BCL6 modulators used in methods for treating cancer or autoimmune diseases

Abstract

This document provides compounds and compositions thereof for regulating BCL6. In some embodiments, the compounds and compositions are provided for treating cancer or autoimmune diseases. In some embodiments, the compounds have the formula (IA): (IA).

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 538,402, filed September 14, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure generally relates to compounds, compositions, and methods of preparation, as well as the use of said compounds and compositions for the treatment of cancer or autoimmune diseases. Background Technology

[0003] BCL6 (B-cell lymphoma 6) is a member of the BTB / POZ-zinc finger family, containing an N-terminal BTB / POZ domain and a zinc finger at the C-terminus. As a transcription factor for follicular helper T (Tfh) cells, BCL6 is essential for the formation of germinal centers (GCs) in naive B cells and is therefore necessary for antibody affinity maturation. BCL6 was initially discovered as an oncogene in diffuse large B-cell lymphoma (DLBCL), and its role is associated with many types of disease, including B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer (NSCLC) (Cardenas et al., ClinCancer Res 2017, 23, 885-893). The N-terminal BTB / POZ domain binds to and recruits co-repressor molecules (such as SMRT, NCOR1, and BCOR) to form class I and class II histone deacetylase complexes, while the C-terminal zinc finger binds 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 the RNA expression of its targets, including several key tumor suppressor factors. Overexpression of BCL6 (common in malignancies such as non-Hodgkin's lymphoma (NHL)) leads to ectopic inhibition of cell cycle and DNA repair checkpoint proteins, resulting in uncontrolled cell proliferation and tumorigenesis.

[0004] GC reactions are known to induce increased production of pathogenic autoantibodies leading to several diseases, suggesting the potential therapeutic applicability of methods that inhibit or degrade BCL6. Structural characterization of the cocrystal structure of the BCL6 BTB / POZ domain and co-repressor indicates that binding occurs at the lateral groove formed by the interface between the 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 binding to this site have been investigated with the aim of utilizing the binding affinity to the lateral groove to make BCL6 a druggable target.

[0005] Protein degradation is a highly regulated and crucial process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins are achieved through the ubiquitin-proteasome pathway (UPP). UPP is central to regulating almost all cellular processes. Protein ubiquitination is accomplished by E3 ubiquitin ligases, which bind to proteins and add ubiquitin molecules to them, thereby labeling the proteins for proteasome degradation.

[0006] The use of UPPs for therapeutic purposes has attracted considerable interest (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising therapy utilizes proteolytically targeted chimeras (commonly known as PROTACs) to remove unwanted proteins through protein degradation (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACs are ligand-directed degradative agents that bind E3 ligases to the target protein to be degraded. These divalent molecules typically consist of E3 ligase ligands that are linked to a small molecule of the target protein via a linker portion. PROTACs position the E3 ligase at an appropriate distance and orientation from the target protein, allowing the latter to ubiquitinate. The ubiquitinated target protein is then recognized by the proteasome, where it is degraded.

[0007] Therefore, in one respect, this article provides compounds that target the degradation of BCL6. Summary of the Invention

[0008] In some embodiments, compounds and compositions thereof for regulating BCL6 are described herein. In various embodiments, the compounds and compositions thereof can be used to treat cancer.

[0009] The embodiments of the present invention can be more fully understood by referring to the specific implementation methods and examples, which are intended to illustrate non-limiting implementation methods. Attached Figure Description

[0010] Figure 1 A schematic diagram illustrating the mechanism of BMS-986458 as BCL6-LDD. Compound-induced proximity to the CRBN E3 ligase promotes BCL6 ubiquitination, leading to degradation by the 26S proteasome. In DLBCL, loss of BCL6 results in cell cycle arrest, loss of DNA damage repair, and ultimately cell death via apoptosis.

[0011] Figure 2. BCL6 protein levels evaluated by MSD-ECL at 2 h and 4 h after treatment with BMS-986458 in (A) OCI-LY-1 and (B) WSU-DLCL-2, respectively. Relative BCL6 protein levels (C) and 5-day proliferation response (D) of the two diastereomers BMT-648592 (solid circles) and BMT-648599 (solid rhombuses) relative to BMS-986458 (1:1 mixture) (solid squares) were independently assessed in OCI-LY-1. Complete degradation of BCL6 was achieved in OCI-LY-1 cells within 2 h (F) after treatment with 10 nM BMS-986458, and greater than 90% BCL6 degradation was maintained for 5 days when administered at 10 nM (G), as demonstrated by Western blotting. No 5-day antiproliferative response (H) to BMS-986458 observed in the OCI-LY-1 CRBN- / - parental control was detected (H). Concentrations are listed in µM. Abbreviations: DC50, concentration at half maximum degradation; DMSO, dimethyl sulfoxide; POC, percentage of DMSO control.

[0012] Figure 3. Mass spectrometric proteomics analysis of OCI-LY-1 cells treated with BMS-986458. The volcano plot shows the high substrate specificity of compound-induced degradation at 4 h of treatment (A). BCL6 degradation was maintained at 24 h, however, the levels of downstream functional effectors were also affected (B). Historical novel substrates associated with CRBN-based degradation mechanisms (IKZF1, IKZF2, IKZF3, ZFP91, CSNK1A1, GSPT1) are highlighted in blue. Statistically robust thresholds were established, with FDR p-values ​​< 0.05 highlighted in yellow and red squares. A cutoff value for meaningful biological impact was established at a log fold change of + / - 1, indicated by a vertical red dashed line. Concentrations are listed in µM. Abbreviation: FDR, False Discovery Rate.

[0013] Figure 4 Acute and delayed antiproliferative responses following BMS-986458 treatment. AUC values ​​(μM • h) describe the antiproliferative response to BMS-986458 after 5 days (diagonal fill) and 10 days (solid fill) treatment within the equivalent dose range (0.015–100 nM). 10-day DRC was modulated by the proliferation factor obtained after 5 days of treatment on a DMSO-only control. Activity was assessed using a CTG chemiluminescent cell viability assay. GCB COO is indicated by (*).

[0014] Figure 5 Apoptotic and antiproliferative responses to BMS-986458 in acute and delayed-response cell lines. Viability (triangular data points, solid regression; left axis) and apoptosis (circular data points, dashed regression; right axis) after 5 days of exposure to doses up to 40 nM of BMS-896458 in six DLBCL cell line models representing both acute and delayed-response categories. Apoptotic activity was assessed using flow cytometry. Abbreviations: PoC, percentage of control; FC, flow cytometry; AUC, area under the concentration-time curve.

[0015] Figure 6. Correlation between BMS-986458 antiproliferative response and BCL6 expression level. Ranking of 10-day AUC values ​​of responses to BMS-986458 from DLBCL cell lines (6A). Delayed-onset susceptibility and resistance models were defined using a 10-day AUC < 7 μM • h threshold, as indicated by the black solid line. Ranking of BMS-986458 susceptibility as a function of baseline BCL6 protein expression level (6B).

[0016] Figure 7. Antiproliferative and apoptotic responses of doxorubicin-resistant DLBCL models to BMS-986458. Viability and apoptosis curves (A) after 5 days of exposure to serially diluted doxorubicin or BMS-986458 in three acquired doxorubicin-resistant (dashed lines) and corresponding matched parental DLBCL cell lines (solid lines). Western blot analysis of the response of the acquired doxorubicin-resistant DLBCL models and their corresponding matched parental lines to a single 10 nM dose of BMS-986458 over a 72-h treatment period (B). Abbreviation: DoxR, doxorubicin resistance.

[0017] Figure 8 Plasma / tumor exposure and percentage of BCL6 degradation in OCI-LY-1 xenografts following administration of 30 mg / kg BMS-986458 (bID x 5 or bID x 3). (The text also mentions approximately 500 mm...)3 Female CB.17-SCID mice with OCI-LY-1 tumors were administered BMS-986458 twice daily at 30 mg / kg for five consecutive days (BID×5, AP9506) or three consecutive days (BID×3, AP9721) (n = 4 mice / time point). Plasma and tumor samples were harvested at 6, 10, and 14 h after the last dose to determine BMS-986458 concentrations. Tumors were treated to detect BCL6 levels using Western blotting (image above). Plasma (blue line) and tumor (red line) concentrations of BMS-986458 (left axis) are plotted in the graph below. The green bars represent the percentage of BCL6 degradation in tumors treated with BMS-986458 compared to the mediator. The percentage of BCL6 degradation was calculated relative to the mediator control (0% BCL6 degradation). Statistical analysis was performed on all treatment groups using one-way ANOVA and Dunnett's multiple comparisons test, and the data were compared with the mediator control group. Results are presented as means, with error bars representing the standard error of the means. Abbreviations: BCL6, B-cell lymphoma 6; h, hours; BIDx5, twice daily for 5 consecutive days; BIDx3, twice daily for 3 consecutive days; ****p < 0.0001.

[0018] Figure 9 The antitumor activity of BMS-986458 (study AP9776) was observed in the OCI-LY-1 xenograft model after twice-daily (BID) administration for 21 consecutive days. Female CB.17-SCID mice were administered the drug in 5 x 10⁻⁶ cells of 1:1 matrix gel. 6 One OCI-LY-1 tumor cell was inoculated into the right abdomen. At the start of treatment, mice were randomly assigned to treatment groups (n = 9 mice / group). Treatment with the test product began on day 19, at which time the average tumor volume was approximately 196 mm. 3 Tumor volume reduction was calculated as the mean difference in tumor volume between mice treated with BMS-986458 and mice treated with the vector. Day 37 was the final tumor measurement day. Results are presented as mean values, with error bars representing SEM. Statistical analysis was performed on all treatment groups using two-way ANOVA and Bonferroni's multiple comparisons test, and the data presented were compared with the vector control group. Abbreviations: BID, twice daily administration; vector, 10% Captisol in 25 mM citrate buffer, pH 3; ****p < 0.0001.

[0019] Figure 10. BCL6 degradation in OCI-LY-1 tumors treated with BMS-986458 twice daily for 21 consecutive days, collected at 6 h (A), 10 h (B), and 14 h (C) after the final dose. Degradation began on day 19, at which time the mean tumor volume was approximately 196 mm. 3 Three days after final tumor measurement, on day 40, each BMS-986458 treatment group (n=9 mice) was divided into three cohorts (3 mice per cohort) for PD and PK sampling. Tumors were collected at 6, 10, and 14 h after the final dose and were split in half for PD and PK analysis. For PD analysis, tumors were processed into lysates, and BCL6 protein degradation was analyzed by Western blotting (top, blot image). Plasma and tumor BMS-986458 concentrations and BCL6 degradation are plotted in the bottom (curve graph). Results are presented as mean integral intensity values, where error bars represent the standard error of the mean. Statistical analysis was performed on all treatment groups using one-way ANOVA with Dunnett's multiple comparison test, and the data presented were compared with the mediator control group. Abbreviation: BID, administered twice daily; mediator: 10% Captisol in 25 mM citrate buffer, pH 3; ****p < 0.0001, administered to female CB.17-SCID mice in 5 x 10 μL of 1:1 matrix gel. 6 One OCI-LY-1 tumor cell was inoculated into the right abdomen.

[0020] Figure 11. BMS-986458 treatment-induced loss of follicular helper T cell identity and perturbation of cytokine secretion. Phenotypic responses to BMS-986458 were evaluated in iTfh isolated from PBMCs from three independent healthy donors. A shows the treatment timeline followed by iTfh differentiation induced by naive CD4+CD45RA+ T cells and the time settings of flow analysis using the illustrated gating strategy (B). Analysis of iTfh on day 4 shows the induction of BCL6 expression, expression of the Tfh surface marker CXCR5 / PD1, and secretion of the canonical Tfh cytokine IL-21 (C). BMS-986458 dose- and time-dependent regulation of BCL6 protein and Tfh phenotype by loss of CXCR5+PD1+, as determined by flow cytometry (DF). IL-10 and IL-121 secretion were assessed using ECL-MSD on days 4 and 8 post-BMS-986458 treatment (Figure G). Nonlinear regression analysis was performed using GraphPad Prism v9.4.0. Two-way ANOVA was used to evaluate the significance of donor variations in all measurements, with significance = p > 0.05 (Figure H). Abbreviations: ActA, activin A; iTfh, follicular helper T cells; D4, day 4; DMSO, dimethyl sulfoxide; ns, not significant.

[0021] Figure 12 BMS-986458 treatment did not affect the viability or maturation kinetics of ex vivo neutrophils. CD34+ cells derived from HD bone marrow were exposed to a specified concentration of BMS-986458 for 14 consecutive days, with treatment and cell culture medium refreshed every two days. Neutrophil maturation stages were assessed over time by flow cytometry. Data represent the mean percentage of cells in each bone marrow population from three donors. Abbreviation: DMSO, dimethyl sulfoxide.

[0022] Figure 13A A flowchart of the BOIN design in the first stage of section A1 of Example B4.

[0023] Figure 13B A flowchart of the TITE-BOIN12 design in Phase 2 of Part A1 of Example B4. Detailed Implementation definition

[0024] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be interpreted as specifying the presence of the stated features or components mentioned, but do not exclude the presence or addition of one or more features, components, or groups thereof. Furthermore, the terms “comprising” and “including” are intended to include examples covered by the term “consisting of”. Therefore, the term “consisting of” may be used in place of the terms “comprising” and “including” to provide more specific embodiments of the invention.

[0025] The term "composed of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the stated features or components that constitute the subject matter. In another embodiment, the term "composed of" excludes any other features or components from the scope of any subsequent enumeration, except those features or components that are not necessary for the technical effect to be achieved.

[0026] As used herein, the term "or" should be interpreted as 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." Exceptions to this definition only arise when a combination of elements, functions, steps, or actions is inherently mutually exclusive in some way.

[0027] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer within the listed range and (where appropriate) its fraction (such as one-tenth and one-hundredth of an integer). Furthermore, unless otherwise indicated, any numerical ranges listed herein relating to any physical characteristic (such as polymer subunits, size, or thickness) shall be understood to include any integer within the listed 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.

[0028] "Amino" refers to the -NH2 group.

[0029] "Cyano" refers to the -CN group.

[0030] "Nitro" refers to the -NO2 group.

[0031] "O-" refers to the -O- group.

[0032] "Oxide group" refers to the =O group.

[0033] "Thiodiol" refers to the =S group.

[0034] "Imine" refers to the =NH group.

[0035] "Oxime group" refers to the =N-OH group.

[0036] "Hydrazine" refers to the =N-NH2 group.

[0037] "alkyl" refers to a straight-chain or branched hydrocarbon chain group that consists only of carbon and hydrogen atoms, contains no unsaturated groups, and has one to fifteen carbon atoms (e.g., C1-C1). 15 Alkyl group). In some embodiments, the alkyl group comprises one to thirteen carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., C5-C6 alkyl). 15 Alkyl group. In other embodiments, the alkyl group comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group 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 (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halogroup, cyano, nitro, oxo, thioxyl, imino, oxime, trimethylsilyl, -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)t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0038] "alkyl-OH" refers to unbranched or branched alkyl groups 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 group substituted with one or more -OH groups. Alkyl-OH may contain multiple hydroxyl groups attached to the same or more carbon atoms.

[0039] "Alkoxy" refers to a group of the formula -O-alkyl that is bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above.

[0040] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having two to twelve carbon atoms. In some embodiments, the alkenyl group contains two to eight carbon atoms. In other embodiments, the alkenyl group contains two to four carbon atoms. The alkenyl group is attached to the remainder of the molecule by a single bond, for example, ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, pent-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted with one or more of the following substituents: halogroup, cyano, nitro, oxo, thionyl, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)Ra -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) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0041] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. In some embodiments, the alkynyl group contains two to eight carbon atoms. In other embodiments, the alkynyl group has two to four carbon atoms. The alkynyl group is attached to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted with one or more of the following substituents: haloyl, cyano, nitro, oxo, thionyl, imino, oxime, trimethylsilyl, -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) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0042] "alkylene" or "alkylene chain" refers to a straight-chain or straight-chain divalent hydrocarbon chain that connects the remainder of a molecule to a group, consisting only of carbon and hydrogen, without unsaturation, and having one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the remainder of the molecule and to the group via single bonds. The attachment points of the alkylene chain to the remainder of the molecule and to the group can be via one carbon atom in the alkylene chain or via any two carbons in the chain. In some embodiments, the alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in the specification, the alkylene chain is optionally substituted with one or more of the following substituents: halogroup, cyanogroup, nitrogroup, oxogroup, thionyl group, imino group, oxime group, trimethylsilyl group, -OR group. 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) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aIndependently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0043] "Aryl" refers to a group derived from aromatic monocyclic or polycyclic hydrocarbon ring systems by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon from five to eighteen carbon atoms, wherein at least one ring in the ring system is completely unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, naphthalene, and naphthalene. Unless otherwise specified in the specification, the term "aryl" or the prefix "aromatic" (such as in "arylalkyl") is intended to include aryl groups optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, haloyl, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryl-alkenyl, optionally substituted arylyynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, 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 -OR c -C(O)N(R a )2、-Rb -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise indicated.

[0044] "Aryl group" refers to the formula -R c aryl groups, wherein R c It is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for the aryl group.

[0045] "Aryl" refers to the formula -R d -aryl groups, where R d It is an alkenyl chain as defined above. The aryl portion of the aryl group is optionally substituted as described above for the aryl group. The alkenyl chain portion of the aryl group is optionally substituted as defined above for the alkenyl group.

[0046] "Arotyne group" refers to the formula -R e -aryl groups, where R e It is an alkynyl chain as defined above. The aryl portion of the arylyl group is optionally substituted as described above for the aryl group. The alkynyl chain portion of the arylyl group is optionally substituted as defined above for the alkynyl chain.

[0047] A "carbocyclic group" is a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, comprising a fused or bridging ring system having three to fifteen carbon atoms. In some embodiments, the carbocyclic group contains three to ten carbon atoms. In other embodiments, the carbocyclic group contains five to seven carbon atoms. The carbocyclic group is attached to the remainder of the molecule by a single bond. The carbocyclic group can be saturated (i.e., containing only a single C-C bond) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclic groups are also called "carbocyclic groups". Examples of monocyclic carbocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclic groups are also called "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term "carbocyclic" is intended to include carbocyclic groups optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, haloyl, fluoroalkyl, oxoyl, thionyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted areneyl, optionally substituted arynyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, 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) t R a (where t is 1 or 2), -S(O)t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, Rb is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight-chain or branched alkylene or alkenyl chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise indicated.

[0048] "Carbocycloalkyl" refers to the formula -R c - A carbocyclic group, wherein R c It is an alkylene chain as defined above. The alkylene chain and carbocyclic group may optionally be substituted as defined above.

[0049] "Carbonyl" refers to the formula -C(O)R 10 R 20 The group, wherein R 10 and R 20 Independently selected from -OH, halogen, cyano, nitro, oxo, thionyl, imino, oxime, trimethylsilyl, -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) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0050] "Halogen" or "halogen" refers to a substituent of bromine, chlorine, fluorine, or iodine.

[0051] "Haloalkyl" refers to an alkyl group as defined above, substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. In some embodiments, the haloalkyl group has one to six carbon atoms and is substituted with one or more halogen groups (C1-C6 haloalkyl), or the haloalkyl group has one to five carbon atoms and is substituted with one or more halogen groups (C1-C5 haloalkyl), or the haloalkyl group has one to three carbon atoms and is substituted with one or more halogen groups (C1-C3 haloalkyl). The halogen groups may be all the same or different. Unless otherwise specifically stated, the haloalkyl group is optionally substituted.

[0052] "Fluoroalkyl" refers to an alkyl group as defined above, substituted with one or more fluorine groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of a fluoroalkyl group may optionally be substituted as defined above for alkyl groups.

[0053] A "heterocyclic group" refers to a stable 3- to 18-membered non-aromatic ring group comprising two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system comprising a fused or bridging ring system. The heteroatoms in the heterocyclic group may optionally be oxidized. One or more nitrogen atoms (if present) may optionally be quaternized. The heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via any atom of one or more rings. Examples of such heterocyclic groups include, but are not limited to, dioxacyclopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the term "heterocyclic" is intended to include heterocyclic groups as defined above, optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, haloyl, fluoroalkyl, oxoyl, thionyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted areneyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, 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 -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(Ra )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise indicated.

[0054] "N-heterocyclic group" or "N-attached heterocyclic group" refers to a heterocyclic group as defined above, containing at least one nitrogen atom and wherein the attachment point of the heterocyclic group to the remainder of the molecule is via a nitrogen atom in the heterocyclic group. The N-heterocyclic group may optionally be substituted as described above for heterocyclic groups. Examples of such N-heterocyclic groups include, but are not limited to, 1-morpholino, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolyl, imidazolinyl, and imidazolinyl.

[0055] A “C-heterocyclic group” or “C-attached heterocyclic group” refers to a heterocyclic group as defined above, containing at least one heteroatom and wherein the attachment point of the heterocyclic group to the remainder of the molecule is via a carbon atom in the heterocyclic group. The C-heterocyclic group may optionally be substituted as described above for heterocyclic groups. Examples of such C-heterocyclic groups include, but are not limited to, 2-morpholino, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, 2-, or 3-pyrrolidinyl, etc.

[0056] "Heterocyclic alkyl" refers to formula -R c - A heterocyclic group, wherein R c It is an alkylene chain as defined above. If the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkyl group is optionally substituted as defined above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkyl group is optionally substituted as defined above for the heterocyclic group.

[0057] "Heterocyclic alkoxy" refers to the formula -OR c Heterocyclic groups are groups bonded via oxygen atoms, where R c It is an alkylene chain as defined above. If the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkoxy group is optionally substituted as defined above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkoxy group is optionally substituted as defined above for the heterocyclic group.

[0058] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group comprising two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Heteroaryls include fused or bridging ring systems. One or more heteroatoms in the heteroaryl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl can be attached to the remainder of the molecule via any atom of one or more rings.Examples of heteroaryl groups include, but are not limited to, azirrolyl, acridine, benzimidazolyl, benzoindolyl, 1,3-benzo[1,4]dioxazinyl, benzofuranyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxaneyl, benzonaphthofuranyl, benzo[1,4]oxazolyl, benzo[2,4]dioxaneyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl (benzothienyl (benzothiophenyl)), benzothien[3,2-d]pyrimidinyl, benzotriazolyl, and benzene. [4,6]imidazo[1,2-a]pyridyl, carbazolyl, cenolinyl, cyclopentadieno[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentadieno[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cenolinyl, 6,7-dihydro-5H-benzo[6,7] Cycloheptatrien[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, furano[3,2-c]pyridyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclo Octatetraeno[d]pyridyl, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indazinyl, isoxazolyl, 5,8-bridged methylene-5,6,7,8-tetrahydroquinazolinyl, naphridyl, 1,6-naphridinoneyl, oxadiazolyl, 2-oxozazolyl, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl The group includes pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, 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-cycloheptano[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyridino[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).Unless otherwise specified in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, alkynyl, haloyl, fluoroalkyl, haloalkenyl, haloalkynyl, oxoyl, thionyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted areneyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, 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 -OR 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) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R aIndependently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise indicated.

[0059] "N-Heteroaryl" refers to a heteroaryl group as defined above, which contains at least one nitrogen atom, and wherein the attachment site of the heteroaryl group to the remaining portion of the molecule is via the nitrogen atom in the heteroaryl group. The N-heteroaryl group may optionally be substituted as described above for heteroaryl groups.

[0060] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the attachment point of the heteroaryl group to the remainder of the molecule is via a carbon atom in the heteroaryl group. The C-heteroaryl group may optionally be substituted as described above for heterocyclic groups.

[0061] "Heteroarylalkyl" refers to the formula -R c - A heteroaryl group, wherein R c It is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroaryl alkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroaryl alkyl group is optionally substituted as defined above for the heteroaryl group.

[0062] "Heteroarylalkoxy" refers to the formula -OR c A heteroaryl group bonded via an oxygen atom, wherein R c It is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0063] The embodiments of this disclosure are intended to cover pharmaceutically acceptable salts, tautomers, isotopes and stereoisomers of the compounds provided herein, such as those of formula (I).

[0064] As used herein, the term "one or more pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable, non-toxic acids or bases (including inorganic acids and bases as well as organic acids and bases). Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made of lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, aminoanilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furanoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Therefore, specific examples of salts include hydrochloride, formate, and methanesulfonate. Others are well known in the field; see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton, PA (1995).

[0065] As used herein and unless otherwise stated, the terms "stereoisomer" or "stereoisomer-pure" mean a stereoisomer of a particular compound that substantially does not contain other stereoisomers of that compound. For example, a stereoisomer-pure compound having one chiral center will substantially not contain the opposite enantiomers of the compound. A stereoisomer-pure compound having two chiral centers will substantially not contain other diastereomers of the compound. Typical stereoisomer-pure compounds comprise, by weight, more than about 80% of one stereoisomer of the compound and less than about 20% of other stereoisomers of the compound, more than about 90% of one stereoisomer of the compound and less than about 10% of other stereoisomers of the compound, more than about 95% of one stereoisomer of the compound and less than about 5% of other stereoisomers of the compound, or more than about 97% of one stereoisomer of the non-compound and less than about 3% of other stereoisomers of the compound. The compounds disclosed herein may have a chiral center and may exist as racemates, single enantiomers, or diastereomers, and mixtures thereof. All such isomeric forms are included in the embodiments disclosed herein, including mixtures thereof.

[0066] The embodiments disclosed herein cover the use of the pure stereoisomers of the disclosed compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL., Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); Wilen, SH., Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, Indiana, 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 & BusinessMedia, 2007); Subramanian, G. Chiral Separation Techniques: A PracticalApproach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0067] "Tautomers" refer to the equilibrium isomers of a compound. The concentration of these isomers will depend on the environment in which the compound is found and can vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomers, which are referred to as tautomers of each other: .

[0068] As will be readily understood by those skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of this disclosure.

[0069] Polymers obtained by defining substituents with an infinite number of additional substituents, or similar indeterminate structures (e.g., substituted aryl groups having substituted alkyl groups, wherein the substituted alkyl group itself is substituted by a substituted aryl group, the substituted aryl group is further substituted by a substituted heteroalkyl group, etc.), are not intended to be included herein. Similarly, the above definitions are not intended to include disallowed substitution patterns (e.g., methyl groups substituted with five fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art.

[0070] It should also be noted that the compounds disclosed herein may contain atomic isotopes in non-natural proportions at one or more atoms. For example, the compounds may contain radioactive isotopes (such as, for example, tritium). 3 H), Iodine-125 ( 125 I), sulfur-35 ( 35 S) or carbon-14 ( 14 C)) radioactive labeling, or can be done using deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15 ( 15N) isotope enrichment. As used herein, an "isotope" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from that of its natural isotopes. "Isotopically enriched" can also refer to a compound containing at least one such atom having an isotopic composition different from that of its natural isotopes. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents, such as cancer therapeutic agents, research reagents (e.g., binding assay reagents), and diagnostic reagents (e.g., in vivo imaging agents). All isotopic variations of the compounds described herein, whether or not radioactive, are intended to be covered within the scope of the embodiments provided herein. In some embodiments, isotopes of the compounds disclosed herein are provided, for example, isotopes enriched in deuterium, carbon-13, and / or nitrogen-15. As used in this article, "deuteration" means that at least one hydrogen (H) has been deuterated (by D or 2 H-indication) substitute compounds, i.e., compounds enriched in deuterium at at least one site.

[0071] This disclosure also includes “deuterated analogues” of the compounds described herein, wherein one to n hydrogen atoms attached to carbon atoms are replaced with deuterium, where n is the number of hydrogen atoms in the molecule. When multiple deuterium atoms are present in a compound, the deuterium atoms may be on the same part of the molecule (e.g., on a single alkyl group or a single ring) or on different parts of the molecule (e.g., on a separate alkyl group or a separate ring). Such compounds can exhibit increased metabolic resistance and are therefore used to increase the half-life of any compound when administered to mammals, particularly humans. 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 using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0072] It should be understood that, independent of stereoisomerism or isotopic composition, each compound disclosed herein may be provided in the form of any pharmaceutically acceptable salt discussed herein. Similarly, it should be understood that the isotopic composition may vary independently of the stereoisomerism of each compound mentioned herein. Furthermore, while the isotopic composition is limited to those elements present in the respective compounds or their salts disclosed herein, it may also vary independently of the choice of pharmaceutically acceptable salts of the respective compounds.

[0073] It should be noted that if there is a difference between the structure depicted and the name of the structure, the structure depicted will be given greater weight.

[0074] As used herein, “treatment” means the complete or partial relief of a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or the slowing or halting of the further progression or worsening of these symptoms; or the reduction or elimination of one or more causes of the disorder, disease, or condition itself. In one implementation, the disorder is cancer or its symptoms as described herein.

[0075] As used herein, “prevention” means a method that delays and / or eliminates all or part of the onset, recurrence, or spread of a barrier, disease, or condition; prevents a subject from acquiring the barrier, disease, or condition; or reduces the risk of a subject acquiring the barrier, disease, or condition. In one implementation, the barrier is cancer or a symptom of cancer as described herein.

[0076] The term “effective amount” in relation to the compounds disclosed herein means the amount that is sufficient to treat or prevent the disorder, disease or ailment or its symptoms disclosed herein.

[0077] As used herein, the terms “subject” or “patient” include animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment, mammals, and in another embodiment, humans. In one embodiment, a subject is a person who has a BCL6-mediated disease or symptoms thereof, or a person at risk of developing a BCL6-mediated disease or symptoms thereof.

[0078] While various features of the invention can be described in the context of a single embodiment, these features may also be provided individually 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. compound

[0079] In one respect, this paper provides a compound of formula (IA): (IA) Or its pharmaceutically acceptable salt, wherein: X 1 and X 2 Each is independently either N or CH, provided that X is the condition. 1 and X 2 At least one of them is N; R 1a and R 1b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 2a and R 2b Each can be independently H, C1-C6 alkyl, -O (C1-C6 alkyl), -OH, halogroup, C1-C6 haloalkyl, or C1-C6 alkyl-OH. Or R 2a and R 2b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups. Or R 2a and R 2b Together they form an oxygen group; Or R 1a and R 2a Together they form bridging C2-C3 alkylene groups; R 3a and R 3b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 4a and R 4b Each is independently an H, a halogroup, or a C1-C6 alkyl group. Or R 4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups; R 5a and R 5b Each is independently H, a halogroup, or a C1-C6 alkyl group; w is 0 or 1; R 6 It is an H or C1-C6 alkyl group; R 7 It is an H or C1-C6 alkyl group; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 It is Cl or -CN; R 9 It is F; X 3 It is N or CH; z is 0 or 1; R 10a and R 10b Each is independently either an H group or a halogenated group; R 11 It is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5 to 6-membered heterocyclic group), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH or -(C1-C6 alkylene)-NH(C1-C6 alkyl). The heterocyclic group contains 1-3 heteroatoms selected from N, O and S; R 12 It is H, a halogroup, or a C1-C6 alkyl group; R 13 It is an H or a halogroup; R 14 It is an H or C1-C6 alkyl group; X 4 Is it N or CR? 15 ; R 15 It is an H or C1-C6 alkyl group; X 5 and X 6 Each is independently N or CH; and Is it a single bond or a double bond? One or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0080] In another aspect, this paper provides a compound of formula (I): (I) Or its pharmaceutically acceptable salt, wherein: X 1 and X 2 Each is independently either N or CH, provided that X is the condition. 1 and X 2 At least one of them is N; R 1a and R 1b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 2a and R 2b Each can be independently H, C1-C6 alkyl, -OH, halogroup, or C1-C6 alkyl-OH. Or R 2a and R 2b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups. Or R 2a and R 2b Together they form an oxygen group; Or R 1a and R 2a Together they form bridging C2-C3 alkylene groups; R 3a and R 3b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 4a and R 4b Each is independently an H, a halogroup, or a C1-C6 alkyl group. Or R4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups; R 5a and R 5b Each is independently H, a halogroup, or a C1-C6 alkyl group; w is 0 or 1; R 6 It is an H or C1-C6 alkyl group; R 7 It is an H or C1-C6 alkyl group; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 It is Cl or -CN; R 9 It is F; X 3 It is N or CH; z is 0 or 1; R 10a and R 10b Each is independently either an H group or a halogenated group; R 11 It is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5 to 6-membered heterocyclic group), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH or -(C1-C6 alkylene)-NH(C1-C6 alkyl). The heterocyclic group contains 1-3 heteroatoms selected from N, O and S; R 12 It is H, a halogroup, or a C1-C6 alkyl group; R 13 It is an H or a halogroup; R 14 It is an H or C1-C6 alkyl group; X 4 Is it N or CR? 15 ; R 15 It is an H or C1-C6 alkyl group; X 5 and X 6 Each is independently N or CH; and Is it a single bond or a double bond? One or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0081] In some implementation schemes, X 1 It is CH and X 2 It is N. In some implementations, X 1It is N and X 2 It is CH. In some implementations, X 1 and X 2 Both are N.

[0082] In some implementation schemes, R 1a It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R 1a It is H, a halogroup, or a C1-C3 alkyl group. In some embodiments, R 1a It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 1a It is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0083] In some implementation schemes, R 1a It is H.

[0084] In some implementation schemes, R 1a It is a halogenated group. In some implementations, R 1a It is F, Cl, Br, or I. In some implementations, R 1a It is F.

[0085] In some implementation schemes, R 1a It is a C1-C6 alkyl group. In some embodiments, R 1a It is a C1-C3 alkyl group. In some embodiments, R 1a It is methyl, ethyl, or propyl. In some embodiments, R 1a It is a methyl group.

[0086] In some implementation schemes, R 1b It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R 1b It is H, a halogroup, or a C1-C3 alkyl group. In some embodiments, R 1b It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 1b It is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0087] In some implementation schemes, R 1b It is H.

[0088] In some implementation schemes, R 1b It is a halogenated group. In some implementations, R 1b It is F, Cl, Br, or I. In some implementations, R 1b It is F.

[0089] In some implementation schemes, R 1a and R 1bEach is independently H, a halogroup, or a C1-C3 alkyl group. In some embodiments, R 1a and R 1b Each is independently H, F, Cl, Br, I, methyl, ethyl, or propyl. In some embodiments, R 1a and R 1b Each is either H or -CH3.

[0090] In some implementation schemes, R 1b It is a C1-C6 alkyl group. In some embodiments, R 1b It is a C1-C3 alkyl group. In some embodiments, R 1b It is methyl, ethyl, or propyl. In some embodiments, R 1b It is a methyl group.

[0091] In some implementation schemes, R 2a It is H, C1-C6 alkyl, -O (C1-C6 alkyl), -OH, halogroup, C1-C6 haloalkyl, or C1-C6 alkyl-OH. In some embodiments, R 2a It 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 It is H, methyl, ethyl, propyl, -OCH3, -OH, F, Cl, Br, I, -CF3, -CHF2, -CCl3, -CH2OH, -(CH2CH2)OH or -(CH2CH2CH2)OH.

[0092] In some implementation schemes, R 2a It is H.

[0093] In some implementation schemes, R 2a It is a C1-C6 alkyl group. In some embodiments, R 2a It is a C1-C3 alkyl group. In some embodiments, R 2a It is methyl, ethyl, or propyl. In some embodiments, R 2a It is a methyl group.

[0094] In some implementation schemes, R 2a It is -O (C1-C6 alkyl). In some embodiments, R 2a It is -O (C1-C3 alkyl). In some embodiments, R 2a It is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some implementations, R 2a It is -OCH3.

[0095] In some implementation schemes, R 2a It is -OH.

[0096] In some implementation schemes, R 2a It is a halogenated group. In some implementations, R 2a It is F, Cl, Br, or I. In some implementations, R 2a It is F.

[0097] In some implementation schemes, R 2a It is a C1-C6 haloalkyl group. In some embodiments, R 2a It is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 2a It is a C1-C3 haloalkyl group. In some embodiments, R 2a It is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 2a It is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 2a It is -CF3.

[0098] In some implementation schemes, R 2a It is a C1-C6 alkyl-OH. In some embodiments, R 2a It is a C1-C3 alkyl-OH. In some embodiments, R 2a It is -CH2OH, -(CH2CH2)OH, or -(CH2CH2CH2)OH. In some embodiments, R 2a It is -CH2OH.

[0099] In some implementation schemes, R 2b It is H, C1-C6 alkyl, -OH, halogroup, or C1-C6 alkyl-OH. In some embodiments, R 2b It is H, C1-C3 alkyl, -OH, F, Cl, Br, I, or C1-C3 alkyl-OH. In some embodiments, R 2b It is H, methyl, ethyl, propyl, -OH, F, Cl, Br, I, -CH2OH, -(CH2CH2)OH or -(CH2CH2CH2)OH.

[0100] In some implementation schemes, R 2b It is H.

[0101] In some implementation schemes, R 2b It is a C1-C6 alkyl group. In some embodiments, R 2bIt is a C1-C3 alkyl group. In some embodiments, R 2b It is methyl, ethyl, or propyl. In some embodiments, R 2b It is a methyl group.

[0102] In some implementation schemes, R 2b It is -O (C1-C6 alkyl). In some embodiments, R 2b It is -O (C1-C3 alkyl). In some embodiments, R 2b It is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some implementations, R 2b It is -OCH3.

[0103] In some implementation schemes, R 2b It is -OH.

[0104] In some implementation schemes, R 2b It is a halogenated group. In some implementations, R 2b It is F, Cl, Br, or I. In some implementations, R 2b It is F.

[0105] In some implementation schemes, R 2b It is a C1-C6 haloalkyl group. In some embodiments, R 2b It is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 2b It is a C1-C3 haloalkyl group. In some embodiments, R 2b It is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 2b It is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 2b It is -CF3.

[0106] In some implementation schemes, R 2b It is a C1-C6 alkyl-OH. In some embodiments, R 2b It is a C1-C3 alkyl-OH. In some embodiments, R 2b It is -CH2OH, -(CH2CH2)OH, or -(CH2CH2CH2)OH. In some embodiments, R 2b It is -CH2OH.

[0107] In some implementation schemes, R 2a and R 2bTogether with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms to which they are attached, they form spiroC3-C4 cycloalkyl groups. In some embodiments, R 2a and R 2b Together with the carbon atoms to which they are attached, they form spirocyclic butyl groups.

[0108] In some implementation schemes, R 2a and R 2b Together they form an oxygen group.

[0109] In some implementation schemes, R 1a and R 1b Both are H, and R 2a and R 2b At least one of them is not H.

[0110] In some implementation schemes, R 1a and R 2a Together, they form a bridging C2-C3 alkylene group. In some embodiments, R 1a and R 2a Together they form a bridging ethylene group.

[0111] In some implementation schemes, R 3a It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R 3a It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 3a It is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0112] In some implementation schemes, R 3a It is H.

[0113] In some implementation schemes, R 3a It is a halogenated group. In some implementations, R 3a It is F, Cl, Br, or I. In some implementations, R 3a It is F.

[0114] In some implementation schemes, R 3a It is a C1-C6 alkyl group. In some embodiments, R 3a It is a C1-C3 alkyl group. In some embodiments, R 3a It is methyl, ethyl, or propyl. In some embodiments, R 3a It is a methyl group.

[0115] In some implementation schemes, R 3b It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R3b It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 3b It is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0116] In some implementation schemes, R 3b It is H.

[0117] In some implementation schemes, R 3b It is a halogenated group. In some implementations, R 3b It is F, Cl, Br, or I. In some implementations, R 3b It is F.

[0118] In some implementation schemes, R 3b It is a C1-C6 alkyl group. In some embodiments, R 3b It is a C1-C3 alkyl group. In some embodiments, R 3b It is methyl, ethyl, or propyl. In some embodiments, R 3b It is a methyl group.

[0119] In some implementation schemes, R 4a It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R 4a It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 4a It is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0120] In some implementation schemes, R 4a It is H.

[0121] In some implementation schemes, R 4a It is a halogenated group. In some implementations, R 4a It is F, Cl, Br, or I. In some implementations, R 4a It is F.

[0122] In some implementation schemes, R 4a It is a C1-C6 alkyl group. In some embodiments, R 4a It is a C1-C3 alkyl group. In some embodiments, R 4a It is methyl, ethyl, or propyl. In some embodiments, R 4a It is a methyl group.

[0123] In some implementation schemes, R 4b It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R 4b It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 4bIt is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0124] In some implementation schemes, R 4b It is H.

[0125] In some implementation schemes, R 4b It is a halogenated group. In some implementations, R 4b It is F, Cl, Br, or I. In some implementations, R 4b It is F.

[0126] In some implementation schemes, R 4b It is a C1-C6 alkyl group. In some embodiments, R 4b It is a C1-C3 alkyl group. In some embodiments, R 4b It is methyl, ethyl, or propyl. In some embodiments, R 4b It is a methyl group.

[0127] In some implementation schemes, R 4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups. In some embodiments, R 4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C4 cycloalkyl groups. In some embodiments, R 4a and R 4b Together with the carbon atoms to which they are attached, they form spirocyclic butyl groups.

[0128] In some implementation schemes, R 3a R 3b R 4a and R 4b Each is H.

[0129] In some implementation schemes, R 3a and R 3b At least one of them is not H, and R 4a and R 4b At least one of them is not H.

[0130] In some implementation schemes, R 5a It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R 5a It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 5a It is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0131] In some implementation schemes, R 5a It is H.

[0132] In some implementation schemes, R5b It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R 5b It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 5b It is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0133] In some implementation schemes, R 5b It is H.

[0134] In some implementation schemes, R 5a and R 5b Each is H.

[0135] In some implementation schemes, R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b At least one of them is not H.

[0136] In some implementation schemes, R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b One, two, or three of them are not H.

[0137] In some implementation schemes, R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b One or both of them are not H.

[0138] In some implementations, w is 0. In some implementations, w is 1.

[0139] In some implementation schemes, yes: .

[0140] In some implementations, x and y are both 0. In some implementations, x is 0 and y is 1. In some implementations, x is 1 and y is 0.

[0141] In some implementation schemes, R 6 It is an H or C1-C6 alkyl group. In some embodiments, R 6 It is an H or C1-C3 alkyl group. In some embodiments, R 6 It is H, methyl, ethyl, or propyl.

[0142] In some implementation schemes, R 6 It is H.

[0143] In some implementation schemes, R 6 It is a C1-C6 alkyl group. In some embodiments, R 6 It is a C1-C3 alkyl group. In some embodiments, R 6 It is methyl, ethyl, or propyl. In some embodiments, R 6 It is a methyl group.

[0144] In some implementations, x is 0, y is 1, and R 6 It is H.

[0145] In some implementations, x is 0, y is 1, and R 6 It is a C1-C6 alkyl group. In some embodiments, x is 0, y is 1, and R 6 It is a C1-C3 alkyl group. In some embodiments, x is 0, y is 1, and R 6 It is a methyl group.

[0146] In some implementation schemes, R 7 It is an H or C1-C6 alkyl group. In some embodiments, R 7 It is an H or C1-C3 alkyl group. In some embodiments, R 7 It is H, methyl, ethyl, or propyl.

[0147] In some implementation schemes, R 7 It is H.

[0148] In some implementation schemes, R 7 It is a C1-C6 alkyl group. In some embodiments, R 7 It is a C1-C3 alkyl group. In some embodiments, R 7 It is methyl, ethyl, or propyl. In some embodiments, R 7 It is a methyl group.

[0149] In some implementations, x is 1, y is 0, and R 7 It is H.

[0150] In some implementations, x is 1, y is 0, and R 7 It is a C1-C6 alkyl group. In some embodiments, x is 1, y is 0, and R 7 It is a C1-C3 alkyl group. In some embodiments, x is 1, y is 0, and R 7 It is a methyl group.

[0151] In some implementation schemes, R 8 It is Cl. In some implementations, R 8 Yes - CN.

[0152] In some implementation schemes, R 9 It is F.

[0153] In some implementation schemes, X 3 It is N. In some implementations, X 3 It is CH.

[0154] In some implementations, z is 0. In some implementations, z is 1.

[0155] In some implementation schemes, R 10a It is an H or a halogenated group. In some implementations, R 10a It is H, F, Cl, Br, or I.

[0156] In some implementation schemes, R 10a It is H.

[0157] In some implementation schemes, R 10a It is a halogenated group. In some implementations, R 10a It is H, F, Cl, Br, or I. In some implementations, R 10a It is F.

[0158] In some implementation schemes, R 10b It is an H or a halogenated group. In some implementations, R 10b It is H, F, Cl, Br, or I.

[0159] In some implementation schemes, R 10b It is H.

[0160] In some implementation schemes, R 10b It is a halogenated group. In some implementations, R 10b It is H, F, Cl, Br, or I. In some implementations, R 10b It is F.

[0161] In some implementation schemes, R 11It is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclic group), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl), wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 11 It is H, C1-C3 alkyl, -(C1-C3 alkylene)-(5 to 6-membered heterocyclic group), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH, or -(C1-C3 alkylene)-NH(C1-C3 alkyl), wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 11 It is H, C1-C3 alkyl, -(C1-C3 alkylene)-(5- to 6-membered heterocyclic group), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH, or -(C1-C3 alkylene)-NH(C1-C3 alkyl), wherein the heterocyclic group contains 1-2 heteroatoms selected from N and O. In some embodiments, R 11The following are the radicals: H, methyl, ethyl, propyl, -CD3, -(CH2)-(5 to 6-membered heterocyclic group), -(CH2CH2)-(5 to 6-membered heterocyclic group), -(CH2CH2CH2)-(5 to 6-membered heterocyclic group), -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -(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)CH2CH3, -CH2CH2-N(H)CH3, -CH2CH2-N(H)CH2CH3, -CH2CH2-N(H)CH2CH3, -CH2CH2CH2-N(H)CH2CH3, -CH2CH2CH2-N(H)CH2CH3 or -CH2CH2CH2-N(H)CH2CH2CH3, wherein the heterocyclic group contains 1-2 heteroatoms selected from N and O.

[0162] In some implementation schemes, R 11 It is H.

[0163] In some implementation schemes, R 11 It is a C1-C6 alkyl group. In some embodiments, R 11 It is a C1-C3 alkyl group. In some embodiments, R 11 It is methyl, ethyl, propyl, or -CD3. In some embodiments, R 11 It is -CH3. In some implementations, R 11 It includes one or more deuterium atoms. In some implementations, R 11 It is -CD3. In some implementations, R 11 It is -CH2CH3. In some implementations, R 11 It is -CH(CH3)2.

[0164] In some implementation schemes, R 11It is -(C1-C6 alkylene)-(5 to 6-membered heterocyclic group), wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 11 It is -(C1-C3 alkylene)-(5 to 6-membered heterocyclic group), wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 11 It is -(C1-C3 alkylene)-(5 to 6-membered heterocyclic group), wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N and O. In some embodiments, R 11 yes .

[0165] In some implementation schemes, R 11 It is -(C1-C6 alkylene)-O(C1-C6 alkyl). In some embodiments, R 11 It is -(C1-C3 alkylene)-O(C1-C3 alkyl). In some embodiments, R 11 It is -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, or -CH2CH2CH2OCH2CH2CH3. In some implementations, R 11 It is -CH2CH2OCH3.

[0166] In some implementation schemes, R 11 It is a C1-C6 haloalkyl group. In some embodiments, R 11 It is a C1-C5 haloalkyl group. In some embodiments, R 11 It is -CF3, -CH2CH2F3, -(CH2)2CHF3, -(CH2)3CF3, -CH2CF(CH3)2, -CH2CF2CH3, -CH2CF3, -CH2CH2CF(CH3)2, -CH2CH2CF2CH3, or -CH2CH2CF3. In some embodiments, R 11 It is -(CH2)3CF3, -CH2CF2CH3, -CH2CH2CF(CH3)2 or -CH2CF(CH3)2.

[0167] In some implementation schemes, R 11 It is a C1-C6 alkyl-OH. In some embodiments, R 11 It is a C1-C5 alkyl-OH. In some embodiments, R 11It is -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH(OH)(CH3) or -CH2CH2C(OH)(CH3)2. In some embodiments, R 11 It is -CH2CH2C(OH)(CH3)2.

[0168] In some implementation schemes, R 11 It is -(C1-C6 alkylene)-NH(C1-C6 alkyl). In some embodiments, R 11 It is -(C1-C3 alkylene)-NH(C1-C3 alkyl). In some embodiments, R 11 It 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, R 11 It is -CH2CH2N(H)CH3.

[0169] In some implementation schemes, yes: .

[0170] In some implementation schemes, R 12 It is H, a halogroup, or a C1-C6 alkyl group. In some embodiments, R 12 It is H, F, Cl, Br, I, or a C1-C3 alkyl group. In some embodiments, R 12 It is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0171] In some implementation schemes, R 12 It is H.

[0172] In some implementation schemes, R 12 It is a halogenated group. In some implementations, R 12 It is F, Cl, Br, or I. In some implementations, R 12 It is F.

[0173] In some implementation schemes, R 12 It is a C1-C6 alkyl group. In some embodiments, R 12 It is a C1-C3 alkyl group. In some embodiments, R 12 It is methyl, ethyl, or propyl. In some embodiments, R12 It is a methyl group.

[0174] In some implementation schemes, yes: .

[0175] In some implementation schemes, R 13 It is an H or a halogenated group. In some implementations, R 13 It is H, F, Cl, Br, or I.

[0176] In some implementation schemes, R 13 It is H.

[0177] In some implementation schemes, R 13 It is a halogenated group. In some implementations, R 13 It is F, Cl, Br, or I. In some implementations, R 13 It is F.

[0178] In some implementation schemes, R 14 It is an H or C1-C6 alkyl group. In some embodiments, R 14 It is an H or C1-C3 alkyl group. In some embodiments, R 14 It is H, methyl, ethyl, or propyl.

[0179] In some implementation schemes, R 14 It is H.

[0180] In some implementation schemes, R 14 It is a C1-C6 alkyl group. In some embodiments, R 14 It is a C1-C3 alkyl group. In some embodiments, R 14 It is methyl, ethyl, or propyl. In some embodiments, R 14 It is a methyl group.

[0181] In some implementation schemes, R 14 It is H. In some implementations, R 14 It is a methyl group.

[0182] In some implementation schemes, X 4 It is N. In some implementations, X 4 It is CR 15 .

[0183] In some implementation schemes, R 15 It is an H or C1-C6 alkyl group. In some embodiments, R 15 It is an H or C1-C3 alkyl group. In some embodiments, R 15 It is H, methyl, ethyl, or propyl.

[0184] In some implementation schemes, R 15 It is H.

[0185] In some implementation schemes, R 15 It is a C1-C6 alkyl group. In some embodiments, R 15 It is a C1-C3 alkyl group. In some embodiments, R 15 It is methyl, ethyl, or propyl. In some embodiments, R 15 It is a methyl group.

[0186] In some implementation schemes, X 5 It is N. In some implementations, X 5 It is CH.

[0187] In some implementation schemes, X 6 It is N. In some implementations, X 6 It is CH.

[0188] In some implementation schemes, It is a single bond. In some implementations, It is a double bond.

[0189] In some implementation schemes, yes: .

[0190] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (II): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 7 R 8 R 9 R 10a R 10b R 11 R 12 R 13 R 14 R 15 X 1 X 2 X 3 X 4 X 5 X 6 w, z and It is as described with respect to formula (IA) or formula (I).

[0191] In some embodiments, the compound of formula (IA) or (I) is a compound of formula (IIa): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 7 R 8 R 9 R 11 R 12 R 13 R 14 R 15 X 1 X 2 X 3 X 4 X 5 X 6 w, z and It is as described with respect to formula (IA) or formula (I).

[0192] In some embodiments, the compound of formula (IA) or (I) is a compound of formula (IIb): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 7 X 1 X 2 w is as described with respect to equation (IA) or equation (I).

[0193] In some embodiments, the compound of formula (IA) or (I) is a compound of formula (IIc): Where R 1a R 1bR 2a R 2b R 3a R 3b R 4a R 4b R 7 X 1 and X 2 It is as described for formula (IA) or (I).

[0194] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (III): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6 R 8 R 9 R 10a R 10b R 11 R 12 R 13 R 14 R 15 X 1 X 2 X 3 X 4 X 5 X 6 w, z and It is as described with respect to formula (IA) or formula (I).

[0195] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (IIIa): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6 R 8 R 9 R11 R 12 R 13 R 14 R 15 X 1 X 2 X 3 X 4 X 5 X 6 w, z and It is as described for formula (IA) or (I).

[0196] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (IIIb): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b and R 11 It is as described with respect to formula (IA) or formula (I).

[0197] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (IV): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 8 R 9 R 10a R 10b R 11 R 12 R 13 R 14 R 15 X 1 X 2 X 3 X 4 X 5 X 6 w, z and It is as described with respect to formula (IA) or formula (I).

[0198] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (IVa): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 8 R 9 R 11 R 12 R 13 R 14 R 15 X 1 X 2 X 3 X 4 X 5 X 6 w, z and It is as described with respect to formula (IA) or formula (I).

[0199] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (IVb): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b X 1 X 2 w is as described with respect to equation (IA) or equation (I).

[0200] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (IVc): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a R4b X 1 and X 2 It is as described with respect to formula (IA) or formula (I).

[0201] In some embodiments, the compound of formula (IA) or formula (I) is a compound of formula (IVd): Where R 1a R 1b R 2a R 2b R 3a R 3b R 4a and R 4b It is as described with respect to formula (IA) or formula (I).

[0202] It should be understood that any compound described herein may include one or more hydrogen atoms replaced by deuterium. Any one or more of the substituents in formula (IA) or formula (I) may be deuterated, such as X 1 X 2 X 3 X 5 X 6 R 1a R 1b R 3a R 3b R 4a R 4b R 5a R 5b R 6 R 7 R 10a R 10b R 11 R 12 R 13 R 14 and R 15 One or more of them. For example, in some implementations, R 11 It is a deuterated group, such as -CD3.

[0203] In this specification, it should be understood that all descriptions, variations, embodiments, or aspects of formula (IA) or formula (I) are equally applicable to the other formulas detailed herein, where applicable, and are described equally as if each description, variation, embodiment, or aspect were listed separately and individually for all formulas. It should also be understood that all descriptions, variations, embodiments, or aspects of formula (IA) or formula (I) are equally applicable to the other formulas detailed herein, where applicable, and are described equally as if each description, variation, embodiment, or aspect were listed separately and individually for all formulas. For example, all descriptions, variations, embodiments, or aspects of formula (IA) or formula (I) are equally applicable where applicable to any formula detailed herein, such as formulas (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), and (IVd), and are described equally as if each description, variation, embodiment, or aspect were listed separately and individually for all formulas.

[0204] In some embodiments, compounds selected from those in Table 1 or pharmaceutically acceptable salts thereof are provided. Although some compounds described in this disclosure (including those in Table 1) are presented in specific stereoisomers and / or non-stereochemical forms, it should be understood that any or all stereochemical forms (including any enantiomers or diastereomers) and any tautomers or other forms of any compound described herein (including those in Table 1) are described. Table 1. Or its pharmaceutically acceptable salt.

[0205] All compounds of formula (IA) or (I) existing in free base or acid form can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art, through treatment with a suitable inorganic or organic base or acid. Salts of compounds of formula (IA) or (I) can be converted into their free base or acid form using standard techniques. Synthesis method

[0206] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided herein. By way of example and not limitation, compounds of formulas (Ia) to (Ih) can be prepared as outlined in schemes 1-4 and the examples set forth herein. It should be noted that those skilled in the art will know how to modify the procedures set forth in the exemplary schemes and examples to obtain the desired products.

[0207] As outlined in Scheme 1, compounds containing a hydroxyindole motif of formula (i-1) can be synthesized by coupling an indole derivative a with an intermediate compound b to form an intermediate compound c, which is then nitrated to form an intermediate compound d. The nitro group is reduced to form an intermediate compound e, which is subsequently coupled with an intermediate f to form a compound of formula (i-1).

[0208] Scheme 2 provides two routes for synthesizing compounds of formula (i-2) containing a glutarimide motif. Indazole derivative g can be coupled with intermediate compound h to obtain intermediate compound i. Deprotection and further reduction of intermediate compound i form intermediate compound j, which is then deprotected to form a compound of formula (i-2). Alternatively, indazole derivative g can be coupled with intermediate compound k to obtain intermediate compound l. Deprotection and further reduction of intermediate compound l form intermediate compound i, which is then deprotected by an amine to form a compound of formula (i-2).

[0209] Scheme 3 provides the synthesis of a compound of formula (i-2) containing a dihydrouridine motif. An indazole derivative n can be coupled with an intermediate compound h to obtain an intermediate compound o, which is then deprotected to form an intermediate compound p, and subsequently deprotected to form a compound of formula (i-2).

[0210] Scheme 4 provides multiple pathways for synthesizing various compounds of formula (IA) or formula (I). Compounds of formula (i-1) can be coupled with various derivatives of compounds of formula (i-2) (denoted as formulas (i-2a) to (i-2h)) to obtain compounds of formulas (Ia) to (Ih). How to use

[0211] Embodiments of this disclosure provide a method for modulating BCL6 in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (IA) or (I). Modulation of BCL6 (e.g., inhibition or activation) can be assessed and demonstrated by a variety of methods known in the art. Whether and to what extent BCL6 is modulated (e.g., inhibition or activation) can be determined using kits and commercially available assays.

[0212] In one aspect, this document provides a method for regulating BCL6, the method comprising contacting BCL6 with an effective amount of a compound of formula (IA) or (I) or any embodiment or variant thereof. In some embodiments, the compound of formula (IA) or (I) inhibits BCL6. In some embodiments, the compound of formula (IA) or (I) causes degradation of BCL6.

[0213] In some embodiments, the 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, formula (IA) or formula (I) The compounds modulate the activity of BCL6 by approximately 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%, and 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%.

[0214] Some embodiments of this disclosure also provide a method for degrading BCL6 in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (IA) or formula (I). The degradation of BCL6 can be assessed and demonstrated by a variety of methods known in the art. Kits and commercially available assays (including cell-based assays) can be used to determine whether BCL6 has been degraded and to what extent.

[0215] In one aspect, this document provides a method for degrading BCL6, the method comprising contacting BCL6 with an effective amount of a compound of formula (IA) or (I) or any embodiment or variant thereof. In some embodiments, the compound of formula (IA) or (I) causes partial degradation of BCL6. In some embodiments, the compound of formula (IA) or (I) causes complete degradation of BCL6.

[0216] In some embodiments, compounds of formula (IA) or (I) degrade 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, formula (IA) or (I) The compounds caused BCL6 to degrade by approximately 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%, and 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%.

[0217] On the other hand, this document provides a method for treating cancer in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (IA) or formula (I). In some embodiments, this document provides a method for preventing cancer in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (IA) or formula (I). Non-limiting examples of cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, colorectal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, benign lymphoma, malignant lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma (NHL), benign melanoma, malignant melanoma, myeloproliferative disorders, sarcoma, Ewing sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, etc. Astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and Schwann cell carcinoma, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, nephroblastoma, teratoma, 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 lymphoma, diffuse large B-cell lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, Waldenström 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.

[0218] In some embodiments, the cancer is a lymphoma, such as B-cell lymphoma. In some embodiments, the cancer is a non-Hodgkin lymphoma, such as 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, intranodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), Burkitt lymphoma, or lymphoplasmacytic lymphoma (Wald's 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).

[0219] In some implementations, the cancer is recurrent and / or refractory.

[0220] In some embodiments, compounds of formula (IA) or (I) are administered as first-line therapy. In other embodiments, compounds of formula (IA) or (I) are administered as non-first-line therapy (e.g., as second-line or subsequent therapy, such as salvage therapy).

[0221] In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need reduces the severity of the subject's cancer (such as tumor size, tumor growth rate, metastasis). In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need stabilizes the cancer (prevents or delays its deterioration). In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need delays the onset or recurrence of cancer. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need slows the progression of cancer. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need provides partial remission of cancer. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need provides complete remission of cancer. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need reduces the dosage of one or more other drugs required to treat cancer. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need enhances the effect of another drug used to treat cancer. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need delays cancer progression. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need improves the quality of life of a subject with cancer. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need prolongs the survival of a subject with cancer.

[0222] In some aspects, this document provides a method for slowing the progression of cancer in a subject, the method comprising administering a compound of formula (IA) or formula (I) to the subject. In some embodiments, this document provides a method for stabilizing 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 cancer. In some embodiments, the method delays the progression of cancer. In some embodiments, the method provides partial or complete remission of cancer.

[0223] On the other hand, this article provides a method for delaying the onset or recurrence of cancer in a subject, the method comprising administering a compound of formula (IA) or formula (I) to the subject.

[0224] In another aspect, this document provides a method for reducing the dosage of one or more other drugs required to treat a subject's cancer, the method comprising administering a compound of formula (IA) or formula (I) to the subject. In some embodiments, this document provides a method for enhancing the effect of another drug used to treat a subject's cancer, the method comprising administering a compound of formula (IA) or formula (I) to the subject.

[0225] A method for delaying the progression of cancer in a subject is also provided herein, the method comprising administering to the subject a compound of formula (IA) or formula (I). In some embodiments, the method improves the quality of life of a subject with cancer. In some embodiments, the method prolongs the survival of a subject with cancer.

[0226] In another aspect, this document provides a method for treating an autoimmune disease in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (IA) or formula (I). In some embodiments, this document provides a method for preventing an autoimmune disease in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (IA) or formula (I). Autoimmune diseases can be classified 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 distinguishing between different types of tissues or target cells. Exemplary organ-specific autoimmune diseases include atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, Graves' 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). This disclosure covers the treatment of all types of autoimmune diseases, including organ-specific and generalized autoimmune diseases, including but not limited to lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, and Goodpasture's syndrome. Hashimoto'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, morphine scleroderma, multiple sclerosis, myasthenia gravis, narcolepsy, neuromuscular myotonia, pemphigus vulgaris, pernicious anemia, 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 Wechsler's granulomatosis.

[0227] On the other hand, this article provides a method for treating TH17-related conditions such as TH17-related autoimmune diseases in subjects of need, the method comprising administering to the subject an effective amount of a compound of formula (IA) or formula (I).

[0228] In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need reduces or alleviates symptoms of an autoimmune disease (such as inflammation, chronic fever, weakness, arthralgia, myalgia, and fatigue). In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need shortens or reduces the duration of symptoms of an autoimmune disease. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need eliminates symptoms of an autoimmune disease. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need delays the onset or relapse of an autoimmune disease. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need slows the progression of an autoimmune disease. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need reduces the dose of one or more other drugs required to treat an autoimmune disease. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need enhances the effect of another drug used to treat an autoimmune disease. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need delays the progression of an autoimmune disease. In some embodiments, administration of a compound of formula (IA) or formula (I) to a subject in need improves the quality of life of a subject with an autoimmune disease.

[0229] In some aspects, this document provides a method for slowing the 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, this document provides a method for 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 an autoimmune disease. In some embodiments, the method delays the progression of an autoimmune disease. In some embodiments, the method improves the quality of life of a subject suffering from an autoimmune disease.

[0230] In another aspect, this document provides a method for reducing the dosage of one or more other drugs 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, this document provides a method for enhancing the effect of another drug used to treat an autoimmune disease in a subject, the method comprising administering a compound of formula (IA) or formula (I) to the subject.

[0231] In some embodiments of any of the methods described herein, a compound of formula (IA) or (I) is administered over 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.

[0232] In some embodiments, the compound of formula (IA) or (I) is administered daily on each day of a 28-day treatment cycle, for example, once or twice daily on each day of a 28-day treatment cycle. In some embodiments, the compound of formula (IA) or (I) is administered daily on days 1-14 of a 28-day treatment cycle and not on days 15-28 of a 28-day treatment cycle, for example, once or twice daily on days 1-14 of a 28-day treatment cycle. In some embodiments, the compound of formula (IA) or (I) is administered daily on days 1-21 of a 28-day treatment cycle and not on days 22-28 of a 28-day treatment cycle, for example, once or twice daily on days 1-21 of a 28-day treatment cycle.

[0233] Administration of compounds of formula (IA) or (I) may continue indefinitely, as described herein, or until a decision is made to discontinue administration due to clinically significant disease progression, unacceptable toxicity, or otherwise. In some embodiments, administration of compounds of formula (IA) or (I) may continue for up to three years, for example, up to two years, and then be discontinued.

[0234] In some embodiments of any of the methods described herein, the compound of formula (IA) or (I) is administered in combination with an additional therapy. Therefore, some embodiments further include administering an additional therapy, such as an additional therapeutic agent, to the subject. In some embodiments, the additional therapy is standard of care (SOC).

[0235] The current SOC for DLBCL is the combination of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and rituximab (R-CHOP). The SOC for second-line relapsed / refractory DLBCL is high-dose chemotherapy followed by autologous stem cell transplantation (autoSCT). CAR-T cell therapy has also been used to treat relapsed / refractory DLBCL. The SOC for FL is anti-CD20 immunotherapy, with or without chemotherapy.

[0236] In some implementations, additional therapies include anti-lymphoma therapies (e.g., anti-lymphoma agents). Anti-lymphoma therapies include the SOCs described herein for DLBCL and FL, as well as cytotoxic agents, radiotherapy, radioimmunotherapy, and autologous and allogeneic grafts. Anti-lymphoma agents include the SOCs described herein for DLBCL and FL (e.g., cyclophosphamide, doxorubicin, vincristine, prednisolone, rituximab), as well as cytotoxic agents and anti-CD20 antibodies.

[0237] Rituximab is a recombinant chimeric mouse / human antibody targeting the CD20 antigen, a hydrophobic transmembrane protein located on normal pre-B lymphocytes and mature B lymphocytes. Upon binding, rituximab triggers a cytotoxic immune response against CD20-positive cells. Rituximab is indicated for a variety of oncology and non-oncology treatments. For example, rituximab is indicated for: (i) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or other anthracycline-based chemotherapy regimens for the treatment of patients with previously untreated diffuse large B-cell CD20-positive NHL; (ii) in combination with CVP (cyclophosphamide, vincristine, prednisolone) chemotherapy for the treatment of patients with previously untreated follicular CD20-positive B-cell NHL; and / or (iii) as a monotherapy for patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL. For example, rituximab has been indicated for: (i) in combination with CHOP chemotherapy for patients with CD20-positive diffuse large B-cell non-Hodgkin lymphoma; (ii) in combination with chemotherapy for patients with previously untreated stage III-IV FL; (iii) as monotherapy for patients with chemotherapy-resistant or stage III-IV FL who have experienced a second or subsequent relapse after chemotherapy; and / or (iv) as maintenance therapy for adult patients with FL who have responded to induction 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 second-line (and subsequent) treatment option for B-cell lymphoma in the NCCN and European Society of Medical Oncology (ESMO) guidelines, and is routinely used in standard practice in these contexts. In addition, in the United States and the European Union, rituximab has been indicated for use in combination with lenalidomide for the treatment of relapsed / refractory FL.

[0238] In some embodiments, the method further includes administering an anti-CD20 antibody (e.g., a therapeutically effective amount of an anti-CD20 antibody), such as rituximab, to the subject. In specific embodiments, the method further includes administering rituximab (e.g., a therapeutically effective amount of rituximab) to the subject. For example, some embodiments include intravenous administration of rituximab (e.g., as an intravenous (IV) infusion). Some embodiments include administering approximately 375 mg / m². 2 Rituximab. Some administration regimens involve intravenous (e.g., IV infusion) administration of approximately 375 mg / m². 2 Rituximab. In some embodiments, rituximab is administered concurrently with a compound of formula (IA) or (I) or within up to 2 hours following a compound of formula (IA) or (I). Some embodiments include 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, for example, up to 6 months. Pharmaceutical Compositions and Routes of Administration

[0239] The compounds described herein can be administered to subjects orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0240] The compounds disclosed herein can be administered to subjects orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylene pyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), and disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or lemon). The pharmaceutical composition may contain calcium sulfate, lubricants (e.g., magnesium stearate, light anhydrous silicate, talc, or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersants (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound of formula (IA) or formula (I) in the pharmaceutical composition may be at a level that will exert the desired effect; for example, at a unit dose of about 0.005 mg / kg of subject body weight to about 10 mg / kg of subject body weight for both oral and parenteral administration.

[0241] The dosage of the compound of formula (IA) or formula (I) to be administered to a subject is quite variable and may depend on the judgment of a healthcare practitioner. Typically, the compounds disclosed herein may be administered one to four times daily at a dose of about 0.001 mg / kg of subject body weight to about 10 mg / kg of subject body weight, but such doses may vary appropriately depending on the subject's age, weight, medical condition, and type of administration. In one embodiment, the dose is about 0.001 mg / kg of subject body weight to about 5 mg / kg of subject body weight, about 0.01 mg / kg of subject body weight to about 5 mg / kg of subject body weight, about 0.05 mg / kg of subject body weight to about 1 mg / kg of subject body weight, about 0.1 mg / kg of subject body weight to about 0.75 mg / kg of subject body weight, or about 0.25 mg / kg of subject body weight to about 0.5 mg / kg of subject body weight. In one embodiment, one dose is administered daily. In any given case, the amount of the compound of formula (IA) or formula (I) administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0242] In some embodiments, the compound of formula (IA) or formula (I) is administered to the 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, the compound of formula (IA) or formula (I) is administered to the subject once daily or twice daily at a dose of about 10 mg / day to about 750 mg / day.

[0243] In certain embodiments, the compound of formula (IA) or (I) is administered to the subject once daily (QD) or twice daily (BID) 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. In other embodiments, administration is QD. Alternatively, administration is BID.

[0244] In another embodiment, this document provides a unit dose formulation comprising a compound of formula (IA) or formula (I) in amounts 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.

[0245] In certain embodiments, this document provides unit-dose formulations comprising about 0.1 mg or 100 mg of a compound of formula (IA) or (I). In some embodiments, unit-dose formulations comprise about 10 mg to about 100 mg of a compound of formula (IA) or (I). In some embodiments, unit-dose formulations comprise about 20 mg of a compound of formula (IA) or (I) (e.g., compound 70 or a pharmaceutically acceptable salt thereof). In some embodiments, unit-dose formulations comprise about 80 mg of a compound of formula (IA) or (I) (e.g., compound 70 or a pharmaceutically acceptable salt thereof).

[0246] In another embodiment, this document provides a unit dose formulation comprising 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 (I).

[0247] Compounds of formula (IA) or (I) may be administered once, twice, three times, four times, or more daily. In certain embodiments, a dose of 100 mg or less is administered as a once-daily dose, and a dose greater than 100 mg is administered twice daily in an amount equal to half the total daily dose. In some embodiments, compounds of formula (IA) or (I) are administered once daily. In some embodiments, compounds of formula (IA) or (I) are administered twice daily.

[0248] The compound of formula (IA) or (I) can be administered orally. In one embodiment, when administered orally, the compound of formula (IA) or (I) is administered with food and water. In another embodiment, the compound of formula (IA) or (I) is dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension. Alternatively, in one embodiment, when administered orally, the compound of formula (IA) or (I) is administered to a subject in a fasting state. For example, in some embodiments, the compound of formula (IA) or (I) is administered to a subject who has not eaten or drunk anything other than water for at least about 2 hours prior to administration of the compound of formula (IA) or (I). In some embodiments, the fasting state begins at least about 2 hours before administration of the compound of formula (IA) or (I) and lasts for at least about 1 hour after administration of the compound of formula (IA) or (I).

[0249] The compounds disclosed herein can also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, transmucosally, by inhalation, or topically to the ear, nose, eye, or skin. The method of administration is determined by the healthcare practitioner and may depend in part on the site of the medical condition.

[0250] In another embodiment, this document provides a composition comprising an effective amount of a compound of formula (IA) or formula (I) and a pharmaceutically acceptable carrier or medium, wherein the pharmaceutically acceptable carrier or medium may comprise excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0251] In some embodiments, the pharmaceutical composition comprises a compound of formula (IA) or (I) and two or more of the following: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silica, and sodium stearoyl fumarate. In some embodiments, the pharmaceutical composition comprises anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silica, and sodium stearoyl fumarate.

[0252] In some embodiments, the composition is in the form of a dispersion (e.g., a spray-dried dispersion). The composition may optionally be coated with a membrane that resists dissolution for a predictable period of time.

[0253] The compound of formula (IA) or (I) may be present in the composition in any effective amount. In some embodiments, the compound of formula (IA) or (I) is present in the composition at 1% 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, the pharmaceutical composition comprises about 35% w / w of the compound of formula (IA) or (I).

[0254] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, and suspensions. In some embodiments, the composition is in the form of tablets or capsules. In some embodiments, the composition is in the form of tablets (e.g., film-coated tablets). In some embodiments, the composition is in the form of capsules.

[0255] The composition can be formulated to contain a daily dose or suitable fractions of a daily dose in a dosage unit, which can be a single tablet or capsule or a suitable volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt such as hydrochloride. Generally, all compositions are prepared according to methods known in medicinal chemistry. Capsules can be prepared by mixing a compound of formula (IA) or formula (I) with a suitable carrier or diluent and filling an appropriate amount of the mixture into capsules. Commonly used carriers and diluents include, but are not limited to, inert powdered substances such as many different kinds of starch; powdered cellulose, especially crystalline cellulose and microcrystalline cellulose; sugars such as fructose, mannitol, and sucrose; cereal powders and similar edible powders.

[0256] Tablets can be prepared by direct compression, wet granulation, dry granulation, or spray drying. Their formulations typically incorporate diluents, binders, lubricants, disintegrants, and compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium 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, and glucose. Natural and synthetic gums are also suitable, including gum arabic, alginate, methylcellulose, and polyvinylpyrrolidone. Polyethylene glycol, ethylcellulose, and waxes can also be used as binders.

[0257] Lubricants may be required in tablet formulations to prevent tablets and punches from sticking together in the dye. Lubricants can be selected from slippery solids such as talc, magnesium stearate and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell upon wetting to break up the tablet and release compounds. They include starch, clay, cellulose, alginate, and gums. More specifically, examples such as corn starch and potato starch, methylcellulose, agar, bentonite, lignocellulose, powdered natural sponges, cation exchange resins, alginate, guar gum, citrus pomace, and carboxymethyl cellulose, as well as sodium lauryl sulfate, can be used. Tablets can be coated with sugar as a flavoring agent and sealant, or with film-forming protectants to modify the tablet's dissolution characteristics. Compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0258] When it is desired to administer compounds of formula (IA) or (I) as suppositories, typical bases can be used. Cocoa butter is a conventional suppository base, which can be modified by adding wax to slightly increase its melting point. Water-miscible suppository bases, particularly those containing polyethylene glycol of various molecular weights, are widely used.

[0259] The effects of compounds of formula (IA) or (I) can be delayed or prolonged through appropriate formulation. For example, slow-dissolving microspheres of compounds of formula (IA) or (I) can be prepared and incorporated into tablets or capsules, or incorporated as slow-release implantable devices. The technique also includes preparing microspheres with several different dissolution rates and filling capsules with a mixture of microspheres. Tablets or capsules can be used with a membrane coating that resists dissolution for a predictable period of time. Parenteral formulations can even be made long-acting by dissolving or suspending compounds of formula (IA) or (I) in an oily or emulsified medium that allows the compound to disperse slowly in serum. In some embodiments, tablets or capsules are formulated for enteric release, for example, by formulating compounds of formula (IA) or (I) together with Eudragit L100-55.

[0260] It should be understood that the pharmaceutical compositions described herein may include mixtures of compounds of formula (IA) or formula (I), including racemic mixtures of any of the compounds described herein. Numbering Implementation Plan

[0261] The compounds useful according to this disclosure are further described through the following embodiments. Features of each embodiment may be combined with any other embodiment where appropriate and practical.

[0262] Implementation scheme P1. A compound of formula (IA): (IA) Or its pharmaceutically acceptable salt, wherein: X 1 and X 2 Each is independently either N or CH, provided that X is the condition. 1 and X 2 At least one of them is N; R 1a and R 1b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 2a and R 2b Each can be independently H, C1-C6 alkyl, -O (C1-C6 alkyl), -OH, halogroup, C1-C6 haloalkyl, or C1-C6 alkyl-OH. Or R 2a and R 2b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups. Or R 2a and R 2b Together they form an oxygen group; Or R 1a and R 2a Together they form bridging C2-C3 alkylene groups; R 3a and R 3b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 4a and R 4b Each is independently an H, a halogroup, or a C1-C6 alkyl group. Or R 4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups; R 5a and R 5b Each is independently H, a halogroup, or a C1-C6 alkyl group; w is 0 or 1; R 6 It is an H or C1-C6 alkyl group; R 7 It is an H or C1-C6 alkyl group; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 It is Cl or -CN; R 9 It is F; X 3 It is N or CH; z is 0 or 1; R 10a and R 10b Each is independently either an H group or a halogenated group; R 11 It is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5 to 6-membered heterocyclic group), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH or -(C1-C6 alkylene)-NH(C1-C6 alkyl). The heterocyclic group contains 1-3 heteroatoms selected from N, O and S; R 12 It is H, a halogroup, or a C1-C6 alkyl group; R 13 It is an H or a halogroup; R 14 It is an H or C1-C6 alkyl group; X 4 Is it N or CR? 15 ; R 15 It is an H or C1-C6 alkyl group; X 5 and X 6 Each is independently N or CH; and Is it a single bond or a double bond? One or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0263] Implementation scheme P2. A compound of formula (I): (I) Or its pharmaceutically acceptable salt, wherein: X 1 and X 2 Each is independently either N or CH, provided that X is the condition. 1 and X 2 At least one of them is N; R 1a and R 1b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 2a and R 2b Each can be independently H, C1-C6 alkyl, -OH, halogroup, or C1-C6 alkyl-OH. Or R 2a and R 2b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups. Or R 2a and R 2bTogether they form an oxygen group; Or R 1a and R 2a Together they form bridging C2-C3 alkylene groups; R 3a and R 3b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 4a and R 4b Each is independently an H, a halogroup, or a C1-C6 alkyl group. Or R 4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups; R 5a and R 5b Each is independently H, a halogroup, or a C1-C6 alkyl group; w is 0 or 1; R 6 It is an H or C1-C6 alkyl group; R 7 It is an H or C1-C6 alkyl group; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 It is Cl or -CN; R 9 It is F; X 3 It is N or CH; z is 0 or 1; R 10a and R 10b Each is independently either an H group or a halogenated group; R 11 It is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5 to 6-membered heterocyclic group), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH or -(C1-C6 alkylene)-NH(C1-C6 alkyl). The heterocyclic group contains 1-3 heteroatoms selected from N, O and S; R 12 It is H, a halogroup, or a C1-C6 alkyl group; R 13 It is an H or a halogroup; R 14 It is an H or C1-C6 alkyl group; X 4 Is it N or CR? 15 ; R 15 It is an H or C1-C6 alkyl group; X 5 and X 6 Each is independently N or CH; and Is it a single bond or a double bond? One or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0264] Implementation scheme P3. The compound or a pharmaceutically acceptable salt thereof as described in implementation scheme P1 or P2, wherein: X 1 It is CH; and X 2 It is N.

[0265] Implementation scheme P4. The compound or a pharmaceutically acceptable salt thereof as described in implementation scheme P1 or P2, wherein: X 1 It is N; and X 2 It is CH.

[0266] Implementation Scheme P5. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P1 or P2, wherein: X 1 and X 2 Each is N.

[0267] Implementation Scheme P6. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P5, wherein: R 1a and R 1b Each is independently H, a halogroup, or a C1-C3 alkyl group.

[0268] Implementation Scheme P7. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P6, wherein: R 1a and R 1b Each is either H or -CH3.

[0269] Implementation Scheme P8. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P7, wherein: R 2a and R 2b Each can be independently H, C1-C3 alkyl, -O (C1-C3 alkyl), -OH, halogroup, C1-C3 haloalkyl, or C1-C3 alkyl-OH. Or R 2a and R 2b Together with the carbon atoms to which they are attached, they form spiroC3-C4 cycloalkyl groups. Or R 2a and R 2bTogether they form an oxygen group.

[0270] Implementation Scheme P9. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P8, wherein: R 2a and R 2b Each can be independently H, -CH3, -OCH3, -OH, F, -CF3, or -CH2OH. Or R 2a and R 2b Together with the carbon atoms to which they are attached, they form spirocyclic butyl groups. Or R 2a and R 2b Together they form an oxygen group.

[0271] Implementation Scheme P10. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P9, wherein R 1a and R 1b Each is H, and R 2a and R 2b At least one of them is not H.

[0272] Implementation Scheme P11. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P9, wherein: R 1a and R 2a Together they form a bridging ethylene group.

[0273] Implementation Scheme P12. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P11, wherein: R 3a and R 3b Each is independently H, a halogroup, or a C1-C3 alkyl group.

[0274] Implementation Scheme P13. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P12, wherein: R 3a and R 3b Each can be H, F, or -CH3 independently.

[0275] Implementation Scheme P14. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P13, wherein: R 4a and R 4b Each is independently an H, a halogroup, or a C1-C3 alkyl group. Or R 4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C4 cycloalkyl groups.

[0276] Implementation Scheme P15. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P14, wherein: R 4a and R 4b Each can be independently H, F, or -CH3. Or R 4a and R 4b Together with the carbon atoms to which they are attached, they form spirocyclic butyl groups.

[0277] Implementation Scheme P16. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P15, wherein R 3a R 3b R 4a and R 4b Each is H.

[0278] Implementation Scheme P17. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P15, wherein R 3a and R 3b At least one of them is not H, and R 4a and R 4b At least one of them is not H.

[0279] Implementation Scheme P18. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P17, wherein: w is 0.

[0280] Implementation Scheme P19. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P17, wherein: w is 1.

[0281] Implementation Scheme P20. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P19, wherein: R 5a and R 5b Each is independently H, a halogroup, or a C1-C3 alkyl group.

[0282] Implementation Scheme P21. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P20, wherein: R 5a and R 5b Each is H.

[0283] Implementation Scheme P22. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P21, wherein R 1a R 1b R 2a R 2b R 3aR 3b R 4a R 4b R 5a and R 5b At least one of them is not H.

[0284] Implementation Scheme P23. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P22, wherein R 1a R 1b R 2a R 2b R 3a R 3b R 4a R 4b R 5a and R 5b One or both of them are not H.

[0285] Implementation Scheme P24. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P23, wherein yes: .

[0286] Implementation Scheme P25. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P24, wherein: x is 1; y is 0; and R 7 It is an H or C1-C3 alkyl group.

[0287] Implementation Scheme P26. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P25, wherein: R 7 It is H or -CH3.

[0288] Implementation Scheme P27. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P24, wherein: x is 0; y is 1; and R 6 It is an H or C1-C3 alkyl group.

[0289] Implementation Scheme P28. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P27, wherein: R 6 It is H or -CH3.

[0290] Implementation Scheme P29. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P24, wherein: x and y are both 0.

[0291] Implementation Scheme P30. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P29, wherein: R 8 It is Cl.

[0292] Implementation Scheme P31. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P29, wherein: R 8 Yes - CN.

[0293] Implementation Scheme P32. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P31, wherein: X 3 It is CH.

[0294] Implementation Scheme P33. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P31, wherein: X 3 It is N.

[0295] Implementation Scheme P34. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P33, wherein:

[0296] z is 0.

[0297] Implementation Scheme P35. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P33, wherein: z is 1.

[0298] Implementation Scheme P36. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P35, wherein: R 10a and R 10b Each is either H or F.

[0299] Implementation Scheme P37. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P36, wherein: R 11 It is H, C1-C3 alkyl, -(C1-C3 alkylene)-(6-membered heterocyclic), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH or -(C1-C3 alkylene)-NH(C1-C3 alkyl). The heterocyclic group contains 1-2 heteroatoms selected from N and O.

[0300] Implementation Scheme P38. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P37, wherein: R 11 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 .

[0301] Implementation Scheme P39. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P38, wherein yes: .

[0302] Implementation Scheme P40. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P39, wherein: R 12 It is H, a halogroup, or a C1-C3 alkyl group.

[0303] Implementation Scheme P41. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P40, wherein: R 12 It is H, F, or -CH3.

[0304] Implementation Scheme P42. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P41, wherein yes: .

[0305] Implementation Scheme P43. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P42, wherein: R 13 It is H or F.

[0306] Implementation Scheme P44. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P43, wherein: R 14 It is an H or C1-C3 alkyl group.

[0307] Implementation Scheme P45. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P44, wherein: R 14 It is H or -CH3.

[0308] Implementation Scheme P46. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P45, wherein: X 4 It is N.

[0309] Implementation Scheme P47. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P45, wherein: X 4 It is CR 15 ;and R 15 It is an H or C1-C3 alkyl group.

[0310] Implementation Scheme P48. The compound or a pharmaceutically acceptable salt thereof as described in Implementation Scheme P47, wherein: X 4 It is CR 15 ;and R 15 It is H or -CH3.

[0311] Implementation Scheme P49. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P48, wherein: X 5 It is N.

[0312] Implementation Scheme P50. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P48, wherein: X 5 It is CH.

[0313] Implementation Scheme P51. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P50, wherein: X 6 It is N.

[0314] Implementation Scheme P52. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P50, wherein: X 6 It is CH.

[0315] Implementation Scheme P53. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P52, wherein: It is a single key.

[0316] Implementation Scheme P54. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P52, wherein: It is a double bond.

[0317] Implementation Scheme P55. The compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P54, wherein yes: .

[0318] Implementation Scheme P56. A compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P55, wherein the compound has formula (II), (III) or (IV): .

[0319] Implementation Scheme P57. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme P56, wherein the compound has formula (IIIb): (IIIb).

[0320] Implementation Scheme P58. A compound selected from the compounds in Table 1 and their pharmaceutically acceptable salts.

[0321] Implementation Scheme P59. A pharmaceutical composition comprising a compound according to any one of Implementation Schemes P1-P58 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0322] Implementation Scheme P60. A method for degrading B-cell lymphoma 6 protein (BCL6), the method comprising contacting BCL6 with an effective amount of a compound according to any one of Implementation Schemes P1-P58 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to Implementation Scheme P59.

[0323] Implementation Scheme P61. A method of treating cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P58 or a pharmaceutical composition according to Implementation Scheme P59.

[0324] Implementation Plan P62. The method described in Implementation Plan P61, wherein the cancer is lymphoma.

[0325] Implementation Plan P63. The method described in Implementation Plan P62, wherein the lymphoma is a diffuse large B-cell lymphoma.

[0326] Implementation Scheme P64. A method for treating an autoimmune disease in a subject in need, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P58 or a pharmaceutical composition according to Implementation Scheme P59.

[0327] Implementation Plan P65. The method described in Implementation Plan P64, wherein the autoimmune disease is selected from atopic dermatitis, asthma, lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, pulmonary hemorrhage nephritis 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, morphine scleroderma, multiple sclerosis, myasthenia gravis, narcolepsy, neuromuscular myotonia, pemphigus vulgaris, pernicious anemia, 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 Wechsler's granulomatosis.

[0328] Implementation Scheme P66. A pharmaceutical composition comprising a compound of the following formula: (70), Or its isomers, or pharmaceutically acceptable salts of the aforementioned substances, and two or more of the following: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silica, and sodium stearoyl fumarate.

[0329] Implementation Scheme P67. The pharmaceutical composition according to Implementation Scheme P66, wherein the compound is , Or its pharmaceutically acceptable salt.

[0330] Implementation Scheme P68. The pharmaceutical composition according to Implementation Scheme P66 or P67, wherein the pharmaceutical composition comprises anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silica, and sodium stearoyl fumarate.

[0331] Implementation Scheme P69. The pharmaceutical composition according to any one of Implementation Schemes P66-P68, wherein the pharmaceutical composition comprises about 35% by weight (w / w) of the compound (70) or an isomer thereof, or a pharmaceutically acceptable salt of the foregoing substance.

[0332] Implementation Scheme P70. The pharmaceutical composition according to any one of Implementation Schemes P66-P69, wherein the pharmaceutical composition is formulated for oral administration.

[0333] Implementation Scheme P71. The pharmaceutical composition according to Implementation Scheme P70, wherein the pharmaceutical composition is formulated for enteric release.

[0334] Implementation scheme P72. A unit dose formulation comprising a pharmaceutical composition according to any one of implementation schemes P66-P71, wherein the compound (70) or an isomer thereof or a pharmaceutically acceptable salt thereof is present in the unit dosage form in an amount of about 10 mg to about 100 mg.

[0335] Implementation scheme P73. The unit dose formulation according to implementation scheme P72, wherein the unit dose formulation comprises about 20 mg or about 80 mg of the compound (70) or an isomer thereof, or a pharmaceutically acceptable salt of the foregoing.

[0336] Implementation scheme P74. The unit dose formulation according to implementation scheme P72 or P73, wherein the unit dose formulation is in the form of a tablet.

[0337] Implementation scheme P75. The unit dose formulation according to implementation scheme P74, wherein the tablet is film-coated.

[0338] Implementation Scheme P76. A method for treating a subject with cancer or an autoimmune disease, the method comprising administering to the subject an effective amount of an anti-CD20 antibody and a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P58, or a pharmaceutical composition according to any one of Implementation Schemes P59 and P66-P71, or a unit dose formulation according to any one of Implementation Schemes P72-P75.

[0339] Implementation Scheme P77. A method for treating a subject with cancer or an autoimmune disease, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P58, or a pharmaceutical composition according to any one of Implementation Schemes P59 and P66-P71, or a unit dose formulation according to any one of Implementation Schemes P72-P75. The compound or a pharmaceutically acceptable salt thereof is administered as follows: (i) daily on each day of a 28-day cycle; or (ii) on days 1-14 of a 28-day cycle and not on days 15-28 of the 28-day cycle; or (iii) on days 1-21 of a 28-day cycle and not on days 22-28 of the 28-day cycle.

[0340] Implementation Scheme P78. A method for treating a subject with cancer or an autoimmune disease, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes P1-P58, or a pharmaceutical composition according to any one of Implementation Schemes P59 and P66-P71, or a unit dose formulation according to any one of Implementation Schemes P72-P75. The compound or a pharmaceutically acceptable salt thereof was administered to the subject once 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.

[0341] Implementation Scheme P79. The method according to Implementation Scheme P76 or P77, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject once 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.

[0342] Implementation scheme P80. The method according to any one of implementation schemes P76-P79, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0343] Implementation scheme P81. The method according to any one of implementation schemes P76-P79, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject twice daily.

[0344] Implementation Scheme P82. The method according to any one of Implementation Schemes P76-P81, wherein the compound or a pharmaceutically acceptable salt thereof is administered as follows: (i) daily on each day of a 28-day cycle; or (ii) on days 1-14 of a 28-day cycle and not on days 15-28 of the 28-day cycle; or (iii) on days 1-21 of a 28-day cycle and not on days 22-28 of the 28-day cycle.

[0345] Implementation scheme P83. The method according to implementation scheme P82, wherein the compound or a pharmaceutically acceptable salt thereof is applied daily on each day of a 28-day cycle.

[0346] Implementation Scheme P84. The method according to Implementation Scheme P82, wherein the compound is administered on days 1-14 of a 28-day cycle, and the compound or a pharmaceutically acceptable salt thereof is not administered on days 15-28 of the 28-day cycle.

[0347] Implementation Scheme P85. The method according to Implementation Scheme P82, wherein the compound is administered on days 1-21 of a 28-day cycle, and the compound or a pharmaceutically acceptable salt thereof is not administered on days 22-28 of the 28-day cycle.

[0348] Implementation Scheme P86. The method according to any one of Implementation Schemes P77-P85, the method further comprising administering an anti-CD20 antibody to the subject.

[0349] Implementation Scheme P87. The method according to Implementation Scheme P76 or P86, wherein the anti-CD20 antibody is rituximab.

[0350] Implementation Plan P88. The method described in Implementation Plan P87, wherein rituximab is administered intravenously.

[0351] Implementation Plan P89. The method described according to Implementation Plan P87 or P88, wherein approximately 375 mg / m² is administered every 28 days. 2 Rituximab.

[0352] Implementation scheme P90. The method according to any one of implementation schemes 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 as follows: (i) daily on each day of the 28-day treatment cycle; or (ii) administered on days 1-14 of the 28-day treatment cycle and not administered on days 15-28 of the 28-day treatment cycle; or (iii) administered on days 1-21 of the 28-day treatment cycle and not administered on days 22-28 of the 28-day treatment cycle.

[0353] Implementation scheme P91. The method according to any one of implementation schemes P76-P90, wherein the method is a method for treating cancer.

[0354] Implementation Plan P92. The method described in Implementation Plan P91, wherein the cancer is lymphoma.

[0355] Implementation Plan P93. The method described in Implementation Plan P92, wherein the lymphoma is a B-cell lymphoma.

[0356] Implementation scheme P94. The method according to implementation scheme P92 or P93, wherein the lymphoma is non-Hodgkin lymphoma.

[0357] Implementation Scheme P95. The method according to any one of Implementation Schemes P92-P94, wherein the lymphoma is diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, or lymphoplasmacytic lymphoma.

[0358] Implementation Plan P96. The method according to Implementation Plan P95, wherein the lymphoma is a diffuse large B-cell lymphoma or a follicular lymphoma.

[0359] Implementation scheme P97. The method according to any one of implementation schemes P91-P96, wherein the cancer is recurrent or refractory. Example

[0360] The following examples are presented in an illustrative rather than limiting manner. Compounds were named using an automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names of chemical structures in accordance with the Cahn-Ingold-Prelog rule supporting stereochemistry. Those skilled in the art can modify the procedures illustrated in the illustrative examples to obtain desired products.

[0361] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or stirring the product with a solution of acid (e.g., an aqueous HCl solution) after chromatographic purification.

[0362] The following abbreviations may be relevant to this application. abbreviation Synthesis Examples General procedure 1: First SNAr to pyrimidine.

[0363] DIPEA (1.1 equivalents) was added to a mixture of 5-amino-1-methylindolin-2-one (1 equivalent) in dry tetrahydrofuran [0.4 M] at -40ºC. A solution of 5-chloro-2,4-difluoropyrimidine (1 equivalent) in dry tetrahydrofuran [1.5 M] was slowly added to the mixture, allowing slow warming to room temperature. The reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was filtered and washed with acetonitrile. The solid was dried under vacuum to give the title compound as a brown solid. General Procedure 2: Buchwald Coupling of Amine with Indazole CBM.

[0364] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1a (1.1 equivalents), an amine (1.0 equivalent), Ruphos-Pd-G3 (0.20 equivalents), and NaOtBu (1.5 equivalents) in 1,4-dioxane [0.3 M] was heated to 90ºC for 16 h and then cooled to room temperature. The mixture was filtered through diatomaceous earth 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 hexane to give the title compound. General Procedure 3: Methylation of Amines

[0365] NaH (4.4 equivalents) was added to a solution of amine (1.0 equivalent, 14.2 mmol) in DMF [0.15 M] and stirred at 0ºC for 1 h. Iodomethane (2.8 equivalents) was added to the mixture at 0ºC. The resulting reaction mixture was stirred at room temperature for 16 h. 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 with PE / EA (15:1) elution to obtain the title compound. General Procedure 4: Reduce CBM with hydrogen.

[0366] A mixture of an indazole intermediate (1.0 equivalent) and Pd / C (10 wt.% palladium; 40% by weight) in EtOH: THF (1:1.5; [0.05 M]) was subjected to hydrogen (1 atm) at 50°C for 4 h. The mixture was degassed with nitrogen and filtered through diatomaceous earth. 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 hexane to give the title compound. General Procedure 5: Deprotect BOC with HCl or TFA.

[0367] A solution of BOC-protected amine (1.0 equivalent) in 1,4-dioxane [0.3 M] was added with 4 N HCl (14 equivalents) in 1,4-dioxane, and the reaction mixture was stirred at room temperature for 12 h. The evaporation was evaporated under reduced pressure to give the title compound as a solid (quantitative), which was used for the next step without further purification. General Procedure 6: SNAr of Decorated TBM and CBM.

[0368] A solution of amine hydrochloride (1.0 equivalent), chloro / fluoropyrimidine (1.0 equivalent), and N,N-diisopropylethylamine (3 to 5 equivalents) in DMSO [0.1–0.2 M] was stirred at 80°C for 2 h. The reaction mixture was filtered and purified by reversed-phase semi-preparative HPLC (10%–100% acetonitrile + 0.1% formic acid in water, 30 min). Fractions containing clean product were combined and lyophilized to give the title compound.

[0369] Example i-1. Synthesis of Intermediate 1: 3-(1-methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride

[0370] Step 1: Synthesis of tert-butyl (1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-4-yl)(methyl)carbamate. 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (300 mg, 0.6000 mmol), 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-daramblanc vial and purged with nitrogen for 1 min. Subsequently, 1,4-dioxane (0.8 mL) was added, and the reaction mixture was stirred overnight at 100ºC. The product was purified from the crude mixture by column chromatography (10 g SNAP column, 0-7% methanol / DCM 25 CV, 7% methanol / DCM 10 CV) to give the title compound as a white solid (106 mg, 0.1673 mmol, 27.8% yield). MS (ESI) m / z 634.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6 ) δ ppm 7.89 (d, J=8.19 Hz, 1H), 7.26 - 7.51 (m, 11 H), 6.88 (d, J=1.59 Hz, 1 H), 6.82 (dd, J=9.17, 1.96Hz, 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, 2H), 1.42 (s, 9H).

[0371] Step 2: Synthesis of tert-butyl (1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-4-yl)(methyl)carbamate. N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-N-methyl-carbamate (106 mg, 0.1700 mmol) and ethanol (4.1813 mL) were dissolved in a 40 mL vial equipped with a stir 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 with hydrogen. The reaction was stirred overnight under a hydrogen balloon. The slurry was filtered through diatomaceous earth and concentrated. The residue was loaded onto a SNAP25G column and purified with 0–50% EtOAC / hexane (containing 2–5% MeOH additive) to give the title compound as a yellow oil (50 mg, 0.110 mmol, 65.6% yield).

[0372] Step 3: Synthesis of 3-(1-methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride. N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester (50 mg, 0.1100 mmol) was added to a vial equipped with a stir bar, and dichloromethane (1 mL) was added. Then, HCl 4N in 1,4-dioxane (0.4400 mmol) was added to the mixture, and the mixture was stirred for 2 hours. The stir bar was removed, and the solvent was removed under vacuum to give the title compound as a grayish-white solid (42 mg, 0.107 mmol, 97.6% yield). Example i-2. Synthesis of intermediate 2: 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride

[0373] Step 1: Synthesis of 6-bromo-3-iodo-1-methyl-indazole. NIS (25.58 g, 113.7 mmol) was added to a solution of 6-bromo-1-methyl-indazole (8.00 g, 37.9 mmol) in DMF (100 mL). The reaction mixture was heated to 150ºC overnight and then cooled to room temperature. The evaporation was carried out under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexane to give the title compound as a solid (4.95 g, 14.7 mmol, 39% yield). MS (ESI) [M+H] + 336.90.

[0374] Step 2: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole. 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 to (2,6-dibenzyloxy-3-pyridinyl)boronic acid (1.99 g, 5.94 mmol), potassium phosphate (3.78 g, 17.81 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(ii) dichloride (0.43 g, 0.5900 mmol) under N2 and stirred at 80ºC for 17 h. LC-MS showed complete consumption of the reactants and the desired MS peak. The reaction was then cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (3 x 40 mL), washed with brine (2 x 40 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, gradient: 0-30% ethyl acetate in petroleum ether) to the title compound (2.1 g, 4.20 mmol, 71% yield) as a pale yellow solid. MS (ES) [M+H] + 500.3. 1 H 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).

[0375] Step 3: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-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) in 1,4-dioxane (53.292 mL) was heated to 110ºC for 28 h and then cooled to room temperature. The mixture was filtered through diatomaceous earth 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 give tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid (2.81 g, 4.53 mmol, 57% yield) as a solid. MS (ESI) [M+H + 620.4; 1 H NMR (500 MHz, CDCl3) δ7.89 (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 = 11.9Hz, 2H), 2.10 (dd, J = 13.0, 2.8 Hz, 2H), 1.48 (s, 9H).

[0376] Step 4: Synthesis of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidin-1-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]amino]piperidin-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 50ºC for 4 h. At this point, only the olefin 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 50ºC for 24 h. The mixture was filtered through diatomaceous earth and washed with MeOH:MeCN (1:1 ratio, 3 x 50.0 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate (495 mg, 0.9496 mmol, 98.085% yield) as a solid. MS (ESI) [M+H] + : 442.4; 1 H 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).

[0377] Step 5: Synthesis of 3-[1-methyl-6-(4-piperidinylamino)indazole-3-yl]piperidine-2,6-dione hydrochloride. Hydrogen chloride 4N (3.45 mL, 13.8 mmol) in 1,4-dioxane was added to a solution of 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (1.22 g, 2.76 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 80ºC for 2 hours. The solid was collected by filtration to give the title compound as a white solid (1.0 g, 2.65 mmol, 96% yield). MS (ESI) m / z 342.2 [M+H] + . 1 H 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, 1H), 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, 2H), 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

[0378] Step 1: Synthesis of tert-butyl carbamate. 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)carbamate was absorbed under N2 atmosphere with mechanical stirring into 1,4-dioxane (1600 mL) in a 3000 mL multi-port RBF equipped with a reflux condenser. Next, tert-butyl carbamate (56.2 g, 480 mmol) was added, followed by K2CO3 (133 g, 959 mmol) and purging for 5 min. XPhos Pd G2 (25.2 g, 32.0 mmol) was then added, purging again for 5 min, and refluxed overnight at 110ºC. The reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The obtained filtrate was evaporated to give the crude product, which was purified using ISCO on silica gel with PE / EtOAc as eluent to give the title compound as a white solid (148 g, 275 mmol, 86% yield). MS (ESI) m / z 537.30 [M+H] + . 1 H NMR(400 MHz, DMSO-d6) δ ppm 9.5 (s, 1H), 7.89 – 7.91 (m, 1H), 7.28 – 7.54 (m, 12H), 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).

[0379] Step 2: Synthesis of tert-butyl (3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)carbamate. Tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)carbamate (25 g, 46.6 mmol) and THF (500 mL) were added to a flask. This mixture was purged with nitrogen for 5 min, and then palladium on carbon (24.79 g, 23.29 mmol) was added, followed by stirring overnight at 55ºC under H2 atmosphere. After this time, the reaction mixture was filtered through diatomaceous earth, washed with THF (2 L), and the resulting filtrate was evaporated to give the title compound as a white solid (15.69 g, 43.8 mmol, 94% yield). MS (ESI) m / z 359.1 [M+H] + ; 1H NMR (400MHz, 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).

[0380] Step 3: Synthesis of the HCl salt of 3-(6-amino-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione. Tert-butyl (3-(2,6-dioxadiidine-3-yl)-1-methyl-1H-indazole-6-yl)carbamate (25 g, 69.8 mmol) was dissolved in 1,4-dioxane (250 mL) in 2 L RBF with magnetic stirring. HCl (4 M in dioxane) (250 mL, 69.8 mmol) was slowly added, and the reaction was then stirred at room temperature for 48 hours. After this time, the mixture was filtered, and the resulting solid was absorbed into methanol and stirred thoroughly for 20 minutes, and then filtered again to give the title compound as a pale yellow solid (18 g, 57.2 mmol, 82% yield). MS (ESI) m / z 259.1 [M+H] + . 1 H NMR(400 MHz, DMSO-d6) δ ppm 7.80 - 7.82 (d, 1 H), 7.53 (s, 1 H), 7.08 - 7.11 (d1 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)piperidin-2,6-dione hydrochloride

[0381] Step 1: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-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 90ºC for 18 h and then cooled to room temperature. The mixture was filtered through diatomaceous earth 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 hexane to obtain the title compound as a solid (550 mg, 89%). 1 H 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.

[0382] Step 2: Synthesis of tert-butyl piperidine-1-carboxylate. To a solution of tert-butyl piperidine-1-carboxylate (550 mg, 0.89 mmol) in DMSO (3.6 mL) and acetic acid (0.9 mL), an aqueous solution of formaldehyde (0.13 mL, 1.8 mmol) and NaBH(OAc)3 (282 mg, 1.3 mmol) were added sequentially. The reaction mixture was stirred at room temperature 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), and brine (5 mL), dried over 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 hexane to give the title compound as a solid (467 mg, 83% yield). 1 H 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.

[0383] Step 3: 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidin-1-carboxylic acid tert-butyl ester. A mixture of 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidin-1-carboxylic acid tert-butyl ester (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 50ºC for 2 h. The mixture was filtered through diatomaceous earth. It was 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 obtain the title compound as a solid (258 mg, 77%). 1 H 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, 5.1Hz, 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.

[0384] Step 4: Synthesis of 3-[1-methyl-6-[methyl(4-piperidinyl)amino]indazole-3-yl]piperidine-2,6-dione; hydrochloride. 4 MHCl (1.42 mL, 5.66 mmol) in 1,4-dioxane was added to a solution of tert-butyl piperidine-1-carboxylate (258 mg, 0.57 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated to 100ºC for 3 h and then cooled to room temperature. The evaporation product was 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), and then dried under vacuum to give the title compound as a solid (217 mg, 92%). 1 HNMR (400 MHz, D2O) δ 7.93 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.31 (d, J = 8.0Hz, 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: No exchangeable protons 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)indoline-2-one

[0385] Step 1: Synthesis of 1-(2-morpholinoethyl)-5-nitroindoline-2-one. Diisopropyl azodicarbonate (1.091 mL, 5.61 mmol) was added dropwise to a stirred solution of triphenylphosphine (1.104 g, 4.21 mmol) in 20 mL of THF under nitrogen atmosphere at 0°C and stirred for 20 min. Then, 2-morpholinoethyl-1-ol (736 mg, 5.61 mmol) was added and stirred for 15 min. Subsequently, 5-nitroindoline-2-one (500 mg, 2.81 mmol) was added, and the mixture was slowly heated to 25°C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by rapid column chromatography on silica gel using 60%–80% ethyl acetate / petroleum ether to give the title compound as a grayish-white solid (273 mg, 0.937 mmol, 24% yield). MS (ESI) [M+H) + 292.0.

[0386] Step 2: Synthesis of 5-amino-1-(2-morpholinoethyl)indoline-2-one. 10% Pd / C (150 mg) was added to a stirred suspension of 1-(2-morpholinoethyl)-5-nitroindoline-2-one (300 mg, 1.030 mmol) in ethanol (5.0 mL) and THF (5.0 mL) under nitrogen at 25ºC. The reaction mixture was stirred for 8 h under hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and the diatomaceous earth pad was washed with ethanol (2 x 50 mL). The filtrate was concentrated under reduced pressure to obtain the title compound as a gray solid (280 mg, 1.071 mmol, 45% yield). 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)indoline-2-one

[0387] Step 1: Synthesis of 5-amino-1-(4,4,4-trifluorobutyl)indoline-2-one: Similar to intermediate 5, and using 4,4,4-trifluorobut-1-ol as the starting material, the title compound was synthesized. Example i-7. Synthesis of intermediate 7: 5-amino-6-fluoro-1-methylindoline-2-one

[0388] Step 1: Synthesis of 6-fluoro-1-methyl-5-nitroindoline-2-one. Sodium nitrate (51.5 mg, 0.605 mmol) was added to a solution of 6-fluoro-1-methylindoline-2-one (100 mg, 0.605 mmol) in TFA (1 mL) at 0ºC, allowing the reaction mixture to warm to room temperature and stirring for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was then quenched with saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to give the title compound as a white solid (100 mg, 0.476 mmol, 79% yield); MS (ESI) m / z 211.0 [M+H] + ; 1 H 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, 2H), 3.28 - 3.33 (m, 43 H), 3.24 (s, 3 H).

[0389] 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) for 2 h at room temperature under hydrogen (1 atm). The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound as a grayish-white solid (80 mg, 0.444 mmol, 93% yield); MS (ESI) m / z 181.2 [M+H] + . Example i-8. Synthesis of intermediate 8: 5-amino-7-fluoro-1-methylindoline-2-one

[0390] Step 1: Synthesis of 7-fluoro-1-methylindolin-2-one. Sodium hydroxide 1N (3.97 mL, 3.97 mmol) and dimethyl sulfate (0.379 mL, 3.97 mmol) were added to a suspension of 7-fluoroindolin-2-one (0.400 g, 2.65 mmol) in water (10 mL). The reaction mixture was stirred at 120ºC for 40 min. LCMS indicated incomplete reaction, with 20% SM remaining. The reaction mixture was quenched with saturated sodium chloride aqueous solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (1 x 25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the title compound 7-fluoro-1-methylindolin-2-one (0.3 g, 1.82 mmol, 69% yield) as a yellow solid; MS (ESI) m / z 331.2 [M+H] + .

[0391] Step 2: Synthesis of 5-amino-7-fluoro-1-methylindoline-2-one. Similar to intermediate 7, and using 7-fluoro-1-methylindoline-2-one as the starting material, the title compound was synthesized. Example i-9. Synthesis of intermediate 9: 5-amino-4-fluoro-1-methylindoline-2-one

[0392] Step 1: Synthesis of 4-fluoro-1-methylindolin-2-one. Sodium hydroxide 1N (9.92 mL, 9.92 mmol) and dimethyl sulfate (0.695 mL, 7.28 mmol) were added to a suspension of 4-fluoroindolin-2-one (1.0 g, 6.62 mmol) in water (18 mL). The reaction mixture was stirred at 120ºC for 40 min. LCMS indicated incomplete reaction with 20% SM remaining. The reaction mixture was quenched with saturated sodium chloride aqueous solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (1 x 25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the title compound (1.48 g, 100%) as a white solid; MS (ESI) m / z 166.2 [M+H] + .

[0393] Step 2: Synthesis of 4-fluoro-1-methyl-5-nitroindoline-2-one. 90% nitric acid (0.195 mL, 4.53 mmol) in 1 mL of sulfuric acid was slowly added to a solution of 4-fluoro-1-methylindoline-2-one (0.68 g, 4.12 mmol) in sulfuric acid (10 mL) at -30ºC. The reaction mixture was stirred at -30ºC and allowed to warm to 0ºC over 30 min. The reaction mixture was poured onto 100 g of ice and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with a saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to give the title compound 4-fluoro-1-methyl-5-nitroindoline-2-one (0.260 g, 1.24 mmol, 30.0% yield) as a yellow solid; MS (ESI) m / z 211.2 [M+H] + .

[0394] Step 3: Synthesis of 5-amino-4-fluoro-1-methylindolin-2-one. A 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) for 2 h at room temperature under hydrogen (1 atm). The reaction mixture was filtered. The eluent was concentrated under reduced pressure to give the title compound as a white solid (44 mg, 0.244 mmol, 86% yield); MS (ESI) m / z 181.2 [M+H] + ; 1 H 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-isopropylindoline-2-one

[0395] Step 1: Synthesis of 1-Isopropyl-5-nitroindoline-2-one: A solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (0.5 g, 2.51 mmol) and propan-2-amine (0.445 g, 7.53 mmol) in DMSO (4 mL) was stirred at 60ºC for 15 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (1 x 25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give 2-(2-(isopropylamino)-5-nitrophenyl)acetic acid (0.528 g, 87%) as a yellow solid. Then, solid 2-(2-(isopropylamino)-5-nitrophenyl)acetic acid (0.528 g) was stirred with 10 mL of 2 N HCl for 15 hours at room temperature. The resulting solid was collected by filtration to give the title compound as a yellow solid (0.45 g, 2.043 mmol, 81% yield); MS (ESI) m / z 221.2 [M+H] + .

[0396] Step 2: Synthesis of 5-amino-1-isopropylindolin-2-one: A 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) for 15 h at room temperature under hydrogen (1 atm). The reaction mixture was filtered. The eluent was concentrated under reduced pressure to give the title compound 5-amino-1-isopropylindolin-2-one (350 mg, 1.840 mmol, 90% yield) as a grayish-white solid; MS (ESI) m / z 191.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.80 (d, J=8.31 ​​Hz, 1H), 6.55 (d, J=1.96 Hz, 1 H), 6.43 (dd, J=8.31, 2.32 Hz, 1 H), 4.72 (br s, 2H), 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-ethylindoline-2-one

[0397] Step 1: Synthesis of 5-amino-1-ethylindoline-2-one: Similar to intermediate 10, the title compound was synthesized using ethylamine hydrochloride as the starting material. Example i-12. Synthesis of intermediate 12: 5-amino-1-(2-hydroxyethyl)indoline-2-one

[0398] Step 1: Synthesis of 5-amino-1-(2-hydroxyethyl)indoline-2-one: Similar to intermediate 10, the title compound was synthesized using 2-aminoethanol as the starting material. Example i-13. Synthesis of intermediate 13: 5-amino-1-(2-methoxyethyl)indoline-2-one

[0399] Step 1: Synthesis of 2-(2-((2-methoxyethyl)amino)-5-nitrophenyl)acetic acid. 2-Methoxyethyl-1-amine (2,377 mg, 5.02 mmol) and DIPEA (0.877 mL, 5.02 mmol) were added to a solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (1,500 mg, 2.51 mmol) in THF (5.0 mL) under nitrogen at 25ºC. The reaction mixture was heated to 60ºC and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (550 mg, 0.543 mmol, 21% yield).

[0400] Step 2: Synthesis of 1-(2-methoxyethyl)-5-nitroindoline-2-one. 1.5 N HCl (3.0 mL) was added to a solution of 2-(2-((2-methoxyethyl)amino)-5-nitrophenyl)acetic acid (550 mg, 2.16 mmol) in water (2.0 mL). The reaction mixture was heated to 60ºC and stirred for 16 h. The reaction mixture was slowly poured into a sodium bicarbonate solution at 0ºC and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a light brown solid (240 mg, 0.95 mmol, 44% yield).

[0401] Step 3: Synthesis of 5-amino-1-(2-methoxyethyl)indoline-2-one. 10% Pd / C (101 mg) was added to a stirred solution of 1-(2-methoxyethyl)-5-nitroindoline-2-one (240 mg, 0.945 mmol) in ethanol (10 mL) at 25ºC under nitrogen. The reaction mixture was stirred for 8 h under hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and the diatomaceous earth 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 in 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

[0402] Step 1: Synthesis of 3,3-dibromo-1-methyl-5-nitro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one. NBS (1.37 g, 7.68 mmol) was added to a stirred solution of 1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (800 mg, 3.66 mmol) in tert-butanol (1 mL) and water (1 mL) 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 (3 x 100 mL). The combined organic layers were evaporated to obtain the crude title compound, which was used without further purification.

[0403] Step 2: Synthesis of 5-amino-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one: Zinc powder (1.30 g, 20.0 mmol) was added 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) and the reaction mixture was stirred at 25ºC for 6 h. The reaction mixture was monitored by TLC and LCMS. After this time, the reaction mixture was evaporated. The resulting residue was alkalized with NaOH solution (100 mL) and extracted with 10% MeOH in DCM. The organic fraction was evaporated to obtain 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)indoline-2-one

[0404] Step 1: Synthesis of 2-methyl-4-(6-nitro-1H-indole-1-yl)but-2-ol: Compound 3-hydroxy-3-methylbutyl-4-methylbenzenesulfonate (2, 2.30 g, 8.02 mmol) and cesium carbonate (3.01 g, 9.25 mmol) were added to a stirred solution of 6-nitro-1H-indole (1, 1.0 g, 6.17 mmol) in DMF (10 mL) at 25ºC. The reaction mixture was heated to 120ºC 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 give a crude compound, which was purified by rapid column chromatography on silica using 20%–30% ethyl acetate / petroleum ether to give the title compound (1.4 g, 5.44 mmol, 88% yield) as a brown semi-solid. MS (ESI) m / z 249.1 [M+H] + .

[0405] Step 2: Synthesis of 3,3-dibromo-1-(3-hydroxy-3-methylbutyl)-6-nitroindoline-2-one. NBS (142 mg, 0.797 mmol) was added to a stirred solution of 2-methyl-4-(6-nitro-1H-indoline-1-yl)but-2-ol (100 mg, 0.380 mmol) in t-BuOH (1 mL) and water (1.0 mL) at 0°C. The reaction mixture was slowly heated 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 sulfate, filtered, and concentrated under reduced pressure to give the title compound (150 mg, 94% yield). The crude product was used in the next step without further purification.

[0406] Step 3: Synthesis of 6-amino-1-(3-hydroxy-3-methylbutyl)indoline-2-one. Zinc powder (116 mg, 1.78 mmol) was added to a stirred solution of 150 mg of 3,3-dibromo-1-(3-hydroxy-3-methylbutyl)-6-nitroindoline-2-one in AcOH (3.0 mL) at 0°C. The reaction mixture was slowly heated to 25°C and stirred for 8 h. The reaction mixture was concentrated under reduced pressure to give the crude compound. The crude product was purified by rapid column chromatography on silica using 6% methanol / DCM to give the title compound as a brown gelatinous solid (100 mg, 0.333 mmol, 87% yield). MS (ESI) m / z 235.2 [M+H] + . Example i-16. Synthesis of intermediate 16: 6-amino-1-(3-hydroxy-3-methylbutyl)-3,3-dimethylindoline-2-one

[0407] Step 1: Synthesis of N-(2-bromo-5-nitro-phenyl)-2-methyl-prop-2-enamide. 2-methylprop-2-enyl chloride (0.45 mL, 4.61 mmol) was added to a solution of 2-bromo-5-nitro-aniline (1.00 g, 4.61 mmol) in DMA (20 mL), and the reaction mixture was stirred at room temperature for 12 h. Water (5.0 mL) was added, and the resulting precipitate was collected by filtration, washed with water (20 mL), and then dried under vacuum to give the title compound as a solid (950 mg, 72%). 1 HNMR (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.

[0408] Step 2: Synthesis of 3,3-dimethyl-6-nitro-indoline-2-one. Triethylamine (1.16 mL, 8.33 mmol), TBAB (1.07 g, 3.33 mmol), and Pd(OAc)₂ (15.0 mg, 0.07 mmol) were sequentially added to a solution of N-(2-bromo-5-nitro-phenyl)-2-methyl-propane-2-enamide (950 mg, 3.33 mmol) in DMF (33 mL) under nitrogen atmosphere, and the reaction mixture was stirred at 80ºC for 1 h. HCOONa (227 mg, 3.33 mmol) was added, and the reaction mixture was stirred at 80ºC 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 over 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 give the title compound as a solid (180 mg, 26%). 1 H NMR (400 MHz, DMSO d6): δ 10.75 (s, 1H), 7.90 (dd, J = 8.2, 2.1 Hz, 1H), 7.60 (d, J = 8.2Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 1.30 (s, 6H). MS (ESI) [M+H] + 207.0.

[0409] Step 3: Synthesis of 1-(3-hydroxy-3-methyl-butyl)-3,3-dimethyl-6-nitro-indoline-2-one. To a solution of 3,3-dimethyl-6-nitro-indoline-2-one (180 mg, 0.87 mmol) in DMF (3 mL), (3-hydroxy-3-methyl-butyl)-4-methylbenzenesulfonate (271 mg, 1.05 mmol) and K₂CO₃ (362 mg, 2.62 mmol) were added sequentially, and the reaction mixture was stirred at 80ºC 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 over 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 give the title compound as a solid (145 mg, 57%). 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.

[0410] Step 4: Synthesis of 6-amino-1-(3-hydroxy-3-methyl-butyl)-3,3-dimethyl-indoline-2-one. A mixture of 1-(3-hydroxy-3-methyl-butyl)-3,3-dimethyl-6-nitro-indoline-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) overnight at room temperature. The mixture was filtered through diatomaceous earth and washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give the title compound as a solid (125 mg, 96%), which was used directly for the next step without further purification. MS (ESI) [M+H] + 263.2. Example i-17. Synthesis of intermediate 17: (2-(5-amino-2-oxoindoline-1-yl)ethyl)(methyl)carbamate tert-butyl ester

[0411] Step 1: Synthesis of 1-(2-(methylamino)ethyl)-5-nitroindoline-2-one: Tert-butyl (2-aminoethyl)(methyl)carbamate (2, 1.750 g, 10.04 mmol) and DIPEA (1.754 mL, 10.04 mmol) were added to a stirred solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (1, 1.0 g, 5.02 mmol) in THF (30 mL) at 25ºC under nitrogen. The reaction mixture was heated to 65ºC and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product as a brown liquid. The crude product was dissolved in water (20 mL) and 6.0 N HCl (6 mL, 36.0 mmol) was added dropwise at 25ºC. The reaction mixture was heated to 65ºC 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 give the title compound (400 mg, 0.909 mmol, 18% yield), which was used for the next step without further purification.

[0412] Step 2: Synthesis of tert-butyl methyl (2-(5-nitro-2-oxoindoline-1-yl)ethyl)carbamate. Under nitrogen atmosphere at 0ºC, DIPEA (0.397 mL, 2.272 mmol) and Boc-anhydride (0.422 mL, 1.818 mmol) were added dropwise to a stirred solution of 1-(2-(methylamino)ethyl)-5-nitroindoline-2-one (400 mg, 0.909 mmol) in DCM (10 mL). The reaction mixture was slowly heated to 25ºC 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 sulfate, filtered, and concentrated under reduced pressure to give a crude compound, which was purified by rapid column chromatography on silica gel with 20%–40% ethyl acetate / petroleum ether to give the title compound (240 mg, 0.697 mmol, 77% yield).

[0413] Step 3: Synthesis of tert-butyl (2-(5-amino-2-oxoindoline-1-yl)ethyl)(methyl)carbamate. 10% Pd / C (120 mg) was added to a stirred solution of tert-butyl (240 mg, 0.716 mmol) of methyl (2-(5-nitro-2-oxoindoline-1-yl)ethyl)carbamate in ethanol (2.5 mL) and THF (2.5 mL) at 25ºC under nitrogen. The reaction mixture was stirred for 6 h under hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and the diatomaceous earth 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 in the next step without further purification. Example i-18. Synthesis of intermediate 18: 5-amino-1-(2,2-difluoropropyl)indoline-2-one

[0414] Step 1: Synthesis of 2,2-difluoropropyl 4-methylbenzenesulfonate. Triethylamine (2.18 mL, 15.61 mmol) was added to a solution of 2,2-difluoroprop-1-ol (1, 1.0 g, 10.4 mmol) in DCM (10 mL) at 25ºC. The mixture was cooled to 0ºC and 4-dimethylaminopyridine (0.127 g, 1.041 mmol) was added, followed by 4-methylbenzenesulfonyl chloride (2.381 g, 12.49 mmol). The reaction mixture was slowly heated to 25ºC and stirred for 16 h. The resulting reaction mixture was added to water (25 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a grayish-white solid (2.0 g, 7.95 mmol, 76% yield). The crude product was used in the next step without further purification. MS (ESI) m / z 268.0 [M+H2O].

[0415] Step 2: Synthesis of 1-(2,2-difluoropropyl)-5-nitro-1H-indole. Cesium carbonate (1507 mg, 4.63 mmol) and 5-nitro-1H-indole (3,500.0 mg, 3.08 mmol) were added to a solution of 2,2-difluoropropyl 4-methylbenzenesulfonate (931 mg, 3.70 mmol) in DMF (5 mL) at 25°C. The mixture was heated to 120°C and stirred for 16 h. The reaction mixture was quenched by adding 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 sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography on silica using 35%–40% ethyl acetate / petroleum ether to give the title compound as a pale yellow solid (250.0 mg, 0.997 mmol, 32% yield). MS (ESI) m / z 240.9 [M+H] + .

[0416] Step 3: Synthesis of 3,3-dibromo-1-(2,2-difluoropropyl)-5-nitroindoline-2-one. NBS (373 mg, 2.094 mmol) was added fractionally 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. The reaction mixture was slowly heated 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 layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow solid (350.0 mg, 0.619 mmol, 62% yield). MS (ESI) m / z 415.0 [M+H] + .

[0417] Step 4: Synthesis of 5-amino-1-(2,2-difluoropropyl)indoline-2-one. Zinc powder (202 mg, 3.10 mmol) was slowly added to a stirred solution of 3,3-dibromo-1-(2,2-difluoropropyl)-5-nitroindoline-2-one (350.0 mg, 0.619 mmol) in acetic acid (5.0 mL) at 25ºC and stirring was continued for 6 h. The reaction mixture was concentrated under reduced pressure and diluted by adding 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 sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brown solid (150.0 mg, 0.299 mmol, 48% yield). 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)indoline-2-one

[0418] Step 1: Synthesis of 5-amino-1-(3-fluoro-3-methylbutyl)indoline-2-one. Similar to intermediate 18, the title compound was synthesized using 3-fluoro-3-methylbut-1-ol as the starting material. Example i-20. Synthesis of intermediate 20: 5-amino-1-(2-fluoro-2-methylpropyl)indoline-2-one

[0419] Step 1: Synthesis of 2-fluoro-2-methylpropyltrifluoromethanesulfonate. 2,6-Dimethylpyridine (2.26 mL, 19.5 mmol) was slowly added to a stirred mixture of trifluoromethanesulfonic anhydride (2.75 mL, 16.28 mmol) in DCM (10 mL) at -10ºC, followed by dropwise addition of a solution of 2-fluoro-2-methylprop-1-ol (1.50 g, 16.3 mmol) in DCM (35 mL). The reaction mixture was stirred at 0ºC for 4 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in DCM and washed with 1.0 N HCl solution, followed by washing with saturated bicarbonate solution and then with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (2.5 g, 11.2 mmol, 68% yield) as a brown liquid. The crude product was used for the next step without purification.

[0420] Step 2: Synthesis of 1-(2-fluoro-2-methylpropyl)-5-nitro-1H-indole. Compound 2-fluoro-2-methylpropyltrifluoromethanesulfonate (2419 mg 10.79 mmol) was added to a stirred solution of 5-nitro-1H-indole (700 mg, 4.32 mmol) in DMF (10 mL). The reaction mixture was heated to 100ºC and stirred for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound (600 mg, 2.41 mmol, 56% yield). The crude product was used unpurified for the next step. MS (ESI) m / z 237.1 [M+H] + .

[0421] Synthesis of 5-amino-1-(2-fluoro-2-methylpropyl)indoline-2-one. Bromine (0.218 mL, 4.23 mmol) was added to a stirred solution of 1-(2-fluoro-2-methylpropyl)-5-nitro-1H-indole (100 mg, 0.423 mmol) in tert-butanol (2.0 mL) at 0°C, and the reaction mixture was stirred for 5 min. Water (2 mL) was then slowly added, and the mixture was heated 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 sulfate, filtered, and concentrated under reduced pressure to give 110 mg of crude material. The residue was dissolved in acetic acid (3.5 mL), and zinc powder (88 mg, 1.34 mmol) was added, and the mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was dissolved in ethyl acetate and treated with sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title 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)indoline-2-one

[0422] Step 1: Synthesis of 5-nitro-1-(2,2,2-trifluoroethyl)indoline-2,3-dione. NaH (60% dispersion in mineral oil, 220.0 mg, 5.50 mmol) was added to a solution of 5-nitroindoline-2,3-dione (0.96 g, 5.00 mmol) in DMF (35.0 mL) cooled to 0ºC. After stirring at 0ºC for 45 min, 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.28 g, 5.50 mmol) was added. The reaction mixture was warmed to room temperature 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 and 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 give the title compound as a solid (910.0 mg, 66%). 1 H 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).

[0423] 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 under hydrogen atmosphere at room temperature for 1 h. The mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was concentrated under reduced pressure to give the title compound as a solid (450.0 mg, 92%), which was used for the next step without further purification. MS (ESI) [M+H] + 247.1.

[0424] Step 3: Synthesis of 5-amino-1-(2,2,2-trifluoroethyl)indoline-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 115ºC for 1 h and then cooled to room temperature. The evaporation was evaporated under reduced pressure. The material was purified by reversed-phase chromatography (C18) using a gradient of 10%–70% acetonitrile and water (ammonium formate buffer, pH 4) to give the title compound as a solid (150.0 mg, 35%). 1 H 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 = 9.5Hz, 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

[0425] Step 1: Synthesis of 1-benzyl 4-ethyl 5-oxoazonicycloheptan-1,4-dicarboxylate: BF3OEt2 (1.358 mL, 10.72 mmol) was added to a stirred solution of 4-oxopiperidinyl-1-carboxylate (2.5 g, 10.72 mmol) and ethyl 2-diazolate (9.78 g, 12.86 mmol) in THF (50 mL) at -25ºC. The reaction mixture was stirred at 25ºC for 4 h. The reaction mixture was then alkalized with sodium bicarbonate solution (100 mL) and the organic matter was extracted with EtOAc (3 x 100 mL). The combined organic fractions were dried and concentrated to give a crude material. This crude material was purified by Combi-flash column chromatography, with the product eluting in PE at 15% EA. The fractions containing the product were combined and concentrated to give 1-benzyl 4-ethyl 5-oxoazacycloheptan-1,4-dicarboxylate as a colorless liquid (3.5 g, 3.40 mmol, 31.7% yield). (ESI) [M+H + 320.0, RT = 2.15.

[0426] Step 2: Synthesis of 1-benzyl 4-ethyl 4-methyl-5-oxoazacycloheptane-1,4-dicarboxylate: Cs₂CO₃ (7.14 g, 21.92 mmol) and MeI (1.371 mL, 21.92 mmol) were added to a stirred solution of 1-benzyl 4-ethyl 5-oxoazacycloheptane-1,4-dicarboxylate (3.5 g, 10.96 mmol) in DMF (8 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred at 25°C for 6 h. The reaction mixture was evaporated to obtain a crude material, which was purified by combi-flash column chromatography. The product eluted in PE at 25%–30% EA and the fraction containing the product were combined and concentrated to give 1-benzyl 4-ethyl 4-methyl-5-oxoazacycloheptane-1,4-dicarboxylate (2.5 g, 76%) as a colorless liquid. 1 H 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

[0427] Step 3: Synthesis of benzyl 4-methyl-5-oxozycycloheptane-1-carboxylate: KOH (0.959 g, 17.10 mmol) was added to a stirred solution of 1-benzyl 4-ethyl 4-methyl-5-oxozycycloheptane-1,4-dicarboxylate (2.5 g, 5.70 mmol) in MeOH (20 mL) and water (20 mL) at 25°C. The reaction mixture was stirred at 60°C for 4 h. The reaction mixture was then diluted with water (50 mL) and extracted with DCM (2 x 100 mL). Purification was performed by reversed-phase preparative HPLC using a gradient of 2%–98% MeCN in 5 mm ammonium formate at pH 3.3. Fractions containing the desired product were combined and concentrated to give benzyl 4-methyl-5-oxozycycloheptane-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

[0428] Step 4: Synthesis of benzyl 4-amino-5-methylaziridine-1-carboxylate: Ammonium acetate (4.66 g, 60.5 mmol) and NaCNBH4 (1.140 g, 18.14 mmol) were added to a stirred solution of 4-methyl-5-oxaziridine-1-carboxylate (1.0 g, 3.02 mmol) in 2-propanol (20 mL). The reaction mixture was stirred at 50°C for 3 h and monitored by TLC and LCMS. The reaction mixture was then diluted with water (80 mL) and extracted with DCM (3 x 80 mL). The organic fraction was concentrated to give 4-amino-5-methylaziridine-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-methylazacycloheptan-1-carboxylate

[0429] Step 1: Synthesis of 1-benzyl 3-ethyl 4-oxozylidene-1,3-dicarboxylate: BF3OEt2 (2.72 mL, 21.43 mmol) was added to a stirred solution of 3-oxopiperidinium-1-carboxylate (5.0 g, 21.43 mmol) and ethyl 2-diazolate (21.20 g, 27.9 mmol) in THF (50 mL) at -78ºC. The reaction mixture was warmed to room temperature and stirred at 25ºC for 4 h. The reaction mixture was then alkalized 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 a crude material. This crude material was purified by Combi-flash column chromatography, eluting the product in PE at 20%–30% EA. The fractions containing the product were combined and concentrated to give 1-benzyl 3-ethyl 4-oxoazacycloheptan-1,3-dicarboxylate as a colorless liquid (4.5 g, 10.00 mmol, 46.7% yield). (ESI) [M+H + 320.1, RT = 2.11.

[0430] Step 2: Synthesis of 1-benzyl 3-ethyl 3-methyl-4-oxozycycloheptane-1,3-dicarboxylate: Cs₂CO₃ (6.53 g, 20.04 mmol) and MeI (1.253 mL, 20.04 mmol) were added to a stirred solution of 1-benzyl 3-ethyl 4-oxozycycloheptane-1,3-dicarboxylate (4.0 g, 10.02 mmol) in DMF (1 mL) at 0°C. The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was then warmed to room temperature and stirred at 25°C for 6 h. The reaction mixture was evaporated to obtain a crude material, which was purified by combi-flash column chromatography. The product eluted in PE at 20% EtOAc and the fraction containing the product were combined and concentrated to obtain 1-benzyl 3-ethyl 3-methyl-4-oxoazacycloheptan-1,3-dicarboxylate as a colorless liquid (2.2 g, 5.61 mmol, 56.0% yield). 1 H NMR (400 MHz, DMSO) δ7.32 - 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

[0431] Step 3: Synthesis of benzyl 3-methyl-4-oxozycycloheptane-1-carboxylate: KOH (0.429 g, 7.65 mmol) was added to a stirred solution of 1-benzyl 3-ethyl 3-methyl-4-oxozycycloheptane-1,3-dicarboxylate (1.0 g, 2.55 mmol) in MeOH (7.5 mL) and H₂O (7.5 mL), and the reaction mixture was stirred at 60ºC for 2 h. The reaction mixture was monitored by TLC and LCMS. The reaction mixture was stirred at 60ºC for 4 h. Afterward, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). It was purified by reversed-phase preparative HPLC using a gradient of 2%–98% MeCN in 5 mm ammonium formate at pH 3.3. Fractions containing the desired product were combined and concentrated to obtain benzyl 3-methyl-4-oxozylate-1-carboxylate (550 mg, 76%), which is a yellow oil. 1 H 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

[0432] Step 4: Synthesis of benzyl 4-amino-3-methylazacycloheptan-1-carboxylate: Ammonium acetate (543 mg, 7.04 mmol) and NaCNBH4 (133 mg, 2.112 mmol) were added to a stirred solution of 3-methyl-4-oxozycycloheptan-1-carboxylate (100 mg, 0.352 mmol) in 2-propanol (4 mL). The reaction mixture was stirred at 50°C for 3 h. The reaction mixture was then diluted with water and extracted with EtOAC. The organic fraction was concentrated to give benzyl 4-amino-3-methylazacycloheptan-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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-5-azaspiro[3.5]non-8-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (1)

[0433] Step 1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one. DIPEA (2.37 mL, 13.6 mmol) was added to a solution of 5-amino-1-methylindolin-2-one (2.0 g, 12.3 mmol) in tetrahydrofuran (32 mL) at -40ºC. 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, allowing for slow warming to room temperature. The reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was filtered and washed with acetonitrile (about 50 mL). The solid was dried under vacuum to give the title compound as a brown solid. MS (ESI) [M+H] + 293.1.

[0434] Step 2: Synthesis of tert-butyl 8-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-5-azaspiro[3.5]nonane-5-carboxylate. Decanborane (38 mg, 0.34 mmol) was added to a solution of 3-(6-amino-1-methyl-indazole-3-yl)piperidin-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). The reaction mixture was stirred at room temperature for 5 h, and the evaporation was evaporated under reduced pressure. The residue was purified by reversed-phase chromatography (C18) using a gradient of 0–80% MeCN and 10 mM ammonium formate in water to give the title compound as a solid (325 mg, 76%). MS(ESI) [M+H] + 482.3. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.32 (d, J = 8.7Hz, 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).

[0435] Step 3: Synthesis of 2,2,2-trifluoroacetic acid of 3-[6-(5-azaspiro[3.5]non-8-ylamino)-1-methyl-indazole-3-yl]piperidin-2,6-dione. Trifluoroacetic acid (0.31 mL, 4.1 mmol) was added to a solution of 8-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-5-azaspiro[3.5]nonane-5-carboxylic acid tert-butyl ester (325 mg, 0.67 mmol) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 18 h. The evaporation was evaporated under reduced pressure to give the title compound as a solid, which was used for the next step without further purification. MS (ESI) [M+H] + 382.3. 1HNMR (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 (brs, 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).

[0436] Step 4: Synthesis of 3-[6-[[5-[5-chloro-4-[(1-methyl-2-oxo-indoline-5-yl)amino]pyrimidin-2-yl]-5-azaspiro[3.5]non-8-yl]amino]-1-methyl-indazole-3-yl]piperidine-2,6-dione. 5-((5-azaspiro[3.5]non-8-ylamino)-1-methyl-indazole-3-yl]piperidin-2,6-dione 2,2,2-trifluoroacetic acid (20 mg, 40 µmol) in NMP (0.7 mL) was added to a solution of 3-[6-(5-azaspiro[3.5]non-8-ylamino)-1-methylindolin-2-one 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (11 mg, 40 µmol). The reaction mixture was heated to 160ºC for 18 h and then cooled to room temperature. The crude reaction mixture was purified by reversed-phase chromatography (C18) using a gradient of 0-100% MeCN and water (containing 0.1% formic acid) to give the title compound (13 mg, 44%) as a solid. LCMS: C 34 H 36 The theoretical value of ClN9O3 is 653.3, and the measured value is 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-5-azaspiro[3.5]non-5-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (2)

[0437] Step 1: Synthesis of 2-[2-bis-[3,5-bis-(trifluoromethyl)phenyl]phosphonyl-3,6-dimethoxy-phenyl]-N1,N1,N3,N3-tetramethyl-phenyl-1,3-diamine[2-[2-(methylamino)phenyl]phenyl]-methanesulfonyloxy-palladium. A mixture of palladium(II) methanesulfonate dimer (406 mg, 0.53 mmol) and 2-[2-bis-[3,5-bis-(trifluoromethyl)phenyl]phosphonyl-3,6-dimethoxy-phenyl]-N1,N1,N3,N3-tetramethyl-phenyl-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 room temperature 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 give the title compound (1.08 g, 90%) as a yellow solid. 1 H 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). 19 F NMR (471 MHz, MeOD-d4) δ –64.20, –64.42. 31 P NMR (203 MHz, MeOD-d4) δ 33.80.

[0438] Step 2: Synthesis of N-[5-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-5-azaspiro[3.5]non-8-yl] tert-butyl carbamate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (600 mg, 1.20 mmol), N-(5-azaspiro[3.5]non-8-yl)carbamate tert-butyl ester (375 mg, 1.56 mmol), NaOtBu (288 mg, 3.0 mmol), and 2-[2-bis-[3,5-bis-(trifluoromethyl)phenyl]phosphoalkyl-3,6-dimethoxy-phenyl]-N1,N1,N3,N3-tetramethyl-phenyl-1,3-diamine[2-[2-(methylamino)phenyl]phenyl]-methylsulfonyloxy-palladium (137 mg, 0.12 mmol) in cyclopentylmethyl ether (12 mL) was heated to 85ºC for 4 h and then cooled to room temperature. The mixture was filtered through diatomaceous earth 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 hexane to give the title compound as a solid (600 mg, 76%). MS (ESI) [M+H + 660.2. 1 H 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).

[0439] Step 3: Synthesis of N-[5-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-5-azaspiro[3.5]non-8-yl]-N-methyl-carbamate tert-butyl ester. Iodimethane (198 µL, 3.18 mmol) was added to an ice-cold solution of N-[5-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-5-azaspiro[3.5]non-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), and the mixture was stirred at room temperature 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 fraction was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by reversed-phase chromatography (C18) using a gradient of 20%–100% MeCN and 10 mM ammonium formate in water to give the title compound as a solid (700 mg, 65% bundle yield). MS (ESI) [M+H + 674.4.

[0440] Step 4: Synthesis of N-[5-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-5-azaspiro[3.5]non-8-yl]-N-methyl-carbamate tert-butyl ester. A mixture of N-[5-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-5-azaspiro[3.5]non-8-yl]-N-methyl-carbamate tert-butyl ester (700 mg, 1.04 mmol) and Perlman catalyst (365 mg, 0.26 mmol) in EtOH (15 mL) and THF (15 mL) was stirred at 50ºC for 2 h under a hydrogen atmosphere (1 atm). The mixture was filtered through diatomaceous earth, washed with MeOH (3 x 15 mL), and the filtrate was concentrated to give the title compound as a solid (425 mg, 83%), which was used for 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 = 8.7Hz, 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).

[0441] Step 5: Synthesis of 3-[1-methyl-6-[8-(methylamino)-5-azaspiro[3.5]non-5-yl]indazole-3-yl]piperidine-2,6-dione hydrochloride. A solution of N-[5-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-5-azaspiro[3.5]non-8-yl]-N-methyl-carbamate tert-butyl ester (425 mg, 0.86 mmol) in DCM (4 mL) was added to 4N HCl in 1,4-dioxane (4 mL, 16 mmol), and the mixture was stirred at room temperature for 4 h. The resulting precipitate was collected by filtration, washed with Et2O (2 x 5 mL), and dried under vacuum to give the title compound as a solid (340 mg, 92%), which was used for the next step without further purification. MS (ESI) [M+H] + 396.3. 1H NMR (500MHz, 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).

[0442] Step 6: Synthesis of 3-[6-[8-[[5-chloro-4-[(1-methyl-2-oxo-indoline-5-yl)amino]pyrimidin-2-yl]-methyl-amino]-5-azaspiro[3.5]non-5-yl]-1-methyl-indazole-3-yl]piperidine-2,6-dione. At room temperature, 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindololin-2-one (30 mg, 0.10 mmol) was added to a mixture of 3-[1-methyl-6-[8-(methylamino)-5-azaspiro[3.5]non-5-yl]indazole-3-yl]piperidin-2,6-dione hydrochloride (46.5 mg, 0.11 mmol) and DIPEA (110 µL, 0.61 mmol) in DMSO (1 mL), and the reaction mixture was heated to 80ºC 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 give the title compound as a solid (14.9 mg, 22%). LCMS: C 34 H 36 The theoretical value of ClN9O3 is 667.3, and the measured value is 668.3 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ10.49 (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 is masked by the water signal. Example S3. Synthesis of 3-(6-(((trans)-4-((5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)(methyl)amino)cyclohexyl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3)

[0443] Similar to Example S2, the title compound was synthesized using trans-N-(4-aminocyclohexyl)carbamate tert-butyl ester as the starting material. The title compound was isolated as a grayish-white solid (36.7 mg, 0.05 mmol, 20.6% yield). LCMS: C 33 H 36 The theoretical value for ClN9O3 is 641, and the measured value is 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 = 8.7Hz, 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-2-methylpiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (4)

[0444] Step 1: Synthesis of N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-2-methyl-4-piperidinyl]carbamate. The title compound was synthesized in toluene at 110ºC for 18 h using N-[(2R,4R)-2-methyl-4-piperidinyl]carbamate tert-butyl as a reactant according to General Procedure 2. The title compound (700 mg, 86%) was isolated as a solid by reversed-phase chromatography (C18) using a gradient of 30%–100% MeCN and 10 mM ammonium formate in water. LCMS: C 38 H 43 The theoretical value of N5O4 is 633.3, and the measured value is 635.9 [M+H] + .

[0445] Step 2: Synthesis of N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-2-methyl-4-piperidinyl]-N-methyl-carbamate tert-butyl ester. NaH (151 mg, 3.8 mmol) was added to a solution of N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-2-methyl-4-piperidinyl]carbamate (800 mg, 1.26 mmol) in DMF (13 mL) cooled to 0ºC, and the reaction mixture was stirred at 0ºC for 15 min. Iodomethane (0.24 mL, 3.79 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted by 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) and brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (C18) using a gradient of 30%–100% MeCN and 10 mM ammonium formate in water to give the title compound as a solid (700 mg, 86%). LCMS: C 39 H 45 The theoretical value of N5O4 is 647.4, and the measured value is 648.4 [M+H] + .

[0446] Step 3: Synthesis of 3-(6-((2R,4R)-4-((5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-2-methylpiperidin-1-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-2-methyl-4-piperidinyl]-N-methyl-carbamate tert-butyl ester as the starting material using general procedures 4, 5, and 6. The crude residue was purified by reversed-phase chromatography (C18) using a gradient of 10%–70% MeCN and 10 mM ammonium formate in water to give the title compound as a solid (19 mg, 25%). LCMS C 33 H 36 The theoretical value of ClN9O3 is 641.3, and the measured value is 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-2-methyl-6-oxopiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (5)

[0447] Step 1: Synthesis of 6-methylpiperazin-2-one. Under nitrogen atmosphere at 0ºC, 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 to a Boc-anhydride (2.24 mL, 9.64 mmol). The reaction mixture was slowly heated to 25ºC and stirred for 3 h. The reaction mixture was treated with 0.5N 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 give the title compound as a grayish-white solid (1.81 g, 8.43 mmol, 96% yield). The crude product was used in the next step without further purification.

[0448] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)-3-methyl-5-oxopiperazine-1-carboxylate. A stirred solution of 6-methylpiperazine-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 iodide (I) (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 100ºC 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 sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude product was purified by rapid column chromatography on silica using 80%–100% ethyl acetate / petroleum ether to give the title compound as a grayish-white solid (650 mg, 0.779 mmol, 26% yield). MS (ESI) m / z 634.8 [M+H] + .

[0449] Step 3: Synthesis of 3-(6-(4-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-2-methyl-6-oxopiperazin-1-yl)-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione: The synthesis of the title compound was completed using general procedures 4, 5, and 6, starting with 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)-3-methyl-5-oxopiperazin-1-carboxylic acid tert-butyl ester. LCMS C 31 H 30 The theoretical value of ClN9O4 is 627.2, and the measured value is 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).

[0450] The examples in Table 2 below were prepared using their respective commercial starting materials and intermediates found in this document, following the general procedures outlined in the table. Example S52. Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (52)

[0451] Step 1: Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. 3-[1-methyl-6-(4-piperidinylamino)indazole-3-yl]piperidin-2,6-dione (40.3 mg, 0.120 mmol), 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindoline-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-darabinose vial equipped with a stir bar and heated to 80ºC overnight. The reaction mixture was filtered and purified by reversed-phase semi-preparative HPLC (10%-100% acetonitrile + 0.1% formic acid in water, 30 min). Fractions containing clean product were combined and lyophilized to give the title compound as a grayish-white solid (3.0 mg, 0.0049 mmol, 4.9% yield). LCMS C 31 H 32 The theoretical value of ClN9O3 is 613.2, and the measured value is 614.2 [M+H]. + ; 1 H 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 relative -(R)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (monomer, stereochemistry undetermined) (53)

[0452] Step 1: Synthesis of relative -(R)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindololin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione. The product of Example S52 was then separated at 22ºC using preparative HPLC (with a Regis Whelk-O1 SS, 21 x 250 mm, 5 u column, 1 mL / min flow rate, isocratic elution in 100% MeCN (additive-free)). The title compound was separated as the first elution peak, Rt = 11.0 min. LCMS C 31 H 32 The theoretical value of ClN9O3 is 614.2, and the measured value is also 614.2 [M+H]. + ; 1 H 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 relative -(S)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (monomer, stereochemistry undetermined) (54)

[0453] Step 1: Synthesis of relative -(S)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindololin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione. The product of Example S52 was then separated at 22ºC using preparative HPLC (with a Regis Whelk-O1 SS, 21 x 250 mm, 5 μ column, 1 mL / min flow rate, isocratic elution in 100% MeCN (additive-free)). The title compound was separated as the first elution peak, Rt = 18.9 min. LCMS C 31 H 32 The theoretical value of ClN9O3 is 614.2, and the measured value is also 614.2 [M+H]. + ; 1 H 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-2,6-dione (55)

[0454] Step 1: Synthesis of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine. Sodium hydride (0.150 g, 3.76 mmol) was added to a solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (1 g, 3.58 mmol) in DMF (20 mL) at 0ºC, and the reaction mixture was stirred for 30 min. Sodium hydride (0.150 g, 3.76 mmol) was then added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for another hour. The reaction mixture was quenched with a saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with a saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the title compound as a white solid (0.75 g, 2.56 mmol, 71% yield); MS (ESI) m / z 293.8 [M+H] + ; 1 H 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).

[0455] Step 2: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine. A 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) for 15 h at 100ºC. After this time, the reaction mixture was quenched with saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the title compound as a white solid (520 mg, 1.14 mmol, 67% yield); MS (ESI) m / z 456.8 [M+H] + ;1 H 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, 2H), 5.44 (s, 2 H), 4.04 (s, 3 H).

[0456] 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-carboxylic acid. Cesium carbonate (713 mg, 2.189 mmol) was added 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 (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (237 mg, 1.094 mmol) in 1,4-dioxane (5 mL). The reaction mixture was degassed with argon for 1 min and then stirred at 100ºC for 15 h. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated sodium chloride aqueous solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the crude product. The crude product was further purified by reversed-phase semi-preparative HPLC (10%-100% acetonitrile + 0.1% TFA in water for 30 min). The fractions containing the clean product were combined and lyophilized to give the title compound as a white solid (120 mg, 0.188 mmol, 17% yield); MS (ESI) m / z 636.8 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm7.95 (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).

[0457] Step 4: Synthesis of 3-(6-((((3R,4R)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-2,6-dione. A solution of (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-hydroxypiperidin-1-carboxylic acid tert-butyl ester (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) for 15 h at 50ºC under hydrogen (1 atm). The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was then stirred for 30 min at room temperature with 1 mL of TFA in DCM (1 mL). Volatiles were removed under reduced pressure to give the desired product as a TFA salt (67 mg, 0.187 mmol, 99% yield), which was used without further purification.

[0458] Step 5: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-2,6-dione. DIPEA (0.10 mL, 0.57 mmol) was added to a solution of 3-(6-(((3R,4R)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-2,6-dione (68 mg, 0.190 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindoline-2-one (55.5 mg, 0.190 mmol) in DMSO (3 mL). The reaction mixture was stirred at 80ºC for 16 h. The reaction mixture was filtered and purified by reversed-phase semi-preparative HPLC (10%-100% acetonitrile + 0.1% formic acid in water for 30 min). Fractions containing clean product were combined and lyophilized to give the title compound as a white solid (3.7 mg, 5.86 µmol, 3.09% yield); 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, 1H), 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).

[0459] Example S56. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3,3-difluoro-1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (56)

[0460] Step 1: Synthesis of 3,3-difluoro-5-nitroindoline-2-one. Diethylaminosulfur trifluoride (4.06 g, 25.2 mmol) was added dropwise to a suspension of 5-nitroindoline-2,3-dione (2.2 g, 11.5 mmol) in dichloromethane (50 mL) at -78ºC. The reaction mixture was allowed to warm to room temperature and stirred for 2 days. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-75% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the title compound 3,3-difluoro-5-nitroindoline-2-one (1.52 g, 7.10 mmol, 62.0% yield) as a yellow solid; MS (ESI) m / z 215.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm11.89 (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).

[0461] Step 2: Synthesis of 3,3-difluoro-1-methyl-5-nitroindoline-2-one. DBU (0.485 mL, 3.22 mmol) was added to a solution of 3,3-difluoro-5-nitroindoline-2-one (0.53 g, 2.475 mmol) in DMF (1 mL), followed by the addition of 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 solution (25 mL) and then extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through diatomaceous earth, and concentrated. The crude product was purified by silica gel column chromatography (0-80% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the title compound as a yellow solid (0.339 g, 1.485 mmol, 60% yield); 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).

[0462] 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 for 15 h at room temperature under hydrogen (45 psi). The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the title compound (300 mg, 1.514 mmol, 96% yield) as a yellow solid; MS (ESI) m / z 199.2 [M+H] + ; 1 H 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).

[0463] Step 4: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3,3-difluoro-1-methyl-2-oxoindololin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using 5-amino-3,3-difluoro-1-methylindololin-2-one and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione hydrochloride as starting materials using general procedures 1 and 6. The reaction mixture was filtered and purified by reversed-phase semi-preparative HPLC (10%-100% acetonitrile + 0.1% formic acid in water for 30 min). Fractions containing clean product were combined and lyophilized to give the title compound as a yellow solid (8 mg, 0.012 mmol, 23.46% yield); MS (ESI) m / z 664.2 [M+H] + ; 1HNMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1 H), 8.94 (s, 1 H), 8.03 - 8.14 (m, 2H), 7.77 (br d, J=8.56 Hz, 1 H), 7.31 (d, J=8.80 Hz, 1 H), 7.21 (d, J=8.44Hz, 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, 1H), 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-indoline-5-yl)amino]pyrimidin-2-yl]-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indazole-3-yl]piperidin-2,6-dione (57)

[0464] Step 1: Synthesis of O5-ethyl-4-[[(1R)-1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylic acid tert-butyl ester. PTSA (1.39 g, 8.1 mmol) was added to a solution of O1-tert-butylO3-ethyl-4-oxopiperidinium-1,3-dicarboxylic acid ester (22 g, 81 mmol) and (1R)-1-phenylethylamine (12.5 mL, 97.2 mmol) in toluene (400 mL), and the mixture was heated to reflux for 18 h using a Dean-Stark trap. The mixture was cooled to room temperature and washed with saturated aqueous solutions 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 through a silica pad, washed with DCM (2 x 100 mL), and concentrated to give the title compound (30.2 g, 99%) as an oil, which was used for the next step without further purification. MS (ESI) [M+H] + 375.2. 1 H 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).

[0465] 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: Sodium triacetoxyborohydride (34 g, 160 mmol) was added fractionally 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) cooled to 0ºC in MeCN (200 mL) and AcOH (100 mL) for 2 h, and the reaction mixture was stirred at 0ºC for 2 h. The mixture was then cooled to -10ºC and slowly treated with 1 M aqueous solution of NaOH (100 mL), 4 M aqueous solution of NaOH (100 mL), 6 M aqueous solution of NaOH (100 mL), and subsequently slowly treated with 50% aqueous solution of NaOH (50 mL). The mixture was warmed to room temperature 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 0-50% EtOAc gradient in hexane to give a 4:1 mixture of the title compound (14.8 g, 98%) as an oil. A portion (7 g) of the 4:1 mixture of the title compound was separated by SFC to obtain tert-butyl O3-ethyl(3S,4R)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate (3.7 g) in an oily form and the title compound tert-butyl O3-ethyl(3R,4S)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate (1.1 g) in an oily form.

[0466] Step 3: Synthesis of tert-butyl (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate. LiBH4 (1.33 mL, 2.66 mmol) was added 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), and the mixture was heated to reflux for 2 h, then cooled to room temperature. 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 give the title compound (404 mg, 91%) as an oil, which was used for the next step without further purification. MS (ESI) [M+H]+ 335.3.

[0467] Step 4: Synthesis of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl)oxymethyl]-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate tert-butyl ester. Tert-butyl chloride dimethylsilane (218 mg, 1.45 mmol) and imidazole (123 mg, 1.81 mmol) were sequentially added to a solution of (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate tert-butyl ester (404 mg, 1.21 mmol) in DCM (5 mL), and the reaction mixture was stirred at room temperature 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 give the title compound (540 mg, 99%) as an oil, which was used for the next step without further purification. Note: SFC analysis confirmed the presence of only one diastereomer. MS (ESI) [M+H] + 449.4. 1 H 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).

[0468] Step 5: Synthesis of tert-butyl piperidine-1-carboxylate (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silyl)oxymethyl]piperidine-1-carboxylate. A mixture of tert-butyl 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 65ºC for 2 h. The mixture was filtered through diatomaceous earth and washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure to give the title compound as a solid (320 mg, 79%), which was used for the next step without further purification. MS (ESI) [M+H] + 345.3. 1 H 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).

[0469] Step 6: Synthesis of tert-butyl piperidine-1-carboxylate (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-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), (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 90ºC for 16 h and then cooled to room temperature. The residue was purified by column chromatography on silica gel using a 0-50% EtOAC gradient in hexane to give the title compound as a solid (458 mg, 67%). Note: The reaction was repeated and the crude residues were combined before purification. MS (ESI) [M+H] + 764.4. 1 H 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 = 7.9Hz, 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 = 15.0Hz, 6H).

[0470] Step 7: Synthesis of tert-butyl piperidine-1-carboxylate (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylate. A mixture of tert-butyl piperidine-1-carboxylate (458 mg, 0.60 mmol) and Perlman catalyst (210 mg, 0.15 mmol) in EtOH (10 mL) and THF (10 mL) was subjected to hydrogenation (1 atm) for 2 h at 50ºC. The mixture was filtered through diatomaceous earth and washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure to give the title compound as a solid (350 mg, quantified), which was used in the next step without further purification. MS (ESI) [M+H + 586.4.

[0471] Step 8: Synthesis of 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indazole-3-yl]piperidine-2,6-dione dihydrochloride. A solution of (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.60 mmol) in DCM (2.5 mL) was mixed with 4N HCl (1.5 mL, 6.0 mmol) in 1,4-dioxane and stirred at room temperature for 2 h. The resulting precipitate was collected by filtration, washed with Et2O (3 x 5 mL), and dried under vacuum to give the title compound as a solid (250 mg, 77%), which was used for 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).

[0472] Step 9: Synthesis of 3-[6-[[(3S,4R)-1-[5-chloro-4-[(1-methyl-2-oxo-indoline-5-yl)amino]pyrimidin-2-yl]-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indazole-3-yl]piperidin-2,6-dione. 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indoline-2-one (35 mg, 0.12 mmol) and DIPEA (0.10 mL, 0.60 mmol) in DMF (2 mL) were added to a mixture at room temperature, and the reaction mixture was heated to 80ºC for 2 h. 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 give the title compound as a solid (22.1 mg, 28%). LCMS C 32 H 34 The theoretical value of ClN9O4 is 643.2, and the measured value is 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 = 8.4Hz, 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-(hydroxymethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (58)

[0473] Step 1: Synthesis of 3-(6-(((3R,4S)-1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-(hydroxymethyl)piperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. Similar to Example S57, the title compound was synthesized starting with other diastereomers isolated from Step 2 of Example S57. 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 give the title compound as a solid (5.5 mg, 14%). LCMS C 32 H 34 The theoretical value of ClN9O4 is 643.2, and the measured value is 644.3 [M+H].+ ; 1 H 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-oxoindololin-5-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidin-2,6-dione (59)

[0474] Step 1: Synthesis of 6-bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine. NIS (5.11 g, 22.7 mmol) was added to a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (3.75 g, 18.9 mmol) in MeCN (90 mL). The reaction mixture was heated to 85ºC for 18 h and then cooled to room temperature. The evaporation was carried out under reduced pressure, and the residue was purified by column chromatography on silica gel using a gradient of 0–15% EtOAc in hexane to give the title compound as a solid (6.05 g, 98%). MS (ESI) [M+H] + 324.0.

[0475] Step 2: Synthesis of 6-bromo-3-iodo-1-methyl-pyrazolo[4,3-b]pyridine. Similar to General Procedure 3, the title compound was synthesized using 6-bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine as the starting material.

[0476] Step 3: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-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-pyridinyl)boronic acid (5.36 g, 7.99 mmol, an intermediate provided by Celgene), Pd(PPh3)2Cl2 (374 mg, 0.53 mmol), and Na2CO3 (2.66 mL, 5.33 mmol) in a 2 M aqueous solution in 1,4-dioxane (18 mL) was heated to 80ºC for 16 h and then cooled to room temperature. The evaporator was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel using a gradient of 0-20% EtOAc in hexane to give the title compound as a solid (835 mg, 62%). MS (ESI) [M+H + 502.2.

[0477] Step 4: Synthesis of N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-b]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester. The title compound was synthesized in toluene using 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-b]pyridine and N-methyl-N-(4-piperidinyl)carbamate tert-butyl ester as starting materials, according to General Procedure 2.

[0478] Step 5: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidin-2,6-dione. The title compound was synthesized using N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-b]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester as the starting material using general procedures 4, 5, and 6. 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 give the title compound as a solid (5.4 mg, 12%). LCMS C 31 H 33ClN 10 The theoretical value for O3 is 628.2, and the measured value is 629.3 [M+H]. + ; 1 H 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 = 7.9Hz, 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-oxoindololin-5-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)piperidin-2,6-dione (60)

[0479] Step 1: 6-Bromo-3-iodo-1H-pyrazolo[4,3-c]pyridine: NIS (7.95 g, 35.4 mmol) was added to a solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (3.5 g, 17.7 mmol) in MeCN (177 mL). The reaction mixture was heated to 85ºC for 18 h and then cooled to room temperature. Water (50 mL) was added and the resulting precipitate was collected by filtration, washed with water (50 mL) and DCM (50 mL), and dried under vacuum to give the title compound as a solid (6.21 g, quantified). MS (ESI) [M+H] + 325.8. 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.57 (s, 1H).

[0480] Step 2: 6-Bromo-3-iodo-1-methylpyrazolo[4,3-c]pyridine. NaH (60% dispersion in mineral oil, 31 mg, 0.77 mmol) was added to a mixture of 6-bromo-3-iodo-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.31 mmol) in DMF (2 mL) at 0ºC, and the reaction mixture was stirred at 0ºC for 15 min. A solution of iodomethane (50 µL, 0.77 mmol) in DMF (1 mL) was added, and the reaction was warmed to room temperature 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, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 10%–35% EtOAc in hexane to give the title compound as a solid (46 mg, 44%). 1 H NMR (400MHz, DMSO-d6) δ 8.58 (d, J = 1.0 Hz, 1H), 8.09 (d, J = 1.0 Hz, 1H), 4.05 (s, 3H).

[0481] Step 3: 6-Bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-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-pyridinyl)boronic acid (595 mg, 0.89 mmol), Pd(PPh3)2Cl2 (41.5 mg, 60 µmol), and Na2CO3 (300 µL, 0.59 mmol) in a 2 M aqueous solution in 1,4-dioxane (1.5 mL) was heated to 80ºC for 16 h and then cooled to room temperature. 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 hexane to give the title compound as a solid (99.0 mg, 67%). 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).

[0482] Step 4: N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-c]pyridine (1.44 g, 2.87 mmol), N-methyl-N-(4-piperidinyl)carbamate tert-butyl ester (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 90ºC for 16 h and then cooled to room temperature. The evaporator was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0-40% EtOAc in hexane to give the title compound as a solid (1.08 g, 59%). 1 H 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 = 12.5Hz, 2H), 2.72 – 2.66 (m, 1H), 2.64 (s, 3H), 1.80 – 1.52 (m, 4H), 1.40 (s, 9H).

[0483] Step 5: N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester. A mixture of N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester (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) for 2 h at room temperature. The mixture was filtered through diatomaceous earth 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 hexane to give the title compound as a solid (927 mg, quantified). MS (ESI) [M+H + 457.4.

[0484] Step 6: 3-[1-methyl-6-[4-(methylamino)-1-piperidinyl]pyrazolo[4,3-c]pyridin-3-yl]piperidin-2,6-dione hydrochloride. To a solution of N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl (927 mg, 2.03 mmol) in DCM (40.6 mL), 4 N HCl in 1,4-dioxane (5.08 mL, 20.3 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with Et2O (20 mL), filtered, and washed with Et2O (2 x 10 mL) to give the title compound as a solid (688 mg, 86%), which was used for 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 = 13.4Hz, 2H), 1.75 – 1.57 (m, 2H).

[0485] Step 7: 3-[6-[4-[[5-chloro-4-[(1-methyl-2-oxo-indoline-5-yl)amino]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-1-methyl-pyrazolo[4,3-c]pyridin-3-yl]piperidin-2,6-dione: 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindoline-2-one (34 mg, 0.12 mmol) and DIPEA (0.2 mL, 1.16 mmol) were added sequentially to a solution of 3-[1-methyl-6-[4-(methylamino)-1-piperidinyl]pyrazolo[4,3-c]pyridin-3-yl]piperidin-2,6-dione hydrochloride (50 mg, 0.13 mmol) in DMSO (1.6 mL). The reaction mixture was heated to 100ºC for 18 h and then cooled to room temperature. 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 give the title compound as a solid (18.6 mg, 25%). LCMS C 31 H 33 ClN 10 The theoretical value for O3 is 628.2, and the measured value is 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-oxoindoline-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (61)

[0486] Step 1: Synthesis of 1-methyl-6-nitroindoline-2,3-dione. Sodium hydride (0.312 g, 7.81 mmol) was added to a stirred solution of 6-nitroindoline-2,3-dione (1.0 g, 5.20 mmol) in DMF (20 mL) under nitrogen at 0°C and stirred for 10 min. Iodomethane (0.651 mL, 10.41 mmol) was added to the reaction mixture and the mixture was slowly heated to 25°C. 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 give the title compound, which was purified by rapid column chromatography on silica gel with 40%–50% ethyl acetate / petroleum ether to give the title compound as a grayish-white solid (320 mg, 1.531 mmol, 29% yield).

[0487] Step 2: Synthesis of 1-methyl-6-nitroindoline-2-one. Hydrazine hydrate (144 mg, 2.87 mmol) was added to a stirred solution of 1-methyl-6-nitroindoline-2,3-dione (200 mg, 0.957 mmol) in n-butanol (5.0 mL) at 25ºC. The reaction mixture was heated to 80ºC and stirred for 4 h. The reaction mixture was then cooled to 25ºC and triethylamine (0.533 mL, 3.83 mmol) was added, followed by stirring at 80ºC for 14 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude compound, which was purified by rapid column chromatography on silica gel with 35%–45% ethyl acetate / petroleum ether to give the title compound as a grayish-white solid (40 mg, 0.171 mmol, 18% yield). LCMS result: 193.2 [M+H]. + Rt 1.686 min

[0488] Step 3: Synthesis of 6-amino-1-methylindolin-2-one. 10% Pd / C (20 mg) was added 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) at 25ºC under nitrogen. The reaction mixture was stirred for 6 h under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and the diatomaceous earth 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. 1 H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 8.4Hz, 1H), 6.20-6.18 (m, 2H), 5.11 (brs, 2H), 3.32 (s, 2H), 3.02 (s, 3H).

[0489] Step 4: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindololin-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using 6-amino-1-methylindololin-2-one and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione as starting materials using general procedures 1 and 6. The crude material was purified by preparative HPLC to give the title compound as a grayish-white solid (18 mg, 0.028 mmol, 17% yield). LC-MSC 32 H34 The theoretical value of ClN9O3 is 627.3, and the measured value is 628.3 [M+H]. + ; 1 H NMR (400 MHz, DMSO-d6): δ10.84 (s, 1H), 8.99 (s, 1H), 8.12 (s, 1H), 7.42 (s, 1H), 7.32 (d, J = 8.80Hz, 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-2,6-dione (62)

[0490] Step 1. 6-Chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine: Sodium hydride (0.301 g, 7.51 mmol) was added to a solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (2 g, 7.16 mmol) in DMF (20 mL) at 0ºC. The reaction mixture was stirred for 30 min and then sodium hydride (0.301 g, 7.51 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was treated with a saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with a saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the title compound 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine as a white solid (1.7 g, 5.79 mmol, 81% yield); MS (ESI) m / z 293.8 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=8.31 ​​Hz, 1H), 7.32 (d, J=8.31 ​​Hz, 1H), 4.03 (s, 3H).

[0491] Step 2. (3R,4R)-4-((3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidin-1-carboxylic acid tert-butyl ester: To a solution of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.704 mmol) and N-ethyl-N-isopropylpropyl-2-amine (0.607 mL, 3.41 mmol) in DMSO (1 mL), (3R,4R)-4-amino-3-methylpiperidin-1-carboxylic acid tert-butyl ester (365 mg, 1.704 mmol) was added. The reaction mixture was stirred at 120ºC for 48 h. The reaction mixture was filtered and purified by reversed-phase semi-preparative HPLC (10%-100% acetonitrile + 0.1% formic acid in water for 30 min). Fractions containing clean product were combined and lyophilized to give the title compound as a white solid (250 mg, 0.530 mmol, 31.1% yield). 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=7.83Hz, 1 H), 6.33 - 6.46 (m, 1 H), 3.86 - 4.05 (m, 2 H), 3.81 (d, , 1.17 - 1.32 (m, 1H), 0.88(br d, J=4.89 Hz, 3H).

[0492] Step 3. (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-carboxylic acid tert-butyl ester. A solution of (3R,4R)-4-((3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidin-1-carboxylic acid tert-butyl ester (250 mg, 0.530 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine (243 mg, 0.583 mmol) and sodium bicarbonate (98 mg, 1.167 mmol) in a 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) for 15 h at 80ºC. The reaction mixture was quenched with a saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). The desired fraction was concentrated under reduced pressure to give the crude product, which was further purified by reversed-phase semi-preparative HPLC (10%-100% acetonitrile + 0.1% formic acid in water for 30 min). The fractions containing the clean product were combined and lyophilized 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] + ;1 HNMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, J=8.07 Hz, 1 H), 7.64 (d, J=8.80 Hz, 1H), 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, 1H), 1.41 (s, 9 H), 1.24 - 1.32 (m, 2 H), 0.88 (d, J=6.60 Hz, 3 H).

[0493] Step 4. 3-(1-Methyl-6-((((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-2,6-dione. A solution of (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidin-1-carboxylic acid tert-butyl ester (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) for 15 h at 50ºC under hydrogen (1 atm). The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was then stirred for 30 min at room temperature with 1 mL of TFA in DCM (1 mL). 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)piperidin-2,6-dione (60 mg, 0.168 mmol, quantitative yield) as a TFA salt, which was used without further purification.

[0494] Step 5. 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-2,6-dione: The title compound was synthesized using general procedure 6 with 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-2,6-dione hydrochloride (40 mg, 0.102 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindoline-2-one (29.8 mg, 0.102 mmol). The reaction mixture was filtered and purified by reversed-phase semi-preparative HPLC (10%–100% acetonitrile + 0.1% formic acid in water, 30 min). Fractions containing clean product were combined and lyophilized to give the title compound as a white solid (13 mg, 0.02 mmol, 19.4%). MS (ESI) m / z 628.8 [M+H] + ; 1 H 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, 1H), 7.52 (dd, J=8.44, 2.08 Hz, 1 H), 6.87 - 6.98 (m, 2 H), 6.31 (d, J=8.80Hz, 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, 1H), 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (63)

[0495] Step 1: Synthesis of 3-(6-((1-(5-chloro-4-((2-oxoindoline-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. Similar to Example S62 above, the title compound was synthesized using 3-[1-methyl-6-(4-piperidinylamino)indazole-3-yl]piperidin-2,6-dione and 5-aminoindoline-2-one as starting materials. LCMS C 30 H 30 The theoretical value of ClN9O3 is 599.2, and the measured value is 600.0 [M+H]. + ; 1 H 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (64)

[0496] Step 1: Synthesis of 3-(6-((3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione hydrochloride. A mixture of 3-(6-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione (500 mg, 1.94 mmol), tert-butyl 3,3-difluoro-4-oxopiridine-1-carboxylate hydrate (500.9 mg, 2.13 mmol), and decborane (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. The reaction was completed according to LCMS after 2 hours. The reaction was diluted with methanol (1 mL), which caused bubbling. After 10 min, the bubbling subsided and the solution was diluted with ethyl acetate, washed with water and then with brine, dried (sodium sulfate), filtered, and concentrated. The resulting solid was ground with diethyl ether. The resulting solid was then purified by silica gel chromatography using a gradient of 4% methanol and 0-50% ethyl acetate in hexane. The resulting intermediate 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-3,3-difluoro-piperidin-1-carboxylic acid tert-butyl ester (230 mg, 0.4817 mmol, 24.8% yield) was separated and treated with 2 mL of 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 pale yellow powder.

[0497] Step 2: Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione: 3-{6-[(3,3-difluoropiperidin-4-yl)amino]-1-methyl-1H-indazole-3-yl}piperidin-2,6-dione hydrochloride (278 mg, 0.650 mmol), 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindoline-2-one (172 mg, 0.590 mmol), N,N-diisopropylethylamine (0.2 mL, 1.17 mmol), and DMSO (1.17 mL, 1.17 mmol) were prepared. The product was added to a 1-drylan vial equipped with a stir bar and heated to 80ºC for 15 hours. The reaction mixture was filtered and purified by reversed-phase semi-preparative HPLC (10% - 100% acetonitrile + 0.1% formic acid in water, 30 min). Fractions containing clean product were combined and lyophilized to give the title compound (12 mg, 0.0184 mmol, 3.14% yield). 1 H 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (65)

[0498] Step 1: Synthesis of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate. Decanborane (14) (195 mg, 1.74 mmol) was added to a solution of 1-(6-amino-1-methyl-indazole-3-yl)hexahydropyrimidin-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), and the mixture was stirred at room temperature for 6 h. Volatile compounds were removed, and the residue was purified by reversed-phase chromatography (C18) using a gradient of 20%–100% MeCN and 10 mM ammonium formate in water to give the title compound as a solid (450 mg, 27%). MS (ESI) [MH - 477.3.

[0499] Step 2: Synthesis of 1-(6-((1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)dihydropyrimidin-2,4(1H,3H)-dione. The title compound was synthesized using 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]amino]-3,3-difluoro-piperidin-1-carboxylic acid tert-butyl ester as the starting material, according to general procedures 5 and 6. LCMS C 30 H 29 ClF2N 10 The theoretical value of O3 is 650.2, and the measured value is 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, 1.9Hz, 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (66)

[0500] 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-phenylethylamine (2.18 g, 18.0 mmol) in toluene (35 mL) was heated to reflux for 18 h using a Dean-Stark separatory water separator. The mixture was cooled to room temperature and volatiles were removed under reduced pressure. DCM (35 mL) was added, followed by fractional addition of sodium triacetoxyborohydride (7.15 g, 33.7 mmol) over 1 h. The mixture was heated to 50ºC for 18 h. Another batch of sodium triacetoxyborohydride (3.56 g, 16.8 mmol) was added and the reaction mixture was heated to 50ºC for another 6 h. The mixture was cooled to room temperature and volatiles were removed under reduced pressure. A 2 M solution of Na₂CO₃ (50 mL) was added and the mixture was stirred at room temperature for 1 h, 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 give the title compound (4.21 g, 82%) as an oil. 1 H 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).

[0501] Step 2: Synthesis of 4-methylbenzenesulfonate of (4R)-3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate tert-butyl ester. 4-methylbenzenesulfonate hydrate (2.35 g, 12.4 mmol) was added to a solution of 3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate tert-butyl ester (4.21 g, 12.4 mmol) in EtOH (50 mL) at room temperature, and the mixture was heated to 60ºC for 1 h. Volatiles were removed under reduced pressure to give a mixture of diastereomers as solids. The crude mixture of intermediates (6.07 g) was dissolved in a 10:1 mixture of acetone and EtOH (68.5 mL), and the mixture was heated to reflux. The flask was removed from the oil bath and allowed to stand overnight. The precipitated solid was filtered, washed with cold acetone (2 x 1 mL), and dried to obtain the title compound of the first harvest, which was then carried into subsequent processes.

[0502] Step 3: Synthesis of (4R)-3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylic acid tert-butyl ester. The compound (4R)-3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylic acid tert-butyl ester 4-methylbenzenesulfonate (1.99 g, 3.88 mmol) was partitioned between EtOAc (50 mL) and a saturated aqueous solution of NaHCO3 (50 mL). The organic layers were 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 give the title compound (1.30 g, 98%) as an oil. MS (ESI) [M+H] + 341.3. 1 H 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).

[0503] Step 4: Synthesis of tert-butyl (4R)-4-amino-3,3-difluoro-piperidine-1-carboxylate. A mixture of (4R)-3,3-difluoro-4-[[(1SR)-1-phenylethyl]amino]piperidine-1-carboxylate tert-butyl (1.29 g, 3.79 mmol) and 10% Pd / C (202 mg, 0.19 mmol) in EtOH (41 mL) was shaken in a Par flask for 18 h at room temperature under a hydrogen atmosphere (50 psi). The mixture was filtered through diatomaceous earth and washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure to give the title compound (845 mg, 94%) as an oil, which was used for the next step without further purification. MS (ESI) [M-butene]+ 181.0°. [α]D +0.19° (c = 0.142, EtOH). 1 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).

[0504] Step 5: Synthesis of tert-butyl (4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylic acid. At room temperature, tBuXPhos-Pd-G3 (33.9 mg, 40 µmol) was added to a degassed mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (200 mg, 0.40 mmol), (4R)-4-amino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (123 mg, 0.520 mmol), and tBuONa (57.7 mg, 0.60 mmol) in THF (2 mL). The reactor vessel was sealed, and the reaction mixture was heated to 80ºC for 18 h and then cooled to room temperature. Add DCM (10 mL) and filter the mixture onto diatomaceous earth and wash with DCM (3 x 10 mL). Concentrate the volatiles under reduced pressure and purify the residue by column chromatography on silica gel using a gradient of 0-60% EtOAc in hexane to give the title compound as a solid (200 mg, 76%). 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).

[0505] Step 6: Synthesis of 3-(6-(((R)-1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using (4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3,3-difluoro-piperidin-1-carboxylic acid tert-butyl ester as the starting material, according to general procedures 4, 5, and 6. LCMS C 31 H 30 The theoretical value of ClF2N9O3 is 649.2, and the measured value is 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (67)

[0506] Step 1: Synthesis of 3-(6-(((S)-1-(5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione: Similar to Example S66, the title compound was synthesized starting in Step 1 using (1S)-1-phenylethylamine. LCMS C 31 H 30 The theoretical value of ClF2N9O3 is 649.2, and the measured value is 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (68)

[0507] Step 1: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using (3,3-difluoropiperidin-4-yl)carbamate tert-butyl ester as the starting material according to general procedures 2, 4, 5 and 6. LCMSC 31 H 30 The theoretical value for ClF2N9O3 is 649, and the measured value is 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (69)

[0508] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-ethyl-2-oxoindololin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using 5-amino-1-ethylindololin-2-one and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione as starting materials according to General Procedures 1 and 6. LCMS C 33 H 36 The theoretical value of ClN9O3 is 641.3, and the measured value is 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, 1.90Hz, 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 = 7.70Hz, 2H), 4.17 (dd, J = 8.68, 5.14 Hz, 1H), 3.81 (s, 3H), 3.68 (q, J = 7.09Hz, 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 = 7.09Hz, 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (70)

[0509] Step 1: Synthesis of (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 24). A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.92 g, 3.84 mmol), (3R,4R)-4-amino-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (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 90ºC for 20 h. The mixture was cooled to room temperature, filtered through diatomaceous earth, 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 hexane to give the title compound as a solid (1.37 g, 68%). MS (ESI) [M+H + 634.1. 1 H 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).

[0510] Step 2: Synthesis of tert-butyl (3R,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidin-1-carboxylic acid. A mixture of tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidin-1-carboxylic acid (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 at 50ºC under H2 (1 atm) for 9 h. The mixture was filtered through diatomaceous earth 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 give the title compound as a solid (695 mg, 69%). MS (ESI) [M+H + 456.3. 1 H 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).

[0511] Step 3: Synthesis of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione hydrochloride. 4 M HCl (35 mL) in ethyl acetate was added to a solution of (3R,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidin-1-carboxylic acid tert-butyl ester (8 g, 17.6 mmol) in ethyl acetate (35 mL) at 25ºC. After addition, the reaction mixture was stirred at 25ºC for 16 h. The reaction mixture was filtered to give the title compound (8 g, 100% yield) as a grayish-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,2H), 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).

[0512] Step 4: Synthesis of 3-[6-[[(3R,4R)-1-[5-chloro-4-[(1-methyl-2-oxo-indoline-5-yl)amino]pyrimidin-2-yl]-3-methyl-4-piperidinyl]amino]-1-methyl-indazole-3-yl]piperidin-2,6-dione. To a solution of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride (50.0 mg, 0.130 mmol) in DMSO (0.50 mL), 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindololin-2-one (41.1 mg, 0.140 mmol) and DIPEA (90 μL, 0.510 mmol) were sequentially added, and the mixture was heated to 80ºC for 2 h. The reaction mixture was cooled to room temperature and purified directly by preparative HPLC (BEH column, C18) using a gradient of 44%–54% MeCN and 10 mM ammonium formate in water to give the title compound as a solid (13.5 mg, 16%). LC-MSC 32 H 34 The theoretical value of ClN9O3 is 627.3, and the measured value is 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-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (71)

[0513] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindololin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione. The product of Example S70 was then separated at 22ºC using preparative HPLC (with a Regis Whelk-O1 RR or SS column, 1 mL / min flow rate, isocratic elution in 100% ACN (additive-free)). The title compound was eluted as the first peak, Rt = 10.01 min. LCMS C 32 H 34 The theoretical value of ClN9O3 is 627.3, and the measured value is 628.4 [M+H].+ ; 1 H NMR (DMSO-d6, 400MHz) 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-...

Claims

1. A method for treating a subject with cancer or an autoimmune disease, the method comprising administering to the subject an effective amount of an anti-CD20 antibody and a compound of formula (IA): (IA) Or its pharmaceutically acceptable salt, wherein: X 1 and X 2 Each is independently either N or CH, provided that X is the condition. 1 and X 2 At least one of them is N; R 1a and R 1b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 2a and R 2b Each can be independently H, C1-C6 alkyl, -O (C1-C6 alkyl), -OH, halogroup, C1-C6 haloalkyl, or C1-C6 alkyl-OH. Or R 2a and R 2b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups. Or R 2a and R 2b Together they form an oxygen group; Or R 1a and R 2a Together they form bridging C2-C3 alkylene groups; R 3a and R 3b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 4a and R 4b Each is independently an H, a halogroup, or a C1-C6 alkyl group. Or R 4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups; R 5a and R 5b Each is independently H, a halogroup, or a C1-C6 alkyl group; w is 0 or 1; R 6 It is an H or C1-C6 alkyl group; R 7 It is an H or C1-C6 alkyl group; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 It is Cl or -CN; R 9 It is F; X 3 It is N or CH; z is 0 or 1; R 10a and R 10b Each is independently either an H group or a halogenated group; R 11 It is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5 to 6-membered heterocyclic group), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH or -(C1-C6 alkylene)-NH(C1-C6 alkyl). The heterocyclic group contains 1-3 heteroatoms selected from N, O and S; R 12 It is H, a halogroup, or a C1-C6 alkyl group; R 13 It is an H or a halogroup; R 14 It is an H or C1-C6 alkyl group; X 4 Is it N or CR? 15 ; R 15 It is an H or C1-C6 alkyl group; X 5 and X 6 Each is independently N or CH; and Is it a single bond or a double bond? One or more hydrogen atoms in the compound are optionally replaced by deuterium.

2. A method for treating a subject with cancer or an autoimmune disease, the method comprising administering to the subject an effective amount of a compound of formula (IA): (IA) Or its pharmaceutically acceptable salt, wherein: X 1 and X 2 Each is independently either N or CH, provided that X is the condition. 1 and X 2 At least one of them is N; R 1a and R 1b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 2a and R 2b Each can be independently H, C1-C6 alkyl, -O (C1-C6 alkyl), -OH, halogroup, C1-C6 haloalkyl, or C1-C6 alkyl-OH. Or R 2a and R 2b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups. Or R 2a and R 2b Together they form an oxygen group; Or R 1a and R 2a Together they form bridging C2-C3 alkylene groups; R 3a and R 3b Each is independently H, a halogroup, or a C1-C6 alkyl group; R 4a and R 4b Each is independently an H, a halogroup, or a C1-C6 alkyl group. Or R 4a and R 4b Together with the carbon atoms to which they are attached, they form spiroC3-C5 cycloalkyl groups; R 5a and R 5b Each is independently H, a halogroup, or a C1-C6 alkyl group; w is 0 or 1; R 6 It is an H or C1-C6 alkyl group; R 7 It is an H or C1-C6 alkyl group; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 It is Cl or -CN; R 9 It is F; X 3 It is N or CH; z is 0 or 1; R 10a and R 10b Each is independently either an H group or a halogenated group; R 11 It is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5 to 6-membered heterocyclic group), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH or -(C1-C6 alkylene)-NH(C1-C6 alkyl). The heterocyclic group contains 1-3 heteroatoms selected from N, O and S; R 12 It is H, a halogroup, or a C1-C6 alkyl group; R 13 It is an H or a halogroup; R 14 It is an H or C1-C6 alkyl group; X 4 Is it N or CR? 15 ; R 15 It is an H or C1-C6 alkyl group; X 5 and X 6 Each is independently N or CH; and Is it a single bond or a double bond? In the compound, one or more hydrogen atoms are optionally replaced by deuterium. The compound of formula (IA) or its pharmaceutically acceptable salt is administered as follows: (i) daily on each day of a 28-day cycle; or (ii) on days 1-14 of the 28-day cycle, and not on days 15-28 of the 28-day cycle; or (iii) on days 1-21 of the 28-day cycle, and not on days 22-28 of the 28-day cycle; or The compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered to the subject once 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 according to claim 1 or 2, wherein the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered to the subject once 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 according to any one of claims 1-3, wherein the compound of formula (IA) or a pharmaceutically acceptable salt thereof is applied as follows: (i) daily on each day of a 28-day cycle; or (ii) on days 1-14 of a 28-day cycle and not on days 15-28 of the 28-day cycle; or (iii) on days 1-21 of a 28-day cycle and not on days 22-28 of the 28-day cycle.

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

6. The method according to 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 according to claim 6 or 7, wherein approximately 375 mg / m² is administered every 28 days. 2 Rituximab.

9. The method according to 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 as follows: (i) daily on each day of the 28-day treatment cycle; or (ii) on days 1-14 of the 28-day treatment cycle and not on days 15-28 of the 28-day treatment cycle; or (iii) on days 1-21 of the 28-day treatment cycle and not on days 22-28 of the 28-day treatment cycle.

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

11. The method of claim 10, wherein the cancer is 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 non-Hodgkin lymphoma.

14. The method according to 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 a diffuse large B-cell lymphoma or a follicular lymphoma.

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

17. The method according to any one of claims 1-16, wherein the compound has the following formula: (70)， Or its isomers, or pharmaceutically acceptable salts of the aforementioned substances.

18. The method of claim 17, wherein the compound has the following formula: (70)， Or its pharmaceutically acceptable salt.

19. A pharmaceutical composition comprising a compound of the following formula: (70)， Or its isomers, or pharmaceutically acceptable salts of the aforementioned substances, and two or more of the following: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, silica, and sodium stearoyl fumarate.

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

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