pharmaceutical composition of claim 19, wherein the compound (70), or an isomer thereof, or a pharmaceutically acceptable salt of the foregoing, is present in the unit dosage form in an amount of from about 10 mg to about 100 mg.