Ku-DNA binding inhibitors

Abstract

The present disclosure relates to Ku-DNA binding inhibitor compounds, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat cancer.

Description

[0001] 29920-428111 2025-018-02

[0002] KU-DNA BINDING INHIBITORS

[0003] RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 692,820, filed September 10, 2024, the entire disclosure of which is incorporated herein by reference.

[0005] STATEMENT OF GOVERNMENT RIGHTS

[0006] This invention was made with government support under CA247370 awarded by the National Institutes of Health. The Government has certain rights in the invention.

[0007] BACKGROUND

[0008] The DNA damage response (DDR) is a collection of signaling pathways initiated by independent DNA-binding proteins that sense DNA damage and specific DNA structures, including DNA double-strand breaks (DSBs). These sensors, namely MRE11, RPA, and Ku then activate the phosphatidylinositol-3-kinase-related kinases (PIKKs) ATM, ATR, and DNA-PK respectively, to regulate cell cycle, cell death, DNA replication, and DNA repair. Targeting the DDR is a promising therapeutic strategy, as many therapeutic modalities induce cancer cell death through the generation of DNA damage.

[0009] Cancer therapeutics such as ionizing radiation (IR) and chemotherapy exert their therapeutic effect by inducing DNA double-strand breaks (DSBs), one of the most lethal types of DNA damage, to selectively kill rapidly dividing tumor cells. If left unrepaired or are misrepaired, DSBs can lead to chromosomal instability, cell death, or malignant transformation. Cancer cells have developed a complex DNA damage repair mechanism to protect inherent genomic integrity' and instability, in which the majority of DSBs are recognized and repaired at least four different repair mechanism such canonical or classical non-homologous end-joining (NHEJ), homologous recombination (HR), single-strand annealing (SSA). and both resection-dependent and -independent alternative NHEJ (alt-NHEJ) or microhomology-mediated end joining pathways. Among all pathways, canonical or classical NHEJ is the predominant repair pathway that prevents genomic instability by repairing DSBs throughout the cell cycle in mammalian cells. NHEJ is characterized by its rapid response, often repairing up to -80% of all DSBs throughout the cell cycle, particularly outside the S and G2 phases where HR is more active.

[0010] DSBs are induced by ionizing radiation (IR), radiomimetic agents, and other chemotherapeutics that damage DNA directly. DSBs can also be induced during the repair of 29920-428111 2025-018-02

[0011] DNA damage. A variety of pathways can repair DNA DSBs; however, repair-proficient cells will mostly employ the highly efficient and cell cycle-independent, error-prone non- homologous end joining (NHEJ) pathway. Aberrant activation of this NHEJ pathway contributes to therapy resistance in cancer by enhancing DNA repair capacity. In the NHEJ pathway, Ku70 / Ku80 (Ku) heterodimer, a protein complex composed of two subunits-Ku70 (70 kDa) and Ku80 (80 kDa), plays a crucial role in the repair of double-strand DNA breaks (DSBs).

[0012] NHEJ is initiated by the binding of the Ku heterodimer to DNA termini, creating a platform for binding and subsequent activation of DNA-PKcs. When a DSB occurs, the Ku rapidly binds to the exposed DNA ends. This binding protects the DNA from degradation and provides a platform for recruiting other key repair proteins, such as the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to activate downstream repair signaling. Together, Ku and DNA-PKcs form the DNA-PK holoenzyme, which aligns and processes the broken DNA ends for repair. In the absence of DNA-PKcs, Ku is also involved in the recruitment of Artemis for end processing, and Ku promotes the binding of DNA Ligase IV with its cofactors XRCC4 and XLF, ensuring the DNA ends are joined together. Ku suppresses alternative end-joining pathways (e.g., alt-EJ / MMEJ) by outcompeting other DNA end-binding proteins, ensuring that DSB repair proceeds through the more efficient classical NHEJ pathway. The importance of DNA-PK in the IR response has led to the development of several small-molecule DNA-PK inhibitors that target the kinase active site and are being pursued both pre-clinically and clinically.

[0013] Very recent single-molecule imaging studies revealed that Ku is present in a 10-fold excess compared to DNA-PKcs, which in turn is 2-5-fold more abundant than XRCC4 and XLF. Ku is rapidly associated with the vast majority of DNA breaks induced, and DNA-PKcs only binds to approximately 10000 DSBs, regardless of the number of DNA breaks present. In addition to its role in NHEJ, Ku70 / 80 also plays a multifaceted role in other cellular processes, including DNA damage response (DDR), V(D)J recombination, telomere maintenance, and regulation of apoptosis, mainly participating in pathways that control programmed cell death. In DDR, Ku is involved with DNA-PKcs in modulating ATM activity by signaling the ATM- dependent DDR cascade in response to DSBs to regulate cell fate after DNA damage. In this capacity, they phosphorylate ATM and other downstream targets and be phosphorylated by ATM and ATR. This collective response ensures that cancer cells can respond to all types of DNA damage to promote survival. Overall, Ku70 / Ku80 serves as a gatekeeper of genomic 29920-428111 2025-018-02 stability', ensuring rapid and efficient DSB repair via NHEJ while minimizing mutations and chromosomal rearrangements.

[0014] The loss or deficiency of Ku leads to severe defects in NHEJ, causing increased genomic instability-, higher susceptibility to DNA damage-induced apoptosis, and elevated risk of chromosomal translocations, contributing to cancer progression. The upregulated expression of Ku and DNA-PKcs has been associated with aggressive tumor behavior, tumor cell proliferation, metastasis, and resistance to therapy, ultimately leading to poor patient outcomes. The enhanced ability of tumor cells to repair DSBs and activation of DDR are major contributors to chemo- and radiotherapy resistance. Overall, this makes Ku and DNA-PKcs valuable targets for precision oncology, particularly in combination therapies aimed at disrupting DNA repair and DDR mechanisms in tumors.

[0015] As an alternative to ATP mimetic kinase inhibitors, Ku-DNA binding inhibitors (Ku- DBis) may demonstrate in vitro inhibition of Ku binding and DNA-PK activation. DNA-PK inhibitors have emerged as potential cancer therapeutics, and many DNA-PK inhibitors, including NU7441, M3814 (Peposertib), CC-115. VX-984 (M9831), AZD-7648, LY3023414 (Samotolisib), and XRD-0394 (XRad), are currently in preclinical and clinical trials, particularly for sensitizing tumors to radiation and chemotherapy. Despite their promise in cancer therapy, DNA-PK inhibitors face several challenges in clinical development, including normal tissue damage, dose-limiting toxicity, insufficient targeting of tumor tissue, and increased toxicity in combination therapy at maximum tolerable dose (MTD), lack of predictive biomarkers, off-target effects, and poor pharmacokinetics and drug delivery. On the other side, targeting Ku-DNA binding instead of or in addition to DNA-PKcs may offer better tumor selectivity, lower normal cell toxicity, and greater efficacy in overcoming resistance as it is more DNA damage-specific, has a unique capacity to block the formation of end-joining complexes as only one kinase in human cells, DNA-PKcs, requires Ku-DNA binding to be active and Ku activity independent of ATP concentration. Ku-DNA binding inhibitors (Ku- DBi’s) can have a minimal impact on alternative pathways or off-target toxicity- and have a great potential for synthetic lethality with HR-deficient tumors and enhancing response in combination with ionizing radiation. PARP inhibitors, and chemotherapy.

[0016] Through initial optimization of Ku-DBi, a series of compounds were identified with potent in vitro inhibition of DNA-PK and NHEJ-catalyzed DSB repair. Although the initial series of compounds demonstrated on-target cellular activity and sensitization to IR and other DSB-inducing treatments, the limited cellular uptake and poor solubility of these Ku-DBis necessitated the use of serum-free media for cellular Ku-DBi treatment. Thus, although DNA- 29920-428111 2025-018-02

[0017] PK inhibitors show strong in vitro potency, their clinical advancement has been limited by poor selectivity, low tumor accumulation, and systemic toxicity, preventing achievement of maximum tolerated doses.

[0018] Thus, there exists a need to develop Ku-DBis that exhibit improved cellular uptake while retaining potent Ku inhibitory activity.

[0019] SUMMARY

[0020] In one aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula wherein each of RA, RB, and Rc, ring D, L, and X is as defined herein.

[0021] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (II) wherein each of ‘"=”, RA, RB, and Rc, ring D, and X is as defined herein.

[0022] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (III) 29920-428111 2025-018-02 wherein each of X, R1, R2, R3, R4, m, n, o, and p is as defined herein.

[0023] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof having the formula (IV) wherein each of ‘"=”, X, R1, R2, R3, R4, m, n, o, and p is as defined herein.

[0024] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof having the formula (V) wherein each of X, R1, R2, R3, and R4is as defined herein.

[0025] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the disclosure and at least one pharmaceutically acceptable excipient.

[0026] In certain aspects, the present disclosure provides a method of treating a disease (e.g., a cancer, such as lung cancer) in a subject in need thereof comprising administering to the subject a compound or composition of the disclosure.

[0027] In certain aspects, the present disclosure provides a method of treating a disease (e.g., a cancer, such as lung cancer) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or composition of the disclosure. 29920-428111 2025-018-02

[0028] BRIEF DESCRIPTION OF THE FIGURES

[0029] FIGURE 1A shows chemical structures of Ku-DBi s developed by extensive SAR studies with their biochemical activity.

[0030] FIGURE IB shows the prediction of chemical structure of 35 (GL-3392) in aZ-isomer and E-isomer conformation.

[0031] FIGURE 2A illustrates the structure-guided design strategy’, highlighting a pocket surrounding the pyrazolone ring of compound 7 (245) that can be exploited through a cyclization approach for chemical optimization, as revealed by molecular docking studies. Ku70 / 80 heterodimer is shown as a cartoon model, compound 7 (245) is shown as a ball and stick carbon model, key amino acids are shown in carbon model, and the DNA ring structure is shown in a circular stick model. The dashed lines indicate interaction with amino acid side chains, and K-K stacking interactions are shown in a solid dumbbell. Interaction distances indicated in A°.

[0032] FIGURE 2B shows the overall SAR approach to optimize the structural scaffold of 2- oxindole to improve potency and drug-like properties.

[0033] FIGURE 3A shows the optimized Ku-DBis chemical structures.

[0034] FIGURE 3B shows in vitro Ku-DNA binding inhibition is determined by EMSA.

[0035] FIGURE 3C shows a graph of the quantification Ku-DNA binding inhibition. Data are presented as the mean of duplicate determinations.

[0036] FIGURE 3D shows a graph of Ku-DBi inhibition of DNA-PK kinase activity. Data are presented as the mean of duplicate determinations.

[0037] FIGURE 3E shows a graph of cellular uptake of Ku-DBis assessed in H460 NSCLC cells. Cells w ere cultured in RPMI media supplemented with 10% Fetal bovine serum. Data are presented as the mean of duplicate determinations. ***P =0.0009, **P=0.0019 as calculated by one-way ANOVA with Sidak's multiple comparisons tests.

[0038] FIGURE 3F shows a graph of Ku-DBis cellular uptake time-course in H460 cells. Data are presented as the mean of duplicate determinations.

[0039] FIGURE 3G shows a graph of cellular uptake of Ku-DBis assessed in A549 NSCLC cells. A549 cells were incubated with 10 pM Ku-DBi for 4h. After incubation, extracted samples in methanol were analyzed by HPLC, and picomoles of compound per million cells were calculated. Cells were cultured in RPMI media supplemented with 10% Fetal bovine serum. Data are presented as the mean of duplicate determinations. ***p =0.0009, **P=0.0014 as calculated by one-way ANOVA with Sidak's multiple comparisons tests. 29920-428111 2025-018-02

[0040] FIGURE 3H shows a graph of cellular uptake of Ku-DBis assessed in H460 NSCLC cells in different cell culture media. Optimem is a serum free media. Similar uptake may indicate that this series of compounds is able to be taken up into cell largely independent of the media and its protein content.

[0041] FIGURE 4A shows the potential SOM for Ku-DBi 34 based on the P450 SOM predicted by Schrodinger Maestro Suite 2024. The tool combines molecular docking with quantum mechanical calculations, incorporating Hammett and Taft-type parameters and 3D spatial information, to identify likely sites of metabolism and assess the intrinsic reactivity of CYP3A4. The circles visually highlight sites within the molecule likely to serve as sites of metabolism (SOMs) based on the analysis. The size of the circle indicates the overall SOM score, the larger the circle, the higher the predicted propensity’ for metabolism at that site.

[0042] FIGURE 4B shows sites of metabolism (SOM) intrinsic reactivity for compound 34 and it refers to the inherent tendency of a specific site on a molecule to undergo metabolism by a CYP450 enzy me. A positive reactivity value indicates that a particular atom or region is more likely to participate in a metabolic reaction, whereas a negative value suggests reduced susceptibility to metabolism.

[0043] FIGURE 4C shows a representation of a strategy to improve metabolic stability involved masking a high-propensity SOM on the oxindole ring by substituting the 5-(para) position hydrogen with a fluorine atom or a trifluoromethoxy group.

[0044] FIGURE 5A shows a molecular docking study with compound 35 (GL-3392) using PDB: 1JEQ and 1JEY. Molecular interactions of compound 35 (in carbon) with Ku70 / 80 heterodimer [key amino acids are shown in carbon (Ku70), carbon (Ku80) and cartoon is shown],

[0045] FIGURE 5B shows 2D interactions of 35 (GL-3392) with Ku70 / 80 heterodimer amino acid residues.

[0046] FIGURE 5C shows a molecular docking study’ with compound 53 (GL-3609) using PDB: 1JEQ and 1JEY. Molecular interactions of compound 53 (in carbon) with Ku70 / 80 heterodimer [key’ amino acids are shown in carbon (Ku70), carbon (Ku80) and cartoon is shown],

[0047] FIGURE 5D shows overlay of tetrazoles 53 (GL-3609, carbon) and 7 (245, carbon) highlighting their superimposed binding poses. The solid arrow denotes key differences in their interactions with the Ku70 / 80 heterodimer. Interaction with amino acid side chains is indicated with the dashed lines, cation -it interactions are shown in a solid one-sided dumbbell, and z - 29920-428111 2025-018-02 stacking interactions are shown in a solid dumbbell. The DNA helical structure is depicted in dots and cartoon sticks. Interaction distances are indicated in A”.

[0048] FIGURE 6A shows a graph of interaction between Ku70-Ku80 with 3392 measured by MST (Microscale Thermophoresis) with a Ka of 2. 1 + / - 0.3 pM. The estimated bound fraction is plotted as a function of ligand concentration.

[0049] FIGURE 6B shows (i) a graph of impact of ligand 3392 on the thermostability and aggregation propensity of Ku70-Ku80, in particular, the ratio of intrinsic fluorescence at 350 nm divided by 330 nm;(ii) a graph of impact of ligand 3392 on the thermostability and aggregation propensity of Ku70-Ku80, in particular, the turbidity measurement;(iii) a graph of impact of ligand 3392 on the thermostability and aggregation propensity of Ku70-Ku80, in particular, the first derivative of the ratio; and (iv) a graph of impact of ligand 3392 on the thermostability and aggregation propensity of Ku70-Ku80, in particular, the cumulant radius measured by DLS as a function of temperature.

[0050] FIGURE 7A shows a graph of the measurement of raw initial fluorescence of protein in the presence of ligand 3392: concentration range from 98 nM to 200 pM in a 1 : 1 dilution series of 12 points.

[0051] FIGURE 7B shows a graph of the raw initial fluorescence before denaturation of complex form (capillaries n°l, n°2, n°3) and Apo form (capillaries n°10, n°l 1, n°12).

[0052] FIGURE 7C shows a graph of the raw initial fluorescence after denaturation. Denaturation consisted of centrifuging the remaining tubes (1 to 3 and 10 to 12) prepared in the original binding assay for at least 10 minutes at =15,000g, carefully removing the supernatants, mixing each with SD-mix (4% SDS, 40 mM DTT), and finally incubating for 5 minutes at 95°C to denature the protein.

[0053] FIGURE 8A shows a graph of single-agent Ku-DBi activity of 3392 in comparison with NU-7441 in p53-null H1299 NSCLC cell line. The indicated cell lines were plated and treated with the indicated agent for 48 h, and cell viability was determined as described. Data represent the mean ± SEM of triplicate determinations.

[0054] FIGURE 8B shows a graph of single-agent Ku-DBi activity of 3392 in comparison with NU-7441 in A549 adenocarcinoma cell line. The indicated cell lines were plated and treated with the indicated agent for 48 h, and cell viability was determined as described. Data represent the mean ± SEM of triplicate determinations.

[0055] FIGURE 8C shows a graph of single-agent Ku-DBi activity' of 3392 in comparison with NU-7441 in H460 large cell lung carcinoma cell line. The indicated cell lines were plated and 29920-428111 2025-018-02 treated with the indicated agent for 48 h, and cell viability was determined as described i. Data represent the mean ± SEM of triplicate determinations.

[0056] FIGURE 8D shows a graph of single-agent Ku-DBi activity of 3392 in comparison with NU-7441 in ATM-null 1423 cell line. The indicated cell lines were plated and treated with the indicated agent for 48 h, and cell viability7was determined as described. Data represent the mean ± SEM of triplicate determinations.

[0057] FIGURE 9A shows an isobologram analysis for 3392 and bleomycin combination in H460 cells and -response matrix for inhibition.

[0058] FIGURE 9B shows a surface plot for HSA and Bliss independence additive models for synergy7assessment. Data were analyzed using the Synergy7finder tool (https: / / synergyfinder.fimm.fi / synergy).

[0059] FIGURE 9C shows a graph of analysis of 3392 in combination with IR in A549 cells. Tukey's multiple comparisons test, simple effects within rows. **** p<0.0001, **p <0.005, *p<0.05.

[0060] FIGURE 9D shows a graph of analysis of 3392 in combination with IR in H23 cells. Tukey's multiple comparisons test, simple effects within rows. **** p<0.0001. **p <0.005. *p<0.05.

[0061] FIGURE 10 shows a graph of Ku-DBi 3392 sensitivity7to bleomycin in wild-ty pe (WT) and Ku 80-null MEFs cells. MEF cells were pre-treated with vehicle or 20 pM 3392 for 24 h and then increasing concentrations of bleomycin for 48 h after which cell viability was determined by CCK-8. Data are presented as the mean and SEM of triplicate determinations.

[0062] FIGURE 11 A shows a graph of the indicated cell line (MDA-MB-436) that were plated and treated with increasing concentrations of the indicated single agents and cellular viability was determined by CCK-8 assay. Data are presented as the mean ± SEM of triplicate determinations.

[0063] FIGURE 1 IB shows a graph of the indicated cell line (MDA-MB-468) that were plated and treated with increasing concentrations of the indicated single agents and cellular viability was determined by CCK-8 assay. Data are presented as the mean ± SEM of triplicate determinations.

[0064] FIGURE 11C shows a graph of bleomycin sensitization activity that was determined for the Ku-DBi and NU-7441 in the indicated cell line (MDA-MB-436). Data are presented as the mean ± SEM of triplicate determinations. 29920-428111 2025-018-02

[0065] FIGURE 11D shows a graph of bleomycin sensitization activity that was determined for the Ku-DBi and NU-7441 in the indicated cell line (MDA-MB-468). Data are presented as the mean ± SEM of triplicate determinations.

[0066] FIGURE 12A shows a graph of decreased sensitivity to Doxorubicin mediated by Ku- DBi in MDA-436 cells. Cells were pre-treated for 3 h with vehicle or 20 pM 3392 prior to 72 h treatment with increasing concentrations of Doxorubicin. Data are presented as the mean and SEM of tnplicate determinations

[0067] FIGURE 12B shows a graph of decreased sensitivity to Doxorubicin mediated by Ku- DBi in MDA-436 cells. Pre-treatment with vehicle or 20 pM 3392 and media removed after 3 h, prior 72 h doxorubicin treatment after which cell viability was determined by CCK-8. Data are presented as the mean and SEM of triplicate determinations

[0068] FIGURE 13A shows a schematic of the experimental design for combination Ku-DBi and IR treatment of NSCLC in vivo. A549 CDX tumors were implanted in NRG mice, and Ku- DBi treatments were delivered via intratumoral injection 4h prior to IR. Two hours after IR, tumors were collected and processed for protein extraction.

[0069] FIGURE 13B shows a Western blot analysis from CDX tumor extracts assessing DNA- PKcs and y-H2AX.

[0070] FIGURE 13C shows a graph of the quantification of the protein expression data presented in Figure 13B. Data are shown as mean ± SEM (vehicle n = 3, 3392 n = 3, IR n = 3, combination n = 4). Statistical analysis was performed using Fisher's Least Significant Difference test of the individual comparisons indicated. Significant differences are indicated by an * p < 0.05, ** p<0.01, *** p < 0.001.

[0071] FIGURE 13D shows a graph of the quantification of the protein expression data presented in Figure 13B. Data are shown as mean ± SEM (vehicle n = 3, 3392 n = 3, IR n = 3, combination n = 4). Statistical analysis was performed using Fisher's Least Significant Difference test of the individual comparisons indicated. Significant differences are indicated by an * p < 0.05, ** p<0.01, *** p < 0.001.

[0072] FIGURE 13E shows representative 20X images of Ki-67 images, Sb: 100mm. Inset. The inset shows whole tumor sections for each treatment. Sb: 3mm. Images were acquired using the Aperio ScanScope CS system.

[0073] FIGURE 13F shows a Western blot detection of Ki -67 from the tumor tissue extracts.

[0074] FIGURE 13G shows a graph of the quantification of the data presented in Figure 13F. Data are shown as mean ± SEM (vehicle n = 3, 3392 n = 3, IR n = 3, combination n = 4). Statistical analysis was performed using Fisher's Least Significant Difference test of the 29920-428111 2025-018-02 individual comparisons indicated. Significant differences are indicated by an * p < 0.05, ** p<0.01, *** p < 0.001.

[0075] FIGURE 14A shows a schematic of the experimental design for combination Ku-DBi and IR treatment of NSCLC in vivo. A549 cells were cultured in flasks until there were enough to implant 2 million cells / mouse into the right flank of each mouse. After the tumors were given time to grow, male and female mice were treated with IP injections of either vehicle or Ku- DBi (3393). 2 hours later half of each treatment group received 5 Gy of radiation at the tumor site or no radiation but were anesthetized like the irradiated group.

[0076] FIGURE 14B shows a graph of average A549 tumor volume. NRG mice were randomized into 4 treatment groups once the A549 tumors reached an average of 86 mm3. Each group had a mix of male and female mice. Mice were treated on days 0, 7. 14, and 21 with either an IP injection of 120 mg / kg 3393 in 20% DMSO in PBS (3393 and Combo groups) or 20% DMSO in PBS (Vehicle and IR groups) and 2 hours later they were either anesthetized (Vehicle and 3393 groups) or anesthetized and the tumor received 5 Gy radiation treatment (IR and Combo groups). Data points represent the mean tumor volume of the group and error bars represent the SEM.

[0077] FIGURE 14C shows a graph of individual A549 tumor weights. On day 27 post the first treatment with 3393 and / or x-ray, all mice were sacrificed, and the tumors were removed and weighed. Tumor weights for each mouse in each of the 4 groups are plotted. The horizontal line represents the mean for that group. Significant differences in tumor weight (p<0.05) were seen between the vehicle group and each of the other 3 groups. In addition, there was a significant difference (p<0.05) between the group that received 3393 alone and the group that received the combination of 3393 and radiation.

[0078] FIGURE 15A shows a schematic of the experimental design for combination Ku-DBi and IR treatment of NSCLC in vivo. A549 cells were cultured in flasks until there were enough to implant 2 million cells / mouse into the right flank of each mouse. After the tumors were given time to grow, male mice were treated with IP injections of either vehicle or Ku-DBi (3392). 2 hours later half of each treatment group received 5 Gy of radiation at the tumor site or no radiation but were anesthetized like the irradiated group.

[0079] FIGURE 15B shows a graph of average A549 tumor volume. NRG mice were randomized into 4 treatment groups once the A549 tumors reached an average of 222 mm3. Mice were treated on days 0, 7, and 14 with either an IP injection of 120 mg / kg 3393 in 20% DMSO in PBS (3393 and Combo groups) or 20% DMSO in PBS (Vehicle and IR groups) and 2 hours later they were either anesthetized (Vehicle and 3393 groups) or anesthetized and the 29920-428111 2025-018-02 tumor received 5 Gy radiation treatment (IR and Combo groups). The IR only and Combo (3392 + IR) groups received a 4thtreatment on day 21. The tumors of all mice were measured every 3-4 days during the course of their treatment and after their last treatment until the day they were sacrificed due to their tumor reaching the maximum allowed size (2000 mm3). Data points represent the mean tumor volume of the group and error bars represent the SEM.

[0080] FIGURE 16 shows a graph of concentration of 3392 in serum. Serum was obtained from 9 female NRG mice 2 hours post injection with 20 mg / kg, 40 mg / kg. or 80 mg / kg of 3392 in 10% DMSO in PBS (3 mice at each dose level). Serum was analyzed by the Clinical Pharmacology Analytical Core to obtain the concentration of 3392. Individual serum values are shown (dots), along with the mean (columns) and SD (error bars) for each dose level.

[0081] FIGURE 17A shows a five-dose bar graph of the growth inhibition of 50 % (GBo) for 3392 treatments.

[0082] FIGURE 17B shows a five- dose mean graph as a function of the total growth inhibition (TGI) for Ku-DBi 3392, 3395, 3618, and 3649. Individual cell lines are plotted relative to the average response (midpoint). Cells more sensitive to the average are drawn to the right, while cells less sensitive than the average are drawn to the left.

[0083] FIGURE 17C shows a graph of IC50 values calculated for each cell line.

[0084] FIGURE 17D shows a comparative analysis (COMPARE) for Ku-DBi against existing DNA-PK inhibitors from five-dose screening GI50 data. Heat map by the delta value of the GBo data. The light color indicates the highest potency, whereas the dark color represents the lowest potency. The results are reported as growth %: treated cell growth as a % of control cell growth with a correction for the number of cells at time zero.

[0085] DETAILED DESCRIPTION

[0086] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended clauses.

[0087] For the sake of brevity7, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their 29920-428111 2025-018-02 entireties. If a definition set forth in this section is contrary to or otherw ise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0088] As used herein and in the appended clauses, the singular forms “a,” “an,"’ and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the clauses may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of clause elements, or use of a “negative” limitation.

[0089] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0090] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity7for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

[0091] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary7skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0092] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods w ell known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e g., Loudon, Organic Chemistry, Fourth Edition, New7York: Oxford University Press. 2002, pp. 360-361. 1084-1085; Smith and March. March's Advanced 29920-428111 2025-018-02

[0093] Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0094] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0095] As used herein and in connection with chemical structures depicting the various embodiments described herein, and , each represent a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portion

[0096] I) A > of A-B defined by the group or chemical structure A can be represented by represents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portion of A-B defined by the group or chemical structure B can be represented by ” represents a bond to B and the point of covalent bond attachment to A.

[0097] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. 29920-428111 2025-018-02

[0098] DEFINITIONS

[0099] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.

[0100] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well know n in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g., “Principles of Neural Science". McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al.. “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, Mass. (2000).

[0101] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary' of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

[0102] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0103] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.

[0104] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, 29920-428111 2025-018-02 livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0105] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0106] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0107] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0108] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, 29920-428111 2025-018-02 bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g.. to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0109] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0110] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, and the nature and extent of the condition being treated, such as cancer. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0111] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0112] It is understood that substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art. as well as those methods set forth below7, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0113] As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but 29920-428111 2025-018-02 not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy. aryl, cycloalkyl, heterocyclyl. amino, aminoalkyl, cyano, haloalkyl. haloalkoxy, — OCO — CH2 — O-alkyl, — OP(O)(O-alkyl)2or — CH2 — OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted. As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to Ci-C 10 straight-chain alkyl groups or Ci-Cio branched-chain alkyl groups. Preferably, the “alkyl” group refers to Ci -Cd straight-chain alkyl groups or Ci-Ce branched- chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alky l groups or Ci-C4branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1 -propyl, 2 -propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. The “alk 1” group may be optionally substituted.

[0114] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O) — . preferably alkylC(O) — .

[0115] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH — .

[0116] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O — . preferably alkylC(O)O — .

[0117] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0118] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0119] The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Ci- 30 for straight chains. C3-30 for branched chains), and more preferably 20 or fewer.

[0120] Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyd groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc. 29920-428111 2025-018-02

[0121] The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A C i-ealkyl group, for example, contains from one to six carbon atoms in the chain.

[0122] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[0123] The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl S — .

[0124] The term “amide”, as used herein, refers to a group wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0125] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by

[0126] K wherein each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0127] The term “aminoalky 1”, as used herein, refers to an alkyl group substituted with an amino group.

[0128] The term “aralky l”, as used herein, refers to an alkyl group substituted with an aryl group.

[0129] The term “ary ’ as used herein includes substituted or unsubstituted aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 10-membered ring, more preferably a 6-membered or a 10-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include phenyl, phenol, aniline, naphthyl, anthryl, and the like. In some instances, the term 29920-428111 2025-018-02

[0130] “biaryr, as used herein, includes a substituted or unsubstituted ary l including two adjoining aromatic rings in which each atom of the ring is carbon. Preferably the ring is a 10-membered ring. Biaryl groups include naphthyl, and the like.

[0131] Moreover, the term “aryl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted ar l groups, the latter of which refers to aryl moieties having substituents replacing a hydrogen.

[0132] The term “carbamate” is art-recognized and refers to a group wherein R9and R10independently represent hydrogen or a hydrocarbyl group.

[0133] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0134] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo [2.2. l]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH- indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0135] The term “carbonate” is art-recognized and refers to a group — OCCh — .

[0136] The term “carboxy”, as used herein, refers to a group represented by the formula — CO2H.

[0137] The term “ester”, as used herein, refers to a group — C(O)OR8, wherein R8represents a hydrocarbyl group. 29920-428111 2025-018-02

[0138] The term “ketone”, as used herein, refers to a group — C(O)R7. wherein R7represents a hydrocarbyl group (e.g., alkyl, aryl, heteroaryl).

[0139] The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of ahydrocarbyl group may be hydrocarbyl-0 — . Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

[0140] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0141] The term “haloalkoxy” as used herein, refers to an alkoxy group substituted with one or more halo group. A representative haloalkoxy group includes trifluoromethoxy.

[0142] The term “haloalkyl” as used herein, refers to an alkyl group substituted with one or more halo group. A representative haloalkyl group includes trifluoromethyl.

[0143] The term “hydrazine” as used herein, refers to a group represented by the structure

[0144] R3

[0145] R. ,N. ,

[0146] N R2

[0147] R , wherein R, R1, R2, and R3independently represent hydrogen or a hydrocarbyl group.

[0148] The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0149] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic ring structures, preferably 5- to 12-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. The term “monocyclic heteroaryl”, as used herein, includes substituted or unsubstituted aromatic single-ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one or two heteroatoms. Monocyclic heteroary l groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term “bicyclic heteroaryl”, as used herein, includes substituted or unsubstituted aromatic ring including two adjoining aromatic rings, preferably 8- to 12-membered rings, whose ring structures include at 29920-428111 2025-018-02 least one heteroatom, preferably one or two heteroatoms. Bicyclic heteroaryl groups include, for example, oxindole, indole, indazole, azaindole, azaindazole, benzofuran, benzothiophene, benzothiazole, benzopyran, benzothiadiazole, benzooxadiazole, quinoline, isoquinoline, quinazoline, thiadiazole, chromone, quinolone, and the like.

[0150] Moreover, the terms “heteroaryl” and “hetaryl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted heteroaryl and hetaryl groups, the latter of which refers to heteroaryl and hetaryl moieties having substituents replacing a hydrogen. In an exemplary embodiment, a heteroaryl or bicyclic heteroaryl includes an oxindole, depicted by the structure H . In an exemplary embodiment, a compound of the formula H can be represented by the structure H

[0151] The term “heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0152] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0153] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0154] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbonhydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not 29920-428111 2025-018-02 carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0155] The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0156] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alky l, alkenyl, alkynyl. or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy. lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0157] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0158] The term “phosphonate” is art-recognized and refers to the group — PO(OR)2, or a pharmaceutically acceptable salt thereof, wherein each R independently represents a hydrogen or a hydrocarbyl group. Examples of phosphonate groups include, but are not limited to, — PO(OH)2and — PO(OEt)2.

[0159] The term “phosphate” is art-recognized and refers to the group — OPO(OR)2, or a pharmaceutically acceptable salt thereof, wherein each R independently represents a hydrogen or a hydrocarbyl group.

[0160] The term “sulfate” is art-recognized and refers to the group — OSChH, or a pharmaceutically acceptable salt thereof.

[0161] The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae wherein R9and R10independently represents hydrogen or hydrocarbyl.

[0162] The term “sulfoxide” is art-recognized and refers to the group — S(O) — . 29920-428111 2025-018-02

[0163] The term “sulfonate” is art-recognized and refers to the group SChH, or a pharmaceutically acceptable salt thereof.

[0164] The term “sulfone” is art-recognized and refers to the group — S(O)2-R9, wherein R9represents hydrocarbyl (e.g., alkyl, aryl, heteroaryl).

[0165] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl. a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alky Ithi o, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0166] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

[0167] The term “thioester”, as used herein, refers to a group — C(O)SR8or — SC(O)R8wherein R8represents a hydrocarbyl.

[0168] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0169] The term “urea” is art-recognized and may be represented by the general formula 29920-428111 2025-018-02 wherein each R9and R10independently represent hydrogen or a hydrocarbyl.

[0170] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0171] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0172] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

[0173] The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formula I. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non- pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0174] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. 29920-428111 2025-018-02

[0175] Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.

[0176] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers. For example, a compound having a double bond represented by “=”or “^=” or “=—=■’ may refer to a Z-isomer, an E-isomer, or a mixture of both Z- and E-isomers.

[0177] Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure. For example, an oxindole may be represented by the structure

[0178] “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety' of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Pat. Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0179] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter. 29920-428111 2025-018-02 diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

[0180] The term “Log of solubility’’, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter.

[0181] The term “LogP” (also referred to as the logarithm of the octanol-water partition coefficient) as used herein is used in the art to to quantify the lipophilicity7of a compound (i.e., how readily it dissolves in fatty substances (like octanol) versus water). A high positive logP may indicate a hydrophobic compound that prefers the organic (fatty) phase, while a low or negative logP indicates a hydrophilic compound that prefers the aqueous (watery) phase.

[0182] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity' and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0. 1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to I g daily. The total dosage may be given in single or divided dosage units (e g., BID, TID, QID).

[0183] REPRESENTATIVE EMBODIMENTS

[0184] Compounds of the present disclosure find utility in the treatment and prevention of cancer. For example, the compounds of the present disclosure may target upstream events in the non-homologous end joining (NHEJ) pathway — specifically, the Ku-DNA interaction. An object of the present disclosure is to provide a series of oxindole derivatives with improved solubility, chemical stability, metabolic stability, and significantly enhanced cellular uptake, while retaining in vitro Ku, DNA-PK activity, and in vivo on-target activity.

[0185] In one embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (I) 29920-428111 2025-018-02 wherein each of RA, RB, and Rcis independently aryl or heteroaryl, each of which may be optionally substituted; ring D is aryl or heteroaryl, each of which may be optionally substituted;

[0186] X is S, NH, or O; is a single bond or a double bond; and

[0187] L is alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, or aminoalkyl.

[0188] In another embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (II) wherein each of RA, RB, and Rc, ring D, and X are as defined herein.

[0189] In another embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (Ila) wherein each of ‘"=”, RA, RB, and Rc, X, and p are as defined herein.

[0190] In another embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (Ila) 29920-428111 2025-018-02 wherein each of RA, RB, and Rc, and X are as defined herein.

[0191] In another embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (III) wherein each of X, R1, R2, R3, R4, m, n, o, and p are as defined herein.

[0192] In another embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (IV) wherein each of ‘"=”, X, R1, R2, R3, R4, m, n, o, and p are as defined herein.

[0193] In another embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (V) 29920-428111 2025-018-02 wherein each of ”=". X, R1, R2, R3, and R4is as defined herein.

[0194] In another embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (Va) wherein each of X. R1. R2, R3, and R4is as defined herein.

[0195] In another embodiment, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula (Vb) wherein each of X. R1, R2, R3, and R4is as defined herein.

[0196] In some embodiments, RAis aryl (e.g., Ce-Cio aryl) or heteroaryl (e.g., 5- to 12- membered heteroaryl), each of which may be optionally substituted. In some embodiments, RAis optionally substituted aryl (e.g., Cs-Cio aryl) or optionally substituted heteroaryl (e.g., 5- to 12-membered heteroaryl). In some embodiments, RAis optionally substituted Ce-Cio aryl (e.g., optionally substituted phenyl). In some embodiments. RAis substituted Cs-Cio aryl (e.g., 29920-428111 2025-018-02 substituted phenyl). In some embodiments, RAis optionally substituted 5- to 12-membered heteroaryl.

[0197] In some embodiments, RAis aryl (e.g., Ce-Cio aryl) or heteroaryl (e.g., 5- to 12- membered heteroaryl), each of which may be optionally substituted by R2. In some embodiments, RAis ar l (e.g., Ce-Cio aryl) or heteroaryl (e.g., 5- to 12-membered hctcroaryl). each of which may be optionally substituted by 1 or 2 of R2(e.g., n is 1 or 2). In some embodiments, RAis Ce-Cio aryl (e.g.. phenyl) optionally substituted by R2. In some embodiments, RAis Ce-Cio aryl (e.g., phenyl) optionally substituted by 1 or 2 of R2(e.g., n is 1 or 2). In some embodiments, RAis Ce-Cio aryl (e.g., phenyl) optionally substituted by 1 of R2(e.g., n is 1). In some embodiments, RAis 5- to 12-membered heteroaryl optionally substituted by R2. In some embodiments, RAis 5- to 12-membered heteroaryl optionally represents a point of covalent attachment to L and represents a point of covalent attachment to the rest of the compound.

[0198] In some embodiments, RAis substituted (e.g., n is 1 or 2) with aryl, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl. ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted. In some embodiments, RAis substituted (e.g., n is 1 or 2) with halo, alkoxy (e.g., methoxy), haloalkyl, or haloalkoxy. In some embodiments, RAis substituted aryl (e.g., fluorophenyl or methoxyphenyl). In certain preferred embodiments, RAis substituted phenyl (e.g., fluorophenyl or methoxyphenyl).

[0199] In some embodiments, RBis aryl (e.g., Ce-Cio aryl) or heteroaryl (e.g., 5- to 12- membered heteroaryl), each of which may be optionally substituted. In some embodiments, RBis optionally substituted aryl (e.g., Cs-Cio and) or optionally substituted heteroaryl (e.g., 5- to 12-membered heteroaryl). In some embodiments, RBis optionally substituted Cg-Cio aryl (e.g., optionally substituted phenyl). In some embodiments, RBis substituted Ce-Cio and (e.g., substituted phenyl). In some embodiments, RBis optionally substituted 5- to 12-membered heteroaryl.

[0200] In some embodiments, RBis aryl (e.g., Cs-Cio aryl) or heteroaryl (e.g., 5- to 12- membered heteroaryl), each of which may be optionally substituted by R3. In some 29920-428111 2025-018-02 embodiments, RBis and (e.g., Cs-Cio aryl) or heteroaryl (e.g., 5- to 12-membered heteroary l), each of which may be optionally substituted by 1 or 2 of R3(e.g., o is 1 or 2). In some embodiments, RBis Ce-Cio aryl (e.g., phenyl) optionally substituted by R3. In some embodiments, RBis Ce-Cio aryl (e.g., phenyl) optionally substituted by 1 or 2 of R3(e.g., o is 1 or 2). In some embodiments, RBis Ce-Cio ary l (e.g., pheny l) optionally substituted by 1 of R3(e.g., o is 1). In some embodiments. RBis 5- to 12-membered heteroaryl optionally substituted by R3. In some embodiments, RBis 5- to 12-membered heteroaryl optionally substituted by 1 or 2 of R3(e.g., o is 1 or 2).

[0201] In some embodiments, RBis substituted (e.g., o is 1 or 2) with aryl, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted. In some embodiments, RBis substituted (e.g., o is 1 or 2) with alkoxy (e.g., methoxy) or haloalkoxy (e.g., trifluoromethoxy). In some embodiments, RBis substituted aryl, such as substituted phenyl (e.g., methoxyphenyl, such as such as 3 -methoxy phenyl, or trifluoromethoxyphenyl, such as 3- trifluoromethoxyphenyl). In certain preferred embodiments,

[0202] ” represents a point of covalent attachment to L.

[0203] In some embodiments, -RA-L-RBis

[0204] In some embodiments, -RA-L-RBis

[0205] 29920-428111 2025-018-02

[0206] In some embodiments, Rcis aryl (e.g., C6-C10 aryl) or heteroaryl (e.g., 5- to 12- membered heteroaryl), each of which may be optionally substituted. In some embodiments, Rcis optionally substituted aryl (e.g., Ce-Cio aryl) or optionally substituted heteroaryl (e.g., 5- to 12-membered heteroaryl). In some embodiments, Rcis optionally substituted Ce-Cio aryl (e.g., optionally substituted phenyl). In some embodiments. Rcis substituted Cs-Cio aryl (e.g., substituted phenyl). In some embodiments, Rcis optionally substituted 5- to 12-membered heteroaryl.

[0207] In some embodiments, Rcis aryl (e.g., Cs-Cio aryl) or heteroaryl (e.g., 5- to 12- membered heteroaryl), each of which may be optionally substituted by R1. In some embodiments, Rcis aryl (e.g., Cs-Cio aryl) or heteroaryl (e.g., 5- to 12-membered heteroaryl), each of which may be optionally substituted by 1 or 2 of R1(e g., m is 1 or 2). In some embodiments, Rcis Ce-Cio aryl (e.g., phenyl) optionally substituted by R1. In some embodiments, Rcis Ce-Cio aryl (e.g., phenyl) optionally substituted by 1 or 2 of R1(e.g., m is 1 or 2). In some embodiments, Rcis Ce-Cio aryl (e.g., phenyl) optionally substituted by 1 of R1(e.g., m is 1). In some embodiments, Rcis 5- to 12-membered heteroaryl optionally substituted by R1. In some embodiments, Rcis 5- to 12-membered heteroaryl optionally substituted by 1 or 2 of R1(e.g., m is 1 or 2).

[0208] In some embodiments, Rcis substituted (e.g.. m is 1 or 2) with aryl, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted. In some embodiments, Rcis substituted (e.g., m is 1 or 2) with ester, carboxy, optionally substituted heteroaryl, amide, sulfone, sulfonamide, phosphate, or phosphonate. In some embodiments, Rcis substituted (e.g., m is 1 or 2) with ester (e.g., -C(O)Oalkyl, such as - 29920-428111 2025-018-02

[0209] C(O)OEt) or carboxy (e.g., -C(O)OH). In some embodiments, Rcis substituted aryl (e.g., carboxyphenyl, such as 3- carboxyphenyl). embodiments,

[0210] In some embodiments, ring D is aryl (e.g., Cs-Cio aryl) or heteroaryl (e.g., 5- to 12- membered heteroaryl), each of which may be optionally substituted. In some embodiments, ring D is optionally substituted aryl (e.g., Ce-Cio aryl) or optionally substituted heteroaryl (e.g., 5- to 12-membered heteroaryl). In some embodiments, ring D is optionally substituted Ce-Cio aryl (e.g., optionally substituted phenyl). In some embodiments, ring D is substituted Ce-Cio aryl (e.g., substituted phenyl). In some embodiments, ring D is optionally substituted 5- to 12- membered heteroaryl.

[0211] In some embodiments, ring D is aryl (e.g., Ce-Cio aryl) or heteroaryl (e.g., 5- to 12- membered heteroaryl), each of which may be optionally substituted by R4. In some embodiments, ring D is aryl (e.g., Ce-Cio aryl) or heteroaryl (e.g., 5- to 12-membered heteroaryl), each of which may be optionally substituted by 1 or 2 of R4(e.g., p is 1 or 2). In some embodiments, ring D is Ce-Cio aryl (e.g., phenyl) optionally substituted by R4. In some embodiments, ring D is Ce-Cio aryl (e.g., phenyl) optionally substituted by 1 or 2 of R4(e.g., p is 1 or 2). In some embodiments, ring D is unsubstituted Ce-Cio aryl (e.g., p is 0). In some embodiments, ring D is unsubstituted phenyl (e.g., p is 0). In some embodiments, ring D is 5- to 12-membered heteroaryl optionally substituted by R4. In some embodiments, ring D is 5- to 12-membered heteroaryl optionally substituted by 1 or 2 of R4(e.g., p is 1 or 2). 29920-428111 2025-018-02

[0212] In some embodiments, ring D is substituted (e.g., p is 1 or 2) with aryl, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl. ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted. In some embodiments, ring D is substituted (e.g., p is 1 or 2) with alkoxy or haloalkoxy. In some embodiments, ring D is unsubstituted (e.g.. p is 0). In some embodiments, ring D is unsubstituted and (e.g.. phenyl). In certain preferred embodiments, ring D is unsubstituted phenyl.

[0213] In some embodiments, each of RA, RB, Rc, and ring D is optionally substituted and (e.g., C6-C10 aryl, such as phenyl). In some embodiments, RAis substituted aryl (e.g., fluorophenyl or methoxyphenyl) and RBis substituted aryl (e.g.. methoxyphenyl or trifluoromethoxyphenyl). In some embodiments, RAis substituted aryl (e.g., fluorophenyl or methoxyphenyl), RBis substituted aryl (e.g., methoxyphenyl or trifluoromethoxyphenyl), and Rcis substituted ary l (e.g., carboxyphenyl). In some embodiments, RAis substituted ary 1 (e.g., fluorophenyl or methoxyphenyl). RBis substituted aryl (e.g., methoxyphenyl or trifluoromethoxyphenyl), Rcis substituted aryl (e.g., carboxyphenyl), and ring D is unsubstituted ary 1 (e.g., phenyl).

[0214] In some embodiments, each of R1, R2, R3, and R4, when present, is independently ary l, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted.

[0215] In some embodiments, each of R1, when present, is independently ary l, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl. ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may' be optionally substituted. In some embodiments, each of R1, when present, is independently ester, carboxy, optionally substituted heteroaryl, amide, sulfone, sulfonamide, phosphate, or phosphonate. In some embodiments, each of R1, when present, is independently ester or carboxy.

[0216] In some embodiments, each of R2, when present, is independently aryl, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted. In some embodiments, each of R2, when present, is independently halo (e.g., 29920-428111 2025-018-02 fluoro), alkoxy (e.g., methoxy), haloalkyl (e.g., trifluoromethyl), or haloalkoxy (e.g., trifluoromethoxy). In some embodiments, each of R2, when present, is independently halo (e.g., fluoro) or alkoxy (e.g., methoxy). In some embodiments, R2is halo (e.g., chloro or fluoro). In some embodiments, R2is alkoxy (e.g., methoxy).

[0217] In some embodiments, each of R3, when present, is independently ary l, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted. In some embodiments, each of R3, when present, is independently alkoxy (e.g., methoxy) or haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R3is alkoxy (e.g., methoxy). In some embodiments, R3is haloalkoxy (e.g., trifluoromethoxy).

[0218] In some embodiments, each of R4, when present, is independently aryl, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted. In some embodiments, each of R4, when present, is independently halo (e.g., fluoro), alkoxy (e.g., methoxy) or haloalkoxy (e.g., trifluoromethoxy). In some embodiments, each of R4, when present, is independently halo (e.g., fluoro) or haloalkoxy (e.g., trifluoromethoxy).In some embodiments, each of R4. when present, is independently alkoxy (e.g.. methoxy) or haloalkoxy (e.g., trifluoromethoxy).

[0219] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1.

[0220] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1.

[0221] In some embodiments, o is 0, 1, or 2. In some embodiments, o is 1 or 2. In some embodiments, o is 0. In some embodiments, o is 1.

[0222] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1.

[0223] In some embodiments. X is S. NH, or O. In some embodiments, X is NH or O. In some embodiments, X is NH. In some embodiments, X is O.

[0224] In some embodiments, is a single bond or a double bond. In some embodiments, is a single bond, including an R isomer, an S isomer, or a mixture of R and isomers. In some embodiments, is a double bond. In some embodiments, when is a double bond, the double bond may be a Z-isomer, an E-isomer, or a mixture of Z- and E-isomers. In 29920-428111 2025-018-02 certain illustrative embodiments, the includes a single bond (e.g., an R isomer, an S isomer, or mixture thereof) represented by and a double bond (e.g., a Z-isomer, an E-isomer, or mixture

[0225] In some embodiments, L is alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy (e.g., combination of one or more alkoxy), urea, hydrazine, or aminoalkyl. In some embodiments, L is an amide (e.g., -NHC(O)-) or ester (e.g.. -OC(O)-). In some embodiments, L is a divalent linker covalently connecting RAand RB. For example, when L is amide, then RA-L-RBis RA-NHC(O)-RBor RA-C(O)NH-RB. In some embodiments, L is a combination of at least two of alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy (e.g., combination of one or more alkoxy), urea, hydrazine, or aminoalkyl. In some embodiments, L is an amide (e.g., -NHC(O)-).

[0226] In some embodiments, X is O, L is amide, is a double bond, RAis substituted aryl (e.g., methoxyphenyl), RBis substituted aryl (e.g., trifluoromethoxyphenyl, such as 3- trifluoromethoxyphenyl), Rcis substituted aryl (e.g., carboxyphenyl, such as 3- carboxyphenyl), and ring D is unsubstituted aryl (e.g., phenyl). 29920-428111 2025-018-02

[0227] In some embodiments, X is O, L is amide, is a double bond, RAis substituted aryl (e.g., fluorophenyl), RBis substituted aryl (e.g., trifluoromethoxyphenyl, such as 3- trifluoromethoxyphenyl), Rcis substituted aryl (e.g., carboxyphenyl, such as 3- carboxyphenyl), and ring D is unsubstituted aryl (e.g., phenyl). In some embodiments, the compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof is selected from Table A or Table B. or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the compound is selected from the group consisting of:

[0229] 29920-428111 2025-018-02 or a pharmaceutically acceptable salt thereof. 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02 29920-428111 2025-018-02

[0230] Series A Series B 29920-428111 2025-018-02 29920-428111 2025-018-02

[0231] In some embodiments, the compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof has a LogP of greater than about 3, such as greater than about 4, greater than about 4.5, greater than about 5, greater than about 5.5, greater than about 6, greater than about 6.5, or greater than about 7. For example, the compound may have a LogP of about 3 to about 7.5, such as about 4 to about 7.5, about 5 to about 7.5, or about 6 to about 7.5.

[0232] In some embodiments, the compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof has a total polar surface area (TPSA) of less than about 140 A2, such as less than about 135 A2, less than about 130 A2, less than about 125 A2, less than about 120 A2, less than about 1 15 A2, less than about 1 10 A2, less than about 105 A2, less than about 100 A2, less than about 95 A2, or less than about 90 A2. For example, the compound may have a TPSA of about 80 A2to about 140 A2, such as about 80 A2to about 130 A2, about 80 A2to about 120 A2, about 80 A2to about 110 A2, or about 80 A2to about 100 A2. 29920-428111 2025-018-02

[0233] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

[0234] PHARMACEUTICAL COMPOSITIONS

[0235] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0236] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the disclosure. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have 29920-428111 2025-018-02 incorporated therein, for example, a compound of the disclosure. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0237] The phrase '‘pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0238] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0239] A pharmaceutical composition (or preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g.. sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein. 29920-428111 2025-018-02

[0240] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0241] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the disclosure, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary', shaping the product.

[0242] Formulations of the disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0243] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol 29920-428111 2025-018-02 monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0244] A tablet may be made by compression or molding, optionally with one or more accessory' ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0245] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0246] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as. for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl 29920-428111 2025-018-02 alcohol, ethyl carbonate, ethyl acetate, benzy l alcohol, benzy l benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0247] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0248] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0249] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0250] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0251] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary' propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0252] Transdermal patches have the added advantage of providing controlled delivery' of a compound of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0253] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, 29920-428111 2025-018-02 subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0254] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0255] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0256] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0257] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) 29920-428111 2025-018-02 and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0258] For use in the methods of this disclosure, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0259] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0260] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0261] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0262] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity' of the patient's condition, the disorder being treated, the stability of the compound, and. if desired, another type of therapeutic agent being administered with a compound of the disclosure. A larger total dose can be delivered by multiple administrations of the agent. Methods to 29920-428111 2025-018-02 determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed.. 1814-1882. herein incorporated by reference).

[0263] In general, a suitable daily dose of an active compound used in the compositions and methods of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0264] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0265] The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.

[0266] In certain embodiments, compounds of the disclosure may be used alone or conjointly administered with another type of therapeutic agent.

[0267] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the disclosure in the compositions and methods of the present disclosure. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine. IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to. I -hydroxy -2-naphthoic acid. 2,2-dichloroacetic acid. 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1 -ascorbic acid, 1 -aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic 29920-428111 2025-018-02 acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d- glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1 -malic acid, malonic acid, mandelic acid, methanesulfonic acid , naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, 1 -pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1 -tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0268] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0269] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0270] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alphatocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein, such as a compound of Formula I-IV. In certain embodiments, the pharmaceutical compositions further comprise a pharmaceutically acceptable excipient.

[0271] In certain embodiments, compounds of the disclosure may be racemic. In certain embodiments, compounds of the disclosure may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee. 40% ee, 50% ee. 60% ee, 70% ee. 80% ee, 90% ee, or even 95% or greater ee. In certain embodiments, compounds of the disclosure may have more than one stereocenter. In certain such embodiments, compounds of the disclosure may be enriched in one or more diastereomers. For example, a compound of the disclosure may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de. 29920-428111 2025-018-02

[0272] In certain embodiments, compounds of the disclosure are prodrugs of the compounds described herein. For example, wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or a carboxylic acid present in the parent compound is presented as an ester. In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).

[0273] In certain embodiments, the pharmaceutical compositions may be for use in treating or preventing a condition or disease as described herein.

[0274] The compounds described herein are useful, for example, as therapeutics for the treatment of diseases, such as cancer. In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the disclosure and at least one of a pharmaceutically acceptable excipient.

[0275] In certain aspects, the present disclosure provides a method of treating a disease (e.g., a cancer such as lung cancer) in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound or composition of the disclosure. In certain aspects, the present disclosure provides a method of treating cancer in a patient, comprising administering to a patient in need thereof an effective amount of a compound or composition of the disclosure.

[0276] In certain aspects, the compounds and pharmaceutical compositions of the disclosure specifically target Ku. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of DNA-PK (e.g.. IR-induced DNA-PK autophosphorylation) or NHEJ-catalyzed DSB repair. In preferred embodiments, methods of treating a target cancer are described.

[0277] In certain aspects, the present disclosure provides methods of inhibiting Ku binding. In certain aspects, the present disclosure provides methods of inhibiting Ku binding and DNA- PK activation. In certain aspects, the present disclosure provides methods of inhibiting DNA- PK (e.g., IR-induced DNA-PK autophosphorylation). In certain aspects, the present disclosure provides methods of inhibiting NHEJ-catalyzed DSB repair. In certain aspects, the present disclosure provides methods of decreasing expression in a proliferation marker (e.g., Ki-67). In certain aspects, the present disclosure provides methods of treating cancer with the compounds of the present disclosure in combination with a radiotherapy (e.g., ionizing radiation (IR), radiomimetic agent(s), and other chemotherapeutics that damage DNA). For example, a method of treating cancer may include administering compounds of the present disclosure simulataneously with a radiotherapy (e.g., ionizing radiation (IR), radiomimetic 29920-428111 2025-018-02 agents (e.g., bleomycin), and other chemotherapeutics that damage DNA). before a radiotherapy, after a radiotherapy, or any combination thereof.

[0278] In certain aspects, the present disclosure provides methods of treating cancer. In certain aspects, the present disclosure provides methods of treating lung cancer (e.g., non-small cell lung cancer (NSCLC)) and breast cancer (e.g., triple negative breast cancer (TNBC)). In certain aspects, the present disclosure provides methods of treating lung cancer (e.g., non-small cell lung cancer (NSCLC)).

[0279] In certain aspects, the compounds of the present disclosure are for use in inhibiting Ku binding. In certain aspects, the compounds of the present disclosure are for use in inhibiting Ku binding and DNA-PK activation. In certain aspects, the compounds of the present disclosure are for use in inhibiting DNA-PK (e.g., IR-induced DNA-PK autophosphorylation). In certain aspects, the compounds of the present disclosure are for use in inhibiting NHEJ- catalyzed DSB repair. In certain aspects, the compounds of the present disclosure are for use in decreasing expression in a proliferation marker (e.g., Ki-67). In certain aspects the compounds of the present disclosure are for use in treating cancer in combindation with radiotherapy (e.g., ionizing radiation (IR), radiomimetic agents (e.g., bleomycin), and other chemotherapeutics that damage DNA). For example, the compounds of the present disclosure may be administered simulataneously with a radiotherapy (e.g., ionizing radiation (IR), radiomimetic agents, and other chemotherapeutics that damage DNA), before a radiotherapy, after radiotherapy, or any combination thereof.

[0280] In certain aspects, the compounds of the present disclosure are for use in treating cancer. In certain aspects, the compounds of the present disclosure are for use in treating lung cancer (e.g., non-small cell lung cancer (NSCLC)) or breast cancer (e.g., triple negative breast cancer (TNBC)). In certain aspects, the compounds of the present disclosure are for use in treating lung cancer.

[0281] In certain aspects, the present disclosure provides methods of treating a mammal suffering from cancer. In certain aspects, the present disclosure provides methods of treating a mammal suffering from lung cancer (e.g., non-small cell lung cancer (NSCLC)) or breast cancer (e.g., triple negative breast cancer (TNBC)). In certain aspects, the present disclosure provides methods of treating a mammal suffering from lung cancer.

[0282] It w ill be appreciated that certain advantages can be gained from applying any of the compounds described herein to genome editing methodologies or technologies. For example, inhibiting the NHEJ pathway to increase the efficiency of the HDR DNA repair pathway will increase the efficiency of genome editing methodologies or technologies. One advantage of 29920-428111 2025-018-02 targeting Ku lies in the early role Ku plays in the NHEJ DNA repair pathway. Without being bound by theory, Ku is believed to be responsible for initiation of the NHEJ pathway by binding to the termini of broken DNA. Thus, inhibiting the initial molecular event in the NHEJ pathway, Ku interactions with DNA ends, Ku inhibition proves to efficiently block NHEJ catalyzed repair, and drive the processing enzy mes to allow HDR mediated recombination with the appropriate donor DNA molecule. On the contrary, prior technologies have inhibited the final step, ligation of the DNA strands through, for example, DNA Ligase IV. Such downstream interference with the NHEJ repair pathway may provide incomplete NHEJ processing of the DSB, but it also renders the break unable to be repaired by HDR as well, resulting in cell death. An advantage of targeting Ku is that the DSB will remain unprocessed and eligible for HDR engagement, and thus represents a true increase in the number of cells that are capable of HDR activity. Furthermore, inhibiting NHEJ can decrease non-specific gene editing, which is significant in some settings, such as, researchers using the technology to generate genetically modified products or for use in clinical applications subject to regulatory7review7. Additionally, decreasing non-specific gene editing products will allow for easier screening to identify rare targeting events, as researchers will not have to screen large population of recombinants to eliminate the non-specific gene editing events.

[0283] Genome editing has found application in numerous areas of clinical medicine and biotechnological research. For example, genome editing for therapeutic use has been the subject of a great deal of research and may prove to be a promising therapy in many diverse diseases including, but not limited to, hemophilia B, HIV, Duchenne muscular dystrophy (DMD), Hepatitis B (Hep B), SCID, cataracts, cystic fibrosis, hereditary tyrosinemia and cancer. In addition, genome editing has been applied to the biotechnological and genetic research as a tool to understand the function of genes and for the manipulation of genes. Genome editing has been used for gene disruption, gene addition and gene correction in cells from numerous organisms including but not limited to human, zebrafish, bovine, rat, Arabidopsis, C. elegans, hamster, Drosophila, rice, mouse, maize, tobacco, and the like. In addition, a wide range of genes have been manipulated by gene editing technology7including, but not limited to, CCR5, TCR, gol, ntl, kra. GGTA1, LDLR, ACAN12, p65. EMX1. PVALB. IgM, Rab38, ADH1, TT4, ben-1, rex-1, sdc-1, DHFR, yellow, OsSWEET14, OCT4, PITX3, F9 (coagulation Factor IX), Rosa26, AAVS1, VEGF-A, ty rosine hydroxylase, fam46c, smad5, IPK1, IL2RG, Al AT, HBB, SNCA. SuRA, SurRB, and the like. In addition, genome editing technologies have been applied in agricultural research. 29920-428111 2025-018-02

[0284] It will be appreciated that the compounds described herein can be applied to any genome editing methodology or technology known to one of skill in the art, and that the identity of the genome editing methodology or technology is not particularly limited in anyway. It will be appreciated that the various genome editing technologies known in the art are typically classified according to the type of engineered nuclease being applied in the technology. Exemplary genome editing technologies useful in connection with the compounds described herein include, but are not limited to, CRISPR / Cas9, TALEN, Zn Finger, and meganuclease. CRISPR

[0285] Clustered Regularly Interspaced Short Palindromic repeat (CRISPR)-associated nuclease Cas9 introduces DNA double-stand breaks (DSBs) at targeted sequences. The CRISPR-Cas9 system comprises a programmable nuclease that targets DNA through an RNA- DNA interaction and by protein-DNA interactions. The CRISPR-Cas9 system comprises a plasmid encoding the Cas9 endonuclease and a plasmid encoding a CRISPR RNA (crRNA) specific for a DNA sequence. The CRISPR-Cas9 system is programmable by selecting a crRNA specific for the DNA target. The CRISPR-Cas9 system is reprogrammable by changing the crRNA in the crRNA plasmid. See for example, United States Patent No. 8,697,359; United States Patent Publication No. US20150031134; United States Patent Publication No. US20150044772; United States Patent Publication No. US20150024500, incorporated herein by reference.

[0286] Preparing a CRISPR-Cas9 system comprises identifying a target DNA sequence. Once the target DNA sequence is identified, a guide RNA (gRNA) comprising the crRNA with a trans-activating RNA (tracrRNA) is prepared by PCR. As an example, the prepared gRNA can then be co-transfected with mRNA coding Cas9 into a target cell, in addition to other mechanisms of delivery. An illustrative method for preparing the gRNA is the GeneArt™ Method by ThermoFisher. Another illustrative method for preparing the gRNA is by cloning the target sequence into a pCas Guide vector as provided by Origene. The pCas Guide vector can be co-transfected with donor vector comprising left and right homologous arms into target cells. The CRISPR-Cas9 system can then be transfected or transduced into a target cell. Illustrative target cell lines include the mammalian cell lines HEK. 293. CHO, A549. U2OS. HEP-2, MDCKII, Vero76, A375, Hela, HepG2, HACAT, HCT116, HepaRG, Jurkat, WT macrophages, and TF-1, although any suitable bacterial, yeast, mammalian or plant cell is comprehended. The target cell lines also include plant lines. As another example, the requisite proteins and enzymes for CRISPR / Cas9 can be directly introduced into the target cells. TAEEN 29920-428111 2025-018-02

[0287] Transcription activator-like effector nucleases (TALENs) introduce DNA DSBs at targeted sequences. The TALEN system comprises a programmable nuclease that targets DNA through a protein-DNA interaction. The TALEN system comprises linking together a TALE monomer with a non-specific nuclease. Each TALE monomer comprises a series of TALES that are each specific for a single DNA base pair. The plurality TALEs are linked together to recognize a specific DNA sequence (14-20 bp per monomer) and conjugated to a nuclease to introduce the DSB into the targeted DNA. The TALEN system is programmable by selecting the appropriate combination of TALE domains specific for the DNA target. The TALEN system is reprogrammable by interchanging the TALE domains in the TALE monomer by molecular cloning. See, for example, United States Patent Publication No. US20150071906; incorporated herein by reference.

[0288] Preparing the TALEN system comprises identifying a target DNA sequence. The target DNA sequence can be provided to a vendor to produce a TALEN specific for the target DNA sequence. An illustrative method for preparing the TALEN is by providing the target DNA to a vendor, for example ThermoFisher. Illustratively, the vendor will clone the requisite TALEs into a vector comprising a nuclease to produce the TALEN system. The TALEN is then transfected or transduced into the target cell. Target cells include bacterial cells, mammalian cells, yeast cells, and plant cells.

[0289] Zn Finger

[0290] Zn-finger nucleases (ZFNs) introduce DNA DSBs at targeted sequences. The ZFN system comprises a programmable nuclease that targets DNA through a protein-DNA interaction. The ZFN system comprises linking together a zinc-finger monomer with a nonspecific nuclease. Each zinc-finger monomer comprises a plurality of Cys2-His2 zinc-finger domains that each recognize a specific 3-base pair combination of DNA. The plurality of Cys2- His2 zinc-finger domains are linked together to form the Zn-finger monomer that recognizes a specific DNA sequence (9-18 bp per monomer) and conjugated to a nuclease to insert a DSB near the targeted site. The ZFN system is programmable by selecting the appropriate combination of zinc-finger domains specific for the DNA target sequence. The ZFN system is reprogrammable by linking together different Cys2-His2 zinc-finger domains specific for a target DNA sequence. See for example. United States Patent Publication No. US20150093802; United States Patent Publication No. US20150064790; incorporated herein by reference.

[0291] Preparing the ZFN system comprises identifying a target DNA sequence. The target DNA sequence can then be provided to a vendor to produce a ZFN specific for the target DNA. An illustrative vendor is Sigma Aldrich which prepares a CompoZr™ kit. Illustratively, upon 29920-428111 2025-018-02 supplying the target DNA sequence, the vendor will use an algorithm to design ZFN candidates targeting the gene region of interest. The ZFN candidates can then be validated. The validated ZFNs in a plasmid can then be transfected or transduced into a target cell. Target cells include bacterial cells, mammalian cells, yeast cells, and plant cells.

[0292] Meganucleases

[0293] Meganucleases introduce DNA DSBs at targeted sequences. The meganuclease system comprises a programmable nuclease that targets >14 bp of DNA through a protein-DNA interaction. Retargeting the meganucleases requires changing the domains that recognize the target DNA.

[0294] In some embodiments, at least one programmable nuclease is transfected into a target cell, and the cell is contacted with at least one compound of the present disclosure. In some embodiments, at least one programmable nuclease is transfected into a target cell using a transfection reagent. Alternatively, in some embodiments, at least one programmable nuclease is electroporated into a target cell. In some embodiments, at least one programmable nuclease is packaged in at least one AAV vector and transduced into a target cell. In some embodiments, a programmable nuclease may be packaged into a single AAV vector, or alternatively, may be packaged into more than one AAV vector. In some embodiments, the methods described herein include additional steps depending on the ty pe of genome editing technology7being used, such as CRISPR / Cas9, TALEN, Zn Finger, or meganuclease. One of skill in the art will readily appreciate that the steps and reagents described in the paragraphs above for each of the representative technologies can be used in connection with the present teachings.

[0295] In addition, the present disclosure provides for kits of parts directed to genome editing technologies in connection with the compounds described herein. In one aspect, the present disclosure provides a kit comprising one or more of the components described herein. In some embodiments, the kit comprises a vector system and instructions for using the kit. In some embodiments, the vector system comprises (a) a first regulatory element operably linked to a tracr mate sequence and one or more insertion sites for inserting one or more guide sequences upstream of the tracr mate sequence, wherein when expressed, the guide sequence directs sequence-specific binding of a CRISPR complex to a target sequence in a eukaryotic cell, wherein the CRISPR complex comprises a CRISPR enzyme complexed with (1) the guide sequence that is hybridized to the target sequence, and (2) the tracr mate sequence that is hybridized to the tracr sequence: and / or (b) a second regulatory element operably linked to an enzyme-coding sequence encoding said CRISPR enzyme comprising a nuclear localization 29920-428111 2025-018-02 sequence. In some embodiments, the kit comprises components (a) and (b) located on the same or different vectors of the system; and (c) at least one compound as described herein.

[0296] ALTERNATIVE EMBODIMENTS or a pharmaceutically acceptable salt thereof, wherein each of RA. RB. and Rcis independently aryl or heteroaryl, each of which may be optionally substituted; ring D is aryl or heteroaryl, each of which may be optionally substituted;

[0297] X is S, N, or O;

[0298] “=■’ is a single bond or a double bond; and

[0299] L is alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, or aminoalkyl.

[0300] 2. The compound of clause 1, wherein the compound is of formula (II) or a pharmaceutically acceptable salt thereof.

[0301] 3. The compound of clause 1 or 2, wherein RBis optionally substituted aryl (e.g., optionally substituted phenyl).

[0302] 4. The compound of clause 1, 2, or 3, wherein Rcis optionally substituted aryl (e.g., optionally substituted phenyl).

[0303] 5. The compound of any one of clauses 1-4, wherein RAis optionally substituted aryl (e.g., optionally substituted phenyl). 29920-428111 2025-018-02

[0304] 6. The compound of any one of clauses 1-5, wherein ring D is optionally substituted aryl (e.g., optionally substituted phenyl).

[0305] 7. The compound of clause 1 or 2, wherein the compound is of formula (III) or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R4is independently aryl, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted; and each of m, n, o, and p is independently 0, 1 , or 2.

[0306] 8. The compound of clause 1 or 2, wherein the compound is of formula (IV) or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R4is independently aryl, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted; and each of m, n, o, and p is independently 0, 1 , or 2. 29920-428111 2025-018-02

[0307] 9. The compound of any one of the preceding clauses, wherein Rcis substituted (e.g., m is 1 or 2), for example, with ester, carboxy, optionally substituted heteroaryl, amide, sulfone, sulfonamide, phosphate, or phosphonate.

[0308] 10. The compound of any one of the preceding clauses, wherein RAis substituted (e.g.. n is 1 or 2), for example, with halo, alkoxy, haloalkyl, or haloalkoxy.

[0309] 11. The compound of any one of the preceding clauses, wherein RBis substituted (e.g., o is 1 or 2), for example, with alkoxy or haloalkoxy.

[0310] 12. The compound of any one of the preceding clauses, wherein ring D is substituted (e.g., p is 1 or 2), for example, with alkoxy or haloalkoxy.

[0311] 13. The compound of any one of the preceding clauses, wherein ring D is unsubstituted (e.g., p is 0).

[0312] 14. The compound of any one of the preceding clauses, wherein X is O.

[0313] 15. The compound of any one of clauses 1-13, wherein X is N.

[0314] 16. The compound of any one of the preceding clauses, wherein is a single bond.

[0315] 17. The compound of any one of clauses 1-15. wherein is a double bond.

[0316] 18. The compound of clause 1. selected from Table A or Table B.

[0317] 19. A pharmaceutical composition comprising a compound according to any one of the preceding clauses and at least one pharmaceutically acceptable excipient.

[0318] 20. A method of treating a disease (e.g., a cancer such as lung cancer) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of clauses 1-18.

[0319] INCORPORATION BY REFERENCE

[0320] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. 29920-428111 2025-018-02

[0321] EQUIVALENTS

[0322] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0323] CHEMICAL SYNTHESIS METHODS

[0324] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula I-IV.

[0325] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art: 29920-428111 2025-018-02 29920-428111 2025-018-02

[0326] The proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below.

[0327] General. All chemicals used for synthesis were purchased from Aldrich, Alfa Aesar, Acros, Fisher Scientific, AK Scientific, and Combi-Blocks Chemical Co. (USA) and used without further purification. Anhydrous solvents were obtained from Fisher Scientific or Aldrich and used directly. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere. NMR spectra were recorded at 400 MHz using Bruker AV NMR spectrometer. NOESY NMR spectra was recorded at 500 MHz using Bruker AV NMR spectrometer.13C NMR spectra were recorded at 101 MHz using Bruker AV NMR spectrometer.13C Attached-Proton-Test (APT) NMR was recorded at 101 MHz using Bruker AV NMR spectrometer, the signals of CH and CH3 are negative, but CH2 and quaternary carbons including the solvent carbon are positive.19F NMR spectra were recorded at 376 MHz using Bruker AV NMR spectrometer. The chemical shifts were reported as <5 ppm relative to TMS, using the residual solvent peak as the reference unless otherwise noted. All coupling constants (J) are given in hertz. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet), number of protons, and coupling constants. Thin layer chromatography w as performed using Merck silica gel 60 F-254 thin layer plates, which were developed using one of the following techniques: UV fluorescence (254 nm), alkaline potassium permanganate solution (0.5% w / v) or ninhydrin (0.2% w / v) and iodine vapors. The products were purified with column chromatography. LCMS analyses of compounds were obtained using a Shimadzu LC-20 AT instrument connected to a Shimadzu 1300 HPLC system, and both instruments were connected to a Shimadzu photodiode array (PDA) UV detector. The chemical purity of target compounds was >95% determined by' analytical HPLC (Shimadzu LC-20 AD instrument). A Cl 8 reverse phase column (Nova-Pak® 4 pm, 3.9 mm x 1.5 mm) was used as the stationary7phase, and water / acetonitrile (both containing 0.1% TFA) w as used as the mobile phase (gradient 10-90% ACN / H2O. flow 1 mL / min, run time 20 min). UV absorbance at wavelengths of 214 and 254 nm were recorded.

[0328] All final compounds were purified by recrystallization or flash column chromatography, and the analytical and spectroscopic data confirmed their purity and structures, as detailed in the experimental procedures. 29920-428111 2025-018-02

[0329] The synthetic schemes, procedures, and characterization of the Ku-DBis are provided below. Ku-DBis (10 mM) and NU-7441 (5 mM) (Cat: 3712, TOCRIS) were dissolved in dimethyl sulfoxide (DMSO) and stored at room temperature. Scheme Al. General synthetic scheme for synthesis of compounds GL-3392 (35), GL-

[0330] 3618 (33), GL-3395 (34) and GL-3649 (32).

[0331] Reagents and conditions: a) Cui, DMEDA, K2CO3, ACN, 90 °C for 6 h, 64%; b) PdCl2(PPh3)2, K2CO3, Toluene :EtOH:H2O, 100 °C for 24 h, 72-89%; c) AcOH, 110 °C for 16 h, 67-72%; d) HATU, DIPEA, DMF, rt for 16 h, 77-91%; e) LiOH, THF:H2O, rt for 16 h, 75- 87%.

[0332] General procedure for the Synthesis of compound 10a ethyl 3-(2-oxoindolin-l-yl) benzoate (10a). To the stirred suspension of indolin-2-one 8a (0.5 g, 3.75 mmol, 1 eq.) and ethyl 3-iodobenzoate 9a (1.03 g, 3.75 mmol, 1 eq) in acetonitrile (15 mL) was added K2CO3(1.03 g, 7.51 mmol, 2 eq). The mixture was degassed with argon for 5 min. and then 1 ,2-dimethylethylenediamine (0.06 mg, 0.75 mmol, 0.2 eq), and 29920-428111 2025-018-02

[0333] Cui (0.071g, 0.375 mmol, 0. 1 eq) were added. The resultant mixture was heated at 90 °C for 6 h, then the mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate (2 x 20 mL). The filtrate was washed with brine solution. The organic layer was dried over Na2SOr and concentrated under reduced pressure. The crude residue was purified by column chromatography using 5-20% EtOAc in hexanes as the eluent to give ethyl 3-(2- oxoindolin-l-yl) benzoate (10a) as a pale yellow solid (0.675 g, 64% yield). TLC: 50% EtOAc in hexanes. R / = 0.6; visualized with UV. 'H NMR (400 MHz, DMSO): d 8.03 - 8.00 (m. 1H). 7.97 (brs, 1H), 7.73 -7.72 (m, 1H), 7.36 (d, J= 7.62 Hz, 1H), 7.21(t, J = 7.62 Hz, 1H), 7.07 (t J= 6.88 Hz, 1H), 6.72 (d, J= 7.37 Hz, 1H) 4.34 (q, J= 7.14 Hz, 2H), 3.77 (s, 2H), 1.32 (t, J= 5.6 Hz, 3H).13C NMR (101 MHz, DMSO): d 173.9, 165.0, 144.3, 134.9. 131.4, 131.2, 130.1, 128.4, 127.3. 124.9, 124.7. 122.6, 108.5, 61.1. 35.4. 14.1. MS (ESI) mlz = 282. 1 [M + H]+.

[0334] General procedure for the synthesis of compounds 13b-13c.

[0335] A solution of K2CO3 (2 equiv) in water (10 mL) was added to a mixture of 5-bromo-2- furaldehyde Ila (2 g, 11.42 mmol, 1 eq.) and 5-borono-2-fluorobenzoic acid (12b) / 5-borono- 2-methoxybenzoic acid (12c) (13.71 mmol, 1.2 eq) in toluene / ethanol (1 : 1, v / v, 40 mL). The mixture was degassed with nitrogen for 10 min, and then Pd(PPh3)4 (0.05 eq.) was added. The reaction mixture was stirred at 100 °C for 24 h, then the reaction mixture was cooled to room temperature, filtered through celite, and washed with water and ethanol (2 x 10 mL). The solvent was evaporated under reduced pressure to give a solid residue. The residue was diluted with water (20 mL) and the pH was adjusted to 2-3 by the addition of 6 N HC1 solution, the precipitate was formed. The solid precipitate was filtered and washed with 20-30% EtOAc in hexane to afford the title product. Compounds 13b-13c were synthesized by an above synthetic procedure using appropriate starting materials.

[0336] 2-fluoro-5-(5-formylfuran-2-yl)benzoic acid (13b). 13b was prepared by an abovedescribed procedure using 5-bromo-2-furaldehyde Ila (3.0 g, 17. 14 mmol, 1 eq) and 5-borono- 2-fluorobenzoic acid 12b (3.78 g, 20.57 mmol, 1.2 eq) as a starting material, yellow solid (72% yield). TLC: 5% MeOH in DCM, R / = 0. 1; visualized with UV. ' H NMR (400 MHz, DMSO): d 13.5 (s. 1H), 9.62 (s, 1H), 8.31 - 8.28 (m, 1H). 8.15 - 8.11 (m. 1H), 7.66 (t, J= 3.29 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.38 (t, .7= 3.54 Hz, 1H).13C NMR (101 MHz, DMSO): d 178.0, 164.5, 162.7, 160.1, 156.2, 151.9, 131.2 - 131. l(d, JC-F = 14.11 Hz, 1C), 128.1, 125.3, 120.3 - 120.2 (d, JC-F = 12.25 Hz, 1C), 118.4- 118.2 (d, JC-F = 22.81 Hz, 1C), 109.3. MS (ESI) mlz = 233.1 [M - H]’. 29920-428111 2025-018-02

[0337] 5-(5-formylfuran-2-yl)-2-methoxybenzoic acid (13c). 13c was prepared by aboveprocedure described for 13a, using 5-bromo-2-furaldehyde Ila (3.0 g. 17.2 mmol, 1 eq) and 5-borono-2-methoxybenzoic acid 12c (4.04 g, 20.64 mmol, 1.2 eq) as a starting material. Yellow solid (89% yield). TLC: 5% MeOH in DCM, I = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO): b 12.95 (brs, 1H), 9.57 (s, 1H), 8.10 (s, 1H), 7.99 (d, J = 9.25 Hz, 1H), 7.63 (s. 1H), 7.25 (d, J = 9.25 Hz. 2H), 3.88 (s. 3H).13C NMR (101 MHz, DMSO): b 177.5, 166.7, 159.0, 157.6, 151.4, 129.7, 127.3, 125.8. 122.1. 120.8. 113.3. 107.9. 56.1. MS (ESI) m / z = 245.1 [M - H] .

[0338] General procedure for the synthesis of compounds 14b-14c.

[0339] Ethyl 3-(2-oxoindolin-l-yl) benzoate 10a (0.6 g, 2.13 mmol, 1 eq.) and 2-fluoro-5-(5- formylfuran-2-yl)benzoic acid (13b) / 5-(5-formylfuran-2-yl)-2-methoxybenzoic acid (13c) (2.13 mmol, 1 eq.) were dissolved in glacial acetic acid (20 mL). The reaction mixture was refluxed with stirring for 16 h. The solvent was removed under reduced pressure and solid residue was suspended in EtOH, fdtered, and washed with EtOH, EtOAc, and DCM (2 times each) to yield the desired product. Compounds 14b-14c were synthesized by an above synthetic procedure using appropriate starting materials.

[0340] (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2- fluorobenzoic acid (14b). Red solid (67% yield). TLC: 5% MeOH in DCM, R / = 0.1 ; visualized with UV. 'H NMR (400 MHz, DMSO): b 8.68 (d, J = 7.7 Hz, 1H), 8.55 (d, J = 6.7 Hz. 1H), 8.26 - 8.18 (m, 1H), 8.06 (d, J= 9.1 Hz, 2H), 7.82 (d, J= 8.0 Hz, 1H), 7.76 (t, J= 7.8 Hz, 1H), 7.55 (d, J= 4.4 Hz, 3H), 7.49 (d, J= 3.6 Hz, 1H), 7.36 (t, J= 7.7 Hz, 1H), 7.28 (t, J= 7.4 Hz, 1H), 6.87 (d, J= 7.8 Hz, 1H), 4.36 (q, J= 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H);1?C NMR (101 MHz, DMSO): <5 167.86, 165.47. 164.83, 164.80, 160.38, 156.96, 151.06. 144.12, 141.98, 135.02, 132.15, 131.88, 130.73, 130.42, 130.33, 129.22, 128.27, 128.04, 126.74, 126.01, 123.11, 122.64, 122.22, 121.99, 121.32, 121.20, 119.55, 119.45, 118.53, 118.30, 117.21, 111.85, 110.33, 61.62, 14.60. MS (ESI) m / z = 496. 1 [M - H] .

[0341] (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolm-3-ylidene)methyl)furan-2-yl)-2- methoxybenzoic acid (14c). yellow solid (72% yield). TLC: 5% MeOH in DCM, R / = 0.2; visualized with UV.JH NMR (400 MHz, DMSO): b 8.66 (d, J = 5.42 Hz, 1H), 8.34 (s, 1H), 8.09-7.98 (m, 3H). 7.79-7.74 (m, 2H), 7.52 (s, 2H), 7.34.7.25 (m, 4H), 6.86 (d, J = 6.97 Hz, 1H), 4.35 (q, J = 5.72 Hz, 2H), 3.91 (s, 3H), 1.32 (t, J = 9.53 Hz, 3H).13C NMR (101 MHz, DMSO): b 177.5, 167.6, 166.7, 165.0, 158.9, 157.1, 150.0, 142.4, 134.9, 131.6, 131.3, 130.2, 29920-428111 2025-018-02

[0342] 129.4, 129.2, 128.4, 127.4, 127.2, 126.7, 125.3, 123.6, 122.5, 122.0, 121.2, 121.1, 120.2, 119.2, 113.7, 113.3. 109.4, 108.9. 107.8, 61.1, 56.1, 14.1. MS (ESI) mlz = 508.1 [M - H] .

[0343] Synthetic procedure for Amide coupling to provide compounds 18-21.

[0344] Ethyl (Z)-3-( 3-((5-( 4-methoxy-3-( ( 3-(trifluoromethoxy)phenyl)carbamoyl)phenyl) furan-2-yl)methylene)-2-oxoindolin-l-yl)benzoate (21). To the solution of (Z)-5-(5-((l-(3- (ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2-methoxybenzoic acid (14c) (0.6 g, 1.17 mmol, 1 eq) and HATU (0.672 g, 0.176 mmol, 1.5 eq) in DMF (10 mL) was added DIPEA (0.631 mL, 3.53 mmol, 3 eq), and the mixture was stirred for 10 min at room temperature under an argon atmosphere, then 3-(trifluoromethoxy)aniline 15b (0. 173 mL, 1.29 mmol, 1.1 eq) was added. The resultant reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into the ice-cold water and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with saturated NaHCCh (2 x 20 mL), followed by brine solution (2 x 20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude solid product. The crude product was triturated with 20% EtOAc in hexanes (2-3 times) to afford 21 (0.61 g, Tl% yield) as a red solid. TLC: 50% EtOAc in hexanes. Ry = 0.5; visualized with UV. 'H NMR (400 MHz, DMSO): 3 10.55 (s, 1H), 8.66 (d, J= 8.61 Hz, 1H), 8.34-8.26 (m, 1H), 8.12-8.00 (m, 3H), 7.99- 7.94 (m, 1H), 7.80-7.78 (m, 1H), 7.75-7.71 (m, 1H), 7.67-7.63 (m, 1H), 7.52-7.46 (m, 3H), 7.37-7.32 (m, 2H), 7.29-7.21 (m, 2H), 7.11-7.08 (m, 1H), 6.86-6.83 (m, 1H), 4.35 (q. . / 7,02 Hz. 2H), 3.94 (s, 3H), 1.33 (t, .7= 7.03 Hz. 3H).13C NMR (101 MHz, DMSO): 3 177.9, 167.5, 165.0, 164.5. 159.0, 157.6. 157.3, 157.2. 157.1, 151.4. 150.1, 148.5. 143.3, 140.6. 134.8, 131.5,

[0345] 130.5, 130.1, 129.3, 128.8, 128.6, 128.4, 128.0, 127.3, 126.7, 126.2, 125.9, 125.6, 125.3, 123.6,

[0346] 121.6, 121.2, 121.1, 120.2, 119.3, 118.3, 115.7, 113.6, 112.8, 111.7, 109.6, 108.9, 108.0, 61.1, 56.2, 14.1. LCMS (ESI) mlz = 669. 1 [M + H]+.

[0347] Ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)Juran- 2-yl)methylene)-2-oxoindolin-l-yl)benzoate (19). Compound 19 was synthesized by an above synthetic procedure described for the preparation of 21 using (Z)-5-(5-((l-(3- (ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2-fluorobenzoic acid (14b) (1.8 g, 3.62 mmol, 1 eq) and 3-(trifluoromethoxy)aniline 15b (0.769 g, 4.34 mmol, 1.2 eq) as starting materials. Red solid (1.9 g, 80% yield). TLC: 50% EtOAc in hexanes, Ry= 0.2; visualized with UV. 'H NMR (400 MHz, DMSO): 3 10.95 (s, 1H), 8.65 (d, J = 7.7 Hz. 1H), 8.36 - 8.28 (m, 1H). 8.18 (s, 1H). 8.05 (d, J = 9.4 Hz, 2H), 7.93 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.75 (dd, J = 13.5, 7.6 Hz, 2H), 7.65 (t, J = 9.2 Hz, 1H), 7.57 (d, J = 2.2 Hz, 2H), 7.54 (d, 29920-428111 2025-018-02

[0348] J = 7.7 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.24 - 7. 13 (m, 2H), 6.86 (d, J = 7.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H). 1.34 (1, J = 7.2 Hz, 3H).13C NMR (101 MHz, DMSO). 3 167.96, 165.50, 162.99, 158.28, 156.33, 151.21, 148.98, 143.10, 140.82, 135.27, 132.06, 131.81, 131.20, 130.68, 130.14, 128.97, 127.87, 126.22, 125.98, 125.82, 125.35, 124.23, 123.05, 121.49, 120.72, 120.64, 118.89, 116.66, 112.28, 111.51, 109.54, 61.60, 14.60. LCMS (ESI) m / z = 657.1 [M + H]+.

[0349] Ethyl (Z)-3-(3-((5-(4-methoxy-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoate (20). Compound 20 was synthesized by an above synthetic procedure described for the preparation of 21 using (Z)-5-(5-((l-(3- (ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2-methoxybenzoic acid (14c) (0.6 g, 1.17 mmol, 1 eq) and 3 -methoxy aniline 15a (0.146 mL, 1.29 mmol, 1.1 eq) as starting materials. Red solid (0.66 g, 91% yield). TLC: 50% EtOAc in hexanes, R / = 0.4; visualized with UV. 'H NMR (400 MHz, DMSO): <5 10.25 (s, 1H), 8.68 (d, J = 8.97 Hz. 1H), 8.09-8.06 (m, 1H). 8.04-8.02 (m, 2H). 7.97-7.95 (m, 1H). 7.80-7.78 (m, 1H). 7.73 (t, J= 7.85 Hz, 1H), 7.52-7.51 (m, 1H), 7.49-7.47 (m, 1H), 7.41 (d, J= 9. 15 Hz, 1H), 131 (d, J= 3.92 Hz, 1H), 7.31-7.28 (m, 2H), 7.26-7.24 (m, 2H), 6.86-6.85 (m, 1H), 6.72-6.67 (m, 1H), 4.35 (q, J = 7.71 Hz, 2H), 3.99 (s, 3H), 3.77 (s, 3H), 1.33 (t,J= 7.10Hz, 3H).,3C NMR (101 MHz, DMSO): 3 177.5, 167.6, 165.0. 164.1, 163.9, 160.0. 159.5, 157.7, 157.2. 156.6, 155.3, 152.7. 151.4, 151.0, 150.0, 148.0, 142.3, 140.1, 134.8, 131.5, 131.3, 130.1, 129.9, 129.5, 129.4, 128.4, 127.9, 127.4, 126.2, 125.9, 125.6, 125.5, 125.3, 123.6, 122.6, 122.0, 121.6, 121.2, 120.2, 119.3, 113.3, 112.8, 112.0, 111.9, 109.6, 108.9. 107.7, 106.3, 105.5. 105.4, 61.1, 56.3, 55.1, 14.1. LCMS (ESI) m / z = 615.1 [M + H]+.

[0350] Ethyl (Z)-3-(3-((5-( 4-fluoro-3-(( 3-methoxyphenyl)carbamoyl)phenyl) furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoate (18). Compound 18 was synthesized by an above synthetic procedure described for the preparation of 21 using (Z)-5-(5-((l-(3- (ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2-fluorobenzoic acid (14b) (0.6 g, 1.20 mmol, 1 eq) and 3 -methoxy aniline 15a (0.163 mL, 1.44 mmol, 1.2 eq) as starting materials. Red solid (0.59 g, 81% yield). TLC: 50% EtOAc in hexanes, R / = 0.4; visualized with UV. Isomer data:1H NMR (400 MHz, DMSO): <5 10.63 (s, 1H), 8.66 (d, J = 7.7 Hz, 1H), 8.29 (d, J = 6.4 Hz, 1H), 8.16 (t, J = 6.5 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.76 (t, J= 1A Hz, 1H), 7.63 (t, J= 9.0 Hz, 1H), 7.57 (d, J= 2.2 Hz, 2H), 7.55 - 7.50 (m, 1H), 7.46 (s, 1H), 7.37 - 7.26 (m, 3H), 7.21 (t, J= 13 Hz, 1H), 6.86 (d, J= 7.9 Hz, 1H), 6.75 (d, J= 7.8 Hz, 1H), 4.35 (dd, J= 7.9, 5.9 Hz, 2H), 3.77 (d. J= 1.9 Hz, 3H).13C NMR 29920-428111 2025-018-02

[0351] (101 MHz, DMSO) 3 167.97, 165.51, 162.61, 160.03, 156.43. 151.18, 143.09, 140.38, 135.28, 132.07. 131.82, 130.69. 130.19, 128.97. 127.88, 126.32, 126.15, 125.38, 123.08, 121.49, 120.68, 1 12.53, 111.46, 109.98, 109.54, 106.03, 61.60, 55.53, 14.61. LCMS (ESI) m / z = 603. 1 [M + H]+.

[0352] Synthesis of compounds GL-3392 (35), GL-3618 (33), GL-3395 (34) and GL-3649 (32).

[0353] Synthesis of (Z)-3-(3-((5-(4-methoxy-3-((3-

[0354] (trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2-oxoindolin-l-yl)benzoic acid (GL-3392; 35). To a stirred suspension of ester 21 (0.3 g, 0.448 mmol, 1 eq) in THF:H2O (2: 1, 3 mL) was added LiOH (0.107 g, 4.48 mmol, 1 eq). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to get solid residue. The residue was diluted with water and acidified with 20% citric acid solution to adjust pH 2-3 then extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The crude product was purified using 2-5% MeOH in DCM (1% AcOH in DCM) solvent system on flash column chromatography. The product was then crystallized in EtOH, and solid was collected, washed with EtOAc and then hot solutions of 20-30% EtOAc in hexanes to give target compound GL- 3392 (35) (0.216 g, 75% yield) as a yellow solid. TLC: 10% MeOH in DCM, R / = 0.3; visualized with UV. 'H NMR (400 MHz, DMSO): 3 13.3 (bs, 1H), 10.60 (s, 1H), 8.67 (d, J = 6.51 Hz, 1H), 8.25 (d, J= 3.6 Hz, 1H). 8.11 (dd, .7= 6.31 Hz, 2.81 Hz, 1H), 8.03-8.02 (m, 1H), 8.01-7.99 (m, 2H). 7.97 (brs, 1H), 7.77-7.75 (m, 1H), 7.73-7.69 (m. 1H), 7.54-7.53 (m. 2H), 7.50 (d, J =7.83 Hz, 1H), 7.44 (d, .7 = 8.70 Hz, 1H), 7.40 (d, .7 = 4.06 Hz, 1H), 7.31 -7.27 (m, 1H), 7.25-7.23 (m, 1H), 7.13-7.11 (m, 1H), 6.86 (d, J = 6.55 Hz, 1H). 3.98 (s, 3H).13C NMR (101 MHz, DMSO): 3 167.5, 166.6, 164.5, 157.2, 150.1, 148.5. 142.4, 140.6, 134.7. 131.1, 130.6, 130.0. 129.4, 128.6. 128.0, 127.4. 125.8, 125.6, 125.3, 123.6, 123.5, 122.5, 121.6, 121.2, 1 19.3, 118.3, 115.7, 113.2, 111.7, 109.6, 109.0, 56.3.19F NMR (376 MHz, DMSO): 3 -56.63 (s, 3F). LCMS (ESI) m / z = 639. 15 [M - H] . HPLC purity: 99.21% (fa = Z isomer at 11.29 mm and E isomer at 11.67 min).

[0355] (Z)-3-(3-((5-(4-fluoro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid (GL-3618; 33). Target compound GL-3618 (33) was synthesized by an above synthetic procedure described for the preparation of GL-3392 (35) using ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-

[0356] (trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2-oxoindolin-l- 29920-428111 2025-018-02 yl)benzoate 19 (0.02 g, 0.03 mmol, 1 eq) as starting materials. Yellow solid (0.015 g, 78% yield). TLC: 10% MeOH in DCM. R / = 0.3; visualized with UV. 'H NMR (400 MHz. DMSO): b 13.24 (brs, 1H), 10.92 (s, 1H), 8.65 (d, J= 9.03 Hz, 1H), 8.31 (d, J= 5.75 Hz, 1H), 8.17 (brs, 1H), 8.03 - 8.00 (m, 2H), 7.91 (s, 1H), 7.86 - 7.72 (m, 3H), 7.63 (t, J = 9.85 Hz, 1H), 7.56 - 7.51 (m, 4H), 7.28 (t, J = 7.39 Hz, 1H), 7.20 - 7.14 (m, 2H), 6.86 (d, J = 8.21 Hz, 1H).1?C NMR (101 MHz, DMSO): b 167.4, 166.6, 162.5, 155.8, 150.7, 148.5, 142.6, 140.3. 134.6,

[0357] 131.1, 130.7. 130.0, 129.6. 128.6, 128.5. 127.4, 125.7. 125.5, 124.8. 123.7, 122.5. 121.0, 120.3.

[0358] 120.1, 118.4, 117.6, 116.1, 111.8, 111.0, 109.0, 61.1.19F NMR (376 MHz, DMSO): <5 -56.67 (s, 3F), -113.1 (s, IF). LCMS (ESI) mlz = 627.15 [M - H] ". HPLC purity: 96.52% (fa = Z isomer at 10.77 min and A isomer at 11.25 min).

[0359] (Z)-3-(3-((5-(4-methoxy-3-( 3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid (GL-3395; 34). Target compound GL-3395 (34) was synthesized by an above synthetic procedure described for the preparation of GL-3392 (35) using ethyl (Z)-3-(3-((5-(4-methoxy-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoate 20 (0.2 g, 0.32 mmol, 1 eq) as starting materials. Yellow solid (0.292 g, 87% yield). TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO): b 10.29 (s, 1H), 8.26 (d. J= 3.77 Hz, 1H), 8.09 (dd, J= 8.28 Hz, 2.26 Hz, 1H), 8.02-7.98 (m, 2H), 7.72-7.68 (m, 2H), 7.54 (s, 2H), 7.48 (s, 1H), 7.43-7.39 (m, 2H), 7.34-7.23 (m, 4H), 6.85 (d, J = 7.53 Hz, 1H), 6.70 (dd, J = 8.23 Hz, 1.75 Hz, 1H), 3.98 (s, 3H), 3.76 (s, 3H).13C NMR (101 MHz, DMSO): b 167.5, 166.9, 163.9, 159.5, 157.2, 150. 1,

[0360] 142.5, 140.1, 134.6, 133.6, 130.6, 129.7, 129.6, 129.4, 128.5, 127.9, 127.4, 125.9, 125.6, 125.2,

[0361] 123.6, 122.5. 121.6, 120.1, 119.3, 113.2, 112.2, 109.5, 109.1, 109.0, 105.5. 56.3. 55.0. LCMS (ESI) mlz = 585.15 |M - H] . HPLC purity: 98.18% (fa = Z isomer at 10.33 min and E isomer at 10.76 min).

[0362] (Z)-3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2-yl)methylene)- 2-oxoindolin-l-yl)benzoic acid (GL-3649; 32). Target compound GL-3649 (32) was synthesized by an above synthetic procedure described for the preparation of GL-3392 (35) using ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoate 18 (0.3 g, 0.49 mmol, 1 eq) as starting materials. Yellow solid (0.220 g, 76% yield). TLC: 10% MeOH in DCM, R^= 0.2; visualized with UV. 'H NMR (400 MHz, DMSO): b 13.2 (brs, 1H), 10.63 (s, 1H), 8.64 (d, J= 7.37 Hz, 1H), 8.27 (brs, 1H), 8.14 ( brs, 1H), 8.03 - 8.00 (m, 2H), 7.75 - 7.71 (m, 2H), 7.61 - 7.47 (m, 5H), 7.32 - 7.29 (m, 3H), 7.21 - 7.19 (m, 1H), 6.85 (d, J= 7.37 Hz, 1H), 6.73 (d, J= 7.37 Hz, 1H), 3.76 29920-428111 2025-018-02

[0363] (s, 3H).13C NMR (101 MHz, DMSO): S 167.5, 166.6, 162.1, 159.9, 159.5, 157.8, 155.9, 150.7, 142.6, 139.9. 139.3, 133.5, 134.6, 132.4, 131.1, 130.0, 129.7, 128.6, 128.2, 127.4, 126.0, 125.7, 124.9, 123.7, 122.6, 121.0, 120.2, 117.8, 112.0, 111.0, 109.5, 109.1, 105.5, 55.0.19F NMR (376 MHz, DMSO): -113.1 (s, IF). LCMS (ESI) m / z = 573.15 [M - H] .

[0364] Scheme 1. Synthesis of compounds 30-51. 29920-428111 2025-018-02

[0365] Reagents and conditions: a) Cui, DMEDA, K2CO3, ACN, 90 °C for 6 h, 64-72%; b) PdCl2(PPh3)2, K2CO3, Toluene:EtOH:H2O, 100 °C for 24 h, 78-89%; c) AcOH, 110 °C for 16 h, 67-72%; d) HATU, DIPEA, DMF, rt for 16 h, 77-91%; e) i. LiOH, THF H2O, rt for 16 h, 75-91% or li. LiOH, MeOH:THF:H2O, rt for 16 h, 78-87%; f) 6N NaOH, THF, rt for 1 h, 80%; g) NaBH4, MeOH. 0 °C to rt for 16 h, 62-65% or H2, Pd / C in EtOH. rt for 16 h. 65%. or NiCh, NaBH4, MeOH:THF, rt for 3-5 h, 60-72%.

[0366] Scheme 2. Synthesis of Analogs 52, 53, 61 & 62. 29920-428111 2025-018-02

[0367] Reagents and conditions: a) Et N.HCl, NaN3, DMF, 120 °C for 16 h, 44-50%; b) 4N NaOH, EtOH, rt for 5 h, 89%; c) i. SOCh, 70 °C for 16 h, ii. CH3NH2. DCM, 0 °C to rt for 3 h, 76%; d) EtL K2CO3. DMF, 100 °C for 16 h, 78%; e) AcOH, 110 °C for 16 h, 65%; f) Cui, DMEDA, K2CO3, ACN, 90 °C for 16 h, 64%; g) LiOH, THF:H2O, rt for 16 h, 74%; h) HATU, DIPEA, DMF, rt for 16 h, 57-64%.

[0368] Scheme 3. Synthesis of Analogs 68 -73. 29920-428111 2025-018-02

[0369] Reagents and conditions: a) HATU, DIPEA, DMF, rt for 16 h, 70-80%; b) Pd(OAc)2, X-phos, CS2CO3, toluene, 100 °C for 5 h, 70-77%; c) AcOH. 110 °C for 16 h, 71-77%; d) HATU, DIPEA, DMF, rt for 16 h, 63-75%.

[0370] Scheme 4. Synthesis of Analogs 81 -84.

[0371] Reagents and conditions: a) Pd(OAc)2, PPhs, TEA, EtOH, reflux for 30 h, 82%; b) EDC.HC1, HOBT, DIPEA, DMF, rt for 16 h, 74%; c) Pd(OAc)2, X-phos, CS2CO3, toluene, 100 °C for 5 h. 75%; d) AcOH, 110 °C for 16 h, 76%; e) HATU, DIPEA. DMF, rt for 16 h, 64- 72%; f) TMSBr, DCM, rt for 16 h,75-78%. ethyl 3-(2-oxoindolin-l-yl)benzoate (10a). 10a was provided as described above to give ethyl 3-(2-oxoindolin-l-yl)benzoate (10a) as a pale yellow solid (0.5 g, 50% yield). TLC: 50% EtOAc in hexanes, I = 0.6; visualized with UV. 'H NMR (400 MHz, CDC13): 5 8. 17 - 8.09 (m, 2H), 7.64 (d, J = 3.7 Hz, 2H), 7.35 (d, J = 7.4 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.5 Hz. 1H), 6.80 (d. J = 7.9 Hz, 1H), 4.42 (q, J= 7.1 Hz, 2H), 3.76 (s, 2H), 1.42 (t, J= 7.1 Hz. 3H); MS (ESI) m / z = 282. 11 [M+H]+. Another synthesis was performed to give ethyl 3-(2- oxoindolin-l-yl)benzoate 10a as a pale yellow solid (0.675 g, 64% yield). TLC: 50% EtOAc 29920-428111 2025-018-02 in hexanes. Rf = 0.6; visualized with UV. NMR (400 MHz, CDCh): 8 8.13-8.12 (m. 2H), 7.64 (d, J= 3.7 Hz, 2H). 7.35 (d, J= 7.4 Hz, 1H). 7.25 (t. J= 7.8 Hz. 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.80 (d, J= 7.9 Hz, 1H), 4.42 (q, J= 7.1 Hz, 2H, OCH2\ 3.76 (s, 2H), 1.42 (t, J= 7.1 Hz, 3H, CHs).

[0372] 3-(2-oxoindolin-l-yl)benzonitrile (10b). 10b was prepared by an above-described procedure for 10a using indolin-2-one 8a (0.5 g, 3.75 mmol, 1 eq.) and 3-iodobenzonitrile 9b (0.86 g, 3.75 mmol, 1 eq) in 1,4-dioxane (20 mL) as a starting material, pale brown solid (0.3 g, 34% yield). TLC: 50% EtOAc in hexanes, R / = 0.6; visualized with UV. 'l l NMR (400 MHz, CDC13): 5 7.80 (d, J= 2.0 Hz. 1H), 7.77 - 7.65 (m, 3H), 7.37 (d, J= 7.4 Hz. 1H), 7.31 - 7.25 (m, 2H), 7. 15 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 3.77 (s, 2H); MS (ESI) m / z = 235.09 [M+H]+. Another synthesis was performed to give the product as a pale brown solid (0.637 g, 72% yield). TLC: 50% EtOAc in hexane, Rf = 0.6; visualized with UV. 'H NMR (400 MHz, CDCh): <5 7.80 (d, J= 2.0 Hz, 1H), 7.77-7.65 (m, 3H), 7.37 (d, J= 1A Hz, 1H), 7.31-7.25 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 3.77 (s, 2H). ethyl 3-(5-fluoro-2-oxoindohn-l-yl)benzoate(10c). 10c was prepared by an abovedescribed procedure for 10a using 5-fluoroindolin-2-one 8b (0.5 g, 3.31 mmol, 1 eq.) and ethyl 3 -iodobenzoate 9a (0.91 g, 3.75 mmol, 1 eq) as a starting material, pale brown solid (0.5 g, 50% yield). TLC: 50% EtOAc in hexanes. R<= 0.65; visualized with UV. 'H NMR (400 MHz, CDC13): 5 8.15 - 8.01 (m, 2H), 7.65 - 7.53 (m, 2H), 7.07 (ddt, J= 7.9, 2.5, 1.2 Hz, 1H), 6.91 (td, J= 9.0, 2.7 Hz, 1H), 6.70 (dd, J= 8.6, 4.3 Hz, 1H), 4.39 (q, J= 7.2 Hz, 2H), 3.73 (s, 2H), 1.38 (t, J = 7.1 Hz. 3H); MS (ESI) m / z = 300.1 [M+H]+. Another synthesis was performed to give the product as a pale brown solid (0.735 g, 65% yield). TLC: 50% EtOAc in hexane, R / = 0.65; visualized with UV. 'H NMR (400 MHz. CDCh): 8 8.15-8.01 (m, 2H). 7.65-7.53 (m. 2H), 7.07 (dd, J = 7.9, 2.5 Hz, 1H), 6.91 (dd, J = 9.0, 2.7 Hz, 1H), 6.70 (dd, J = 8.6, 4.3 Hz, 1H), 4.39 (q, J= 7.2 Hz, 2H, OCHz), 3.73 (s, 2H), 1.38 (t, J= 7.1 Hz, 3H, Oh). ethyl 3-(2-oxo-5-(trlfluoromelhoxy)indolin-l-yl)benzoate (lOd). lOd was prepared by an above-described procedure for 10a using 5-(trifluoromethoxy)indolin-2-one 8c (0.5 g, 2.30 mmol, 1 eq.) and ethyl 3-iodobenzoate 9a (0.63 g, 2.30 mmol, 1 eq) as a starting material, pale brown solid (0.5 g, 60% yield). TLC: 50% EtOAc in hexanes, R / = 0.65; visualized with UV. ’H NMR (400 MHz, CDC13): 5 8.05 (dt, J= 7.1, 1.8 Hz, 1H), 8.01 (d, J= 2.0 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.16 (d, 2.2 Hz, 1H). 7.03 (dd. J= 8.5, 2.1 Hz, 1H), 6.70 (d, J= 8.6 Hz, 1H),

[0373] 4.33 (q, J= 7.1 Hz, 2H), 3.70 (s, 2H), 1.33 (t, J= 7.1 Hz, 3H); MS (ESI) m / z = 366.1 [M-H]+. Another synthesis was performed to give the product as a pale brown solid (0.915 g, 66% 29920-428111 2025-018-02 yield). TLC: 50% EtOAc in hexane, Ry = 0.65; visualized with UV. 'l l NMR (400 MHz, CDCh): <5 8.05 (dd, J= 7.1, 1.8 Hz, 1H), 8.01 (d, J= 2.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.16 (d, J = 2.2 Hz, 1H), 7.03 (dd, J = 8.5, 2. 1 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.33 (q, J = 7. 1 Hz, 2H, OCH ), 3.70 (s, 2H), 1.33 (t, J= 7.1 Hz, 3H, CHs).

[0374] 2-chloro-5-(5-formylfuran-2-yl)benzoic acid (13a). A solution of K2CO3 (2.37 g, 3 equiv) in water (10 mL) was added to a mixture of 5-bromo-2-furaldehyde Ila (2 g, 11.42 mmol, 1 eq.) and 4-chloro-3-carboxyphenylboronic acid 12a (2.74 g, 13.71 mmol. 1.2 eq.) in toluene / ethanol (1: 1, v / v, 40 rnL). The mixture was degassed with nitrogen for 10 min, and then Pd(PPhs)4 (0.4 g, 0.571 mmol, 0.5 eq.) was added. The reaction mixture was stirred at 100 °C for 16 h, then the reaction mixture was cooled to room temperature, filtered through celite, and washed with water and ethanol (2 x 10 mL). The solvent was evaporated under reduced pressure to give solid residue. The residue was diluted with water (20 mL) and the pH was adjusted to 2-3 by addition of 6 N HC1 solution, precipitate was formed. The solid precipitate was filtered and washed with 20-30% EtOAc in hexane to afford 2-chloro-5-(5-formylfuran- 2-yl)benzoic acid (2.4 g. 84% yield) as an off-white solid. TLC: 5% MeOH in DCM. R = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO): 5 9.64 (s, 1H), 8.21 (s, 1H), 7.99 (d, J= 8.6 Hz, 1H), 7.69 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 3.9 Hz, 1H);13C NMR (101 MHz, DMSO): 5 178.54, 164.94, 164.91, 156.69, 152.40, 131.72, 128.64, 125.74, 118.89, 118.65, 109.84; MS (ESI) m / z = 251.01 [M+H]+.

[0375] 2-fluoro-5-(5-formylfuran-2-yl)benzoic acid (13b). 13b was provided as described above. Another synthesis of 13b was prepared by an above-described procedure described for 13a using 5-bromo-2-furaldehyde Ila (3.0 g, 17.14 mmol, 1 eq.) and 5-borono-2- fluorobenzoic acid 12c (3.78 g, 20.57 mmol, 1.2 eq) as a starting material. Off white solid (3.2 g, 80% yield). TLC: 5% MeOH in DCM, Ry = 0.1; visualized with UV. 'H NMR (400 MHz, CDC13): 5 9.63 (s, 1H), 8.30 (d, J= 6.7 Hz, 1H), 8.19 - 8.09 (m, 1H), 7.67 (d, J= 3.8 Hz, 1H), 7.49 (t, J = 9.6 Hz, 1H), 7.38 (d, J = 3.7 Hz, 1H);13C NMR (101 MHz, DMSO) 5 178.54, 164.94, 156.69, 152.40, 131.72, 131.62, 128.64, 125.74, 125.70, 118.89, 118.65, 109.84; MS (ESI) m / z = 233.03 [M-H]'.

[0376] 5-(5-formylfuran-2-yl)-2-methoxybenzoic acid (13c). 13c was provided as described above. Another synthesis of 13c was prepared by above-procedure described for 13a, using 5- bromo-2-furaldehyde Ila (3.0 g, 17.14 mmol, 1 eq.) and 5-borono-2-methoxybenzoic acid 12c (4.03 g, 20.57 mmol, 1.2 eq) as a starting material. Yellow solid (3.8 g, 89% yield). TLC: 5% MeOH in DCM, Rf = 0. 1 ; visualized with UV. ' H NMR (400 MHz, DMSO): <5 12.95 (brs, 1H), 9.57 (s, 1H), 8.10 (s, 1H), 7.99 (d, J = 9.25 Hz, 1H), 7.63 (s, 1H), 7.25 (d, J = 9.25 Hz, 2H), 29920-428111 2025-018-02

[0377] 3.88 (s, 3H, OCIh).13C NMR (101 MHz, DMSO): 8 177.5, 166.7, 159.0, 157.6, 151.4, 129.7,

[0378] 127.3, 125.8. 122.1, 120.8. 113.3, 107.9, 56.1.

[0379] 5-(5-formylfuran-2-yl)-2-(trifluoromethoxy)benzoic acid (13d). 6d was prepared by above-procedure described for 13a, using 5-bromo-2-furaldehyde Ila (0.5 g, 2.85 mmol, 1 eq.) and 5-borono-2-(trifluoromethoxy)benzoic acid 12d (0.85 g, 3.42 mmol, 1.2 eq) as a starting material. Yellow solid (0.5 g, 58% yield). TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO): 5 13.75 (s. 1H), 9.66 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.18 (dd, J= 8.6, 2.4 Hz, 1H), 7.69 (d, J= 3.8 Hz, 1H), 7.64 (dd, J= 8.5, 1.6 Hz, 1H), 7.49 (d, J = 3.8 Hz, 1H).13C NMR (101 MHZ, DMSO) 8 178.73, 165.30, 156.13, 152.67, 147.11, 132.52, 132.49. 132.00, 131.91, 130.33, 129.28, 129.16, 128.63, 128.26, 127.44, 125.54, 124.22, 110.81: MS (ESI) m / z = 299.02 [M-H]’. Another synthesis was performed to give the product as a yellow solid (0.69g, 81% yield). TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO-de): d 13.75 (s, 1H), 9.66 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.6, 2.4 Hz, 1H), 7.69 (d, J= 3.8 Hz, 1H), 7.64 (dd, J= 8.5, 1.6 Hz, 1H), 7.49 (d, J = 3.8 Hz, 1H).13C NMR (101 MHz, DMSO-de): 8 178.7, 165.3, 156.1, 152.6, 147.1. 132.5,

[0380] 132.4, 132.0, 131.9, 130.3, 129.2, 129.1, 128.6, 128.2, 127.4, 125.5, 124.2, 1 10.8.

[0381] 2-Chloro-5-(5-formyl-lH-pyrrol-2-yl)benzoic acid (13e): 13e was prepared by an above-described procedure using 5-bromo-lH-pyrrole-2-carbaldehyde 11b (0.4 g, 2.296 mmol, 1 eq) and 5-borono-2-chlorobenzoic acid 12a (0.5 g. 2.528 mmol, 1.1 eq) as a starting material. Off white solid (0.454 g. 79% yield). TLC: 5% MeOH in DCM, R = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO-de): 8 13.55 (s, 1H), 12.63 (s, 1H), 9.56 (s, 1H), 8.34 (d, J= 2.4 Hz, 1H), 8.08-8.00 (m, 1H), 7.61 (d, J= 8.4 Hz, 1H), 7.14-7.08 (m, 1H), 6.91 (dd, .7= 4.0, 2.3 Hz, 1H).

[0382] 2-Fluoro-5-(5-formyl-lH-pyrrol-2-yl)benzoic acid (13f): 13f was prepared by an above-described procedure for 13a by using 5-bromo-lH-pyrrole-2-carbaldehyde lib (0.5 g, 2.873 mmol, 1 eq) and 5-borono-2-fluorobenzoic acid 12b (0.793 g, 4.310 mmol, 1.5 eq) as a starting material, off white solid, (0.554 g, 82% yield). TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. ‘H NMR (400 MHz, DMSO-de): 8 12.58 (s, 1H), 9.52 (s, 1H), 8.38 (d, J = 6.9 Hz, 1H), 8.16 - 8.07 (m, 1H), 7.44 - 7.34 (m, 2H), 7.09 (d, J= 3.9 Hz, 1H), 6.82 (s, 1H).13C NMR (101 MHz, DMSO): 8 178.5, 164.9, 164.9, 156.6, 152.4, 131.7, 131.6, 128.6, 125.7, 125.7, 118.8. 118.6, 109.8; MS (ESI) m / z = 232.04 [M-H]’.

[0383] Alternative Synthesis of 2-chloro-5-(5-formyl-lH-pyrrol-2-yl)benzoic acid (13e). To a solution of 5-bromo-lH-pyrrole-2-carbaldehyde 11b (0.4 g, 2.296 mmol, 1 eq.) and 5-borono- 29920-428111 2025-018-02

[0384] 2-chlorobenzoic acid 12a (0.5 g, 2.528 mmol, 1.1 eq.) in toluene: EtOH: water (15 mL, 1 : 1: 1) was added K.2CO3 (0.73 g. 6.896 mmol. 3.0 eq.).The mixture was purged and degassed with nitrogen for 5 min, then was added PdC12(PPh?)2 (0.16 g, 0.229 mmol, 0.1 eq.). The resultant reaction mixture was heated at 100 °C for 24 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was diluted with cold water (20 mL) and acidified with 2N HC1 to adjust the pH 4.0, precipitate was formed, filtered to yield pure title product 13e (0.42 g, 30% yield) as off white solid. TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. 1H NMR (400 MHz, DMSO): 5 13.55 (s, 1H), 12.63 (s, 1H), 9.56 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.08 - 8.00 (m, 1H), 7.61 (d, J= 8.4 Hz. 1H), 7.14 - 7.08 (m, 1H), 6.91 (dd, J= 4.0, 2.3 Hz, 1H).

[0385] Alternative Synthesis of 2-chloro-5-(5-formyl-lH-pyrrol-2-yl)benzoic acid (13f). 13f was prepared by an above-described procedure for 13e by using 5-bromo-lH-pyrrole-2- carbaldehyde lib (0.5 g, 2.873 mmol. 1 eq) and 5-borono-2-fluorobenzoic acid 12b (0.793 g, 4.310 mmol, 1.5 eq) as a starting material, off white solid. (0.5 g, 74% yield). TLC: 5% MeOD in DCM, R = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO): 5 12.58 (s, 1H), 9.52 (s, 1H), 8.38 (d, J = 6.9 Hz, 1H), 8. 16 - 8.07 (m, 1H), 7.44 - 7.34 (m, 2H), 7.09 (d, J = 3.9 Hz, 1H), 6.82 (s, 1H). 13C NMR (101 MHz, DMSO): 5 178.54, 164.94, 164.91, 156.69, 152.40, 131.72. 131.62, 128.64, 125.74, 125.70. 118.89, 118.65, 109.84; MS (ESI) m / z = 232.04 [M- H]+.

[0386] (Z)-2-chloro-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)benzoic acid (14a). ethyl 3-(2-oxoindolin-l-yl)benzoate 10a (0.6 g, 2.13 mmol, 1 eq.) and 2-chloro-5-(5-formylfuran-2-yl)benzoic acid 13a (0.534 g, 2.13 mmol, 1 eq.) were dissolved in glacial acetic acid (20 mL). The reaction mixture was reflux with stirring for 3 h. Solvent was removed under reduced pressure and solid residue was suspended in EtOH. filtered, washed with EtOH. EtOAc, and DCM (2 times each) to obtain 14a (0.8 g, 73% yield) as a red solid. TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. Major Z- isomer data: 'H NMR (400 MHz, DMSO): 8 8.69 (d, J= 7.6 Hz, 1H), 8.05 (d, J= 6.7 Hz, 3H), 7.83 (d, J= 7.9 Hz, 1H), 7.76 (t, J= 7.5 Hz, 2H), 7.54 (d, J= 5.4 Hz, 2H), 7.49 (d, J= 8.5 Hz, 1H), 7.42 (s, 1H), 7.33 (dt. J = 2L3, 7.6 Hz, 2H), 6.87 (d, J= 7.7 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H).13C NMR (101 MHz, DMSO): 8 169.31, 167.91, 165.50, 165.14, 151.43, 148.96, 141.42, 132.04, 131.82, 131.22, 130.99, 130.86, 130.66, 127.87, 117.94, 115.42, 111.44, 61.59, 24.51, 14.59; MS (ESI) m / z = 512.09 [M-H]'. 29920-428111 2025-018-02

[0387] Compounds 14b-i were synthesized by an above synthetic procedure described for the preparation of 14a using appropriate starting materials. Compounds 14b and 14c were also provided as described above.

[0388] (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2- fluorobenzoic acid (14b). 14b was provided as described above. Another synthesis of 14b was provided by an above synthetic procedure described for the preparation of 14a. Red solid (0.8 mg, 74% yield). TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. Major Z-isomer data: ‘H NMR (400 MHz, DMSO): 5 8.68 (d, J= 7.7 Hz, 1H), 8.55 (d, J= 6.7 Hz, 1H), 8.26 - 8.18 (m, 1H), 8.06 (d, J= 9.1 Hz, 2H), 7.82 (d, J= 8.0 Hz, 1H), 7.76 (t, J= 7.8 Hz, 1H), 7.55 (d, J = 4.4 Hz, 3H), 7.49 (d, J= 3.6 Hz. 1H), 7.36 (t, J= 7.7 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.8 Hz. 1H), 4.36 (q. J = 7.1 Hz, 2H). 1.34 (t, J = 7.1 Hz, 3H);13C NMR (101 MHz, DMSO) 5 167.86, 165.47, 164.83, 164.80, 160.38, 156.96, 151.06, 144.12, 141.98, 135.02, 132.15, 131.88, 130.73, 130.42, 130.33, 129.22, 128.27, 128.04, 126.74, 126.01, 123.11, 122.64, 122.22, 121.99, 121.32, 121.20, 119.55, 119.45, 118.53, 118.30, 117.21, 111.85, 110.33. 61.62, 14.60; MS (ESI) m / z = 496. 12 [M-H]'. Another synthesis was performed to give the product as a red solid (67% yield). TLC: 5% MeOH in DCM, R / = 0. 1 ; visualized with UV. 'H NMR (400 MHz, DMSO-de): b 8.68 (d, J= 7.7 Hz, 1H), 8.55 (d, J= 6.7 Hz, 1H), 8.26-8.18 (m, 1H), 8.06 (d, J = 9 A Hz, 2H), 7.82 (d, J= 8.0 Hz, 1H), 7.76 (t, J= 7.8 Hz, 1H), 7.55 (d, J = 4.4 Hz. 3H), 7.49 (d, J= 3.6 Hz. 1H), 7.36 (t, J= 7.7 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 4.36 (q. J = 7.1 Hz. 2H, OCH21.34 (t, J = 7.1 Hz, 3H. CHs).13C NMR (101 MHz, DMSO-de): b 167.8, 165.4, 164.8, 164.8, 160.3, 156.9, 151.0, 144.1 , 141.9, 135.0, 132.1, 131.8, 130.7, 130.4, 130.3, 129.2, 128.2, 128.0, 126.7, 126.0, 123.1, 122.6, 122.2, 121.9,

[0389] 121.3, 121.2, 119.5, 119.4. 118.5, 118.3, 117.2, 111.8, 110.3, 61.6, 14.6.

[0390] (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2- methoxybenzoic acid (14c). 14c was provided as described above. Another synthesis of 14c was provided by an above synthetic procedure described for the preparation of 14a. Yellow solid (72% yield). TLC: 5% MeOH in DCM, Rr = 0.2; visualized with UV. ' H NMR (400 MHz, DMSO-de): 5 8.66 (d, J = 5.42 Hz. 1H), 8.34 (s, 1H), 8.09 - 7.98 (m, 3H), 7.79 - 7.74 (m, 2H), 7.52 (s. 2H). 7.34-7.25 (m, 4H). 6.86 (d, J = 6.97 Hz, 1H). 4.35 (q, J = 5.72 Hz, 2H, OCH2). 3.91 (s, 3H, OCH3), 1.32 (t, J = 9.53 Hz, 3H, CH3).13C NMR (101 MHz, DMSO-de): 5 177.5, 167.6, 166.7, 165.0, 158.9, 157.1, 150.0, 142.4, 134.9, 131.6, 131.3, 130.2, 129.4, 129.2, 128.4,

[0391] 127.4, 127.2, 126.7, 125.3, 123.6, 122.5, 122.0, 121.2, 121.1, 120.2, 119.2, 113.7, 113.3, 109.4, 108.9, 107.8. 61.1. 56.1, 14.1. 29920-428111 2025-018-02

[0392] (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2 (tr i fluor omethoxy)benzoic acid (14d). Orange solid (0.4 mg, 66% yield). TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO): 8 9.66 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.6, 2.4 Hz, 1H), 8.10 - 8.02 (m, 2H), 7.78 - 7.75 (m, 2H), 7.72 - 7.68 (m, 1H), 7.66 (dd, J= 5.2, 1.4 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.49 (d, J = 3.8 Hz. 1H), 7.21 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 4.36 (q, J = 7.1 Hz. 2H), 1.33 (t. J = TA Hz. 3H);13C NMR (101 MHz, DMSO) 6 182.93, 165.50. 165.42, 151.61. 151.37, 143.21, 142.20, 138.40, 137.78, 134.34, 133.72, 132.70, 132.52, 132.49, 132.07,

[0393] 132.00, 131.93, 131.91, 131.83, 131.80, 130.79, 130.67, 129.45, 129.29, 129.17, 127.89,

[0394] 127.73. 125.21, 124.23. 111.10, 61.62, 14.61; MS (ESI) m / z = 562.11 [M-H]’. Another synthesis was performed to give the product as an orange solid (68% yield). TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO-de): b 9.66 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.6, 2.4 Hz, 1H), 8.10-8.02 (m, 2H), 7.78-7.75 (m, 2H), 7.72-7.68 (m, 1H), 7.66 (dd, J= 5.2, 1.4 Hz, 1H), 7.64-7.59 (m, 2H), 7.49 (d, J= 3.8 Hz, 1H), 7.21 (t, J= 7.5 Hz, 1H), 6.84 (d, J= 7.9 Hz, 1H), 4.36 (q, J= TA Hz, 2H, OCHs), 1.33 (t, J = 7.1 Hz, 3H, CHs).13C NMR (101 MHz, DMSO): b 182.9, 165.5, 165.4,

[0395] 151.6, 151.3, 143.2, 142.2, 138.4, 137.7, 134.3, 133.7, 132.7, 132.5, 132.4, 132.0, 132.0, 131.9, 131.9, 131.8, 131.8, 130.7, 130.6, 129.4, 129.2, 129.1, 127.8, 127.7, 125.2, 124.2, 111.1, 61.6,

[0396] 14.6.

[0397] (Z)-2-Chloro-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindoUn-3-ylidene)methyl)- lH-pyrrol-2-yl)benzoic acid (14e): Red solid (0.145 g, 71 % yield). TLC: 10% MeOH in DCM, R = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO-de): b 13.76 (s, 1H, ), 8.09 (d, J = 10.3 Hz, 2H), 8.01-7.95 (m, 2H), 7.91-7.67 (m, 4H), 7.59 (d, J= 8.5 Hz, 1H), 7.19 (s. 2H), 7.07 (d, J= 13.4 Hz. 2H), 6.77 (d. J= 7.6 Hz, 1H), 4.36 (d, J= 7.2 Hz, 2H, OCHsf 1.33 (t, J = 7.2 Hz, 3H, CHs).

[0398] (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)-lH-pyrrol-2- yl)-2-fluorobenzoic acid (14f): Orange solid; (0.585g, 68% yield). TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO-de): b 13.44 (s, 1H, NH), 9.51 (s, 1H), 8.39 (dd, 6.8, 2.4 Hz. 1H), 8.11 (d. J= 10.0 Hz, 3H), 7.83 (dd. J= 11.5. 7.2 Hz. 2H). 7.73 (d, J= 8.7 Hz, 1H), 7.41 (dd, J= 18.6, 9.7 Hz, 3H), 7.20 (dd, J= 16.5, 7.5 Hz, 2H), 7.09 (t, J = 5.2 Hz, 2H), 6.83 (t, J = 3.0 Hz, 1H), 4.37 (q, J= 7.0 Hz, 2H, OCHz), 1.34 (t, J = 7.1 Hz. 3H, CHs .

[0399] (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-5-fluoro-2-oxoindolin-3- ylidene)methyl)furan-2-yl)-2-fluorobenzoic acid (14g). Orange solid (0.4 mg 77% yield). TLC: 29920-428111 2025-018-02

[0400] 5% MeOH in DCM, R / = 0.1; visualized with UV. Major Z-isomer data:JH NMR (400 MHz, DMSO): 8 13.56 (s, 1H), 8.43 (dd, J = 6.8, 2.5 Hz, 1H), 8.36 (dd, J = 9.4, 2.7 Hz, 1H), 8.24 - 8.17 (m, 1H), 8.08 - 8.02 (m, 2H), 7.82 (dt, J = 8.1, 1.6 Hz, 1H), 7.76 (t, J = 7.7 Hz, 2H), 7.64 - 7.59 (m, 2H), 7.58 - 7.54 (m, 1H), 7.51 (d, J = 3.7 Hz, 1H), 7.19 (td, J = 8.8, 2.6 Hz, 1H), 6.86 (dd, J = 8.7, 4.4 Hz, 1H), 4.36 (q, J= 7.1 Hz, 3H), 1.34 (t, J = 7. 1 Hz, 4H).13C NMR (101 MHz, DMSO) 8 172.49, 165.49, 156.80, 151.09, 139.37, 135.24, 132.00, 131.85, 130.71,

[0401] 127.85. 126.35, 126.07, 121.88, 61.61, 21.53. 14.61; MS (ESI) m / z = 514. 11 [M-H]'. Another synthesis was performed to give the product as an orange solid (69% yield). TLC: 5% MeOH in DCM, R / = 0.1; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO-de): 8 13.56 (s, 1H), 8.43 (dd, J = 6.8, 2.5 Hz. 1H), 8.36 (dd, J = 9.4, 2.7 Hz, 1H). 8.24-8.17 (m, 1H), 8.08-8.02 (m. 2H), 7.82 (dd, J = 8.1, 1.6 Hz. 1H), 7.76 (t, J = 7.7 Hz, 2H), 7.64-7.59 (m, 2H), 7.58-7.54 (m, 1H), 7.51 (d, J= 3.7 Hz, 1H), 7.19 (dd, J = 8.8, 2.6 Hz, 1H), 6.86 (dd, J = 8.7, 4.4 Hz, 1H), 4.36 (q, J= 7.1 Hz, 2H, OCHd), 1.34 (t, J = 7.1 Hz, 3H, CHs).13C NMR (101 MHz, DMSO-do): 8 172.4, 165.4, 156.8, 151.0, 139.3, 135.2, 132.0, 131.8, 130.7, 127.8, 126.3, 126.0, 121.8. 61.6, 21.5, 14.6.

[0402] (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxo-5-(trifluoromethoxy)indolin-3- ylidene)methyl)furan-2-yl)-2-fluorobenzoic acid (14h). Orange solid (0.3 mg 62% yield). TLC: 5% MeOH in DCM R = 0.1; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO): 8 13.58 (s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.39 (dd, J = 6.8, 2.4 Hz, 1H), 8.19 - 8.12 (m. 1H), 8.07 (d. J = 7.7 Hz, 2H). 7.83 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.64 (d, .7 = 3.8 Hz, 1H), 7.51 (d, .7= 3.7 Hz, 1H), 7.47 (t, .7= 9.4 Hz, 1H), 7.35 (d, .7= 8.6 Hz, 1H), 6.92 (d, J= 8.6 Hz, 1H), 4.36 (q, J= 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO) 8 167.86, 165.47, 164.83, 164.80, 160.38. 156.96, 151.06, 144.12, 141.98, 135.02. 132.15, 131.88. 130.73, 130.42. 130.33, 129.22, 128.27, 128.04, 126.74, 126.01, 123.1 1, 122.64, 122.22, 121.99, 121.32, 121.20, 119.55, 119.45, 118.53, 1 18.30, 117.21,

[0403] 111.85, 110.33, 61.62, 14.60; MS (ESI) m / z = 580.10 [M-H]'. Another synthesis was performed to give the product as an orange solid (71% yield). TLC: 5% MeOH in DCM R / = 0.1; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO-de): 8 13.58 (s, 1H), 8.52 (d. J = 2.5 Hz. 1H). 8.39 (dd. J = 6.8, 2.4 Hz, 1H). 8.19-8.12 (m, 1H), 8.07 (d, J = 7.7 Hz, 2H), 7.83 (d, J= 8.0 Hz, 1H), 7.76 (t, J= 7.8 Hz, 1H), 7.65 (s, 1H), 7.64 (d, J= 3.8 Hz, 1H), 7.51 (d, .7= 3.7 Hz, 1H), 7.47 (t, J= 9.4 Hz, 1H), 7.35 (d, J= 8.6 Hz, 1H), 6.92 (d, J= 8.6 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.34 (t, J= 7.1 Hz, 3H);13C NMR (101 MHz, DMSO-de): 5 167.8, 165.4. 164.8, 164.8. 160.3, 156.9. 151.0, 144.1. 141.9, 135.0, 132.1, 131.8, 130.7, 130.4, 29920-428111 2025-018-02

[0404] 130.3, 129.2, 128.2, 128.0, 126.7, 126.0, 123.1, 122.6, 122.2, 121.9, 121.3, 121.2, 119.5, 119.4,

[0405] 118.5, 118.3. 117.2, 111.8. 110.3, 61.6, 14.6.

[0406] (Z)-5-(5-((l-(3-cyanophenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2- fluorobenzoic acid (14i). Orange solid (0.63 mg 65% yield). TLC: 10% MeOH in DCM R / = 0.2; visualized with UV. Major Z-isomer data:!H NMR (400 MHz, DMSO): 5 13.57 (s, 1H), 9.64 (s. 1H), 8.68 (d. J= 7.7 Hz, 1H), 8.54 (d, J= 6.6 Hz, 1H). 8.21 (d, J= 7.8 Hz, 1H), 8.08 (s, 1H). 7.96 (d, J= 8.1 Hz, 2H). 7.91 (d, J= 8.2 Hz, 1H). 7.81 (t. J= 8.0 Hz. 1H), 7.56 (d. J = 4.0 Hz, 2H), 7.49 (d, J= 3.0 Hz, 1H), 7.38 (dd, J= 13.7, 5.7 Hz, 2H), 7.30 (t, J= 7.4 Hz, 1H),

[0407] 6.94 (d, J = 7.8 Hz, 1H);13C NMR (101 MHz, DMSO) 5 178.59, 167.81, 156.09, 151.29,

[0408] 142.60. 135.72, 132.70, 132.30, 132.07, 132.03, 131.40, 130.89, 130.18, 128.32, 128.23,

[0409] 127.16. 126.59, 125.36. 123.27, 121.42. 120.64, 120.57. 118.57, 113.01, 112.00, 110.47,

[0410] 109.63; MS (ESI) m'z = 449.1 [M-H]+. Another synthesis was performed to give the product as an orange solid (67% yield). TLC: 10% MeOH in DCM R = 0.2; visualized with UV. Major Z-isomer data:JH NMR (400 MHz, DMSO-de): <5 13.57 (s, 1H), 9.64 (s, 1H), 8.68 (d, J= 7.7 Hz. 1H), 8.54 (d, J = 6.6 Hz, 1H). 8.21 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.91 (d, ,7= 8.2 Hz, 1H), 7.81 (t, J= 8.0 Hz, 1H), 7.56 (d, J= 4.0 Hz, 2H), 7.49 (d, J= 3.0 Hz, 1H), 7.38 (dd, J= 13.7, 5.7 Hz, 2H), 7.30 (t, J= 7.4 Hz, 1H), 6.94 (d, J= 7.8 Hz, 1H);13C NMR (101 MHz, DMSO-dfi): b 178.5, 167.8, 156.0, 151.2, 142.6, 135.7, 132.7, 132.3, 132.0, 132.0, 131.4, 130.8, 130.1, 128.3, 128.2, 127.1, 126.5, 125.3, 123.2, 121.4, 120.6, 120.5, 118.5, 113.0, 112.0. 110.4, 109.6.

[0411] Alternative Synthesis of (Z)-2-chloro-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2- oxoindolm-3-ylidene)methyl)-lH-pyrrol-2-yl)benzoic acid l4e The suspension of ethyl 3-(2- oxoindolin-l-yl)benzoate 10a (0.1 g. 0.353 mmol, 1.0 eq.) and 2-chloro-5-(5-formyl-lH- pyrrol-2-yl)benzoic acid 13e (0.088 g, 0.345 mmol, 1.0 eq.) in acetic acid (10 mL) was heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure to give solid residue. The residue was diluted with cold water (50 mL), formed solid was filtered and dried under vacuum to get crude solid. The crude was triturated with 20% EtOAc:hexane and filtered to give title product 14e (0. 15 g, 83% yield) as red color solid. TLC: 10% MeOH in DCM, Ry = 0.1; visualized with UV. ’H NMR (400 MHz, DMSO): 5 13.76 (s, 1H), 8.09 (d, J= 10.3 Hz, 2H), 8.01 - 7.95 (m. 2H), 7.91 - 7.67 (m, 4H), 7.59 (d, J= 8.5 Hz. 1H), 7.19 (m, 2H). 7.07 (d, J= 13.4 Hz. 2H), 6.77 (d, J= 7.6 Hz. 1H), 4.36 (d, J= 7.2 Hz, 2H), 1.33 (t, J= 7.2 Hz, 3H). 29920-428111 2025-018-02

[0412] Alternative Synthesis of (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3- ylidene)methyl)-lH-pyrrol-2-yl)-2-fluorobenzoic acid (14f) 14f was prepared by an abovedescribed procedure for 14e by using ethyl 3-(2-oxoindolin-l-yl) benzoate 10a (0.4g, 1.423 mmol, 1 eq) and 2-fluoro-5-(5-formyl-lH-pyrrol-2-yl)benzoic acid 13f (0.331 g, 1.423 mmol, 1 eq) as a starting material, orange solid; (0.4 g, 56% yield). TLC: 5% MeOD in DCM, R = 0.1; visualized with UV.1H NMR (400 MHz, DMSO): 5 13.44 (s, 1H). 9.51 (s, 1H), 8.39 (dd, J= 6.8. 2.4 Hz. 1H). 8. 11 (d. J= 10.0 Hz, 3H), 7.83 (dd, J= 11.5. 7.2 Hz. 2H), 7.73 (d. J= 8.7 Hz, 1H), 7.41 (dt, J = 18.6, 9.7 Hz, 3H), 7.20 (dt, J = 16.5, 7.5 Hz, 2H), 7.09 (t, J = 5.2 Hz, 2H), 6.83 (t, J= 3.0 Hz, 1H), 4.37 (q, J= 7.0 Hz, 2H), 1.34 (t, J= 1A Hz, 3H); MS (ESI) m / z = 495.14 [M-H]+. ethyl (Z)-3-(3-((5-(4-chloro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoate 16 (GL-3385). To the solution of (Z)-2-chloro-5-(5- ((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene) methyl)furan-2-yl)benzoic acid 14a (0.2 g, 0.39 mmol. 1 eq) and HATU (0.22 g. 0.58 mmol, 1.5 eq) in DMF (5 mL) was added DIPEA (213 pL, 1.16 mmol, 3 eq), and the mixture was stirred for 10 min at room temperature under an argon atmosphere, then 3-methoxy aniline 15a (48 mg, 0.39 mmol, 1 eq) was added. The resultant reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into the ice-cold water and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with saturated NaHCO? (2 x 20 mL), followed by brine solution (2 x 20 mL). The combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure to give crude solid product. The crude product was triturated with 20% EtOAc in hexanes (2-3 times) to afford 16(0.17 g. 70% yield) as a red solid. TLC: 50% EtOAc in hexanes. R / = 0.4; visualized with UV. Isomer data: 'H NMR (400 MHz, DMSO) 5 10.71 (d. J = 2.5 Hz, 1H), 8.62 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 8.11 - 8.00 (m, 3H), 7.85 - 7.78 (m, 2H), 7.75 (dt, J= 9.0, 4.5 Hz, 1H), 7.57 (dt, J = 5.8, 2.9 Hz, 3H), 7.45 (s, 1H), 7.35 - 7.22 (m, 3H), 7.19 - 7.12 (m, 1H). 6.87 - 6.81 (m, 1H), 6.74 (d, J= 7.3 Hz, 1H), 4.35 (qd, J= 6.9, 3.8 Hz, 2H). 3.76 (d, J= 2.5 Hz, 3H). 1.33 (ddd, J= 8.5, 7.0. 2.0 Hz. 3H);13C NMR (101 MHz, DMSO): 5 167.97, 165.51 , 162.61 , 160.03, 156.43, 151.18, 143.09, 140.37, 135.28, 132.07, 131.82, 130.69, 130.18, 128.97, 127.88, 126.14, 125.37, 124.21, 123.09, 121.49, 120.68, 112.53, 111.45, 109.99, 109.54. 106.04, 61.61, 55.53, 14.61; MS (ESI) m / z = 619.16 [M+H]+. Another synthesis was performed to afford 16 (0. 19 g, 78% yield) as a red solid. TLC: 50% EtOAc in hexane, R = 0.4; visualized with UV. Isomer data:1H NMR (400 MHz, DMSO- de): d 10.71 (brs, 1H, CONH). 8.62 (d, J= 7.8 Hz, 1H), 8.17 (d, J= 2.7 Hz, 1H), 8.11-8.00 (m, 29920-428111 2025-018-02

[0413] 3H), 7.85-7.78 (m, 2H), 7.75 (d, J = 9.0, 4.5 Hz, 1H), 7.57 (dd, J= 5.8, 2.9 Hz, 3H), 7.45 (s, 1H), 7.35-7.22 (m. 3H), 7.19-7.12 (m, 1H). 6.87-6.81 (m, 1H), 6.74 (d, J = 7.3 Hz, 1H), 4.35 (q, J= 6.9, 3.8 Hz, 2H, OCH23.76 (d, J= 2.5 Hz, 3H, OCH31.33 (, J= 8.5, Hz, 3H, CH?).13C NMR (101 MHz, DMSO-de): 3 167.9, 165.5, 162.6, 160.0, 156.4, 151.1, 143.0, 140.3, 135.2, 132.0, 131.8, 130.6, 130.1, 128.9, 127.8, 126.1, 125.3, 124.2, 123.0, 121.4, 120.6, 112.5,

[0414] 111.4, 109.9, 109.5, 106.0. 61.6, 55.5, 14.6. HPLC purity: 97.88% (1R = Z isomer at 11.42 min and E isomer at 11.99 min).

[0415] Compounds 17-22 and 24-29 were synthesized by an above synthetic procedure described for the preparation of 16 using appropriate starting materials. ethyl (Z)-3-(3-((5-(4-chloro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)fiiran- 2-yl)methylene)-2-oxoindolin-l-yl)benzoate 17 (GL-3388). Red solid (0.2 g, 50% yield). TLC: 50% EtOAc in hexanes, R / = 0.4; visualized with UV. Isomer data: 'H NMR (400 MHz, CDCh): 5 8.61 (d, J= 7.6 Hz, 1H), 8.38 (s, 1H), 8.25 (d, J= 2.3 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J= 7.6 Hz, 1H), 7.83 (dd, J= 8.4, 2.4 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.62 (t, J = 7.7 Hz. 1H), 7.55 (t, J = 7.6 Hz. 2H), 7.47 (s. 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.29 (s. 1H), 7. 19 (t. J= 7.6 Hz. 1H), 7.07 (d. J= 8.2 Hz. 1H), 7.02 (d. J= 3.7 Hz. 1H), 6.95 (d. J = 3.8 Hz. 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.44 - 4.35 (m, 2H), 1.40 (td, J = 7.2, 1.8 Hz, 3H).13C NMR (101 MHz, CDC13). 5 172.73, 172.66, 170.26, 169.89, 160.83, 156.18, 147.93, 145.60, 142.37, 140.03. 139.98, 136.80. 136.56, 136.00, 135.43, 134.94, 133.24, 132.62, 129.95, 129.83, 127.74. 126.20, 125.82, 125.33, 123.45. 116.97. 116.84, 66.35. 19.35; MS (ESI) m>z = 673. 14 [M+H]+. Another synthesis was performed to give the product as a red solid (82% yield). TLC: 50% EtOAc in hexane, R / = 0.4; visualized with UV. Isomer data: 'H NMR (400 MHz, CDCh): 5 8.61 (d. J= 7.6 Hz, 1H), 8.38 (s, 1H), 8.25 (d, J= 2.3 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J= 7.6 Hz. 1H), 7.83 (dd, J = 8.4. 2.4 Hz. 1H), 7.77 (s. 1H), 7.67 (d. J= 8.0 Hz. 1H), 7.62 (t, J= 7.7 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.47 (s, 1H), 7.41 (t, J= 8.2 Hz, 1H), 7.29 (s, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.07 (d, J= 8.2 Hz, 1H), 7.02 (d, J= 3.7 Hz, 1H), 6.95 (d, J= 3.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.44 - 4.35 (m, 2H), 1.40 (t, J = 7.2, Hz, 3H, CH? .13C NMR (101 MHz, CDCh). 3 172.7. 172.6, 170.2, 169.8, 160.8, 156.1. 147.9, 145.6, 142.3, 140.0, 139.9, 136.8,

[0416] 136.5, 136.0. 135.4, 134.9. 133.2, 132.6. 129.9, 129.8. 127.7, 126.2. 125.8, 125.3. 123.4, 116.9. 1 16.8, 66.3, 19.3. HPLC purity: 97.88% ( / i< = Z isomer at 12.27 min and E isomer at 12.80 min). ethyl (Z)-3-(3-((5-( 4-fluoro-3-(( 3-methoxyphenyl)carbamoyl)phenyl) furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoate 18 (Gl-3394). Red solid (0.14 g. 57% yield). TLC: 50% EtOAc in hexanes, R / = 0.4; visualized with UV. Isomer data: 'H NMR (400 MHz, 29920-428111 2025-018-02

[0417] DMSO): 5 10.63 (s, 1H), 8.66 (d, J= 7.7 Hz, 1H), 8.29 (d, J= 6.4 Hz, 1H), 8.16 (t, J = 6.5 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.82 (d, J= 8.0 Hz, 1H), 7.76 (1, J= 7.4 Hz, 1H), 7.63 (t, J= 9.0 Hz, 1H), 7.57 (d, J= 2.2 Hz, 2H), 7.55 - 7.50 (m, 1H), 7.46 (s, 1H), 7.37 - 7.26 (m, 3H), 7.21 (t, J = 7.3 Hz, 1H), 6.86 (d, J= 7.9 Hz, 1H), 6.75 (d, J= 7.8 Hz, 1H), 4.35 (dd, J= 7.9, 5.9 Hz, 2H), 3.77 (d, J = 1.9 Hz, 3H);13C NMR (101 MHz, DMSO) 5 167.97, 165.51, 162.61, 160.03, 156.43. 151.18, 143.09. 140.38, 135.28, 132.07, 131.82, 130.69, 130.19, 128.97, 127.88, 126.32. 126.15, 125.38, 123.08, 121.49, 120.68, 112.53. 111.46. 109.98. 109.54, 106.03, 61.60. 55.53, 14.61 ; MS (ESI) m z = 603.19 [M + H]+. Another synthesis was performed to give the product as a red solid (86% yield). TLC: 50% EtOAc in hexane, R / = 0.4; visualized with UV. Isomer data: 'H NMR (400 MHz, DMSO-de): 3 10.63 (s, 1H, CONH). 8.66 (d, J= 7.7 Hz, 1H), 8.29 (d, J= 6.4 Hz, 1H). 8. 16 (t. J= 6.5 Hz. 1H), 8.09-8.01 (m, 2H), 7.82 (d. J= 8.0 Hz. 1H), 7.76 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 9.0 Hz, 1H), 7.57 (d, J = 2.2 Hz, 2H), 7.55-7.50 (m, 1H), 7.46 (s, 1H), 7.37-7.26 (m, 3H), 7.21 (t, J= 7.3 Hz, 1H), 6.86 (d, J= 7.9 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 4.35 (q, J = 7.9Hz, 2H, OCHz 3.77 (t, J = 1.9 Hz, 3H, C£U);13C NMR (101 MHz, DMSO-de): <5 167.9, 165.5, 162.6, 160.0, 156.4, 151.1, 143.0, 140.3, 135.2, 132.0, 131.8, 130.6, 130.1, 128.9, 127.8, 126.3, 126.1, 125.3, 123., 121.4, 120.6, 112.5, 1 11.4, 109.9, 109.5, 106.0, 61.6, 55.5, 14.6; LCMS (ESI) m / z= 601.45 [M-H] . HPLC purity: 97.14% (fa = Z isomer at 11.70 min and E isomer at 12.15 min). ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-(trifluoromelhoxy)phenyl)carbamoyl)phenyl)fiiran- 2-yl)methylene)-2-oxomdolin-l-yl)benzoate 19 (GL-3391). Red solid (0.085 g. 32% yield). TLC: 50% EtOAc in hexanes, R / = 0.3; visualized with UV. Isomer data: ’H NMR (400 MHz, DMSO): 5 10.95 (s, 1H), 8.65 (d, J= 7.7 Hz, 1H), 8.36 - 8.28 (m, 1H), 8.18 (s, 1H), 8.05 (d, J = 9.4 Hz, 2H), 7.93 (s, 1H), 7.82 (d, J= 7.9 Hz, 1H), 7.75 (dd, J= 13.5, 7.6 Hz, 2H), 7.65 (t, J = 9.2 Hz. 1H), 7.57 (d. J= 2.2 Hz. 2H), 7.54 (d, J= 7.7 Hz, 2H), 7.29 (t, J= 7.6 Hz, 1H), 7.24 - 7.13 (m, 2H), 6.86 (d, J= 7.8 Hz, 1H), 4.36 (q, J= 1A Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, DMSO). 5 167.96, 165.50, 162.99, 158.28, 156.33, 151.21, 148.98, 143.10,

[0418] 140.82, 135.27, 132.06, 131.81, 131.20, 130.68, 130.14, 128.97, 127.87, 126.22, 125.98,

[0419] 125.82. 125.35, 124.23. 123.05, 121.49, 120.72, 120.64, 118.89, 116.66, 112.28, 111.51, 109.54. 61.60, 14.60; MS (ESI) m / z = 657.16 [M+H]+. Another synthesis was performed to give the product as a red solid (84% yield). TLC: 50% EtOAc in hexane, R / = 0.3; visualized with UV. Isomer data: 'H NMR (400 MHz, DMSO-de): 3 10.95 (s, 1H), 8.65 (d, J = 7.7 Hz, 1H), 8.36 - 8.28 (m, 1H), 8.18 (s, 1H), 8.05 (d, J= 9.4 Hz, 2H), 7.93 (s, 1H), 7.82 (d, J = 1.9 Hz. 1H), 7.75 (dd, J= 13.5, 7.6 Hz, 2H). 7.65 (t. J= 9.2 Hz, 1H), 7.57 (d, J= 2.2 Hz, 2H), 7.54 (d, J= 7.7 Hz, 2H), 7.29 (t, J= 7.6 Hz, 1H), 7.24-7.13 (m, 2H), 6.86 (d, J= 7.8 Hz, 1H), 4.36 29920-428111 2025-018-02

[0420] (q, J= 7.1 Hz, 2H, OCH2), 1.34 (t, J = 7.2 Hz, 3H, CHs);13C NMR (101 MHz, DMSO-de): 3 167.9, 165.5. 162.9, 158.2, 156.3, 151.2, 148.9, 143.1, 140.8, 135.2, 132.0, 131.8, 131.2, 130.6, 130.14, 128.9, 127.8, 126.2, 125.9, 125.8, 125.3, 124.2, 123.0, 121.4, 120.7, 120.6, 118.8, 116.66, 112.2, 111.5, 109.5, 61.6, 14.6; MS (ESI) m z = 657.16 [M+H]+. HPLC purity: 97.84% (1R = Z isomer at 12.50 min and E isomer at 12.99 min). ethyl (Z)-3-(3-((5-(4-methoxy-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoate (20). Red solid (91% yield). TLC: 50% EtOAc in hexane, R / = 0.4; visualized with UV. 'H NMR (400 MHz, DMSO): 3 10.25 (s, 1H, CONH), 8.68 (d, J= 8.97 Hz, 1H), 8.09-8.06 (m, 1H), 8.04-8.02 (m, 2H), 7.97-7.95 (m, 1H), 7.80-7.78 (m, 1H), 7.73 (t, .7= 7.85 Hz, 1H), 7.52-7.51 (m, 1H), 7.49-7.47 (m, 1H), 7.41 (d, .7= 9.15 Hz, 1H), 7.37 (d, J= 3.92 Hz, 1H). 7.31-7.28 (m, 2H). 7.26-7.24 (m, 2H). 6.86-6.85 (m, 1H), 6.72- 6.67 (m, 1H), 4.35 (q, J= 7.71 Hz, 2H, OCHz\ 3.99 (s, 3H, OCH3\ 3.77 (s, 3H, OCH3), 1.33 (t, J= 7. 10 Hz, 3H, C77.0-13C NMR (101 MHz, DMSO-de): 0' 177.5, 167.6, 165.0, 164.1, 163.9, 160.0, 159.5, 157.7, 157.2, 156.6, 155.3, 152.7, 151.4, 151.0, 150.0, 148.0, 142.3, 140.1, 134.8,

[0421] 131.5, 131.3, 130.1, 129.9, 129.5, 129.4, 128.4, 127.9, 127.4, 126.2, 125.9, 125.6, 125.5, 125.3,

[0422] 123.6, 122.6. 122.0, 121.6. 121.2, 120.2. 119.3, 113.3. 112.8, 112.0. 111.9, 109.6. 108.9, 107.7.

[0423] 106.3, 105.5, 105.4, 61.1, 56.3, 55.1, 14.1. ethyl (Z)-3-(3-( (5-(4-methoxy-3-( (3-

[0424] (lrifluoromelhoxy)phenyl)carbamoyl)phenyl)furan-2-yl)melhylene)-2-oxoindolin-l- yl)benzoate (21). Red solid (77% yield). TLC: 50% EtOAc in hexane. R / = 0.5; visualized with UV. 'H NMR (400 MHz, DMSO-de): 3 10.55 (s, 1H, CONEEy 8.66 (d, J= 8.61 Hz, 1H), 8.34- 8.26 (m, 1H), 8.12-8.00 (m, 3H), 7.99-7.94 (m, 1H), 7.80-7.78 (m, 1H), 7.75-7.71 (m, 1H),7.67- 7.63 (m, 1H), 7.52-7.46 (m, 3H), 7.37-7.32 (m, 2H). 7.29-7.21 (m, 2H), 7.11-7.08 (m, 1H), 6.86-6.83 (m, 1H), 4.35 (q, J= 7.02 Hz, 2H, OCH2), 3.94 (s, 3H, OCH3). 1.33 (t. J= 7.03 Hz, 3H, CHs).13C NMR (101 MHz, DMSO-de): 3 177.9, 167.5, 165.0, 164.5, 159.0, 157.6, 157.3,

[0425] 157.2, 157.1, 151.4, 150.1, 148.5, 143.3, 140.6, 134.8, 131.5, 130.5, 130.1, 129.3, 128.8, 128.6,

[0426] 128.4, 128.0, 127.3, 126.7, 126.2, 125.9, 125.6, 125.3, 123.6, 121.6, 121.2, 121.1, 120.2, 119.3,

[0427] 118.3, 115.7, 113.6, 112.8. 111.7, 109.6, 108.9, 108.0, 61.1, 56.2. 14.1. ethyl (Z)-3-(3-((5-(3-( (3-methoxyphenyl)carbamoyl)-4-

[0428] (trifluoromethoxy)phenyl)furan-2-yl)methylene)-2-oxoindolin-l-yl)benzoate (22). Red solid (0. 123 g, 50% yield). TLC: 50% EtOAc in hexanes, R / = 0.2; visualized with UV. Isomer data: 'H NMR (400 MHz. DMSO): 5 10.72 (s, 1H), 8.65 (d. J = 7.6 Hz, 1H). 8.30 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 8.7, 2.3 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.86 - 7.80 (m, 1H), 7.80 - 7.72 (m, 2H), 7.61 (d, J = 3.7 Hz, 1H), 7.59 (d, J = 4.2 Hz, 2H), 7.43 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 29920-428111 2025-018-02

[0429] 5.0 Hz, 2H), 7.27 (d, J = 7.5 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.75 (dt, J = 5.5, 3.0 Hz, 1H), 4.36 (q, J = 7.1 Hz. 2H), 3.77 (s, 3H), 1.34 (t, J = 7.1 Hz. 3H).13C NMR (101 MHz, DMSO) 5 167.92, 165.50, 163.19, 160.05, 155.87, 151.59, 145.29, 143.19, 140.38, 135.25, 132.51, 132.05, 131.83, 130.68, 130.27, 130.20, 128.98, 128.73, 127.88, 127.52, 125.78, 125.20, 124.28, 123.38, 123.17, 121.77, 121.44, 121.17, 120.55, 112.47, 112.40. 109.95, 109.55, 106.02, 61.60, 55.54, 14.60; MS (ESI) m / z = 669.18 [M+H]+. Another synthesis was performed to give the product as a red solid (80% yield). TLC: 50% EtOAc in hexane, R / = 0.2; visualized with UV. Isomer data: 'H NMR (400 MHz, DMSO-de): <5 10.72 (s, 1H, CONH). 8.65 (d, J= 7.6 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 8.7, 2.3 Hz, 1H), 8.09-8.01 (m, 2H), 7.86-7.80 (m, 1H), 7.80 - 7.72 (m, 2H), 7.61 (d, J= 3.7 Hz, 1H), 7.59 (d, J= 4.2 Hz, 2H), 7.43 (d, J= 2.3 Hz, 1H). 7.31 (d, J= 5.0 Hz, 2H). 7.27 (d, J= 7.5 Hz, 1H), 7.21 (t, J= 7.6 Hz, 1H), 6.85 (d, J= 7.8 Hz, 1H), 6.75 (m, 1H), 4.36 (q, J= 7.1 Hz, 2H, OCH2 3.77 (s, 3H, OCHs 1.34 (t, J= 7.1 Hz, 3H, CHs).13C NMR (101 MHz, DMSO-de): <5 167.9,

[0430] 165.5, 163.1, 160.0, 155.8, 151.5, 145.2, 143.1, 140.3, 135.2, 132.5, 132.0, 131.8, 130.6, 130.2, 130.2, 128.9, 128.7, 127.8, 127.5, 125.78, 125.2, 124.2, 123.3, 123.1, 121.7, 121.4. 121.1,

[0431] 120.5, 112.4. 112.4, 109.9. 109.5, 106.0, 61.6. 55.5. 14.6.

[0432] Ethyl (Z)-3-( 3-((5-( 4-chloro-3-( ( 3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2- yl)methylene)-2-oxoindolin-l-yl)benzoate 23 (GL-3365): To the solution of (Z)-2-chloro-5-(5- ((1 -(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid 14e (0. 12 g, 0.233 mmol. 1.0 eq.) in dry DMF (5 mL) were added DIPEA (0. 17 mL. 0.355 mmol, 4.0 eq ), EDC.HC1 (0.067 g, 0.350 mmol, 1.5 eq.) and HOBt (0.047 g, 0.350 mmol, 1 .5 eq.) at 0°C and stirred for 10 minutes followed by the addition of 3-methoxy aniline 15a (0.028 g, 0.389 mmol, 1 eq). The resultant reaction mixture was stirred for 16 hours, the reaction mixture poured into ice cold water (30 mL), the formed solid was filtered and dried. Later, purified by column chromatography using 20% EtOAc in di chloromethane to give title compound 23 (0.08 g, 57% yield) as red color solid. TLC: 30% EtOAc:Hexane, R / = 0.5; visualized with UV. 'H NMR (400 MHz, DMSO): 5 13.80 (s, 1H), 10.55 (s, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 2.2 Hz. 1H), 7.88 - 7.81 (m, 2H), 7.77 (d, J= 7.7 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.67 (d, J= 8.4 Hz. 1H), 7.40 (s. 1H), 7.25 - 7.22 (m. 2H), 7.21 - 7.15 (m, 2H), 7.15 - 7.12 (m, 1H), 7.10 - 7.06 (m, 2H), 6.77 (d, J = 7.6 Hz, 1H), 6.69 (dt, J = 5.7, 2.9 Hz, 1H), 4.33 (q, J = 1A Hz, 2H), 3.73 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). Another synthesis was performed to provide compound 23 (0. 112 g, 78% yield) as a red color solid. TLC: 30% EtOAc in Hexane, R / = 0.5; visualized with UV. 'H NMR (400 MHz, DMSO): b 13.80 (s. 1H), 10.55 (s, 1H). 8.06 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.77 (d, J = 7.7 Hz, 1H), 7.74 - 29920-428111 2025-018-02

[0433] 7.69 (m, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7.40 (s, 1H), 7.25 - 7.22 (m, 2H), 7.21 - 7.15 (m. 2H), 7.15 - 7.12 (m, 1H). 7.10 - 7.06 (m, 2H). 6.77 (d, J = 7.6 Hz, 1H), 6.69 (dt, J = 5.7, 2.9 Hz, 1H), 4.33 (q, J= 7.1 Hz, 2H), 3.73 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-melhoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2- yl)methylene)-2-oxomdolin-l-yl)benzoate (40b) To a solution of (Z)-5-(5-((l-(3- (ethoxycarbonyl)phenyl)-2-oxoindolin-3-ylidene)methyl)-lH-pyrrol-2-yl)-2-fluorobenzoic acid 14f (0.2 g, 0.403 mmol, 1 eq) and HATU (0.230 g, 0.604 mmol, 1.5 eq) in DMF (5 mL) was added DIPEA (0.22 mL, 1.209 mmol, 3 eq) at room temperature and stirred for 10 minutes followed by the addition of 3-methoxy aniline 15a (0.049 g, 0.403 mmol, 1 eq). The resultant reaction mixture was stirred for 16 hours, the reaction mixture was poured into ice cold water (30 mL), the formed solid was filtered and dried. Later, purified by column chromatography using 5% EtOAc in di chloromethane which give title compound 40b (0.122 g, 50% yield) as orange solid. TLC: 30% EtOAc:Hexane, R / = 0.5; visualized with UV. 'H NMR (400 MHz, CDC13): 5 13.91 (s, 1H). 8.50 (d, J = 7.3 Hz, 1H). 8.44 (d, J = 15.4 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 7.21 (dd, J = 14.6, 7.3 Hz, 2H), 7.15 (s, 1H), 6.93 (d, J = 3.8 Hz, 1H), 6.90 - 6.83 (m, 2H), 6.76 (d, J = 8.4 Hz. 1H), 4.44 (q. J = 7.0 Hz. 2H), 3.88 (s. 3H), 1.43 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CDC13) 8 167.69, 165.72, 160.26, 140.16, 138.84, 136.91, 135.04, 132.31, 131.61, 131.44, 129.78, 129.75, 129.30, 129.00, 128.18, 126.91, 126.31, 124.80, 122.82, 122.78, 118.18, 117.26, 117.00, 115.91, 112.65, 110.92, 110.58, 109.28, 106.16, 61.36, 55.38, 14.34; MS (ESI) m / z = 602.21 [M+H]+. ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)-lH- pyrrol-2-yl)methylene)-2-oxoindolin-l-yl)benzoate (40c) 40c was prepared by an abovedescribed procedure by using (Z)-5-(5-((l-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3- ylidene)methyl)-lH-pyrrol-2-yl)-2-fluorobenzoic acid 14f (0.2 g, 0.403 mmol, 1 eq) and 3- (trifluoromethoxy)aniline 15b (0.071 g, 0.403 mmol, 1 eq) as a starting material, orange solid; (0.1 g, 38% yield). TLC: 50% EtOAc:Hexane, R / = 0.5; visualized with UV. 'H NMR (400 MHz, CDCh): 8 13.97 - 13.85 (m, 1H), 8.58 - 8.45 (m. 2H), 8.23 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.93 - 7.85 (m, 1H), 7.82 - 7.74 (m, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.27 - 7.15 (m, 3H), 7.06 (d, J = 8.2 Hz, 1H), 6.96 - 6.90 (m, 1H), 6.86 (td, J = 4.5, 4.1, 2.3 Hz, 2H), 4.44 (qd, J = 7.2, 1.6 Hz, 2H), 1.43 (td, J = 7. 1, 1.7 Hz, 3H); 13C NMR (101 MHz, CDC13) 8 167.69, 29920-428111 2025-018-02

[0434] 165.71, 149.66, 140.17, 139.01, 136.71, 135.01, 132.31, 131.59, 131.49, 130.08, 129.78, 129.55. 129.46, 129.31. 128.95, 128.18. 126.96, 126.29, 124.76, 122.81, 122.79, 121.56, 121.45, 1 18.47, 118.20, 117.29, 117.03, 116.94, 116.02, 1 13.39, 110.59, 109.30, 61.37, 14.33; MS (ESI) m / z = 656.18 [M+H]+.

[0435] Ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2- yl)methylene)-2-oxomdolin-l-yl)benzoate (24): Orange solid (0.191 g, 79% yield). TLC: 30% EtOAc in Hexane, R / = 0.5; visualized with UV. 'H NMR (400 MHz, CDCh): <5 13.91 (s, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.44 (d. J= 15.4 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J= 7.8 Hz, 1H), 7.87 (d, J= 7.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70 (1, J = 7.8 Hz, 1H), 7.63 (d, J= 7.2 Hz, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 7.21 (dd, J = 14.6, 7.3 Hz, 2H), 7.15 (s, 1H), 6.93 (d, J= 3.8 Hz, 1H), 6.90-6.83 (m, 2H), 6.76 (d, J= 8.4 Hz, 1H), 4.44 (q, J= 7.0 Hz, 2H, OCH23.88 (s, 3H, OCH3) 1.43 (t, J= 7.1 Hz, 3H, CH ).1?C NMR (101 MHz, CDCh): 3 167.6, 165.7, 160.2, 140.1, 138.8, 136.9, 135.0, 132.3, 131.6. 131.4, 129.7, 129.7. 129.3, 129.0, 128.1. 126.9, 126.3. 124.8, 122.8. 122.7, 118.1. 117.2, 117.0. 115.9, 112.6. 110.9, 110.5. 109.2, 106.1, 61.3, 55.3, 14.3.

[0436] Ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)-lH- pyrrol-2-yl)methylene)-2-oxoindolin-l-yl)benzoate (25): Orange solid; (0.205 g, 77% yield). TLC: 50% EtOAc in hexane, R = 0.5; visualized with UV. 'H NMR (400 MHz. CDCh): 3 13.97-13.85 (m, 1H), 8.58-8.45 (m, 2H), 8.23 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.93-7.85 (m, 1H), 7.82-7.74 (m, 2H), 7.70 (t, J= 7.8 Hz, 1H), 7.63 (d, J= 7.2 Hz, 1H), 7.56 (d, J= 1.7 Hz, 1H), 7.51 (d, J= 8.3 Hz, 1H), 7.45-7.37 (m, 1H), 7.27-7.15 (m, 3H), 7.06 (d, J = 8.2 Hz. 1H), 6.96-6.90 (m, 1H). 6.86 (t. J = 4.5, 2H). 4.44 (q J = 7.2, 2H, OCHz), 1.43 (t, J = 7.1, 3H, CHs).13C NMR (101 MHz. CDCh): 3 167.6, 165.7. 149.6. 140.1, 139.0. 136.7. 135.0, 132.3, 131.5, 131.4, 130.0, 129.7, 129.5, 129.4, 129.3, 128.9, 128.1, 126.9, 126.2, 124.7, 122.8, 122.7, 121.5, 121.4, 118.4, 118.2, 117.2, 117.0, 116.9, 116.0, 113.3, 110.5, 109.3, 61.3, 14.3. ethyl (Z)-3-(5-fluoro-3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxomdolin-l-yl)benzoate (26). Red solid (0.150 g, 62% yield). TLC: 50% EtOAc in hexanes, R^ = 0.2; visualized with UV. Isomer data: '14 NMR (400 MHz, DMSO): 5 10.59 (s, 1H), 8.40 (dd, J= 9.5, 2.7 Hz, 1H), 8.24 (dd. J= 6.4, 2.4 Hz, 1H), 8.14 (ddd, J= 7.4, 4.6, 2.3 Hz, 1H). 8.09 - 8.01 (m, 2H). 7.81 (dt, J = 8.0. 1.7 Hz, 1H), 7.75 (L J= 7.7 Hz. 1H), 7.65 - 7.57 (m, 3H), 7.54 (d, J = 3.8 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.15 (td, J= 8.8, 2.7 Hz, 1H), 6.85 (dd, J= 8.7, 4.5 Hz, 1H), 6.73 (dt, J= 5.7, 2.6 Hz, 1H), 4.36 29920-428111 2025-018-02

[0437] (q, J = 7.1 Hz, 2H), 3.76 (s. 3H), 1.34 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, DMSO): 5 167.83. 165.49, 162.48. 159.97, 157.63. 157.02, 151.08, 140.37, 135.22, 131.98, 131.85,

[0438] 130.72, 130.09, 129.02, 127.83, 126.86, 126.40, 126.22, 126.10, 121.85, 1 16.38, 116.15,

[0439] 112.56, 109.94, 106.07, 61.61, 55.51, 14.61; MS (ESI) m / z = 621.18 [M+H]+. Another synthesis was performed to give the product as a red solid (84% yield). TLC: 50% EtOAc in hexane, R / = 0.2; visualized with UV. Isomer data: 'H NMR (400 MHz. DMSO-de): <5 10.59 (s, 1H, COW), 8.40 (dd, J= 9.5, 2.7 Hz, 1H). 8.24 (dd. J= 6.4. 2.4 Hz. 1H). 8.14 (dd, J= 7.4. 4.6, 2.3 Hz, 1H), 8.09-8.01 (m, 2H), 7.81 (dd, J = 8.0, 1.7 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.65-7.57 (m, 3H), 7.54 (d, J= 3.8 Hz, 1H), 7.43 (d, J= 2.6 Hz, 1H), 7.32-7.25 (m, 2H), 7.15 (s, 1H), 6.85 (dd, J = 8.7, 4.5 Hz, 1H), 6.73 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H, OCH2\ 3.76 (s, 3H.OCH}). 1.34 (t, J = 7.1 Hz, 3H. CHS).13C NMR (101 MHz. DMSO-de): <5 167.8, 165.4,

[0440] 162.4, 159.9, 157.6, 157.0, 151.0, 140.3, 135.2, 131.9, 131.8, 130.7, 130.0, 129.0, 127.8, 126.8,

[0441] 126.4, 126.2, 126.10, 121.8, 116.3, 116.1, 112.5, 109.9, 106.0, 61.6, 55.5, 14.6. ethyl (Z)-3-(3-((5-( 4-fluoro-3-(( 3-methoxyphenyl)carbamoyl)phenyl) furan-2- yl)methylene)-2-oxo-5-(trifluoromethoxy)indolin-l-yl)benzoate (27). Red solid (0.122 g. 50% yield). TLC: 50% EtOAc in hexanes, R / = 0.2; visualized with UV. Isomer data: 'H NMR (400 MHz, CDC13): 8.62 (d, J = 2.4 Hz, 1H), 8.59 (dd, J = 7.3, 2.4 Hz, 1H), 8.51 (d, J = 15.3 Hz, 1H), 8.23 - 8.11 (m, 3H), 7.72 - 7.63 (m, 3H), 7.52 (d, J= 2.3 Hz, 1H), 7.42 - 7.30 (m, 2H), 7.18 (dt, J= 10.2, 4.6 Hz, 3H). 7.08 (d, J= 3.7 Hz, 1H), 6.88 (d, J= 8.6 Hz, 1H), 6.78 (dd, J= 8.3, 2.5 Hz, 1H). 4.44 (q, J= 7. 1 Hz, 2H). 3.89 (s. 3H), 1.43 (t, J= 7. 1 Hz, 3H); MS (ESI) m z = 687.18 [M+H]+. Another synthesis was performed to give the product as a red solid (89% yield). TLC: 50% EtOAc in hexane, R / = 0.2; visualized with UV. Isomer data: 'H NMR (400 MHz, CDCh): <5 8.62 (d, J= 2.4 Hz, 1H), 8.59 (dd, J= 7.3, 2.4 Hz, 1H), 8.51 (d. J= 15.3 Hz, 1H), 8.23-8.11 (m. 3H), 7.72-7.63 (m, 3H). 7.52 (d, J= 2.3 Hz, 1H). 7.42-7.30 (m, 2H), 7.18 (m, 3H), 7.08 (d, J= 3.7 Hz, 1H), 6.88 (d, J= 8.6 Hz, 1H), 6.78 (dd, J= 8.3, 2.5 Hz, 1H), 4.44 (q, J= 7.1 Hz, 2H, OCHz), 3.89 (s, 3}3.,OCHS), 1.43 (t, J= 7.1 Hz, 3H, CH3).

[0442] (Z)-5-(5-((l-(3-cyanophenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2-fluoro-N- (3-methoxyphenyl)benzamide (28). Red solid (0.2 g, 54% yield). TLC: 50% EtOAc in hexanes, Rf = 0.3; visualized with UV. Isomer data: ‘H NMR (400 MHz. DMSO): 5 10.61 (s, 1H), 8.66 (d, J = 7.7 Hz, 1H), 8.29 (dd, J = 6.4, 2.3 Hz, 1H), 8.21 - 8.11 (m, 1H), 8.07 (t, J = 1.8 Hz, 1H), 7.96 (d, J= 7.7 Hz, 1H), 7.90 (d, J= 7.9 Hz, 1H), 7.81 (t, J= 7.9 Hz, 1H), 7.62 (t, J= 9.2 Hz, 1H), 7.58 (d, J = 2.7 Hz, 2H), 7.52 (d, J = 3.7 Hz, 1H), 7.45 (d. J = 2.6 Hz, 1H). 7.37 - 7.28 (m, 3H), 7.23 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.78 - 6.72 (m, 1H), 3.78 (s, 3H).13C NMR (101 MHZ, DMSO) 8 167.87, 162.60, 160.04, 156.51, 151.14, 142.68, 140.38, 29920-428111 2025-018-02

[0443] 135.74, 132.42, 132.14, 131.45, 131.01, 130.20, 130.17, 128.75, 128.67, 126.47, 126.31,

[0444] 126.16. 126.13, 125.53. 124.18, 123.24. 121.48, 120.78, 120.47, 118.57, 118.30, 118.07,

[0445] 1 13.04, 112.54, 111.47, 109.99, 109.73, 106.07, 55.54; MS (ESI) m / z = 556.17 [M+H]+.

[0446] Another synthesis was performed to give the product as a red solid (84% yield). TLC: 50%

[0447] EtOAc in hexane, R / = 0.3; visualized with UV. Isomer data: MHz, DMSO-do): 3 10.61 (s, 1H, CONH), 8.66 (d, J= 7.7 Hz, 1H), 8.29 (dd, J= 6.4, 2.3 Hz, 1H), 8.21-8.11 (m, 1H), 8.07 (t, J= 1.8 Hz, 1H), 7.96 (d, J= 7.7 Hz, 1H). 7.90 (d, J= 7.9 Hz, 1H). 7.81 (t. J= 7.9 Hz, 1H), 7.62 (t, J= 9.2 Hz, 1H), 7.58 (d, J= 2.7 Hz, 2H), 7.52 (d, J= 3.7 Hz, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.37-7.28 (m, 3H), 7.23 (t, J= 7.6 Hz, 1H), 6.93 (d, J= 7.9 Hz, 1H), 6.78-6.72 (m, 1H), 3.78 (s, 3H, OCH3).I3C NMR (101 MHz, DMSO-de): <5 167.8, 162.6, 160.0, 156.5,

[0448] 151.1, 142.6. 140.3, 135.7. 132.4, 132.1. 131.4, 131.0. 130.2, 130.1, 128.7, 128.6, 126.4, 126.3,

[0449] 126.1, 126.1, 125.5, 124.1, 123.2, 121.4, 120.7, 120.4, 118.5, 118.30, 118.0, 113.0, 112.5,

[0450] 111.4, 109.9, 109.7, 106.0, 55.5.

[0451] (Z)-5-(5-((l-(3-cyanophenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2-fluoro-N- (3-(trifluoromethoxy)phenyl)benzamide (29). Red solid (0.230 g, 56% yield). TLC: 50% EtOAc in hexanes. R^= 0.3; visualized with UV. Isomer data: 'H NMR (400 MHz, DMSO): 5 10.93 (s, 1H), 8.65 (d, J= 7.7 Hz, 1H), 8.31 (dt, J = 4.8, 2.3 Hz, 1H), 8.17 (ddd, J = 7.1, 4.8, 2.4 Hz, 1H), 8.07 (s, 1H), 7.99 - 7.88 (m, 3H), 7.80 (td, J= 8.0, 2.1 Hz, 1H), 7.74 (d, J= 8.3 Hz. 1H), 7.64 (t, J= 8.9 Hz, 1H), 7.57 (d, J= 2.3 Hz, 2H), 7.53 (dd, J= 10.7, 2.7 Hz, 2H), 7.29 (t, J= 7.7 Hz, 1H). 7.22 (d, J= 7.6 Hz, 1H). 7.17 (t. J= 6.6 Hz. 1H), 6.93 (d. J= 7.9 Hz. 1H).13C NMR (101 MHz, DMSO): 5 167.86, 162.98, 160.82, 158.30, 156.40, 151.17, 149.00, 142.67, 140.82, 135.74, 132.39, 132.12, 131.44, 131.19, 130.98, 130.13, 129.01, 128.92,

[0452] 126.23, 125.96, 125.81, 125.49, 124.20, 123.20, 121.48, 120.76, 120.50, 119.32, 118.90,

[0453] 118.56. 118.36, 118.13. 116.65, 113.04, 112.31, 111.52, 109.72; MS (ESI) m / z = 610.14

[0454] [M+H]+. Another synthesis was performed to give the product as a red solid (86% yield). TLC:

[0455] 50% EtOAc in hexane, Rf= 0.3; visualized with UV. Isomer data: 'HNMR (400 MHz, DMSO- de): 3 10.93 (s, 1H, CONHy 8.65 (d, J = 7.7 Hz, 1H), 8.31 (s, 1H), 8.17 (dd, J = 7.1, 4.8, 2.4 Hz. 1H), 8.07 (s, 1H), 7.99-7.88 (m, 3H), 7.80 (m, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.64 (t, J = 8.9 Hz. 1H), 7.57 (d. J= 2.3 Hz. 2H), 7.53 (dd, J= 10.7, 2.7 Hz, 2H). 7.29 (t. J = 7.7 Hz. 1H). 7.22 (d, J= 7.6 Hz, 1H), 7. 17 (t, J= 6.6 Hz, 1H), 6.93 (d, J= 7.9 Hz, 1H).13C NMR (101 MHz, DMSO-de): 3 167.8, 162.9, 160.8, 158.3, 156.4, 151.1, 149.0, 142.6, 140.8, 135.7, 132.3, 132.1,

[0456] 131.4, 131.1, 130.9, 130.13, 129.0, 128.9, 126.2, 125.9, 125.8, 125.4, 124.2, 123.2. 121.4, 120.7, 120.5. 119.3, 118.9. 118.5, 118.3, 118.1, 116.6, 113.0, 112.3, 111.5. 109.7. 29920-428111 2025-018-02

[0457] (Z)-3-(3-((5-(4-chloro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2-yl)methylene)- 2-oxoindolin-l-yl)benzoic acid (30). To a stirred suspension of ester 16 (0.1 g, 0.16 mmol, 1 eq) in THF:H2O (2: 1, 3 mL) was added LiOH (38 mg, 1.61 mmol, 1 eq). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to get solid residue. The residue w as diluted with water and acidified with 20% citric acid solution to adjust pH 2-3 then extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The product was crystallized in EtOH, and solid was collected, washed with EtOAc and then hot solutions of 20-30% EtOAc in hexanes to give compound 30 (60 mg, 63% yield) as ayellow7solid. TLC: 10% MeOH in DCM, R / = 0.3; visualized with UV. Isomer data: ’H NMR (400 MHz, DMSO): 5 10.72 (s, 1H), 8.63 (d, J = 7.7 Hz. 1H), 8.19 (s, 1H), 8.12 - 7.97 (m, 4H), 7.82 (dd, J = 8.5,

[0458] 2.4 Hz, 1H), 7.74 (dt, J= 14.4, 7.4 Hz, 3H), 7.58 (d, J= 3.2 Hz, 3H), 7.46 (s, 1H), 7.29 (dd, J = 18.3, 8.5 Hz, 4H), 7.16 (t, J= 7.9 Hz, 1H), 6.86 (d, J= 8.0 Hz, 1H), 6.75 (d, J= 7.4 Hz, 1H), 3.77 (d, J = 2.4 Hz, 3H).1?C NMR (101 MHz, DMSO): 5 167.98, 167.05. 164.81, 160.03, 156.16. 151.40, 143.14. 140.39, 138.04. 135.06, 132.79, 131.36, 131.25, 130.98, 130.24, 130.02, 129.94, 129.04, 128.42, 127.84, 126.64, 124.91, 124.80, 124.24, 122.94, 121.48, 121.13, 120.51, 112.42, 111.84, 109.86, 109.40, 105.91, 82.45, 62.04; MS (ESI) m / z = 589.12 [M-H]'. Another synthesis was performed to give compound 30 (78 mg, 82% yield) as a yellow7solid. TLC: 10% MeOH in DCM. R / = 0.3; visualized with UV. Isomer data: ’H NMR (400 MHz, DMSO-de): 8 10.72 (s, 1H. CONH). 8.63 (d. J = 7.7 Hz, 1H), 8.19 (s, 1H), 8.12-7.97 (m, 4H), 7.82 (dd, .7 = 8.5, 2.4 Hz, 1H), 7.74 (s, 3H), 7.58 (d, .7 = 3.2 Hz, 3H), 7.46 (s, 1H), 7.29 (dd, J= 18.3, 8.5 Hz, 4H), 7.16 (t, J= 7.9 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.75 (d, J =

[0459] 7.4 Hz, 1H), 3.77 (s, 3H, OCHs).1?C NMR(101 MHz, DMSO-de): <5167.9, 167.0, 164.8, 160.0, 156.1, 151.4. 143.1, 140.3, 138.0, 135.0, 132.7, 131.3, 131.2, 130.9, 130.2, 130.0, 129.9, 129.0, 128.4, 127.8, 126.6, 124.9, 124.8, 124.2, 122.9, 121.4, 121.1, 120.5, 112.4, 11 1.8, 109.8, 109.4, 105.9, 82.4, 62.0. HPLC purity: 97.15% ( / R = Z isomer at 9.54 min and E isomer at 10.20 min).

[0460] Target compounds 31-35, 37-38, lOf-g, and 40 w ere synthesized by an above synthetic procedure described for the preparation of compound 30 using appropriate starting materials. Each compound was crystallized in EtOH, and solid was collected, washed with EtOAc and then hot solutions of 20-30% EtOAc in hexanes to afford desired final compound. If necessary, the products w ere purified using 2-5% MeOH in DCM (1% AcOH in DCM).

[0461] (Z)-3-(3-((5-(4-chloro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 31 (GL-3389). Orange solid (45 mg, 47% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. H NMR (400 MHz, DMSO): 5 29920-428111 2025-018-02

[0462] 11.05 (s, 1H), 8.62 (d, J= 7.8 Hz, 1H), 8.23 (d, J= 2.4 Hz, 1H), 8.09 (d, J= 8.5 Hz, 1H), 8.03 (d, J = 7.3 Hz, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.84 (d, J = 8.4 Hz. 1H), 7.80 - 7.68 (m. 3H), 7.57 (d, J= 3.2 Hz, 3H), 7.54 (d, J= 8.2 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.16 (q, J= 8.8, 6. 1 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H).13C NMR (101 MHz, DMSO) 5 167.91, 167.09, 165.15, 156.07, 151.44, 149.02, 143.22, 140.85, 137.63, 135.09, 132.81, 131.63, 131.54, 131.25, 130.84. 130.50, 130.23. 129.14, 128.50, 127.93, 126.89, 125.19, 125.09, 124.22, 122.98, 121.45. 121.12, 120.57, 118.70. 116.65. 112.23, 112.09, 109.62; MS (ESI) m / z = 643.09 [M- H]’. Another synthesis was performed to give the product as an orange solid (91% yield). TLC: 10% MeOH in DCM, R = 0.4; visualized with UV. ’H NMR (400 MHz, DMSO-de): 5 11.05 (s, 1H, CONH). 8.62 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 8.5 Hz. 1H), 8.03 (d, J = 7.3 Hz, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.84 (d. J = 8.4 Hz, 1H). 7.80-7.68 (m, 3H), 7.57 (d, J = 3.2 Hz, 3H), 7.54 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.16 (q, J = 8.8, 6.1 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H).13C NMR (101 MHz, DMSO-de): 167.9, 167.0,

[0463] 165.1, 156.0, 151.4, 149.0, 143.2, 140.8, 137.6, 135.0, 132.8, 131.6, 131.5, 131.2, 130.8, 130.5,

[0464] 130.2, 129.1, 128.5, 127.9, 126.8, 125.1. 125.0, 124.2, 122.98, 121.4, 121.1, 120.5. 118.7,

[0465] 116.6, 112.2. 112.0, 109.6. HPLC purity: 95.91% (ZR = Z isomer at 10.63 min and E isomer at 1 1.06 min).

[0466] (Z)-3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2-yl)methylene)- 2-oxoindolin-l -yl)benzoic acid 32 (GL-3649). Red solid (50 mg. 26% yield). TLC: 10% MeOH in DCM. R = 0.2; visualized with UV. Another synthesis was performed to give the product as a yellow solid (76% yield). TLC: 10% MeOH in DCM, R = 0.2; visualized with UV. Isomer data: 'H NMR (400 MHz, DMSO- de): 8 13.2 (brs, 1H, COOH), 10.63 (s, 1H, CONH), 8.64 (d, J = 7.37 Hz, 1H), 8.27 (brs, 1H), 8.14 ( brs, 1H), 8.03-8.00 (m, 2H), 7.75-7.71 (m, 2H), 7.61-7.47 (m, 5H). 7.32-7.29 (m, 3H), 7.21-7.19 (m, 1H), 6.85 (d. J = 7.37 Hz, 1H), 6.73 (d, J= 7.37 Hz, 1H), 3.76 (s, 3H, OCH ).13C NMR (101 MHz, DMSO- de): 8 167.5, 166.6, 162.1, 159.9, 159.5, 157.8, 155.9, 150.7, 142.6, 139.9, 139.3, 133.5, 134.6, 132.4, 131.1, 130.0, 129.7,

[0467] 128.6, 128.2, 127.4, 126.0, 125.7, 124.9, 123.7, 122.6, 121.0, 120.2, 117.8, 112.0, 111.0, 109.5, 109.1, 105.5, 55.0.19F NMR (376 MHZ. DMSO-de): 8 -113.1 (s, IF).

[0468] (Z)-3-(3-((5-(4-fluoro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 33 (GL-3618). yellow solid (10 mg, 52% yield). TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. Another synthesis was performed to give the product as a yellow solid (78% yield). TLC: 10% MeOH in DCM, R = 0.3; visualized with UV. Isomer data: 'H NMR (400 MHz. DMSO- de): 8 13.24 (brs, 1H. COOH). 10.92 (s, 1H, CONH), 8.65 (d, J = 9.03 Hz, 1H), 8.31 (d, J = 5.75 Hz, 1H), 8.17 (brs, 1H), 8.03-8.00 29920-428111 2025-018-02

[0469] (m, 2H), 7.91 (s, 1H), 7.86-7.72 (m, 3H), 7.63 (t, J= 9.85 Hz, 1H), 7.56-7.51 (m, 4H), 7.28 (t, J= 7.39 Hz, 1H), 7.20-7.14 (m, 2H), 6.86 (d, J= 8.21 Hz, 1H).13C NMR (101 MHz, DMSO- de): 3 167.4, 166.6, 162.5, 155.8, 150.7, 148.5, 142.6, 140.3, 134.6, 131.1, 130.7, 130.0, 129.6,

[0470] 128.6, 128.5, 127.4, 125.7, 125.5, 124.8, 123.7, 122.5, 121.0, 120.3, 120.1, 118.4, 117.6, 116.1, 111.8, 111.0, 109.0, 61.1.19F NMR (376 MHz, DMSO- de): <5 -56.67 (s, 3F), -113.1 (s, IF). LCMS (ESI) m / z = 627.40 [M-H] ". HPLC purity: 99.9% (fa = Z isomer at 10.80 min and E isomer at 11.28 min).

[0471] (Z)-3-(3-((5-(4-Methoxy-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 34 (GL-3395): Yellow solid (87% yield). TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO- de): 3 10.29 (s, 1H, CONH). 8.68 (d, J = 8. 14 Hz, 1H), 8.26 (d, J = 3.77 Hz, 1H), 8.09 (dd, J = 8.28, 2.26 Hz, 1H), 8.027.98 (m, 2H), 7.72-7.68 (m, 2H), 7.54 (s, 2H), 7.48 (s, 1H), 7.43-7.39 (m, 2H), 7.34-7.23 (m, 4H), 6.85 (d, J= 7.53 Hz, 1H), 6.70 (dd, J= 8.23 Hz, 1.75 Hz, 1H), 3.98 (s, 3H, OCHs). 3.76 (s, 3H, OCHs).13C NMR (101 MHz, DMSO-de): ri 167.5, 166.9, 163.9, 159.5, 157.2, 150.1, 142.5, 140.1, 134.6, 133.6, 130.6, 129.7, 129.6, 129.4, 128.5, 127.9, 127.4, 125.9,

[0472] 125.6, 125.2, 123.6, 122.5, 121.6, 120.1, 1 19.3, 113.2, 112.2, 109.5, 109.1, 109.0, 105.5, 56.3, 55.0. LCMS (ESI) m / z = 585.15 [M-H]’. HPLC purity: 98.18% (fa = Z isomer at 10.35 min and E isomer at 10.77 min).

[0473] (Z)-3-(3-((5-(4-methoxy-3-((3-(lrifluoromelhoxy)phenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 35 (GL-3392): Yellow solid (75% yield). TLC: 10% MeOH in DCM, R / = 0.3; visualized with UV. ‘H NMR (400 MHz, DMSO-de): ri 13.3 (brs, 1H, COOHy 10.60 (s, 1H, CONH / ), 8.67 (d, J= 6.51 Hz, 1H), 8.25 (d, J= 3.6 Hz, 1H), 8.11 (dd, J= 6.31 Hz, 2.81 Hz, 1H), 8.03-8.02 (m, 1H), 8.01-7.99 (m, 2H), 7.97 (brs, 1H), 7.77 - 7.75 (m, 1H). 7.73-7.69 (m, 1H), 7.54-7.53 (m, 2H), 7.50 (d, J = 7.83 Hz, 1H), 7.44 (d, J = 8.70 Hz, 1H), 7.40 (d, J = 4.06 Hz, 1H), 7.31-7.27 (m, 1H), 7.25-7.23 (m, 1H), 7.13-7.11 (m, 1H), 6.86 (d, J= 6.55 Hz, 1H). 3.98 (s, 3H, OCHs).13C NMR (101 MHz, DMSO-de): 3 167.5,

[0474] 166.6, 164.5, 157.2, 150.1, 148.5, 142.4, 140.6, 134.7, 131.1, 130.6, 130.0, 129.4, 128.6, 128.0, 127.4, 125.8, 125.6, 125.3, 123.6, 123.5, 122.5, 121.6, 121.2, 119.3, 118.3, 115.7, 113.2, 111.7,

[0475] 109.6, 109.0.56.3.19F NMR (376 MHz, DMSO-de): 3 -56.63 (s.3F). LCMS (ESI) m / z = 639.40 [M-H]’. HPLC purity: 99.21% (fa = Z isomer at 11.33 min and E isomer at 1 1.70 min).

[0476] Sodium (Z)-3-(3-((5-(4-methoxy-3-((3-

[0477] (trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2-oxoindolin-l- yl)benzoate 36 (GL-3604): To a solution of (Z)-3-(3-((5-(4-methoxy-3-((3-

[0478] (trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2-oxoindolin-l- 29920-428111 2025-018-02 yl)benzoic acid 35 (60 mg, 0.091 mmol, 1 eq) in THF (3 mL) was added 6N NaOH solution (2 mL). The resultant mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give solid residue. The residue was triturated with cold MeOH and filtered, washed with cold water to afford target product 36 as a sodium salt. Brown solid (50 mg, 80% yield). TLC : 10% MeOH in DCM, R / = 0.1 ; visualized with UV. ' H NMR (400 MHz, DMSO-cL): b 10.61 (s. 1H,CCW77), 8.66 (d, J = 7.80 Hz, 1H), 8.25 (d, J= 2.46 Hz, 1H), 8.10 (d, J = 10.35 Hz. 1H), 7.97 (brs. 1H), 7.94-7.92 (m. 1H), 7.87 (brs. 1H), 7.72 (d. J= 7.36 Hz. 1H), 7.53-7.51 (m, 1H), 7.50 (s, 1H), 7.48-7.42 (m, 3H), 7.38-7.37 (m, 2H), 7.27 (t, J = 7.88 Hz, 1H), 7.20 (t, J = 7.64 Hz, 1H), 7.11 (d, J = 7.42 Hz, 1H), 6.77 (d, J = 7.65 Hz, 1H), 3.98 (s, 3H, OCHs).13C NMR (101 MHz, DMSO-Je): b 166.4, 157.0, 150.2, 143.1, 140.6, 130.5, 129.4, 128.3. 127.2, 125.8, 125.6, 121.0, 120.0,119.7. 118.4, 111.7. 109.5, 109.1, 56.3. HPLC purity: 94.87% (fa = Z isomer at 11.35 min and E isomer at 11.71 min).

[0479] (Z)-3-(3-((5-(3-((3-methoxyphenyl)carbamoyl)-4-(trifluoromethoxy)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 37 (GL-3421). yellow' solid (70 mg, 73% yield). TLC: 10% MeOH in DCM. R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO): 5 13.29 (s, 1H), 10.72 (s, 1H), 8.68 (dd, J = 22.3, 7.6 Hz, 1H), 8.29 (dd, J = 8.1, 2.3 Hz, 1H),

[0480] 8.20 (dd, J= 8.7, 2.3 Hz, 1H), 8.06 - 7.99 (m, 2H), 7.75 (dt, J= 15.4, 7.6 Hz, 2H), 7.64 - 7.54 (m, 2H), 7.47 (d, J = 16.8 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.29 (dq, J= 14.5, 7.0, 6.2 Hz, 3H),

[0481] 7.21 (t, J = 7.5 Hz. 1H), 6.87 (t, J= 6.9 Hz. 1H), 6.74 (td, J= 10.0, 8.5, 4.9 Hz, 1H), 4.00 (s, 1H), 3.77 (d, J= 2.1 Hz, 3H).13C NMR (101 MHz, DMSO): 6 167.91, 167.26, 163.19, 160.05, 155.86, 151.61, 145.29, 143.26, 140.38, 135.04, 132.52, 131.40, 130.40, 130.28, 130.20, 129.13, 128.74, 127.92, 127.51, 125.78, 125.18, 124.28, 123.38, 123.13, 121.77, 121.42, 121.22, 120.52, 112.48, 112.39, 109.96, 109.58, 106.01, 55.54; MS (ESI) m / z = 639.14[M-H]’ . Another synthesis was performed to give the product as a yellow solid (81% yield). TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO-de): b 13.29 (s, 1H, COOH). 10.72 (s, 1H, CONH). 8.68 (dd, J = 22.3, 7.6 Hz, 1H), 8.29 (dd, J = 8.1, 2.3 Hz, 1H), 8.20 (dd, J = 8.7, 2.3 Hz, 1H), 8.06-7.99 (m, 2H), 7.75 (s, 2H), 7.64-7.54 (m, 2H), 7.47 (d, J = 16.8 Hz. 1H), 7.44-7.39 (m, 1H). 7.29 (s, 3H), 7.21 (t, J = 7.5 Hz. 1H), 6.87 (t, J = 6.9 Hz, 1H). 6.74 (s, 1H), 3.77 (s3H, OCH3).13C NMR (101 MHz, DMSO-de): b 167.9.

[0482] 167.2, 163.1, 160.0, 155.8, 151.6, 145.2, 143.2, 140.3, 135.0, 132.5, 131.4, 130.4, 130.2, 130.2, 129.1, 128.7, 127.9, 127.5, 125.7, 125.1, 124.2, 123.3, 123.1, 121.7, 121.4, 121.2, 120.5, 112.4,

[0483] 112.3, 109.9, 109.5, 106.0, 55.5; LCMS (ESI) m / z = 639.50 [M-H]". HPLC purity: 99.7% (fa = Z isomer at 9.98 min and E isomer at 10.32 min). 29920-428111 2025-018-02

[0484] (Z)-3-(3-((5-(4-Chloro-3-((3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 38 (GL-3366): To a solution of ethyl (Z)-3-(3- ((5-(4-chloro-3-((3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2-yl)methylene)-2- oxoindolin-l-yl)benzoate 23 (0.15 g, 0.242 mmol, 1.0 eq.) in THF: water (4 mL 1 :1) was added LiOH (0.017 g, 0.727 mmol, 3.0 eq) at room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and acidified with citric acid solution to adjust the pH 3-4, the formed solid was filtered over Buchner funnel, collected and dried under reduced pressure to give product 38 (0.13 g, 92% yield) as red color solid. TLC: 10% MeOH DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO): 5 13.83 (s, 1H), 10.58 (s, 1H), 8.02 (m. 4H), 7.83 (t, J = 7.8 Hz, 2H), 7.77 - 7.64 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H), 7.29 - 7.05 (m. 6H), 6.80 (q. J = 7.8 Hz. 1H), 6.71 (s. 2H), 3.76 (s. 3H).13C NMR (101 MHz, DMSO) 5 167.52, 167.13, 164.97, 160.01, 140.47, 140.29, 138.27, 136.27, 135.08, 133.34, 132.04, 131.83, 131.24, 130.56, 130.17, 130.08, 129.48, 129.38, 128.31, 127.67, 127.24, 125.99, 125.24, 124.84, 123.46, 123.21, 119.35, 116.45, 112.38, 111.84, 109.88, 109.45. 105.87, 55.52. Another synthesis was performed to give the product as a red solid (0.13 g, 91% yield). TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO-de): 3 13.83 (s, 1H, ), 10.58 (s, 1H, CONH). 8.02 (s, 4H), 7.83 (t, J = 7.8 Hz, 2H), 7.77-7.64 (m, 4H), 7.42 (d, J= 8.4 Hz, 2H), 7.29-7.05 (m, 6H), 6.80 (q, J= 7.8 Hz, 1H), 6.71 (s, 2H), 3.76 (s, 3H, OCH3).13C NMR (101 MHz, DMSO-de): 3 167.5, 167.1, 164.9, 160.0, 140.4, 140.2. 138.2, 136.2. 135.0, 133.3. 132.0, 131.8. 131.2, 130.5. 130.1, 130.0, 129.4, 129.3, 128.3, 127.6, 127.2, 125.9, 125.2, 124.8, 123.4, 123.2, 1 19.3, 1 16.4, 1 12.3, 1 1 1.8, 109.8, 109.4, 105.8, 55.5.

[0485] (Z)-3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid (41b). 41b was prepared by an above-described procedure for 38 by using ethyl (Z)-3-(3-((5-(4-fluoro-3-((3-methoxyphenyl) carbamoyl)phenyl)-lH-pyrrol-2-yl) methylene)-2-oxoindolin-l-yl)benzoate 40b (100 mg, 0.166 mmol. 1 eq) as a starting material, yellow solid; (0.08 g, 84% yield). TLC: 10% MeOH DCM, R / = 0.3; visualized with UV. ‘H NMR (400 MHz, DMSO): 5 13.93 (s, 1H), 10.21 (s, 1H), 8.02 - 7.89 (m, 4H), 7.81 (q, J = 9.4, 7.4 Hz, 2H), 7.56 - 7.41 (m, 4H), 7.36 (d, J = 8.8 Hz, 1H), 7.34 - 7. 12 (m, 5H), 7.07 (d, J = 5.3 Hz, 1H), 6.98 (d, J = 4.2 Hz, 1H), 6.78 - 6.64 (m, 2H), 3.76 (s, 3H).13C NMR (101 MHz. DMSO) 5 168.05. 164.39, 160.04, 157.73, 157.70, 150.56, 142.95, 140.58, 130.39, 130.06, 129.94, 129.06, 128.40, 127.91, 126.48, 29920-428111 2025-018-02

[0486] 126.13, 125.71, 124.13, 123.04, 122.14, 121.65, 120.67, 119.87, 113.73, 112.59, 110.04, 109.63. 109.48, 106.10, 56.84. 55.53; MS (ESI) m / z = 572.17 [M+H]+.

[0487] (Z)-3-(5-fluoro-3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid (lOf). yellow solid (65 mg, 68% yield). TLC: 10% MeOH in DCM, R = 0.2; visualized with UV. 'H NMR (400 MHz. DMSO): 5 10.27 (s, 1H), 8.42 (dd, .7 = 9.8, 2.6 Hz, 1H), 8.15 (d, .7 = 2.4 Hz, 1H), 8.08 (d, .7 = 8.7 Hz, 1H), 8.06 - 7.97 (m, 2H), 7.75 (dt, J = 15.5, 8.0 Hz, 2H), 7.61 (d, J = 3.2 Hz, 2H), 7.50 - 7.34 (m, 3H), 7.26 (dd, J= 13.6, 5.7 Hz, 2H), 7.16 (dd, J= 10.3, 7.6 Hz, 1H), 6.86 (dd, J= 8.7, 4.4 Hz. 1H), 6.70 (d, J= 7.7 Hz. 1H), 3.97 (s, 3H); 13C NMR (101 MHz. DMSO) 5 167.90, 167.07, 164.50,

[0488] 159.97, 158.36, 157.71, 157.64, 150.44, 140.66, 139.12, 135.15, 132.75, 131.54, 130.50,

[0489] 129.98, 129.11, 127.83, 127.73, 127.36, 126.86, 126.10, 122.86, 122.77, 121.94, 121.86, 119.18, 113.37, 112.48, 110.38, 109.52, 105.96, 56.78, 55.49; MS (ESI) m / z = 591.14 [M-H]’.

[0490] (Z)-3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2-yl)methylene)- 2-oxo-5-(trifluoromethoxy)indolin-l-yl)benzoic acid (10g). yellow solid (75 mg, 78% yield). TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO): 5 13.27 (s, 1H), 10.27 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 8.12 - 7.99 (m, 3H), 7.80 (d, J = 7.9 Hz, 1H), 7.74 (t, J= 7.7 Hz, 1H), 7.65 (d, J= 2.0 Hz. 2H), 7.47 (dd, J = 12.0, 3.3 Hz, 2H), 7.35 (d, J= 8.7 Hz, 1H), 7.31 - 7.22 (m, 3H), 6.94 (d, J= 8.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 3.97 (s, 3H).13C NMR (101 MHz, DMSO): 8 167.96, 167.05, 164.35, 159.97, 158.61, 157.80, 150.48, 144.08, 141.85, 140.74, 134.97, 132.92, 131.70, 130.53, 129.91, 129.33, 128.07, 127.53, 127.35, 126.48, 122.88, 122.84, 122.24, 121.95, 119.49, 118.60. 117.22, 112.84, 112.39, 110.61, 110.28, 109.49, 105.88. 56.70, 55.51. 55.48; MS (ESI) m / z = 657.13 |M-H]’.

[0491] (Z)-3-( 3-((5-( 4-methoxy-3-( 3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 39 (GL-3442): To a stirred suspension of ester 25 (0.1 g, 0.16 mmol, 1 eq) in MeOH:THF:H2O (2:2: 1. 5 mL) was added LiOH (40 mg, 1.66 mmol, lo eq). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to get solid residue. The residue was diluted with water and acidified with 20% citric acid solution to adjust pH 2-3 then extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over Na2SOi, and concentrated under reduced pressure. The product was crystallized in EtOH, and solid was collected, washed with EtOAc and then hot solutions of 20-30% EtOAc in hexanes to give target compound 39 (80 mg, 84% yield) as ayellow solid. TLC: 10% MeOH in DCM, R / = 0.3; visualized with UV. 29920-428111 2025-018-02

[0492] ’H NMR (400 MHz. DMSO-do): 8 13.93 (s, 1H, ATT), 10.21 (s, 1H, CONI!). 7.98-7.91 (m, 3H), 7.81-7.77 (m., 2H). 7.51 (d, J = 7.10 Hz, 1H), 7.45-7.44 (m, 2H), 7.36 (d, J = 8.26 Hz, 1H), 7.30-7.12 (m, 4H), 7.06 (brs, 1H), 6.98 (brs,lH), 6.76-6.67 (m, 2H), 3.76 (s, 3H, OCHi 3.76 (s, 3H, OCHs).

[0493] (Z)-3-(3-((5-(4-Fluoro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)-lH-pyrrol- 2-yl)methylene)-2-oxoindolin-l-yl)benzoic acid 40 (GL-3443): 40 was prepared by an abovedescribed procedure for 38 by using ethyl (Z)-3-(3-((5-(4-fluoro-3-((3- (trifluoromethoxy)phenyl)carbamoyl)phenyl)-lH-pyrrol-2-yl)methylene)-2-oxoindolin-l- yl)benzoate 40c (0.1 g, 0.152 mmol, 1 eq) as a starting material, dark orange solid; (0.075 g, 79% yield). TLC: 10% MeOH:DCM, R / = 0.3; visualized with UV. ’H NMR (400 MHz, DMSO): 5 13.83 (s, 1H). 10.84 (s, 1H), 8.10 - 8.02 (m, 3H), 8.00 (s, 1H). 7.90 (s, 1H), 7.84 (t, J = 6.6 Hz, 3H), 7.75 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.21 (dt, J= 18.6, 7.5 Hz, 2H), 7.16 - 7.06 (m, 3H), 6.81 (d, J= 7.6 Hz, 1H).13C NMR (101 MHz, DMSO): 5 167.71, 167.52, 165.23, 156.64, 148.95, 141.12, 140.42, 140.14, 137.79, 134.71, 131.18. 131.09, 130.94. 130.36, 129.88. 129.28, 128.14, 127.56, 127.22, 126.56, 126.18, 125.02. 124.84, 123.77. 123.00, 119.05. 118.85, 118.74. 116.08, 115.09. 1 13.63, 112.25. 1 12.14, 110.56, 109.39, 56.60; MS (ESI) m / z = 626.13 [M-H]+. Target compound 40 was also synthesized by an above synthetic procedure described for the preparation of compound 30 using appropriate starting materials. Orange solid (0.075 g. 79% yield). TLC: 10% MeOH in DCM, R / = 0.3; visualized with UV. 'H NMR (400 MHz. DMSO-de): <5 13.83 (s, 1H, ATT), 10.84 (s, 1H, CONH), 8.10-8.02 (m, 3H), 8.00 (s, 1H), 7.90 (s, 1H), 7.84 (t, .7 = 6.6 Hz, 3H), 7.75 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.57-7.46 (m, 2H), 7.21 (s, 2H), 7. 16-7.06 (m, 3H), 6.81 (d, J = 7.6 Hz, 1H).1?C NMR (101 MHz, DMSO-do): 8 167.7, 167.5. 165.2, 156.6, 148.9. 141.1, 140.4, 140.1, 137.7, 134.7, 131.1, 131.0, 130.9, 130.3, 129.8, 129.2, 128.1, 127.5, 127.2, 126.5, 126.1, 125.0, 124.8, 123.7, 123.0, 119.0, 118.8, 118.7, 116.0, 115.0, 113.6, 112.2, 112.1, 110.5, 109.3, 56.6.

[0494] Target compounds 41-42 were synthesized by an above synthetic procedure described for the preparation of compound 39 using appropriate starting materials. Each compound was crystallized in EtOH, and solid was collected, washed with EtOAc and then hot solutions of 20-30% EtOAc in hexanes to afford desired final compound.

[0495] (Z)-3-(5-fluoro-3-((5-(4-methoxy-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 41 (GL-3422): Yellow solid (87% yield). TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO-de): <5 10.27 (s, 1H, CONH), 8.42 (dd, J = 9.4, 1.6 Hz, 1H), 8.15 (brs,lH), 8.08 (d, J = 8.7 Hz, 1H), 8.03- 29920-428111 2025-018-02

[0496] 8.0 (m, 2H), 7.8-7.7- (m, 2H), 7.60 (s,2H), 7.46-7.38 (m, 3H), 7.28-7.23 (m,2H), 7.17-7.13 (m.lH), 6.87-6.84 (m,lH), 6.69 (d, J = 7.7 Hz. 1H), 3.97 (s. 3H,OC77J), 3.76 (s, 3H,OCHi).13C NMR (101 MHz, DMSO-de): 8 167.4, 166.6, 164.0, 159.5, 157.9, 157.3, 157.2, 150.0,

[0497] 140.2, 138.6, 134.7, 132.3, 131.1, 130.0, 129.5, 128.6, 127.8, 127.4, 127.3, 126.4, 125.6, 122.4,

[0498] 122.3, 121.5, 121.4, 118.7, 115.6, 115.6, 112.9, 112.0, 110.5, 110.3, 109.5, 109.0, 105.5, 56.3, 55.0.

[0499] (Z)-3-( 3-( (5-(4-methoxy-3-( < 3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxo-5-(trifluoromethoxy)indolin-l-yl)benzoic acid 42 (GL-3423): Yellow solid (78% yield). TLC: 10% MeOH in DCM, Rf = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO-de): 8 13.29 (s, 1H, COOH), 10.25 (s, 1H, CONH), 8.56 (s, , 1H), 8.14 (s,lH), 8.07-8.02 (m, 3H). 7.79 (d, J= 7.6 Hz, 1H). 7.73 (1. J= 7.6 Hz, 1H), 7.64 (d. J= 2.0 Hz. 2H), 7.47-7.44 (m, 2H), 7.34-7.22 (m, 3H), 6.93 (d, J= 8.2 Hz, 1H), 6.68 (d, J= 7.4 Hz, 1H), 3.95 (s, 3H, OCHi), 3.75 (s, 3H, OCHi).13C NMR (101 MHz, DMSO-de): 8 167.4, 166.5, 163.,

[0500] 159.4, 158.1, 157.3, 149.9, 143.5, 141.3, 140.2, 134.4, 132.4, 131.2, 130.0, 129.4, 128.8, 127.5, 127.0, 126.8, 125.9, 122.37. 122.34, 121.7. 121.4, 118.9, 118.1. 116.7, 112.3, 111.8. 110.1, 109.7, 108.9. 105.3, 56.1, 54.9.

[0501] 3-(3-((5-(4-chloro-3-((3-methoxyphenyl)carbamoyl)phenyl)fiuran-2-yl)methyl)-2- oxoindolin-l-yl)benzoic acid 43 (GL-3387). To a solution of (Z)-3-(3-((5-(4-chloro-3-((3- methoxyphenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2-oxoindolin-l -yl)benzoic acid 30 (40 mg, 0.067 mmol, 1 eq) in MeOH (3 mL) was added NaBH4 (8.0 mg, 0.203 mmol, 3 eq) at 0 °C. The resultant mixture was stirred at rt for 16 h, then methanol was removed under reduced pressure to give crude residue. The crude residue was purified by column chromatography using 1-3% MeOH in DCM as the eluent to afford target compound (43) as an off white solid (20 mg, 50%). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, CDC13): 5 8.04 (d, J= 6.7 Hz, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.56 (d, J= 6.7 Hz, 2H), 7.40 (d, J= 8.6 Hz, 2H), 7.30 (d, J= 8.7 Hz, 1H), 7.17 (q, J= 7.4 Hz, 2H), 7.12 - 7.03 (m. 2H), 6.70 (dd, J= 12.8, 8.1 Hz, 2H). 6.54 (s, 1H), 6.06 (d. J= 3.2 Hz. 1H), 4.00 (d. .7= 6.2 Hz, 1H), 3.82 (d, .7 = 2.1 Hz, 3H), 3.51 (d, .7 = 12.7 Hz, 1H), 3.41 (dd, .7= 14.5, 6.6 Hz, 1H).1?C NMR (101 MHz, CD3OD SPE) 5 177.06, 160.20, 160.11, 152.19, 150.85, 143.88, 139.39, 136.90, 134.55, 130.74, 129.90, 129.64, 129.51, 129.29, 129.11, 128.98, 128.65, 127.87, 127.44. 125.29, 124.40, 122.98, 112.18, 109.91. 109.72, 108.83, 106.84, 105.78, 54.34, 54.33, 28.45; MS (ESI) m / z = 591.13 [M-H]'. Another synthesis was performed to give compound 43 as an off white solid (25 mg, 62%). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 29920-428111 2025-018-02

[0502] ’H NMR (400 MHz, CDCh): 3 8.04 (d, J = 6.7 Hz, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.56 (d. J = 6.7 Hz. 2H), 7.40 (d, J = 8.6 Hz, 2H). 7.30 (d, J = 8.7 Hz, 1H), 7.17 (q, J =

[0503] 7.4 Hz, 2H), 7.12-7.03 (m, 2H), 6.70 (dd, J= 12.8, 8.1 Hz, 2H), 6.54 (s, 1H), 6.06 (d, J = 3.2 Hz, 1H), 4.00 (d, J = 6.2 Hz, 1H), 3.82 (s, 3H, OCH33.51 (d, J = 12.7 Hz, 1H), 3.41 (dd, J = 14.5, 6.6 Hz, 1H).1?C NMR (101 MHz, CD3OD) 3 177.0, 160.2, 160.1, 152.1, 150.8, 143.8,

[0504] 139.3, 136.9, 134.5, 130.7, 129.9, 129.6, 129.5, 129.2, 129.1, 128.9, 128.6, 127.8, 127.4, 125.2,

[0505] 124.4, 122.9. 112.1, 109.9. 109.7, 108.8, 106.8, 105.7, 54.3, 54.3. 28.4.

[0506] 3-(3-((5-(4-chloro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2- yl)methyl)-2-oxoindolin-l-yl)benzoic acid 44 (GL-3390): 44 was synthesized by an above synthetic procedure described for the preparation of I la using appropriate starting materials, yellow solid (22 mg, 44% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, CDC13): 8 8.05 (s, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J =

[0507] 14.4 Hz, 2H), 7.51 (d, J= 8.3 Hz, 2H), 7.44 (d, J= 8.3 Hz, 1H), 7.37 (d, J= 8.5 Hz, 1H), 7.30 (t, J= 8.2 Hz, 1H). 7.25 (d, J= 8.5 Hz, 1H). 7.1 1 (q, J= 7.5 Hz, 2H). 7.02 (t. J = 7.4 Hz. 1H). 6.96 (d, J= 8.4 Hz, 1H), 6.63 (d, J= 7.8 Hz, 1H), 6.48 (d, J= 3.4 Hz, 1H), 6.01 (d, J= 3.5 Hz, 1H), 3.94 (t, J= 5.2 Hz, 1H), 3.45 (dd, J= 14.7, 4.8 Hz, 1H), 3.35 (dd, J = 14.9, 6.8 Hz, 1H).13C NMR (101 MHz, CDC13): 8 176.11, 169.73, 164.68, 152.08, 150.79, 149.62, 143.68, 138.99. 134.97, 134.66. 131.94, 130.93. 130.67, 130.15, 129.91, 129.66, 128.70, 128.31, 127.83, 126.40, 124.80, 124.56, 123.30, 118.12, 116.88, 112.94, 1 10.16, 109.31, 107.37, 45.13, 29.71, 29.63; MS (ESI) m / z = 645.10 [M-H]'. Another synthesis was performed to give the product as a yellow solid (65% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, CDCh): 3 8.05 (s, 1H). 7.98 (d, J = 6.8 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J = 14.4 Hz, 2H), 7.51 (d, J = 8.3 Hz. 2H), 7.44 (d. J = 8.3 Hz, 1H). 7.37 (d, J = 8.5 Hz. 1H), 7.30 (t, J= 8.2 Hz, 1H), 7.25 (d, J= 8.5 Hz, 1H), 7.1 1 (q, J= 7.5 Hz, 2H), 7.02 (t, J= 7.4 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.63 (d, J= 7.8 Hz, 1H), 6.48 (d, J= 3.4 Hz, 1H), 6.01 (d, J = 3.5 Hz. 1H), 3.94 (t, .7= 5.2 Hz, 1H), 3.45 (dd, J= 14.7, 4.8 Hz, 1H), 3.35 (dd, J= 14.9, 6.8 Hz. 1H).13C NMR (101 MHZ, CDCh): 3 176. 1, 169.7. 164.6, 152.0. 150.7, 149.6. 143.6, 138.9, 134.9, 134.6, 131.9, 130.9, 130.6, 130.1 , 129.9, 129.6, 128.7, 128.3, 127.8, 126.4, 124.8, 124.5, 123.3, 118.1, 116.8, 112.9, 110.1, 109.3, 107.3, 45.1, 29.7, 29.6; LCMS (ESI) m / z = 645.35 [M-H]’.

[0508] 3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2-yl)methyl)-2- oxoindolin-l-yl)benzoic acid (11c). To a suspension of (Z)-3-(3-((5-(4-fluoro-3-((3-

[0509] (methoxy)phenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2-oxoindolin-l-yl)benzoic acid 29920-428111 2025-018-02

[0510] (40 mg, 0.069 mmol, 1 eq) in ethanol (1 mL) was added Pd / C (40 mg, 10% w / w). The resultant mixture was stirred at room temperature under H2 atmosphere for 16 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography using 1-3% MeOH in DCM as the eluent to afford target compound (11c) as pale yellow solid (10 mg, 25%). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 1H NMR (400 MHz, CDC13): 5 8.41 (d, J= 14.1 Hz, 1H), 8.16 (dd, J = 7.5, 2.4 Hz, 1H), 8.06 (t, J = 4.6 Hz, 1H). 7.75 (s, 1H). 7.56 - 7.51 (m, 3H). 7.45 (t. J = 2.2 Hz, 2H), 7.25 (t, J = 6.2 Hz, 3H), 7.14 - 7.01 (m, 2H), 6.73 (dd, J = 8.1, 2.5 Hz, 1H), 6.68 - 6.63 (m, 1H), 6.56 (d, J = 3.3 Hz, 1H), 6.03 (d, J = 3.3 Hz, 1H), 3.85 (s, 4H), 3.52 (s, 2H).nC NMR (101 MHz, CDC13): 5 177.04, 169.07, 160.16, 151.41, 148.95, 142.70, 138.73, 133.98. 131.53, 130.99. 130.02, 129.87. 129.76, 129.18. 127.69, 127.08, 124.54, 124.04,

[0511] 1 16.68, 1 16.42, 112.68, 111.12, 110.85, 109.56, 106.74, 106.20, 55.36, 38.56; MS (ESI) m'z = 575.16 [M-H]’.

[0512] 3-(3-( (5-(4-fluoro-3-(( 3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2- yl)methyl)-2-oxoindolin-l-yl)benzoic acid (lid), l id was synthesized by an above synthetic procedure described for the preparation of 11 c using appropriate starting materials, yellow solid (16 mg, 53% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. ’H NMR (400 MHz, CDC13): 5 9.79 (s. 1H), 8.35 (s, 1H), 8.01 (d, J= 7.5 Hz, 1H), 7.90 (s, 1H). 7.69 (s, 1H), 7.54 (t, J = 10.3 Hz, 3H), 7.42 (d, J = 8.4 Hz, 1H), 7.33 - 7.26 (m, 1H), 7. 16 - 7. 10 (m, 1H), 7.07 (d, J= 7.6 Hz, 1H), 7.02 (d, J= 7.0 Hz, 1H), 6.91 (d, J= 8.8 Hz, 2H), 6.67 (d, J= 7.8 Hz, 1H), 6.48 (s, 1H), 6.02 (s, 1H), 3.98 (s, 1H), 3.50 (d, J= 14.9 Hz, 1H), 3.24 (dd, J= 14.9, 8.1 Hz. 1H).13C NMR (101 MHz, CDC13): 5 176.11. 169.73, 164.68, 152.08. 150.79, 149.62,

[0513] 143.68. 138.99, 134.97. 134.66, 131.94. 130.93, 130.67. 130.15, 129.91. 129.66, 128.70. 128.31, 127.83, 126.40, 124.80, 124.56, 123.30, 118.12, 116.88, 112.94, 110.16, 109.31, 107.37, 45.13, 29.71, 29.63; MS (ESI) m / z = 629.13 [M-H]’.

[0514] 3-(3-((5-(3-((3-methoxyphenyl)carbamoyl)-4-(trifluoromethoxy)phenyl)furan-2- yl)methyl)-2-oxoindolin-l-yl)benzoic acid (lie, also 46 (GL-3424)). To a solution of (Z)-3-(3- ((5-(3-((3-methoxyphenyl)carbamoyl)-4-(trifluoromethoxy)phenyl)furan-2-yl)methylene)-2- oxoindolin-l-yl)benzoic acid (1 g, 0.156 mmol, 1 eq) in methanobTHF (3 mL, 1 : 1) was added NiCb (20 mg, 0.062 mmol, 1 eq) followed by NaBH4 (12 mg, 0.125 mmol, 2 eq) at room temperature. The resultant suspension was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give crude residue. The crude residue was purified by column chromatography using 1-3% MeOH in DCM as the eluent to afford target compound 29920-428111 2025-018-02

[0515] (lie) as a pale yellow solid (25 mg, 25%). TLC: 10% MeOH in DCM, R = 0.4; visualized with UV. 1H NMR (400 MHz, CDC13): 5 8.36 (s, 1H), 8.18 (s. 1H), 8.01 (s, 1H), 7.84 (d, J =

[0516] 9.3 Hz, 1H), 7.53 (d, J = 6.4 Hz, 3H), 7.46 (s, 1H), 7.36 (s, 1H), 7.06 (dt, J = 32.0, 7.8 Hz, 5H), 6.94 - 6.87 (m, 1H), 6.64 (dd, J = 13.9, 7.9 Hz, 2H), 6.58 - 6.45 (m, 1H), 6.08 - 5.92 (m, 1H), 4.11 - 4.02 (m, 1H), 3.97 (s, 1H), 3.78 (s, 3H), 3.49 (d, J = 15.2 Hz, 1H); MS (ESI) m / z = 641.15 [M-H]'.

[0517] Target compounds llf-g were synthesized by an above synthetic procedure described for the preparation of compound lie using appropriate starting materials.

[0518] 3-(5-fluoro-3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methyl)-2-oxoindolin-l-yl)benzoic acid (Ilf). Pale brown solid (20 mg, 40% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, CDCh): 5 9.78 (s, 1H), 8.45 (d. J = 2.4 Hz. 1H), 8.10 (d. J = 7.0 Hz. 1H), 7.94 (s. 1H), 7.64 (d. J= 2.5 Hz. 1H), 7.61 (d, J= 6.0 Hz, 2H), 7.55 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 8.6 Hz, 3H), 7. 10 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.70 (ddd, J = 15.9, 8.7, 3.5 Hz, 3H), 6.58 (d, J= 3.3 Hz. 1H), 6.13 (d, J = 3.2 Hz, 1H), 4.09 (s, 3H), 4.03 (s, 2H). 3.58 (dd, J= 15.0, 4.5 Hz. 1H), 3.34 (dd, J= 15.0, 7.8 Hz, 1H); MS (ESI) m / z = 593.15 [M-H]’.

[0519] 3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2-yl)methyl)-2-oxo-5 (trifluoromethoxy)indolin-l-yl)benzoic acid (11g). yellow solid (10 mg, 23% yield). TLC: 10% MeOH in DCM. R / = 0.4; visualized with UV. 'H NMR (400 MHz. CDCh): 5 9.77 (s. 1H), 8.44 (d, J = 2.4 Hz, 1H), 8. 10 (d, J = 5.9 Hz, 1H), 7.91 (s, 1H), 7.63 - 7.57 (m, 3H), 7.55 (s, 1H), 7.25 (d, J= 8.2 Hz, 1H), 7.09 (d, J= 11.1 Hz, 4H), 6.98 (d, J= 8.6 Hz, 1H), 6.71 (d, J =

[0520] 8.3 Hz, 2H), 6.58 (d. J = 3.3 Hz, 1H), 6. 12 (d, J = 3.3 Hz, 1H), 4.08 (s, 3H), 4.06 - 4.03 (m, 1H), 3.58 (dd, J = 14.9, 4.6 Hz. 1H), 3.37 (dd. J = 14.9. 7.5 Hz, 1H).13C NMR (101 MHz, CDC13) 5 169.60, 163.11, 160.16, 156.21, 152.24, 150.31, 142.36, 139.45, 134.42, 131.84, 131.21, 130.01, 129.59, 128.13, 127.80, 121.90, 121.40, 112.59, 110.28, 106.07, 56.46, 55.38, 55.34, 45.39; MS (ESI) m / z = 659.14 [M-H]'.

[0521] 3-( 3-( (5-(4-methoxy-3-( (3-( trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2- yl)methyl)-2-oxoindolin-l-yl)benzoic acid 45 (GL-3393): To a suspension of (Z)-3-(3-((5-(4- methoxy-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2- oxoindolin-l-yl)benzoic acid 35 (40 mg, 0.062 mmol, 1 eq) in EtOH (1 mL) was added Pd / C (40 mg, 10% w / w). The resultant mixture was stirred at room temperature under H2 atmosphere for 16 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give crude product which w as purified by column chromatography using 29920-428111 2025-018-02

[0522] 1-3% MeOH in DCM as the eluent to afford target compound 45 as yellow solid (26 mg, 65%). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, CDCh): <5 9.85 (s, 1H), 8.41 (s, 1H), 8.07 (d, J= 7.5 Hz, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 7.60 (t, J= 10.63 Hz, 3H), 7.48 (d, J= 8.08 Hz, 1H), 7.37-7.33 (m, 1H), 7.21-7.17 (m, 1H), 7.14-7.08 (m, 2H), 6.97 7.0 Hz, 2H), 6.73 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 6.09 (s, 1H), 4.07 (s, 3H, OCHs

[0523] 4.03 (brs,lH), 3.58-3.55 (m.lH), 3.33-3.28 (m. 1H).13C NMR (101 MHz, CDCh): 8 176.2, 169.8, 164.8. 152.2, 150.9. 149.7, 143.8. 139.1, 135.0. 134.7, 132.0. 131.0, 130.7. 130.2, 130.0. 129.7, 128.8, 128.4, 127.9, 126.5, 124.9, 124.6, 123.4, 121.8, 119.2, 118.2, 117.0, 113.0, 110.2, 109.4, 107.4, 45.2, 29.8, 29.7, 29.4.

[0524] 3-(3-((5-(3-((3-Methoxyphenyl)carbamoyl)-4-(trifluoromethoxy)phenyl)fiiran-2- yl)methyl)-2-oxoindolin-l-yl)benzoic acid 46 (GL-3424): To a solution of (Z)-3-(3-((5-(3-((3- methoxyphenyl)carbamoyl)-4-(trifluoromethoxy)phenyl)furan-2-yl)methylene)-2-oxoindolin-

[0525] 1-yl)benzoic acid 37 (0.1 g, 0.156 mmol, 1 eq) in MeOH:THF (3 mb, 1: 1) was added NiCh (20 mg, 0.062 mmol, 1 eq) followed by NaBH4 (12 mg, 0. 125 mmol, 2 eq) at room temperature. The resultant suspension was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give crude residue. The crude residue was purified by column chromatography using 1-3% MeOH in DCM as the eluent to afford compound 46 as a pale yellow solid (68 mg, 68%). TLC: 0.4; visualized with UV. 'H NMR (400 MHz, CDCh): 8 8.36 (s, 1H). 8.18 (s, 1H), 8.01 (s, 1H), 7.84 (d, J= 9.3 Hz, 1H), 7.53 (d, J= 6.4 Hz, 3H), 7.46 (s, 1H), 7.36 (s, 1H). 7.06 (m, 5H). 6.94-6.87 (m, 1H), 6.64 (dd. J= 13.9, 7.9 Hz, 2H), 6.58-6.45 (m, 1H), 6.08-5.92 (m, 1H), 4.11 -4.02 (m, 1H), 3.97 (s, 1H), 3.78 (s, 3H, OCH33.49 (d, J= 15.2 Hz, 1H).

[0526] Target compounds 47-51 were synthesized by the above synthetic procedure described for the preparation of compound 46 using appropriate starting materials.

[0527] 3-(3-((5-(4-Chloro-3-((3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2-yl)methyl)-

[0528] 2-oxoindolin-l-yl)benzoic acid 47 (GL-3367): To a solution of (Z)-3-(3-((5-(4-chloro-3-((3- methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2-yl)methylene)-2-oxoindolin-l-yl)benzoic acid 38 (0.05 mg, 0.087 mmol, 1 eq) in methanol:THF (2 mL, 1 :1) was added NiCh (12 mg, 0.087 mmol. 1 eq) followed by NaBHr (20 mg, 0.522 mmol, 6 eq). The resultant mixture was stirred at room temperature for 3 h, then solvent was evaporated to give solid residue. The residue was directly loaded on column chromatography and the desired spot was eluted 5% MeOH:DCM which was concentrated under reduced pressure to give product 47 (0.035 g, 70% yield) as a yellow solid. TLC: 10% MeOH:DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, DMSO-de): 8 13.95 (s, 1H, NH 10.61 (s, 1H, CONH). 8.02 (s, 4H), 7.97-7.92 (m, 4H), 29920-428111 2025-018-02

[0529] 7.81 (d, J= 7.12 Hz, 1H), 7.69-7.66 (m, 2H), 7.52-7.43 (m, 3H), 7.27-7.21 (m, 2H), 7.17-7.07 (m. 3H), 6.71 (t, J = 8.24 Hz, 2H), 3.74 (s, 3H. OCHs 3.41-3.33 (m, 2H), 3.17 (brs 1H).13C NMR (101 MHz, DMSO-de): b 168.8, 167.07, 164.55, 159.5, 140.3, 140.0, 137.7, 135.6, 133.4,

[0530] 131.3, 130.7, 129.7, 129.6, 128.88, 128.82, 128.5, 127.7, 127.6, 127.1, 126.5, 125.4, 124.8,

[0531] 124.2, 122.7, 122.4, 118.7, 116.2, 111.9, 111.2, 109.4, 109.0, 105.4, 55.0, 48.6, 29.2.

[0532] 3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2-yl)methyl)-2- oxoindolm-l-yl)benzoic acid (42b). 42b was prepared by an above-described procedure for 47 by using (Z)-3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2- yl)methylene)-2-oxoindolin-l-yl)benzoic acid 41b (0.05 mg, 0.087 mmol. 1 eq) as a starting material, yellow solid; (0.03 g, 60% yield). TLC: 10% MeOH:DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, DMSO): 5 13.23 (s, 1H), 11.18 (s, 1H), 10.15 (s, 1H), 8.01 (d, J = 7.4 Hz, 1H), 7.95 (s, 1H), 7.88 - 7.83 (m, 1H), 7.69 (p, J= 7.7 Hz, 3H), 7.47 (d, J= 16.5 Hz, 1H), 7.23 (ddd, J = 35.5, 16.6. 8.0 Hz, 4H), 7.01 (t. J = 7.5 Hz, 1H), 6.90 (t, J = 6.9 Hz. 1H), 6.73 (d, J= 8.1 Hz, 1H). 6.68 (d, J= 8.7 Hz, 1H). 6.35 (s. 1H), 5.74 (s. 1H), 4.14 (dd, J= 9.0. 4.8 Hz, 1H), 3.76 (s, 3H), 3.48 - 3.40 (m, 1H), 3.04 (dt, J = 15.0, 8.4 Hz, 1H).13C NMR (101 MHz, DMSO): 5 176.31, 167.06, 165.17, 160.01, 154.61, 143.97, 140.73, 135.20, 132.80, 131.45. 130.47, 130.07, 129.97, 129.95, 129.11, 129.01, 128.29, 127.84, 126.90, 126.47, 125.85. 125.03, 124.54, 122.96, 113.00, 112.44, 109.43, 109.01. 108.25. 105.90, 105.42, 65.38, 56.52, 55.49, 45.66, 28.91; MS (ESI) m / z = 574.17 [M-H]+.

[0533] 3-(3-((5-(4-melhoxy-3-((3-melhoxyphenyl)carbamoyl)phenyl)-lH-pyrrol-2-yl)methyl)- 2-oxoindolin-l-yl)benzoic acid 48 (GL-3447): Yellow solid: (0.034 g, 68% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. *H NMR (400 MHz, DMSO-de): b 13.21 (s, 1H, NH), 11.16 (s, 1H, COOHy 10.13 (s, 1H, CONH), 8.00 (d, J = 6.75 Hz, 1H), 7.93 (s, 1H), 7. 71-7.64 (m, 3H). 7.47-7.43 (m, 1H), 7.27-7.14 (m, 4H), 6.99 (t, J = 6.75 1H), 6.89 (t, J= 6.23, 1 H). 6.73-6.66 (m, 2H), 6.46-6.34 (m, 1H), 5.73 (brs. 1H), 4.12-4.10 (m, 1H). 3.89 (s, 3H, OCHs), 3.75 (s, 3H, OCHs), 3.45-3.27 (m, 2H), 3.45-3.37 (m, 1H), 3.04-2.98 (m, 1H).13C NMR (101 MHz, DMSO-de): b 175.8, 166.6, 164.7, 159.5, 154.1, 143.5, 140.2, 140.0, 134.7,

[0534] 132.3, 131.0, 130.4, 130.0, 129.6, 129.5, 128.6, 128.58, 128.50, 127.8, 127.4, 126.4, 126.0,

[0535] 125.4, 124.5, 124.1, 122.5, 112.5, 111.9, 109.3, 108.9, 108.5, 108.0, 107.8, 106.3, 105.4, 104.9, 64.9, 56.0, 55.0, 45.2.

[0536] 3-(3-((5-(4-Fluoro-3-((3-(trifluoromethoxy)phenyl)carbamoyl)phenyl)-lH-pyrrol-2- yl)methyl)-2-oxoindolin-l-yl)benzoic acid 49 (GL-3448): 49 was prepared by an abovedescribed procedure for 47 by using (Z)-3-(3-((5-(4-fluoro-3-((3- 29920-428111 2025-018-02

[0537] (trifluoromethoxy)phenyl)carbamoyl)phenyl)-lH-pyrrol-2-yl)methylene)-2-oxoindolin-l- yl)benzoic acid 40 (0.05 g. 0.079 mmol, 1 eq) as a starting material, yellow solid; (0.02 g. 40% yield). TLC: 10% MeOH:DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, DMSO): 5 11.28 (s, 1H), 10.76 (s, 1H), 8.01 (d, J= 7.5 Hz, 1H), 7.93 (d, J= 8.8 Hz, 2H), 7.89 (d, J= 6.5 Hz, 1H), 7.77 (t, J= 6.8 Hz, 1H), 7.73 - 7.62 (m, 3H), 7.51 (t, J= 8.2 Hz, 1H), 7.34 (t, J= 9.3 Hz. 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 8.4 Hz. 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H). 6.73 (d, J = 7.9 Hz, 1H), 6.48 (d, J = 3.3 Hz. 1H), 5.77 (s. 1H), 4. 13 (dd. J = 9.0, 4.8 Hz, 1H), 3.47 - 3.42 (m, 1H), 3.05 (dd, J = 14.8, 9.0 Hz, 1H).13C NMR (101 MHz, DMSO) 5 176.23, 167.03, 163.81, 158.29, 155.83, 148.97, 143.98, 140.95, 135.19, 132.74, 131.47. 131.08, 130.96, 130.47, 130.22, 129.11, 129.03, 128.95, 128.33, 127.84, 127.38, 127.30. 125.36, 125.20. 125.00, 124.18. 122.97, 121.85. 119.30, 118.77, 117.20, 116.98, 1 16.41, 112.16, 109.05, 108.56, 106.91, 45.61, 28.91; MS (ESI) m z = 628. 15 [M-H]+. Another synthesis was performed to give the product as a yellow solid; (0.036 g, 72% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV.JH NMR (400 MHz, DMSO-de): 3 11.28 (s, 1H, COOH), 10.76 (s, 1H, CONH), 8.01 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.89 (d, J= 6.5 Hz, 1H), 7.77 (t, J= 6.8 Hz, 1H), 7.73-7.62 (m, 3H), 7.51 (t, J = 8.2 Hz, 1H), 7.34 (t, J = 9.3 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.01 (t, J= 7.5 Hz, 1H), 6.91 (d, J= 7.4 Hz, 1H), 6.73 (d, J= 7.9 Hz, 1H), 6.48 (d, J = 3.3 Hz, 1H), 5.77 (s, 1H), 4.13 (dd, J = 9.0, 4.8 Hz, 1H), 3.47-3.42 (m, 1H), 3.05 (dd, J = 14.8. 9.0 Hz, 1H).13C NMR (101 MHz, DMSO-de): 3 176.2, 167.0. 163.8, 158.2. 155.8, 148.9. 143.9, 140.9. 135.1, 132.7. 131.4, 131.0,

[0538] 130.9, 130.4, 130.2, 129.1, 129.0, 128.9, 128.3, 127.8, 127.3, 127.3, 125.3, 125.2, 125.0, 124.1,

[0539] 122.9, 121.8, 119.3, 118.7, 117.2, 116.9, 116.4, 112.1, 109.0, 108.5, 106.9, 45.6, 28.9; LCMS (ESI) m / z = 628.35 | M-111 . HPLC purity: 95.06% ( / R = Z isomer at 9.93 min and E isomer at 10.52 min).

[0540] 3-(5-fluoro-3-((5-(4-methoxy-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methyl)-2-oxoindolin-l-yl)benzoic acid 50 (GL-3425): Pale brown solid (60% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, CDCh): 3 9.75 (s, 1H. CONH). 8.42 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 6.6 Hz, 1H), 7.91 (s, 1H). 7.61-7.57 (m, 3H), 7.52 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.03 Hz, 1H). 6.97 (d. J = 8.6 Hz. 1H). 6.91-6.87 (m, 2H), 6.70-6.63 (m, 2H), 6.55 (d, J= 3.5 Hz, 1H), 6.11 (d, J= 3.2 Hz, 1H), 4.06 (s, 3H, OCHi), 4.03-4.00 (m, 1H), 3.84 (s, 3H, OCH3), 3.55 (dd, J = 14.5, 4.3 Hz, 1H), 3.31 (dd, J= 14.5, 7.2 Hz, 1H). 29920-428111 2025-018-02

[0541] 3-(3-((5-(4-methoxy-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2-yl)methyl)-2- oxo-5-(trifluoromethoxy)indolin-l-yl)benzoic acid 51 (GL-3426): Yellow solid (65% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, CDCh): 8 9.75 (s, 1H, CONH). 8.41 (s, 1H), 8.08 (d, J= 4.26 Hz, 1H), 7.88 (s, 1H), 7.57-7.55 (m, 3H), 7.52 (s, 1H), 7.22 (d, J= 70 Hz, 1H), 7.06 (d, J = 10.90 Hz, 3H), 6.95 (d, J= 8.98 Hz, 1H), 6.68 (d, J =8.98 Hz, 2H), 6.55 (d. J= 3.21 Hz, 1H), 6.09 (d, 3.13 Hz. 1H), 4.O6 (s, 3H. OCHi), 4.05

[0542] (s, 3H, OCHs). 4.03-4.01 (m, 1H). 3.84 (s, 3H, OCH ). 3.55 (dd, J= 14.9, 4.23 Hz, 1H), 3.34 (dd, J= 14.9, 7.0 Hz, 1H).13C NMR (101 MHz, CDCls): 8 175.8, 169.7, 163.2, 160.2, 156.3,

[0543] 152.3, 150.4, 145.0, 142.4, 139.5, 139.1, 134.5, 134.0, 133.7, 131.9, 131.3, 130.1, 129.6, 129.7,

[0544] 129.6, 129.5, 128.2, 127.99. 127.91, 124.8. 122.0, 121.9, 121.5. 119.3, 118.7, 118.3. 112.8,

[0545] 112.7, 112.5. 112.0, 110.6. 110.3, 109.8, 106.5, 106.4, 106.2, 105.6, 56.9, 56.5, 55.44, 45.50.

[0546] (Z)-5-(5-((l-(3-(lH-tetrazol-5-yl)phenyl)-2-oxoirulolin-3-ylidene)methyl)furan-2-yl)- 2-fluoro-N-(3-methoxyphenyl)benzamide 52 (GL-3603). To a solution of (Z)-5-(5-((l-(3- cyanophenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2-fluoro-N-(3- methoxyphenyl)benzamide 28 (0.1 g, 0.18 mmol, 1 eq.) in DMF (3 mb) was added triethylamine hydrochloride salt (0.037 g, 0.27 mmol, 1.5 eq.) followed by NaNs (0.017 g, 0.27 mmol, 1.5 eq ). The resultant mixture was heated at 120 °C for 16 h and then cool to room temperature and acidified with 2N HC1 to adjust pH 3-4, a solid precipitate was formed filtered, and dried over vacuum to give target product. Red solid (20 mg, 19% yield). TLC: 10% NHVMeOH in DCM, R / = 0.2; visualized with UV. Another synthesis was performed to give the product as a red solid (48 mg, 44% yield). TLC: 10% Nl h / MeOH in DCM, Rf = 0.2; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO-de): 5 10.37 (s, 1H, CONH), 8.69 (d. J = 8.58 Hz. 1H), 8.22 (s. 1H), 8.13-8.11 (m. 2H), 7.83-7.78 (m. 2H). 7.73- 7.68 (m, 1H), 7.58-7.53 (m, 2H), 7.42 (s, 1H), 7.34-7.32 (m, 1H), 7.28-7.24 (m, 2H), 7.19 (d, J = 3.47 Hz, 1H), 7.15-7.11 (m, 2H), 7.06-7.02 (m, 1H), 6.94 (d, J = 8.68 Hz, 1H), 6.90 (d, J = 8.29 Hz, 1H), 6.76 (brs, 1H), 6.71-6.70 (m, 1H), 3.74 (s, 3H, OCH3).13C NMR (101 MHz, DMSO-de): 5 167.4, 159.4. 159.1, 149.2. 141.9, 140.3. 130.8, 129.4. 129.2, 126.2. 125.0, 122.5,

[0547] 121.4, 1 17.8, 1 16.9, 115.9, 1 15.7, 1 12.7, 109.2, 107.8, 106.1 , 55.0. HPLC purity: 98.63% (tR= Z isomer at 9.08 min and E isomer at 9.73 min).

[0548] (Z)-5-(5-((l -(3-( 1 H-tetrazol-5-yl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)- 2-fluoro-N-(3-(trifluoromethoxy)phenyl)benzamide 53 (GL-3609). 53 was prepared by an above-described procedure for 52 by using (Z)-5-(5-((l-(3-cyanophenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)-2-fluoro-N-(3 (trifluoromethoxy)phenyl)benzamide 29 (0.12 g, 29920-428111 2025-018-02

[0549] 0.196 mmol, 1 eq.) as a starting material. Red solid (25 mg, 20% yield). TLC: 10% NH3 / MeOH in DCM, R = 0.2; visualized with UV. Another synthesis was performed to give the product 53 as a red solid (65 mg, 50% yield). TLC: 10% NHs / MeOH in DCM, R = 0.2; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO-de): 8 10.64 (s, 1H, CONH). 8.69 (d, J = 9.31 Hz, 1H), 8.24 (s, 1H), 8.12 (t, J= 6.69 Hz, 2H), 7.87 (s, 1H), 7.83 (d, J= 9.61 Hz, 1H),

[0550] 7.78 (brs, 1H), 7.72-7.70 (m, 1H), 7.67-7.65 (m, 1H), 7.61 (brs. 1H), 7.55-7.50 (m. 2H), 7.21- 7.20 (m, 1H), 7.11-7.09 (m. 2H), 7.02-7.00 (m, 1H). 6.97-6.95 (m, 1H), 6.90-6.88 (m. 1H).

[0551] 6.79 (s, 1H).13C NMR (101 MHz, DMSO-de): 8 167.8, 150.7, 149.3, 148.6, 135.4, 130.8, 130.5, 128.9, 127.1, 126.2, 125.0, 122.4, 121.4, 120.4, 119.1, 118.0, 117.2, 115.8, 115.4, 112.5, 108.0, 34.5. HPLC purity: 99.9% (7R = Z isomer at 10.16 min and E isomer at 10.79 min).

[0552] 3-iodobenzoic acid (55). To a stirred solution of ethyl 3 -iodobenzoate 54 (0.5 g, 1.81 mmol, 1.0 eq) in EtOH (10 rnL) was added 2N- NaOH solution at room temperature. The mixture was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure to give semi solid residue. The residue was dissolved in water and acidified with 2N- HC1, a solid precipitate was formed, filtered and wash with pentane to afford target product. White solid (0.4 g, 88% yield). TLC: 10% MeOH in DCM, R = 0.2; visualized with UV.

[0553] 3-iodo-N-methylbenzamide (56). The mixture of 3-iodobenzoic acid 55 (0.3 g, 1.20 mmol, 1 eq) and SOCh (3 rnL) was heated at 70 °C for 16 h. The reaction mass cooled to room temperature and the thionyl chloride was removed under reduced pressure to give solid residue. The solid residue was dissolved in DCM and cooled to 0 °C then methylamine (0. 123 mg, 2.41 mmol, 2 eq) was added. The resultant mixture was warm to room temperature and stirred for 3 h. The reaction mixture was diluted with water (20 mL) and extracted in EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure to give solid product which was triturated with n-pentane and filtered to afford pure target product (56). Brown solid (0.24 g, 76% yield). TLC: 50% EtOAc in Hexane, R / = 0.5; visualized with UV. 'HNMR (400 MHz, CDCh): 5 8.12 (s, 1H), 7.84 (d, J= 8.0 Hz, 1H), 7.74 (d, J= 7.9 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.16 (s, 1H), 3.10 - 3.00 (m, 3H).13C NMR (101 MHz, CDC13) 5 140.28, 135.93, 130.28, 126.08, 126.06, 94.27, 26.97; MS (ESI) m / z = 261.98 [M+H]+. ethyl 2-fliioro-5-(5-formylfuran-2-yl)benzoate (57). To a stirred solution of 2-fluoro-5- (5-formylfuran-2-yl)benzoic acid 13b (0.4 g, 1.708 mmol, 1.0 eq.) in DMF (10 mL) was added K2CO3 (0.47 g, 3.416 mmol. 2 eq) followed by ethyl iodide (0.532 g, 3.416 mmol. 2 eq). The resultant mixture was heated at 100 °C for 16 h, then cooled to room temperature. The reaction 29920-428111 2025-018-02 mixture was poured into ice cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and evaporated on a rotary evaporator under reduced pressure to give the crude product, which was purified on column chromatography using 30% EtOAc in w-hexane. Off white solid (0.35 g, 78% yield). TLC: 50% EtOAc in Hexane, R / = 0.5; visualized with UV. 'H NMR (400 MHz, CDCh): 8 9.70 (d, J = 2.2 Hz, 1H), 8.37 (dd, J= 6.4, 2.8 Hz, 1H), 8.00 (dt. J= 10.3, 3.2 Hz, 1H), 7.35 (d, J= 3.2 Hz, 1H), 7.25 (d. J= 10.3 Hz, 1H). 6.90 (t. J= 3.1 Hz. 1H), 4.47 (qd, J= 22, 2.1 Hz, 2H), 1.45 (td. J = 22, 2.1 Hz, 3H); MS (ESI) m / z = 263.07 [M+H]+. ethyl (Z)-2-fluoro-5-(5-((2-oxomdolm-3-ylidene)methyl)furan-2-yl)benzoate (58). The mixture of ethyl 2-fluoro-5-(5-formylfuran-2-yl)benzoate 57 (0.3 g, 1.14 mmol, 1 eq) and indolin-2-one 8a (0.152 g, 1.14 mmol, 1 eq) in acetic acid (10 mL) was heated at 120 °C for 16 h. The solvent was removed under reduced pressure and solid residue was suspended in EtOH, filtered, washed with EtOH, EtOAc, and DCM (2 times each) to afford 58 (0.28 g. 65% yield) as off white solid. TLC: 50% EtOAc in hexane, R / = 0.4; visualized with UV. Major Z- isomer data: 'H NMR (400 MHz, DMSO): 8 10.61 (s, 1H), 8.48 (dd, J = 13.7, 7.2 Hz, 2H), 8.20 (d, J = 2.6 Hz, 1H), 7.67 - 7.53 (m, 2H), 7.44 (s, 2H), 7.34 (d, J= 11.9 Hz, 2H), 7.13 (t, J= 7.8 Hz, 1H), 6.92 (d, J= 7.7 Hz, 1H), 4.42 (q, J= 2.3 Hz, 2H), 1.35 (t, J= 7.0 Hz. 3H).1?C NMR (101 MHz, DMSO) 8 178.55. 169.73, 155.43, 152.46, 151.46. 143.01, 132.13, 132.03, 130.33, 128.26, 127.00, 124.83, 124.02, 122.66, 121.82, 121.70, 119.1 1, 1 19.01, 118.78, 111.32, 110.41, 110.02, 61.99, 14.61, 14.56; MS (ESI) m'z = 378.12 [M+H]+. ethyl (Z)-2-fluoro-5-(5-( ( l-( 3-(methylcarbamoyl)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)benzoate (59). To a solution of ethyl (Z)-2-fluoro-5-(5-((2- oxoindolin-3-ylidene)methyl)furan-2-yl)benzoate 58 (0.3 g, 0.795 mmol, 1 eq) and 3-iodo-N- methylbenzamide 56 (0.207 g, 0.795 mmol, 1 eq) in acetonitrile was added K2CO3 (220 mg, 1.59 mmol, 2 eq). The mixture was degassed with nitrogen for 5 minutes and then trans-N,N'- Dimethylcyclohexane-l,2-diamine (18 mg, 0.159 mmol, 0.2 eq) followed by Cui (15 mg, 0.079 mmol, 0. 1 eq) were added. The resultant mixture was heated at 85 °C for 16 h then cooled to room temperature and filtered through celite and concentrated under reduced pressure to give crude product. The crude was purified by column chromatography using 20% EtOAc: DCM to afford yellow solid pure product 59 (0.25 g, 61% yield). TLC: 50% EtOAc in Hexane, R / = 0.4; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO): 8 8.63 (d, J= 2.2 Hz, 1H), 8.58 (d, J= 5.1 Hz, 1H), 8.46 (dd, J= 6.6, 2.9 Hz, 1H), 8.22 (dd, J= 8.4, 4.0 Hz, 1H), 7.94 (d, J = 5.8 Hz, 2H), 7.72 - 7.64 (m, 2H), 7.58 (d, J = 9.7 Hz, 1H), 7.53 (q, J = 2.5 Hz, 29920-428111 2025-018-02

[0554] 2H), 7.47 (d, J= 3.5 Hz, 1H), 7.37 (t, J= 7.8 Hz, 1H), 7.27 (t, J= 7.5 Hz, 1H), 6.86 (d, J= 7.8 Hz. 1H), 4.48 - 4.37 (m, 2H), 2.82 (1, J= 3.5 Hz, 3H). 1.36 (Id, J= 7.2, 2.2 Hz, 3H).13C NMR (101 MHz, DMSO): 5 167.95, 166.12, 163.52, 155.99, 151.24, 143.21, 136.32, 134.93, 131.59, 131.50, 130.27, 130.18, 130.05, 127.14, 127.05, 126.16, 125.82, 125.26, 124.10, 123.05, 121.37, 120.76, 120.52, 119.76, 119.65, 119.23, 118.99, 111.51, 109.68, 62.01, 26.79, 14.61; MS (ESI) m / z = 511.17 [M+H]+. Another synthesis was performed to provide a yellow solid pure product 59 (0.26 g. 64% yield). TLC: 50% EtOAc in hexane, R / = 0.4; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO-de): § 8.63 (d, J= 7.7 Hz, 1H), 8.58 (d, J= 5.1 Hz, 1H), 8.46 (dd, J= 6.6, 2.9 Hz, 1H), 8.22 (dd, J= 8.4, 4.0 Hz, 1H), 7.94 (d, J= 5.8 Hz. 2H), 7.72-7.64 (m, 2H), 7.58 (d, J= 9.7 Hz, 1H), 7.53 (q, J= 2.5 Hz, 2H), 7.47 (d, J = 3.5 Hz. 1H), 7.37 (t, J= 7.8 Hz, 1H), 7.27 (t, J= 7.5 Hz, 1H), 6.86 (d. J= 7.8 Hz. 1H), 4.48 - 4.37 (m, 2H, OCH22.82 (t, J= 3.5 Hz, 3H, CH31.36 (m, 3H).13C NMR (101 MHz, DMSO-de): 8 167.9, 166.1, 163.5, 155.9, 151.2, 143.2, 136.3, 134.9, 131.5, 131.5, 130.2, 130.1, 130.0, 127.1, 127.0, 126.1, 125.8, 125.2, 124.1, 123.0, 121.3, 120.7, 120.5, 119.7, 119.6, 119.2, 118.9, 111.5, 109.6. 62.0, 26.7, 14.6.

[0555] (Z)-2-fluoro-5-(5-((l-(3-(methylcarbamoyl)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)benzoic acid (60). To a solution of Ethyl(Z)-2-fluoro-5-(5-((l-(3- (methylcarbamoyl)phenyl)-2-oxoindolin-3-ylidene)methyl) furan-2-yl) benzoate 59 (0.1g, 0.196 mmol, 1 eq) in THF:water (3 mL, 1: 1) was added LiOH (24 mg, 0.98 mmol, 5 eq) at room temperature and stirred for 16 hours. The solvent was concentrated under reduced pressure to give solid residue. The solid residue was diluted with water and acidified with citric acid solution till the pH was 3.0, the formed solid was filtered and washed with n- pentane to give title product 60 (70 mg, 74% yield) as a yellow solid. TLC: 10% MeOH in DCM, R = 0.1 ; visualized with UV. Major Z-isomer data: 1H NMR (400 MHz, DMSO): 5 13.57 (d, J = 113.9 Hz, 1H), 8.68 (d, J = 7.7 Hz, 1H), 8.57 (dd, J = 16.0, 5.9 Hz, 2H), 8.23 (d, J = 6.2 Hz, 1H), 7.95 (d, J= 6.1 Hz. 2H), 7.69 (d, J = 7.8 Hz, 2H). 7.56 (d, J= 5.5 Hz, 2H), 7.52 (d, J = 16.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H). 6.87 (d, .7 = 7.8 Hz, 1H), 2.81 (d, ,7 = 4.5 Hz, 3H).13C NMR (101 MHz, DMSO): 8 167.98, 166.09, 164.90, 164.87, 163.06, 160.46, 156.20, 151.17, 143.21, 136.33, 134.95, 131.18, 131.08, 130.19, 130.07, 127.71, 127.07, 126.02, 125.98, 125.84, 125.35, 124.22, 123.06, 121.41, 120.65, 120.53, 119.12, 118.88. 111.34, 109.65, 26.79; MS (ESI) m / z = 481.12 [M-H]’.

[0556] (Z)-2-fluoro-N-(3-methoxyphenyl)-5-(5-((l-(3-(methylcarbamoyl)phenyl)-2- oxoindolin-3-ylidene)methyl)furan-2-yl)benzamide 61 (GL-3488). To a solution of (Z)-2- 29920-428111 2025-018-02 fluoro-5-(5-((l-(3-(methylcarbamoyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2- yl)benzoic acid 60 (0.1 g, 0.207 mmol. 1 eq) and HATU (0.118 g, 0.310 mmol, 1.5 eq) in DMF (3 mL) was added DIPEA (115 qL, 0.621 mmol, 3 eq) at room temperature and stirred for 10 minutes followed by the addition of 3-methoxy aniline 15a (25 mg, 0.207 mmol, 1 eq). The resultant reaction mixture was stirred for 16 hours and then poured into ice cold water (30 mL) and extracted in EtOAc (2 x 30 mL). The organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by using flash column using 20% EtOAc:DCM to give target product 61 (50 mg, 41% yield) as yellow solid. TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. Major Z-isomer data: 1H NMR (400 MHz, DMSO): 5 10.63 (s, 1H), 8.67 (d, J= 7.7 Hz, 1H), 8.59 (s, 1H), 8.29 (d, J= 6.5 Hz, 1H), 8.16 (s, 1H), 7.95 (s, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.63 (t, J = 9A Hz, 1H), 7.58 (d, J = 3.9 Hz, 2H), 7.53 (s, 1H), 7.46 (s, 1H), 7.32 (q, J= 8.8, 7.6 Hz, 3H), 7.22 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.75 (d, J= 7.8 Hz, 1H), 3.78 (s, 3H), 2.81 (t, J= 3.2 Hz, 3H). 513C NMR (101 MHz, DMSO): 5 168.01, 166.26, 160.05, 156.41, 151.16, 143.22, 140.30, 136.33, 134.94. 130.24, 130.20. 130.06, 127.07. 126.17, 125.84, 125.27, 123.04, 121.39, 120.74, 120.62. 112.63, 111.39, 110.07, 109.69. 106.16. 55.56, 26.79; MS (ESI) m / z = 588.2 [M+H]+. Another synthesis was performed to provide product 61 (70 mg, 57% yield) as a yellow solid. TLC: 10% MeOH in DCM, R -= 0.4; visualized with UV. Major Z-isomer data: 'U NMR (400 MHz, DMSO-de): 3 10.63 (s, 1H,CCWH). 8.67 (d, J= 7.7 Hz, 1H), 8.59 (s, 1H), 8.29 (d, J = 6.5 Hz. 1H), 8.16 (s. 1H), 7.95 (s, 2H), 7.69 (d, J= 8.6 Hz, 2H), 7.63 (t, J= 9.1 Hz, 1H), 7.58 (d, J = 3.9 Hz, 2H), 7.53 (s, 1H), 7.46 (s, 1H), 7.32 (q, J= 8.8, 7.6 Hz, 3H), 7.22 (t, J= 7.5 Hz, 1H), 6.86 (d, J= 8.2 Hz, 1H), 6.75 (d, J= 7.8 Hz, 1H), 3.78 (s, 3H, OCH3), 2.81 (d, J= 3.2 Hz, 3H. CHi).13C NMR (101 MHZ, DMSO-de): 3 168.0, 166.2, 160.0, 156.4. 151.1, 143.2, 140.3,

[0557] 136.3, 134.9. 130.2, 130.2, 130.0, 127.0, 126.1, 125.8, 125.2, 123.0, 121.3, 120.7, 120.6, 112.6,

[0558] 1 11.3, 110.0, 109.6, 106.1, 55.5, 26.7.

[0559] (Z)-2-fluoro-5-(5-((l-(3-(melhylcarbamoyl)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)-N-(3-(trifluoromethoxy)phenyl)benzamide 62 (GL-3489). 21b was prepared by an above-described procedure by using (Z)-2-fluoro-5-(5-((l -(3- (methylcarbamoyl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid 60 (0.1 mg, 0.207 mmol, 1 eq) and 3-trifluoromethoxy aniline 15b (0.036g, 0.207 mmol, 1 eq) as a starting material. Orange solid (50 mg, 38% yield). TLC: 10% MeOH in DCM, R / = 0.4; visualized with UV. Major Z-isomer data: 1H NMR (400 MHz, DMSO): 5 10.95 (s, 1H), 8.66 (d, J = 7.8 Hz, 1H), 8.58 (s, 1H), 8.32 (d, J= 6.5 Hz, 1H), 8.18 (s, 1H), 7.98 - 7.90 (m, 4H), 29920-428111 2025-018-02

[0560] 7.73 (d, J= 9.1 Hz, 1H), 7.70 - 7.63 (m, 3H), 7.58 (d, J = 2.8 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.29 (t, J= 7.8 Hz, 1H), 7.24 - 7.11 (m, 2H). 6.86 (d, J= 8.0 Hz, 1H), 2.81 (t,J= 3.4 Hz, 3H);13C NMR (101 MHz, DMSO): 5 167.97, 166.10, 163.01, 156.33, 151.23, 149.01, 143.25, 140.81, 136.34, 134.93, 131.21, 130.20, 130.07, 127.08, 126.25, 125.99, 125.86, 125.35, 124.20, 123.00, 121.40, 120.75, 120.62, 118.90, 116.68, 112.30, 111.52, 109.71, 26.79; MS (ESI) m / z = 642.17 [M+H]+. Another synthesis was performed to provide the product as an orange solid (85 mg, 64% yield). TLC: 10% MeOH in DCM. R^= 0.4; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO-de): 3 10.95 (s, 1H, CONH), 8.66 (d, J= 7.8 Hz, 1H), 8.58 (s, 1H), 8.32 (d, J = 6.5 Hz, 1H), 8.18 (s, 1H), 7.98-7.90 (m, 4H), 7.73 (d, J =

[0561] 9.1 Hz, 1H), 7.70-7.63 (m, 3H), 7.58 (d, J= 2.8 Hz, 2H), 7.54 (d, J= 8.6 Hz, 2H), 7.29 (t, J= 7.8 Hz. 1H), 7.24-7.11 (m, 2H). 6.86 (d, J = 8.0 Hz, 1H), 2.81 (t, J = 3.4 Hz, 3H).13C NMR (101 MHz, DMSO-de): 3 167.9, 166.1, 163.0, 156.3, 151.2, 149.0, 143.2, 140.8, 136.3, 134.9, 131.2, 130.2, 130.0, 127.0, 126.2, 125.9, 125.8, 125.3, 124.2, 123.0, 121.4, 120.7, 120.6, 118.9, 116.6, 112.3, 111.5, 109.7, 26.7; LCMS (ESI) m / z = 640.40 [M-H] . HPLC purity: 99.9% (fe = Z isomer at 10.63 min and E isomer at 11.06 min).

[0562] 2-(2-bromophenyl)-N-(3-(methylsulfonyl)phenyl)acetamide (65a). To a solution of 2- (2-bromophenyl)acetic acid 63 (0.3 g, 1.395 mmol, 1 eq) and HATU (0.79 g, 2.092 mmol, 1.5 eq) in DMF (5 mL) was added DIPEA (0.7 mL, 4.185 mmol, 3 eq) at room temperature and stirred for 10 minutes followed by the addition of 3-(methylsulfonyl)aniline 64a (0.238 mg, 1.395 mmol, 1 eq). The resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice cold water (30 mL) and the resulted solid was filtered and dried to obtain crude product, which was purified by using flash column using 2% MeOH:DCM to give target product 65a (0.4 g, 74% yield) as white solid. TLC: 5% MeOH in DCM. R / = 0.5; visualized with UV. 1H NMR (400 MHz, CDC13): 5 8.01 - 7.89 (m, 2H), 7.68 (dt, J= 7.5,

[0563] 3.1 Hz, 2H), 7.55 (dd, J = 7.6, 2.6 Hz, 1H), 7.51 (d, J= 5.4 Hz, 1H), 7.46 (d, J= 7.7 Hz, 1H), 7.40 (dt, J = 8.7, 4.2 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 3.97 - 3.92 (m, 2H), 3.07 (d, J = 2.7 Hz. 3H).

[0564] 2-(2-bromophenyl)-N-(3-(methylsulfonamido)phenyl)acetamide (65b). 24b was prepared by an above-described procedure by using 2-(2-bromophenyl)acetic acid 63 (0.2 g, 0.930 mmol, 1 eq) and 3-(methylsulfonyl)aniline 64b (0. 173 g, 0.930 mmol, 1 eq) as a starting material. White solid (0.221g, 61% yield). TLC: 5% MeOH in DCM, R = 0.5; visualized with UV. 1H NMR (400 MHz, DMSO): 5 10.29 (s, 1H), 9.75 (s, 1H), 7.62 (d, J= 8.1 Hz, 1H), 7.54 (s, 1H), 7.40 (dd. J= 16.4, 7.9 Hz. 3H), 7.28 - 7.18 (m, 2H), 6.89 (d, J= 8.2 Hz, 1H), 3.85 (s, 29920-428111 2025-018-02

[0565] 2H), 2.98 (d, J = 2.4 Hz, 3H). MS (ESI) m z = 383.01 [M+H]+. Another synthesis was performed to provide the product as a white solid (0.251g, 70% yield). TLC: 5% MeOH in DCM, R / = 0.5; visualized with UV. 'H NMR (400 MHz, DMSO-de): <5 10.29 (s, 1H, CONH), 9.75 (s, 1H), 7.62 (d, J= 8.1 Hz, 1H), 7.54 (s, 1H), 7.40 (dd, J= 16.4, 7.9 Hz, 3H), 7.28 - 7.18 (m, 2H), 6.89 (d, J= 8.2 Hz, 1H), 3.85 (s, 2H), 2.98 (d, J= 2.4 Hz, 3H).

[0566] 2-(2-bromophenyl)-N-(3-(5-methyl-l.3.4 -oxadiazol-2-yl) phenyl) acetamide (65c). 24c was prepared by an above-described procedure by using 2-(2-bromophenyl)acetic acid 63 (0.2 g, 0.93 mmol, 1 eq) and 3-(5-methyl-l,3,4-oxadiazol-2-yl)aniline 64c (0.162 g, 0.93 mmol, 1 eq) as a starting material. White solid (0.28 g, 80% yield). TLC: 5% MeOH in DCM. R = 0.5; visualized with UV. 1H NMR (400 MHz, CDCh): 5 8.02 (d, J= 2.5 Hz, 1H), 7.70 (t, J = 9.6 Hz, 2H), 7.57 (dd, J= 8.1, 2.1 Hz, 1H), 7.49 (s, 1H), 7.41 - 7.33 (m, 2H), 7.30 (dt, J= .1, 4.3 Hz, 1H), 7.18 - 7.12 (m, 1H), 3.85 (d, J = 2.3 Hz, 2H), 2.53 (t, J = 1.8 Hz, 3H);1?C NMR (101 MHz, CDCh) 5 168.15, 138.57, 134.22, 133.31, 131.85. 129.85, 129.56, 128.25, 124.99, 124.45. 123.02, 122.57, 117.89, 44.96, 11.15; MS (ESI) m / z = 372.04 [M+H]+. l-(3-(methylsulfonyl)phenyl)indolin-2-one (66a). The suspension of 2-(2- bromophenyl)-N-(3-(methylsulfonyl)phenyl)acetamide 65a (0.2 g, 0.543 mmol. 1.0 eq.) and CS2CO3 (0.265 g, 0.815 mmol, 1.5 eq.) in toluene (10 mL) was degassed with nitrogen for 10 minutes then X-phos (25 mg, 0.054 mmol, 0.1 eq.) followed by Pd(OAc)2 (6 mg, 0.027 mmol, 0.05 eq.) were added. The resultant reaction mixture was heated at 100 °C for 5h and then cool to room temperature and filtered through celite. The filtrate was evaporated under reduced pressure to give crude product, which was purified by column chromatography using 2% MeOH in DCM to give target product 66a (0.12 g, 77% yield) as a white solid. TLC: 5% MeOH in DCM, R / = 0.6; visualized with UV. 1H NMR (400 MHz, CDC13): 5 7.98 (s, 1H), 7.95 - 7.89 (m, 1H), 7.69 (t, J= 3.3 Hz, 2H), 7.27 (d, J= 7.7 Hz, 1H), 7.12 - 7.07 (m, 3H), 6.76 (d, J = 8.0 Hz. 1H), 3.68 (s, 2H), 3.04 (d, J= 2.1 Hz, 3H); MS (ESI) m / z = 288.07 [M+H]+.

[0567] N-(3-(2-oxoindolin-l-yl)phenyl)methanesulfonamide (66b). 66b was prepared by an above-described procedure by using 2-(2-bromophenyl)-N-(3- (methylsulfonamido)phenyl)acetamide 65b (0.2 mg, 0.522 mmol, 1.0 eq.) as a starting material. Pale brown solid; (0.1 g, 65% yield). TLC: 50% EtOAc in hexane, R / = 0.3; visualized with UV. ‘H NMR (400 MHz, CDCh): 5 7.52 (ddd, J= 9.9, 8.0, 2.2 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.29 (dt, J= 5.7, 3.2 Hz, 3H), 7.13 (td, J= 7.4, 4.3 Hz. 1H), 7.04 (s, 1H), 6.92 - 6.82 (m, 1H), 3.76 (d, J= 2.5 Hz, 2H). 3.09 (t. J = 1.8 Hz, 3H); MS (ESI) m / z = 303.07 [M+H]+. Another synthesis was performed to provide the product as a pale brown solid; (0.11 g, 70% yield). 29920-428111 2025-018-02

[0568] TLC: 50% EtOAc in hexane, Rf= 0.3; visualized with UV. ’H NMR (400 MHz, CDCh): d 7.52 (dd, J= 9.9, 8.0, 2.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.29 (dd, J= 5.7. 3.2 Hz, 3H), 7.13 (dd, J = 7.4, 4.3 Hz, 1H), 7.04 (s, 1H), 6.92-6.82 (m, 1H), 3.76 (d, J= 2.5 Hz, 2H), 3.09 (t, J= 1.8 Hz, 3H). l-(3-(5-methyl-1.3.4-oxadiazol-2-yl)phenyl)indolin-2-one (66c). 66c was prepared by an above-described procedure by using 2-(2-bromophenyl)-N-(3-(5-methyl-l ,3,4-oxadiazol-2- yl)phenyl)acetamide 65c (0.2 g, 0.537 mmol, 1.0 eq.) as a starting material, pale brown solid; (0.12 g, 77% yield). TLC: 5% MeOD in DCM. R / = 0.5; visualized with UV. ’H NMR (400 MHz, CDCh): 5 8.10 - 7.99 (m. 2H), 7.61 (td, J = 8.1, 2.6 Hz, 1H), 7.54 (d. J = 8.2 Hz. 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.04 (td, J = 7.4, 2.3 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 3.68 (d, J= 2. A Hz, 2H), 2.56 (d, J = 2.5 Hz, 3H).13C NMR (101 MHz, CDC13) 5 174.37, 164.11, 163.99, 144.50, 135.44, 130.54, 129.64, 127.99, 126.21, 125.56, 124.87, 124.76. 124.26, 123.26, 109.36, 36.06, 11.16; MS (ESI) m / z = 292. 11 [M+H]+.

[0569] (Z)-2-fluoro-5-(5-( (l-( 3-(methylsulfonyl)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)benzoic acid (67a). The suspension of l-(3- (methylsulfonyl)phenyl)indolin-2-one 66a (0.2 g, 0.696 mmol, 1 eq.) and 2-fluoro-5-(5- formyl-lH-pyrrol-2-yl)benzoic acid 13b (0.163 g, 0.696 mmol, 1 eq) in acetic acid (10 mL) was heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with cold water (50 mL), the formed solid was fdtered and dried under vacuum to get crude solid. The crude was triturated with 20% EtOAc:hexane and filtered to obtain target product 26a (0.2 g, 57% yield) as dark orange solid. TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO): 5 8.69 (d, J= 7.6 Hz, 1H), 8.54 (s, 1H), 8.33 (d, J= 17. 1 Hz, 1H), 8.20 (d, J= 8.5 Hz, 1H), 8.09 (s, 2H), 8.04 (d, J= 8.4 Hz, 2H), 7.90 (d, J= 10.0 Hz, 3H), 7.56 (d, J= 6.7 Hz, 3H), 7.51 (d, J = 13.7 Hz, 2H), 7.38 (t. J = 8.2 Hz, 2H). 7.32 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H); MS (ESI) m / z = 502.08 [M+H]L Another synthesis was performed to provide product 67a (0.25 g, 73% yield) as dark orange solid. TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. ’H NMR (400 MHz, DMSO-de): 8 8.69 (d, J= 7.6 Hz, 1H), 8.54 (s, 1H), 8.33 (d, J = 17.1 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.09 (s, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 10.0 Hz, 3H), 7.56 (d, J= 6.7 Hz, 3H), 7.51 (d, J= 13.7 Hz, 2H), 7.38 (t, J= 8.2 Hz, 2H), 7.32 (d, J= 7.7 Hz, 1H), 6.95 (d, J= 8.0 Hz, 1H).

[0570] (Z)-2-fluoro-5-(5-((l-(3-(methylsulfonamido)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)benzoic acid (67b). 67b was prepared by an above-described 29920-428111 2025-018-02 procedure by using N-(3-(2-oxoindolin-l-yl)phenyl)methanesulfonamide 66b (0.2 g, 0.662 mmol, 1 eq.) and 2-fluoro-5-(5-formyl-lH-pyrrol-2-yl)benzoic acid 13b (0. 155 g. 0.662 mmol, 1 eq) as a starting material, dark orange solid; (0.166 g, 48% yield). TLC: 10% MeOD in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO): 5 10.05 (s, 1H), 9.64 (d, J = 2.7 Hz, 1H), 8.67 (d, J = 7.7 Hz, 1H), 8.54 (d, J = 6.7 Hz, 1H), 8.31 (d, J = 6.9 Hz, 1H), 8.17 (dd, J = 28.7, 7.6 Hz, 1H), 7.59 - 7.52 (m, 3H), 7.43 - 7.35 (m, 2H), 7.34 - 7.23 (m, 3H), 6.92 (d, J = 8.6 Hz. 1H), 3.10 (d. J = 2.7 Hz, 3H); MS (ESI) m / z = 517.09 [M-H]+. Another synthesis was performed to provide the product as an orange solid; (0.266 g, 77% yield). TLC: 10% MeOH in DCM, R / = 0.2; visualized with UV. 'H NMR (400 MHz, DMSO-de): 3 10.05 (s, 1H), 9.64 (d, J = 2.7 Hz. 1H), 8.67 (d, J = 7.7 Hz, 1H). 8.54 (d, J = 6.7 Hz, 1H), 8.31 (d, J = 6.9 Hz. 1H), 8.17 (dd, J= 28.7, 7.6 Hz, 1H), 7.59-7.52 (m, 3H), 7.43- 7.35 (m, 2H), 7.34-7.23 (m, 3H), 6.92 (d, J= 8.6 Hz, 1H), 3. 10 (d, J= 2.7 Hz, 3H).

[0571] (Z)-2-fluoro-5-(5-( (l-( 3-(5-methyl-l, 3, 4-oxadiazol-2-yl)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)benzoic acid (67c). 67c was prepared by an above-described procedure by using l-(3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl)indolin-2-one 66c (200 mg, 0.687 mmol, 1 eq.) and 2-fluoro-5-(5-formyl-lH-pyrrol-2-yl)benzoic acid 13b (160 mg, 0.687 mmol, 1 eq) as a starting material, dark orange solid; (0.2 g, 57% yield). TLC: 10% MeOD in DCM, R / = 0.3; visualized with UV. 'H NMR (400 MHz. DMSO): 5 8.69 (d. J= 7.3 Hz. 1H), 8.55 - 8.47 (m, 1H), 8.15 (t, J = 5.6 Hz, 1H), 8.07 (s, 2H), 7.85 - 7.75 (m, 3H), 7.55 (s, 2H), 7.46 (s, 1H), 7.35 (q, J = 8.8, 8.2 Hz, 2H), 6.99 - 6.91 (m, 1H), 2.61 (d, J = 3.3 Hz, 3H).13C NMR (101 MHz, DMSO): 5 167.95, 164.74, 163.82, 156.50, 151.07. 142.85, 135.85, 135.81, 135.09. 134.99, 131.33. 131.00, 130.87. 130.34, 130.11, 127.71, 126.06, 125.81, 125.43, 125.32. 124.98, 124.28, 123.27, 121.55, 120.59, 120.49. 118.87. 118.64. 111.16, 109.54, 11.14; MS (ESI) m / z = 506. 11 [M-H]+. Another synthesis was performed to provide the product as an orange solid; (0.25 g, 71% yield). TLC: 10% MeOH in DCM, R = 0.3; visualized with UV. 'H NMR (400 MHz, DMSO-de): 3 8.69 (d, J = 7.3 Hz, 1H), 8.55-8.47 (m, 1H), 8.15 (t, J = 5.6 Hz. 1H), 8.07 (s. 2H), 7.85-7.75 (m, 3H). 7.55 (s, 2H). 7.46 (s, 1H). 7.35 (q, J = 8.8, 8.2 Hz, 2H), 6.99-6.91 (m, 1H), 2.61 (d, J = 3.3 Hz, 3H).13C NMR (101 MHz, DMSO-de): 3 167.9,

[0572] 164.7, 163.8, 156.5, 151.0, 142.8, 135.8, 135.8, 135.0, 134.9, 131.3, 131.0, 130.8, 130.3, 130.1,

[0573] 127.7, 126.0, 125.8, 125.4, 125.3, 124.9, 124.2, 123.2, 121.5, 120.5, 120.4, 118.8, 118.6, 111.1, 109.5, 11.1.

[0574] (Z)-2-fluoro-N-(3-methoxyphenyl)-5-(5-((l-(3-(methylsulfonyl)phenyl)-2-oxoindolm-

[0575] 3-ylidene)methyl)furan-2-yl)benzamide 68 (GL-3492). To a solution of (Z)-2-fluoro-5-(5-((l- 29920-428111 2025-018-02

[0576] (3-(methylsulfonyl)phenyl)-2-oxoindolin-3-ylidene) methyl)furan-2-yl)benzoic acid 67a (0.1 g, 0.198 mmol, 1 eq) and HATU (0.113 g, 0.298 mmol. 1.5 eq) in DMF (3 mL) was added DIPEA (0.11 mL, 0.594 mmol, 3 eq) at room temperature and stirred for 10 minutes followed by the addition of 3-methoxy aniline 15a (0.024 g, 0.197 mmol, 1 eq). The resultant reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice cold water (30 mL) and the resulted solid was filtered and dried to obtain crude product, which was purified by column chromatography using 30% EtOAc:DCM to give target product 68 (90 mg, 75% yield) as a yellow solid. TLC: 5% MeOH in DCM, R / = 0.3; visualized with UV. Major Z-isomer data: 1H NMR (400 MHz, DMSO): 5 10.63 (s, 1H), 8.68 (d, J = 7.7 Hz, 1H), 8.29 (d, J = 6.3 Hz, 1H), 8.16 (d, J = 7.9 Hz. 1H), 8.08 (s, 1H), 8.03 (d, J = 7.2 Hz. 1H), 7.89 (d, J = 9.0 Hz, 2H). 7.64 (d, J= 9.1 Hz, 1H), 7.59 (s, 2H). 7.53 (d, J= 3.5 Hz, 1H), 7.46 (s, 1H), 7.32 (d, J= 9.4 Hz, 3H), 7.24 (t, J= 7.8 Hz, 1H), 6.94 (d, J= 8.0 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 3.78 (s, 3H), 3.33 (s, 3H).13C NMR (101 MHz, DMSO): 5 167.94, 162.63, 160.04, 156.51, 151.13, 142.69, 142.56, 140.33, 135.64, 132.35, 131.39, 130.22, 130.19, 128.81, 126.65. 126.42, 126.26. 126.15, 126.12. 125.50, 125.44, 124.23, 123.28, 121.54, 120.78, 120.50. 1 12.59, 111.45, 110.03, 109.64, 106.11. 55.55, 43.82; MS (ESI) m / z = 609.15 (M+HJ+.

[0577] (Z)-2-fluoro-5-(5-((l-(3-(methylsulfonyl)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)-N-(3-(trifluoromethoxy)phenyl)benzamide 69 (GL-3493). 69 was prepared by an above-described procedure by using (Z)-2-fluoro-5-(5-((l-(3- (methylsulfonyl)phenyl)-2-oxoindolin-3-ylidene) methyl)furan-2-yl)benzoic acid 67a (0.1 g, 0.198 mmol, 1 eq) and 3 -trifluoromethoxy aniline 15b (0.035 g, 0.197 mmol, 1 eq) as a starting material. Orange solid; (50 mg, 38% yield). TLC: 5% MeOD in DCM, R / = 0.3; visualized with UV. H NMR (400 MHz, DMSO): 5 10.95 (s, 1H). 8.73 - 8.63 (m, 1H). 8.33 (d, J = 6.5 Hz. 1H), 8. 18 (d, J = 8.1 Hz, 1H), 8.08 (s, 1H), 8.03 (d, J= 6.8 Hz, 1H), 7.97 - 7.86 (m, 3H), 7.74 (d, J= 8.5 Hz, 2H), 7.65 (t, J= 9.7 Hz, 1H), 7.59 (d, J = 2.9 Hz, 2H), 7.54 (q, J= 3.4 Hz, 2H), 7.35 - 7.28 (m, 1H), 7.22 (t, .7= 7.2 Hz, 1H), 7.17 (d, J= 8.4 Hz, 1H), 6.94 (d, J= 7.9 Hz, 1H).13C NMR (101 MHz. DMSO): 5 167.92, 163.00, 156.41, 151.17, 148.99. 142.70, 142.56, 140.79, 135.62, 132.36, 131.38, 131.22, 130.17, 126.67, 126.22, 125.96, 125.80, 125.54, 125.46, 124.24, 123.24, 121.53, 120.77, 120.51, 118.90, 118.16, 116.69, 112.30, 111.55, 109.64, 43.80; MS (ESI) m / z = 663.12 [M+H]+. Another synthesis was performed to provide the product as an orange solid; (85 mg, 65% yield). TLC: 5% MeOH in DCM, R / = 0.3; visualized with UV. 'H NMR (400 MHz, DMSO-de): d 10.95 (s, 1H), 8.73 - 8.63 (m, 1H), 8.33 (d, J = 6.5 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.08 (s, 1H), 8.03 (d, J= 6.8 Hz, 1H), 7.97 29920-428111 2025-018-02

[0578] - 7.86 (m, 3H). 7.74 (d, J= 8.5 Hz, 2H), 7.65 (t, J= 9.7 Hz, 1H), 7.59 (d, J= 2.9 Hz, 2H), 7.54 (q, J= 3.4 Hz, 2H), 7.35 - 7.28 (m, 1H), 7.22 (t, J= 7.2 Hz, 1H), 7. 17 (d, J= 8.4 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H).13C NMR (101 MHz, DMSO-de): 8 167.9, 163.0, 156.4, 151.1, 148.9, 142.7, 142.5, 140.7, 135.6, 132.3, 131.3, 131.2, 130.1, 126.6, 126.2, 125.9, 125.8, 125.5, 125.4,

[0579] 124.2, 123.2, 121.5, 120.7, 120.5, 118.9, 118.1, 116.6, 112.3, 111.5, 109.6, 43.8; LCMS (ESI) m / z = 661.35 [M-H] HPLC purity: 85. 16% (1R = Z isomer at 10.91 min and E isomer at 11.30 min).

[0580] (Z)-2-fluoro-5-(5-((l-(3-(methylsulfonyl)phenyl)-2-oxoindolin-3- prepared by an above-described procedure by using (Z)-2-fluoro-5-(5-((l-(3- (methylsulfonamido)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid 67b (0.1 g, 0.193 mmol, 1 eq) and 3-methoxy aniline 15a (24 mg, 0.193 mmol, 1 eq) as a starting material, yellow solid; (50 mg, 41% yield). TLC: 5% MeOD in DCM. R / = 0.3; visualized with UV. 'H NMR (400 MHz, DMSO): 5 10.62 (s, 1H), 10.04 (s. 1H), 8.65 (d, J= 7.7 Hz, 1H), 8.28 (d, J= 6.2 Hz, 1H), 8.15 (d, J= 8.9 Hz, 1H), 7.62 (t, J= 8.3 Hz, 2H), 7.58 - 7.54 (m, 3H), 7.51 (s, 1H), 7.45 (s, 1H), 7.32 (d, J = 9.1 Hz, 5H), 7.26 - 7.18 (m, 2H), 6.90 (d, J= 8.0 Hz, 1H),

[0581] 6.74 (d, J = 7.8 Hz, 1H), 3.77 (d, J = 2.7 Hz, 3H), 3.09 (d, J = 2.6 Hz, 3H).13C NMR (101

[0582] MHz, DMSO): 8 167.82, 162.63. 160.02, 156.38, 151.17, 143.16, 140.35. 139.97, 135.60, 132.56, 132.00, 131.90, 130.92, 130.18, 129.30, 129.18, 128.75, 126.43, 126.14, 125.28,

[0583] 124.16, 122.99, 122.25, 121.39, 120.71, 120.61, 119.10, 117.73, 112.54, 111.41, 109.99,

[0584] 109.72, 106.05, 55.52; MS (ESI) m / z = 624.16 [M+H]+. Another synthesis was performed to provide the product as a yellow solid: (78 mg, 65% yield). TLC: 5% MeOH in DCM, R / = 0.3; visualized with UV. 'H NMR (400 MHz. DMSO-de): 8 10.62 (s, 1H, CONH), 10.04 (s. 1H). 8.65 (d, J= 7.7 Hz, 1H), 8.28 (d, J= 6.2 Hz, 1H), 8.15 (d, J= 8.9 Hz, 1H), 7.62 (t, J= 8.3 Hz, 2H), 7.58-7.54 (m, 3H), 7.51 (s, 1H), 7.45 (s, 1H), 7.32 (d, J= 9.1 Hz, 5H), 7.26-7.18 (m, 2H), 6.90 (d, J= 8.0 Hz, 1H), 6.74 (d. J= 7.8 Hz. 1H), 3.77 (d, J= 2.7 Hz, 3H), 3.09 (d, J= 2.6 Hz, 3H).13C NMR (101 MHz, DMSO-de): 8 167.8, 162.6, 160.0, 156.3, 151.1, 143.1, 140.3, 139.9, 135.6, 132.5, 132.0, 131.9, 130.9, 130.1 , 129.3, 129.1 , 128.7, 126.4, 126.1, 125.2, 124.1, 122.9,

[0585] 122.2, 121.3, 120.7, 120.6, 119.1, 117.7, 112.5, 111.4, 109.9, 109.7, 106.0, 55.5.

[0586] (Z)-2-fluoro-5-(5-( (l-( 3-(methylsulfonamido)phenyl)-2-oxoindolin-3- ylidene)methyl)fiuran-2-yl)-N-(3-(trifluoromethoxy)phenyl)benzamide 71 (GL-3512). 71 was prepared by an above-described procedure by using (Z)-2-fluoro-5-(5-((l-(3- (methylsulfonamido)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid 67b (0.1 29920-428111 2025-018-02 g, 0.193 mmol, 1 eq) and 3 -trifluoromethoxy aniline 15b (34 mg, 0.193 mmol, 1 eq) as a starting material, yellow solid; (50 mg, 38% yield). TLC: 5% MeOD in DCM, R / = 0.3; visualized with UV. 'H NMR (400 MHz, DMSO): 5 10.95 (s, 1H), 10.05 (s, 1H), 8.65 (d, J =

[0587] 7.8 Hz, 1H), 8.31 (d, J= 6.3 Hz, 1H), 8. 18 (s, 2H), 7.93 (s, 2H), 7.72 (s, 1H), 7.66 (d, J= 10.3 Hz, 1H), 7.55 (d, J= 14.7 Hz, 5H), 7.31 (s, 3H), 7.18 (s, 2H), 6.90 (d, J= 7.9 Hz, 1H), 3.09 (s, 3H).13C NMR (101 MHz, DMSO): 5 167.92, 163.00, 156.41. 151.17, 142.70, 142.56, 140.79, 135.62. 132.36, 131.38. 131.22, 130.17. 126.67, 126.22. 125.54, 125.46. 124.24, 123.24. 121.53, 120.77, 120.51, 118.90, 116.69, 112.30, 111.55, 109.64, 43.80; MS (ESI) m / z = 678.13 [M+H]+. Another synthesis was performed to provide the product as a yellow solid: (82 mg, 63% yield). TLC: 5% MeOH in DCM. R / = 0.3; visualized with UV. ’H NMR (400 MHz, DMSO-de): 8 10.95 (s, 1H), 10.05 (s, 1H. CONH). 8.65 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 6.3 Hz, 1H), 8.18 (s, 2H), 7.93 (s, 2H), 7.72 (s, 1H), 7.66 (d, J = 10.3 Hz, 1H), 7.55 (d, J = 14.7 Hz, 5H), 7.31 (s, 3H), 7.18 (s, 2H), 6.90 (d, J= 7.9 Hz, 1H), 3.09 (s, 3H).13C NMR (101 MHz, DMSO-ds): <5 167.9, 163.0, 156.4, 151.1, 142.7, 142.5, 140.7, 135.6, 132.3, 131.3, 131.2, 130.1, 126.6, 126.2, 125.5, 125.4, 124.2, 123.2, 121.5, 120.7, 120.5, 118.9, 116.6, 112.3, 111.5, 109.6, 43.8.

[0588] (Z)-2-fluoro-N-(3-methoxyphenyl)-5-(5-((l-(3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl)- 2-oxoindolm-3-ylidene)methyl)furan-2-yl)benzamide 72 (GL-3490). 72 was prepared by an above-described procedure by using (Z)-2-fluoro-5-(5-((l-(3-(5-methyl-l,3,4-oxadiazol-2- yl)phenyl)-2-oxoindolin-3-ylidene) methyl)furan-2-yl)benzoic acid 67c (0.1g, 0.197 mmol, 1 eq) and 3-methoxy aniline 15a (24 mg, 0. 197 mmol, 1 eq) as a starting material, yellow solid; (80 mg, 66% yield). TLC: 5% MeOD in DCM, R / = 0.4; visualized with UV. 'H NMR (400 MHz, DMSO): 5 10.63 (s. 1H), 8.67 (d. J = 7.9 Hz. 1H). 8.34 - 8.26 (m. 1H). 8.16 (t. J = 6.3 Hz, 1H), 8.07 (d, J = 6.2 Hz, 2H), 7.87 - 7.74 (m, 2H), 7.64 (d, J = 9.3 Hz, 1H), 7.58 (d, J =

[0589] 2.8 Hz, 2H), 7.53 (d, J = 3.6 Hz, 1H), 7.46 (s, 1H), 7.38 - 7.28 (m, 3H), 7.22 (t, J = 7.4 Hz,

[0590] 1H), 6.93 (d, J= 8.0 Hz, 1H), 6.75 (d, J= 7.8 Hz, 1H), 3.78 (t, J= 2.2 Hz. 3H), 2.61 (d, J= 2.3 Hz. 3H).13C NMR (101 MHz, DMSO): 5 167.94. 164.74, 163.82, 162.61. 160.03, 156.45, 151.17, 142.94, 140.38, 135.80, 131.36, 130.35, 130.18, 126.46, 126.30, 126.17, 126.14,

[0591] 125.40, 125.34, 125.01, 124.23, 123.13, 121.54, 120.66, 112.54, 111.46, 109.98, 109.61,

[0592] 106.05, 55.53, 11.15; MS (ESI) m / z = 613.19 [M+H]+. LCMS (ESI) m 'z = 611.40 [M-H]". HPLC purity: 99.9% (IR = Z isomer at 10.51 min and E isomer at 11.03 min).

[0593] (Z)-2-fluoro-5-(5-( -( 3-(5-methyl-l, 3, 4-oxadiazol-2-yl)phenyl)-2-oxoindolin-3- ylidene)methyl)furan-2-yl)-N-(3-(trifluoromethoxy)phenyl)benzamide 73 (GL-3491). 73 was 29920-428111 2025-018-02 prepared by an above-described procedure by using (Z)-2-fluoro-5-(5-((l-(3-(5-methyl-l,3,4- oxadiazol-2-yl)phenyl)-2-oxoindolin-3-ylidene) methyl)furan-2-yl)benzoic acid 67c (0.1 g, 0.197 mmol, 1 eq) and 3 -trifluoromethoxy aniline 15b (0.035g, 0. 197 mmol, 1 eq) as a starting material, orange solid; (85 mg, 65% yield). TLC: 5% MeOD in DCM, R / = 0.4; visualized with 10.95 (s, 1H), 8.67 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 6.4 Hz. 1H), 8.18 (d, J = 7.1 Hz, 1H). 8.07 (d, J = 5.2 Hz, 2H), 7.93 (s, 1H), 7.79 (ddt, J = 23.9, 15.4. 7.2 Hz. 3H), 7.65 (t, J = 9.3 Hz. 1H), 7.58 (s, 2H), 7.54 (d. J = 5.6 Hz. 2H), 7.29 (d. J = 7.6 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 2.61 (d, J = 2.6 Hz, 3H); 13C NMR (101 MHz, DMSO) 5 167.96, 164.79, 163.83, 163.02, 156.35, 151.19. 149.01, 142.97, 140.77, 135.78, 131.39, 131.21, 130.38, 130.18, 126.18, 125.36, 125.02. 124.24, 123.11, 121.52, 120.70. 118.93, 116.69, 112.33, 111.50. 54.09, 18.54, 17.17, 1 1.12; MS (ESI) / « z = 667. 16 [M+H]+. LCMS (ESI) m'z = 665.35 [M-H] . diethyl (3-aminophenyl)phosphonate (76). To asolution of 3 -bromoaniline 74 (1 g, 5.81 mmol, 1.0 eq.) and diethyl phosphonate 75 (0.962 g. 6.97 mmol, 1.2 eq.) in ethanol (20 mL) was added triethyl amine (1.2 mL, 8.72 mmol, 1.5 eq ). The reaction mass degassed with nitrogen for 10 minutes then triphenylphosphine (0.228 g, 0.872 mmol, 0.15 eq.) followed by Pd(OAc)2 (0.13g, 0.581 mmol, 0.1 eq.) were added. The resultant reaction mixture was heated at 100 °C for 5h and then cool to room temperature and filtered through celite. The filtrate was evaporated under reduced pressure to give crude product, which was purified by column chromatography using 20% Ethyl acetate in hexane to give title product 76 (1.1 g, 82% yield) as a yellow solid. TLC: 50% EA / hexane R / = 0.2; visualized with UV. 'l l NMR (400 MHz, DMSO-de): 8 7.16 (m. 1H), 6.92 (d, J = 14.62 Hz, 1H), 6.82 - 6.74 (m, 2H), 5.39 (brs. 2H), 4.00 - 3.90 (m. 4H), 1.21 (t, J= 7.81 Hz. 6H).13C NMR (101 MHz, DMSO-de): 8 148.9, 129.2. 127.5, 118.1, 117.5, 116.1, 61.3, 16.2. diethyl (3-(2-(2-bromophenyl)acetamido)phenyl)phosphonate (78). To a solution of 2- (2-bromophenyl)acetic acid 77 (0.4 g, 1.86 mmol, 1.0 eq.) and diethyl (3- aminophenyl)phosphonate 76 (0.426 g, 1.86 mmol, 1 eq.) in DMF (10 mL) was added diethyl isopropyl amine (0.778 mL, 5.58 mmol, 3 eq.) followed by EDC.HC1 (0.534 g, 2.79 mmol, 1.5 eq.) and HOBT (0.377 g, 2.79 mmol, 1.5 eq.). The resultant mixture was stirred at room temperature for 16h, poured into ice cold water and extracted with ethyl acetate (3 x 30mL). The combined organic layer was dried with Na2SO i and concentrated under reduced pressure to give crude product, which was triturated with n-pentane and filtered to give title product 78 (0.55 g, 74% yield) as an off white solid. TLC: 5% MeOH / DCM; R / = 0.5; visualized with 29920-428111 2025-018-02

[0594] UV. *H NMR (400 MHz, DMSO): 5 10.46 (s, 1H), 8.03 (d, J = 14.04 Hz, 1H), 7.81 (d, J = 8.15 Hz, 1H), 7.61 (d, J= 8.60 Hz. 1H), 7.50 - 7.34 (m, 4H), 7.21 (1, J= 7.35 Hz, 1H), 3.99 (q, J= 7.1 Hz, 4H), 3.86 (brs, 2H), 1.22 (t, J = 6.97 Hz, 6H).13C NMR (101 MHz, DMSO-de): 5 168.2, 139.5, 135.4, 132.3, 129.9, 129.4, 129.3, 128.8, 128.0, 127.6, 125.8, 124.6, 122.7, 121.5, 61.7, 43.2, 16.2. diethyl (3-(2-oxoindolin-l-yl)phenyl)phosphonate (79). The suspension of diethyl (3- (2-(2-bromophenyl)acetamido)phenyl)phosphonate 78 (0.54 g, 1.26 mmol, 1.0 eq.) and CS2CO3 (0.825 g, 2.53 mmol, 2 eq.) in toluene (10 mL) was degassed with nitrogen for 10 minutes then X-phos (60 mg. 0. 126 mmol, 0. 1 eq.) followed by Pd(OAc)2 (14 mg. 0.063 mmol, 0.05 eq.) were added. The resultant reaction mixture was heated at 100 °C for 5h, cool to room temperature and filtered through celite. The filtrate was evaporated under reduced pressure to give crude product, which was purified by column chromatography using 3% MeOH in DCM to give target product 79 (0.33 g, 75% yield) as a brown solid. TLC: 5% MeOH in DCM, R / = 0.5; visualized with UV. 'H NMR (400 MHz. DMSO-de): 5 7.79 - 7.69 (m, 4H), 7.37 (d, J = 7.49 Hz, 1H), 7.22 (t, J= 7.72 Hz, 1H), 6.71 (d, J= 8.19 Hz, 1H), 4.07 - 4.02 (m, 4H), 3.76 (s, 2H), 1.24 (t, J = 6.93 Hz, 6H).13C NMR (101 MHz, DMSO-de): d 173.9, 144.2, 134.9, 131.0, 130.6, 130.4. 130.2, 129.2, 127.5, 124.9, 124.8, 122.6, 108.5, 62.06, 62.01, 54.9, 35.4, 16.2, 16.1.

[0595] (Z)-5-(5-((l-(3-(diethoxyphosphoryl)phenyl)-2-oxoindolin-3-ylidene)methyl)fiiran-2- yl)-2-fluorobenzoic acid (80). The suspension of diethyl (3-(2-oxoindolin-l- yl)phenyl)phosphonate 79 ( 0.32 g, 0.926, leq.) and 2-fluoro-5-(5-formyl-lH-pyrrol-2- yl)benzoic acid 13b (0.239 g, 1.01 mmol, 1 eq) in acetic acid (10 mL) was heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with cold water (50 mL), formed solid was filtered and dried under vacuum to get crude solid. The crude was triturated with 20% EtOAc:hexane and filtered to give title product 80 (0.195 g, 37% yield) as brown solid. TLC: 5% MeOH in DCM, R / = 0.2; visualized with UV. Another synthesis was performed to provide product 80 (0.395 g, 76% yield) as a brown solid. TLC : 5% MeOH in DCM, R = 0.2; visualized with UV.1H NMR (400 MHz, DMSO-de): <5 13.45 (brs, 1H, COOH). 9.62 (s, 2H), 8.64 (d, J= 8.02 Hz, 1H), 8.51 (dd, J= 6.65 1.86 Hz, 1H), 8.29 (dd, J= 6.892.22 Hz, 2H), 8.19-8.06 (m, 3H), 7.82 - 7.79 (m, 3H), 7.65 (d, J = 3.12 Hz, 2H), 7.53-7.49 (m, 2H), 7.47-7.45 (m, 2H), 7.37 (d, J =3.54 Hz, 2H), 7.28-7.25 (m, 1H), 6.84 (d, J = 7.82 Hz, 1H), 4.08 (q, J = 6.84 Hz, 4H), 1.26 (t, J = 7.01 Hz, 6H).13C NMR (101 MHZ, DMSO-de): d 178.0, 167.4, 164.8, 164.4, 162.7, 160.1, 156.2, 155.7, 29920-428111 2025-018-02

[0596] 151.9, 150.6, 131.2, 130.5, 130.2, 129.8, 129.4, 129.1, 128.1, 127.2, 125.2, 124.8, 123.8, 122.6, 121.0, 120.0. 120.1, 118.4. 118.1, 109.3, 62.0. 62.03, 16.2, 16.1. diethyl (Z)-(3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)phenyl)phosphonate 81 (GL-3605). To a solution of (Z)-5-(5- ((l-(3-(diethoxyphosphoryl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-2- fluorobenzoic acid 80 (0.085 g, 0.151 mmol, 1 eq) and HATU (0.086 g, 0.227 mmol, 1.5 eq) in DMF (3 rnL) was added DIPEA (0.081 mL, 0.454 mmol, 3 eq) at room temperature and stirred for 10 minutes followed by the addition of 3 -methoxy aniline 15a (0.022 g, 0.181 mmol, 1.2 eq). The resultant reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice cold water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer dried over Na2SO4 and concentrated to afford crude product, which was purified by column chromatography using 100% EtOAc to give pure target product 81 (30 mg. 30% yield) as yellow solid. TLC: 5% MeOH in DCM, R / = 0.4; visualized with UV. Another synthesis was performed to provide product 81 (72 mg. 72% yield) as a yellow solid. TLC: 5% MeOH in DCM, R / = 0.4; visualized with UV. Major Z-isomer data: 'H NMR (400 MHz, DMSO-de): 3 10.60 (s, 1H, CONH), 8.65 (d, J= 7.43 Hz, 1H), 8.27 (d, J = 8.18 Hz, 1H), 8.15-8.13 (m, 1H), 7.80-7.77 (m, 4H), 7.61 (t, J = 9.39 Hz, 1H), 7.56-7.55 (m, 2H), 7.51-7.50 (m, 1H), 7.44 (s, 1H), 7.34-7.28 (m, 3H), 7.20 (t, J= 7.46 Hz. 1H), 6.83 (d, J= 7.74 Hz, 1H), 6.73 (d, J= 8.84 Hz, 1H), 4.04 (q, J= 7.61 Hz, 4H, OCH23.76 (s, 3H, OCHi), 1.25 (t, J= 7.08 Hz, 6H, CHs).13C NMR (101 MHz, DMSO-de): 3 167.4, 162.1, 159.5, 157.8,

[0597] 155.9, 150.7, 142.5, 139.9, 134.8, 131.0, 130.7, 130.4, 130.2, 129.7, 129.4, 129.3, 129.1, 128.1, 126.1, 125.8. 125.6, 124.9. 123.7, 122.6, 121.0, 120.2, 117.8, 112.0, 110.9, 109.5, 105.5, 62.0, 62.03, 55.0, 16.2, 16.1. LCMS (ESI) m / z = 667.55 [M+H]+. HPLC purity: 98.74% (1R = Z isomer at 10.54 min and E isomer at 11.00 min). diethyl (Z)-(3-(3-((5-(4-fluoro-3-((3-

[0598] (trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2-oxoindolm-l- yl)phenyl)phosphonate 82 (GL-3606). 82 was prepared by an above-described procedure by using (Z)-5-(5-((l-(3-(diethoxyphosphoryl)phenyl)-2-oxoindolin-3-ylidene)methyl)furan-2- yl)-2-fluorobenzoic acid 80 (0.4 g, 0.712 mmol. 1 eq) and 3-trifluoromethoxy aniline 15b (0.189 g, 1.068 mmol, 1.5 eq) as a starting material, yellow solid; (0.13 g, 25% yield). TLC: 5% MeOD in DCM, R / = 0.4; visualized with UV. Another synthesis was performed to provide the product as a yellow solid; (0.33 g, 64% yield). TLC: 5% MeOH in DCM, R = 0.4; visualized with UV. 'H NMR (400 MHz, DMSO-de): 3 10.92 (s, 1H,CCWH), 8.64 (d, J= 8.01 29920-428111 2025-018-02

[0599] Hz, 1H), 8.30 (dd, J= 4.33, 2.21 Hz, 1H), 8.18-8.15 (m, 1H), 7.91 (s. 1H), 7.81-7.80 (m. 4H), 7.72 (d, J= 9.02 Hz, 1H), 7.63 (t, J= 9.9 Hz, 1H). 7.56-7.55 (m, 2H). 7.53-7.50 (m, 2H), 7.28 (t, J = 7.40 Hz, 1H), 7.20-7.14 (m, 2H), 6.84 (d, J = 8.65 Hz, 1H), 4.07 (q, J = 6.56 Hz, 4H, OCH ), 1.25 (t, J= 7.37 Hz, 6H, CHs).13C NMR (101 MHz, DMSO-de): 3 167.4, 162.5, 155.8, 150.7, 142.5, 140.3, 131.0, 130.7, 130.4, 129.6, 129.1, 128.5, 125.7, 124.8, 122.6, 121.0, 120.2, 118.4, 116.2, 111.8, 111.0. 109.0, 62.0, 62.03. 16.2, 16.1. LCMS (ESI) m / z = 721.50 [M+H]+. diethyl (Z)-(3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)phenyl)phosphonic acid 83 (GL-3607). To a solution of diethyl (Z)-(3-(3-((5-(4-fluoro-3-((3-methoxyphenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl) phenyl) phosphonate 81 (0.08 g, 0. 120 mmol, 1 eq) in DCM (5 mL) was added TMSBr (0.158 mL, 1.20 mmol, 10 eq) at room temperature. The resultant mixture was stirred at room temperature for 16 hours and solvent was evaporated to give solid residue. The solid residue was triturated with ethyl acetate and filtered, washed with water followed by drying under vacuum to give pure yellow solid title product 83 (40 mg. 54% yield) as yellow solid. TLC: 5% MeOH in DCM, R / = 0.1 ; visualized with UV. Another synthesis was performed to provide product 83 (55 mg, 75% yield) as a yellow solid. TLC: 5% MeOH in DCM, R / = 0. 1 ; visualized with UV. Major Z-isomer data: ’H NMR (400 MHz, DMSO-de): 3 10.60 (s, 1H. CONH), 8.62 (d, J= 9.31 Hz, 1H). 8.25 (s, 1H), 8.12 (s. 1H), 7.73-7.70 (m, 2H), 7.60-7.44 (m, 7H), 7.32-7.29 (m, 3H), 7.17 (brs, 1H), 6.78-6.72 (m, 2H), 3.76 (s, 3H, OCH3).13C NMR (101 MHz, DMSO-de): 3 167.4, 162.1, 160.3, 159.5, 157.8, 155.9, 150. 7, 142.7, 139.9, 134.2, 129.9, 129.1, 128.6, 128.5, 126.7, 125.8, 125.6, 124.8, 123.7, 122.5, 121.0, 120.2, 120.1, 117.8. 117.5, 112.1. 110.9, 109.5, 108.9, 105.6, 55.0.

[0600] (Z)-( 3-(3-( (5-( 4-fluoro-3-( (3-( trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2- yl)methylene)-2-oxoindolin-l-yl)phenyl)phosphonicacid 84 (GL-3608) 84 was prepared by an above-described procedure by using diethyl (Z)-(3-(3-((5-(4-fluoro-3-((3- (trifluoromethoxy)phenyl)carbamoyl)phenyl)furan-2-yl)methylene)-2-oxoindolin-l- yl)phenyl) phosphonate 82 (0.085 g, 0.117 mmol, 1 eq) as a starting material, yellow solid; (0.045 g, 57% yield). TLC: 5% MeOD in DCM, R = 0.1; visualized with UV. Another synthesis was performed to provide the product as a yellow solid: (0.061 g, 78% yield). TLC: 5% MeOH in DCM, R, = 0.1; visualized with UV. 'H NMR (400 MHz, DMSO-de): 3 10.90 (s, 1H, CONH), 8.57 (d, J = 5.60 Hz, 1H), 8.26 (d, J = 5.60 Hz, 1H), 8. 11 (s, 1H), 7.91 (s, 1H), 7.72-7.67 (m, 3H), 7.61-7.47 (m, 7H), 7.20-7. 12 (m,3H), 6.74 (d, J= 7.79 Hz, 1H).13C NMR (101 MHz, DMSO-de): 3 167.4, 162.5, 10.3, 157.8, 155.7, 150.7, 148.5, 142.8, 140.3, 133.9, 29920-428111 2025-018-02

[0601] 130.7,129.5, 129.2, 128.4, 125.7, 125.4, 125.2, 124.6, 123.7, 122.4, 121.4, 120.9, 120.3, 119.9, 118.8, 118.4, 117.8, 117.6, 116.1, 111.8. 110.9, 109.0. LCMS (ESI) m / z = 663.45 [M-H] ’. HPLC purity: 99.9% (ZR = Z isomer at 9. 19 min and E isomer at 9.70 min).

[0602] EXAMPLES

[0603] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following assays and methods may be modified by choice of suitable materials and methods.

[0604] EXAMPLE 1

[0605] Materials and Methods

[0606] Protein purification and preparation

[0607] The Ku 70 / 80 heterodimer was purified from baculovirus-infected Sf9 cells and DNA- PKcs was purified from HeLa cells, or HEK-293 cells.

[0608] For biophysical analyses, full-length Ku heterodimer was expressed in and purified from Sf21 insect cells using a multiBac expression system. Protein labeling was achieved following buffer exchange using an Amicon 50 kDa cutoff concentrator into PBS (10 mM phosphate buffer, pH 7.4, 2.7 mM KC1, 137 mM NaCl) supplemented with 0.005% Tween-20.

[0609] Biophysical analysis

[0610] Microscale thermophoresis (MST)

[0611] Ku heterodimer was labeled using the Monolith NT™ Protein Labeling Kit RED-NHS (2nd generation amine-reactive, NanoTemper Technologies GmbH, MO-L011), following the manufacturer's protocol. Ku-DBi 3392 powder was resuspended in 100% DMSO, and the concentration was adjusted to 50 mM after UV absorbance measurement (absorbance at 417 nm with an extension coefficient equal to 15.2 mM'1cm'1). The ligand stock solution was sonicated in an ultrasonic bath before preparations of the dilution series. The MST and Differential Scanning Fluorometry (DSF) assays contain 5% DMSO to fit the DMSO concentration at the highest ligand concentration (200 pM). The labeled protein (5 nM) was incubated with ligand 3392 ranging from 98 nM to 200 pM in a 12-point 1:1 dilution series. Protein-ligand solutions were incubated for 30 min at room temperature before MST measurements, which were performed in tnplicate. Proteins w ere transferred to capillaries (Monolith NT. Automated Premium Capillary Chips, NanoTemper Technologies GmbH, Miinchen, Germany). The samples w ere analyzed with a Monolith NT...

Claims

1. 29920-428111 2025-018-02WHAT IS CLAIMED IS:or a pharmaceutically acceptable salt thereof, wherein each of RA, RB, and Rcis independently aryl or heteroaryl, each of which may be optionally substituted; ring D is ar l or heteroaryl, each of which may be optionally substituted;X is S, NH, or O;” is a single bond or a double bond; andL is alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, or aminoalkyl.

2. The compound of claim 1 , wherein the compound is of formula (II)or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein RBis optionally substituted aryl (e.g., optionally substituted phenyl, such as methoxyphenyl or trifluoromethoxyphenyl).

4. The compound of claim 3, wherein Rcis optionally substituted aryl (e.g., optionally substituted phenyl, such as carboxyphenyl or tetrazolylphenyl).

5. The compound of claim 4, wherein RAis optionally substituted aryl (e.g.. optionally substituted phenyl, such as halophenyl, methoxyphenyl, or trifluoromethoxyphenyl).

6. The compound of claim 5, wherein ring D is optionally substituted aryl (e.g., optionally substituted phenyl, such as unsubstituted phenyl).29920-428111 2025-018-027. The compound of claim 2, wherein the compound is of formula (III)or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R4is independently and, heteroaryl, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted; and each of m, n, o, and p is independently 0, 1, or 2.

8. The compound of claim 2, wherein the compound is of formula (IV)or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R4is independently and, heteroaryl, halo, haloalkyl. haloalkoxy, alkyl, alkenyl, alkynyl, ether, amino, amide, carbamate, carbonate, carboxy, ester, ketone, sulfate, sulfonamide, sulfoxide, sulfone, sulfonate, thioester, thioether, alkoxy, urea, hydrazine, phosphate, or phosphonate, each of which may be optionally substituted; and each of m, n, o, and p is independently 0, 1, or 2.

9. The compound of claim 8, wherein Rcis substituted (e.g., m is 1 or 2), for example, with ester, carboxy, optionally substituted heteroaryl, amide, sulfone, sulfonamide, phosphate, or phosphonate.

10. The compound of claim 9, wherein RAis substituted (e.g., n is 1 or 2), for example, with halo, alkoxy, haloalkyl, or haloalkoxy.29920-428111 2025-018-0211. The compound of claim 10, wherein RBis substituted (e.g., o is 1 or 2), for example, with alkoxy or haloalkoxy.

12. The compound of claim 11, wherein ring D is substituted (e.g., p is 1 or 2), for example, with alkoxy or haloalkoxy.

13. The compound of claim 11, wherein ring D is unsubstituted (e.g., p is 0).

14. The compound of claim 11, wherein X is O.

15. The compound of claim 11, wherein X is NH.

16. The compound of claim 11, whereinis a single bond.

17. The compound of claim 11, wherein is a double bond.

18. The compound of claim 1, selected from the group consisting of:2"20-428[ 1 j29920-428111 2025-018-02ůzr29920-4281112025-018-0229920-428111 2025-018-02or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according claim 1 and at least one pharmaceutically acceptable excipient.

20. A method of treating a disease (e.g., a cancer such as lung cancer) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to claim 1.

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