Combination therapy

Abstract

Provided herein are combinations comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors, such as the specific YAP / TAZ-TEAD and KRAS inhibitors described herein. Further provided herein are methods of modulating or inhibiting KRAS activity in a cell, comprising administering to the cell an effective amount of such a combination. Further provided herein are methods of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of such a combination.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 190,766, filed May 19, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch in central growth signaling pathways. In response to extracellular signals, Ras undergoes GDP-bound (Ras) exchange, catalyzed by guanine nucleotide exchange factors (GEFs), particularly the SOS1 protein. GDP ) state to GTP-bound (Ras GTP ) state. Active Ras GTP Ras mediates its diverse growth-stimulatory functions through direct interaction with effectors, including Raf, PI3K, and Ral guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity can be further accelerated by interaction with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

[0003] Mutant Ras has reduced GTPase activity, which sustains the activated form of Ras, thereby promoting Ras-dependent signaling and cancer cell survival or proliferation. Ras mutations that affect its ability to interact with GAPs or convert GTP back to GDP result in sustained activation of the protein, resulting in sustained signals that tell cells to continue growing and dividing. Because these signals lead to cell growth and division, overactive RAS signaling can ultimately lead to cancer. Mutations in any one of the three major RAS isoform genes (H-Ras, N-Ras, or K-Ras) are common events in human tumorigenesis. Of the three Ras isoforms (K, N, and H), K-Ras is the most frequently mutated.

[0004] The most common K-Ras (or KRAS) mutations are found at residues G12 and G13 in the P loop and residue Q61. G12C is a frequent mutation in the K-Ras gene (glycine-12 to cysteine). G12C is a single point mutation with a glycine to cysteine ​​substitution at codon 12. This substitution favors an activated state of KRAS and amplifies the signaling pathway leading to tumorigenesis (see, e.g., Hallin et al. (Cancer Discov, 2020, 10(1):54-71), Skoulidis et al. (N. Engl. J. Med., 2021, 384(25):2371-2381), and Hong et al. (N. Engl. J. Med., 2020, 383(13):1207-1217)). G12D, G12V, and G13D are other frequently observed mutations. Ras mutations in cancer are associated with poor prognosis.

[0005] Inactivation of oncogenic Ras in mice results in tumor regression. Therefore, Ras is widely considered to be an exceptionally important oncological target. However, treatment with Ras (e.g., KRAS) inhibitors can result in resistance through bypass of the KRAS / MAPK pathway and activation of the Hippo signaling pathway.

[0006] The Hippo signaling pathway regulates cell proliferation and cell death and determines organ size. This pathway is thought to act as a tumor suppressor in mammals, and disorders of this pathway are often detected in human cancers. This pathway is involved in and / or can regulate the self-renewal and differentiation of stem and progenitor cells. In addition, the Hippo signaling pathway may be involved in wound healing and tissue regeneration. Furthermore, the Hippo signaling pathway crosstalks with other signaling pathways, such as Wnt, Notch, Hedgehog, and MAPK / ERK, which may affect a wide variety of biological events. It is therefore believed that dysfunction of the Hippo signaling pathway may be involved in many human diseases in addition to cancer.

[0007] The Hippo signaling pathway is centered on a cascade of kinases (Hippo-MST1-2 are upstream of Lats1-2 and NDRI-2) that result in the phosphorylation of two transcriptional coactivators, Yes (Yes-associated protein) and TAZ (a transcriptional coactivator with PDZ-binding motifs or tafazzin). Non-phosphorylated, active YAP translocates into the cell nucleus, where its primary target transcription factors are four proteins in the TEAD domain-containing family (TEAD1-TEAD4, collectively referred to as "TEAD"). YAP, together with other TEADs (or other transcription factors such as Smad1, RUNX, ErbB4, and p73), has been shown to induce the expression of various genes, including connective tissue growth factor (CTGF), Gli2, Birc5, Birc2, fibroblast growth factor 1 (FGF1), and amphiregulin (AREG). Like YAP, unphosphorylated TAZ translocates to the cell nucleus, where it interacts with multiple DNA-binding transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ), thyroid transcription factor-1 (TTF-1), Pax3, TBX5, RUNX, TEAD1, and Smad2 / 3 / 4. Many of the genes activated by the YAP / TAZ-transcription factor complex mediate cell survival and proliferation. Thus, under some conditions, YAP and / or TAZ act as oncogenes, and the Hippo signaling pathway acts as a tumor suppressor.

[0008] The Hippo signaling pathway is a regulator of animal development, organ size, and stem cell regulation, and is therefore implicated in cancer development. In vitro, overexpression of YAP or TAZ in breast epithelial cells induces cell transformation through the interaction of both proteins with the TEAD family of transcription factors. Increased YAP / TAZ transcriptional activity induces oncogenic characteristics, such as epithelial-mesenchymal transition (EMT), and has also been shown to confer stem cell properties to breast cancer cells. In vivo, overexpression of YAP or genetic knockout of its upstream regulators MST1-2 in mouse liver induces hepatocellular carcinoma (HCC). Furthermore, when the tumor suppressor NF2 is inactivated in mouse liver, HCC development can be completely blocked by co-inactivation of YAP.

[0009] Deregulation of the Hippo tumor suppressor pathway is thought to be a key event in the development of a wide range of cancer types and malignancies.

[0010] Therefore, pharmacological targeting of the Hippo cascade through inhibition of YAP, TAZ, TEAD, and / or YAP:TEAD protein-protein interactions may be a valuable approach for treating cancers with functional alterations of this pathway. Furthermore, autopalmitoylation of TEAD proteins has been shown to regulate the transcriptional output of the Hippo signaling pathway, and palmitoylation of TEAD transcription factors is required for their stability and function in Hippo signaling, making the lipid-binding pocket an attractive target (see, e.g., Chan et al. (Nat. Chem. Biol. 2016, 12(4):282-289), Noland et al. (Structure, 2016, 24(1):179-186), and Kim et al. (Biological Sciences, 2019, 116(20):9877-9882)). Covalent TEAD inhibitors are described, for example, in Karats et al. (J. Med. Chem. 2020,63,11972-11989), Lu et al. (Acta Pharmaceutica Sinica B, 2021,11(10):3206-3219), Fan et al. (Biorxiv, 2022,DOI:10.1101 / 2022.05.10.491316), and Kaneda et al. (Am. J. Cancer Res., 2020,10(12):4399-4415).

[0011] There is a need for therapies that improve the ability of inhibitors of Ras (e.g., KRAS) and inhibitors of YAP, TAZ, TEAD, and / or YAP:TEAD protein-protein interactions to treat a range of diseases, disorders, and conditions, including cancer. Summary of the Invention

[0012] In one aspect, the present disclosure is directed to a method of modulating YAP / TAZ-TEAD activity, or KRAS activity, or both, in a cell, the method comprising administering to the cell an effective amount of a combination comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

[0013] In another aspect, the present disclosure is directed to a method of inhibiting YAP / TAZ-TEAD activity, or KRAS activity, or both, in a cell, the method comprising administering to the cell an effective amount of a combination comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

[0014] In another aspect, the present disclosure is directed to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

[0015] In one aspect, the present disclosure is directed to a composition comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

[0016] In one aspect, the present disclosure is directed to a kit comprising: (i) an effective amount of a combination comprising one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors; and (ii) instructions for administering the combination to treat cancer in a subject in need thereof.

[0017] In one aspect, the present disclosure is directed to the use of a combination comprising one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors in the manufacture of a medicament for use in treating cancer in a subject in need thereof.

[0018] In one aspect, the present disclosure is directed to a composition comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors, for use in the treatment of cancer.

[0019] In a further aspect, the present disclosure is directed to a process for preparing a composition comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors. [Brief explanation of the drawings]

[0020] The following embodiments are representative of some aspects of the present disclosure.

[0021] [Figure 1] 1 shows the percent inhibition of H2122 cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K1. [Figure 2] 1 shows the percent inhibition of H2122 cells (KRAS G12C) after administration of a combination containing Compound T2 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T2 sensitizes cells resistant to Compound K1. [Figure 3] 1 shows the percent inhibition of H2122 cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K1. [Figure 4] 1 shows the percent inhibition of H2122 cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T4 sensitizes cells resistant to Compound K1. [Figure 5]1 shows the percent inhibition of H2122 cells (KRAS G12C) after administration of a combination containing Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K2. [Figure 6] 1 shows the percent inhibition of H2122 cells (KRAS G12C) after administration of a combination containing Compound T2 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T2 sensitizes cells resistant to Compound K2. [Figure 7] 1 shows the percent inhibition of H2122 cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K2. [Figure 8] 1 shows the percent inhibition of H2122 cells (KRAS G12C) following administration of a combination comprising Compound T4 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T4 sensitizes cells resistant to Compound K2. [Figure 9] 1 shows the growth of 3D soft agar cultures after administration of a combination containing Compound T2 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T2 sensitizes cells resistant to Compound K2. [Figure 10] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K1. [Figure 11] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K1. [Figure 12]1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K1. [Figure 13] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K1. [Figure 14] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K1. [Figure 15] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K1. [Figure 16] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K1. [Figure 17] 1 shows the % inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T10 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T10 sensitizes cells resistant to Compound K1. [Figure 18] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K2. [Figure 19] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K2. [Figure 20] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K2. [Figure 21] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K2. [Figure 22] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K2. [Figure 23] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K2. [Figure 24] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K2. [Figure 25]1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T10 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T10 sensitizes cells resistant to Compound K2. [Figure 26] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K3. [Figure 27] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K3. [Figure 28] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K3. [Figure 29] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K3. [Figure 30] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K3. [Figure 31] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K3. [Figure 32] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K3. [Figure 33] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising compound T10 (a YAP / TAZ-TEAD inhibitor) and compound K3 (a KRAS inhibitor), demonstrating that administration of compound T10 sensitizes cells resistant to compound K3. [Figure 34] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K4. [Figure 35] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K4. [Figure 36] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K4. [Figure 37] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K4. [Figure 38]1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K4. [Figure 39] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K4. [Figure 40] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K4. [Figure 41] 1 shows the percent inhibition of H2030 cells (KRAS G12C) after administration of a combination comprising compound T10 (a YAP / TAZ-TEAD inhibitor) and compound K4 (a KRAS inhibitor), demonstrating that administration of compound T10 sensitizes cells resistant to compound K4. [Figure 42] 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K1. [Figure 43] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K1. [Figure 44] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K1. [Figure 45] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K1. [Figure 46] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K1. [Figure 47] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K1. [Figure 48] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K1. [Figure 49] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T10 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T10 sensitizes cells resistant to Compound K1. [Figure 50] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K2. [Figure 51]Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K2. [Figure 52] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K2. [Figure 53] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K2. [Figure 54] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K2. [Figure 55] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K2. [Figure 56] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K2. [Figure 57] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T10 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T10 sensitizes cells resistant to Compound K2. [Figure 58] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K3. [Figure 59] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K3. [Figure 60] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K3. [Figure 61] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K3. [Figure 62] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K3. [Figure 63] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K3. [Figure 64]Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K3. [Figure 65] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising compound T10 (a YAP / TAZ-TEAD inhibitor) and compound K3 (a KRAS inhibitor), demonstrating that administration of compound T10 sensitizes cells resistant to compound K3. [Figure 66] 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K4. [Figure 67] 1 shows the percent inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K4. [Figure 68] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K4. [Figure 69] 1 shows the percent inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K4. [Figure 70] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) following administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K4. [Figure 71] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K4. [Figure 72] Figure 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K4. [Figure 73] 1 shows the percent inhibition of H358 parental cells (KRAS G12C) after administration of a combination comprising compound T10 (a YAP / TAZ-TEAD inhibitor) and compound K4 (a KRAS inhibitor), demonstrating that administration of compound T10 sensitizes cells resistant to compound K4. [Figure 74] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K1. [Figure 75] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K1. [Figure 76] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K1. [Figure 77]1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K1. [Figure 78] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K1. [Figure 79] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K1. [Figure 80] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K1. [Figure 81] 1 shows the % inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T10 (a YAP / TAZ-TEAD inhibitor) and Compound K1 (a KRAS inhibitor), demonstrating that administration of Compound T10 sensitizes cells resistant to Compound K1. [Figure 82] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K2. [Figure 83]1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K2. [Figure 84] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K2. [Figure 85] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K2. [Figure 86] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K2. [Figure 87] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K2. [Figure 88] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K2. [Figure 89]1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T10 (a YAP / TAZ-TEAD inhibitor) and Compound K2 (a KRAS inhibitor), demonstrating that administration of Compound T10 sensitizes cells resistant to Compound K2. [Figure 90] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K3. [Figure 91] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K3. [Figure 92] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K3. [Figure 93] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K3. [Figure 94] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K3. [Figure 95]1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K3. [Figure 96] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K3 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K3. [Figure 97] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising compound T10 (a YAP / TAZ-TEAD inhibitor) and compound K3 (a KRAS inhibitor), demonstrating that administration of compound T10 sensitizes cells resistant to compound K3. [Figure 98] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T1 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T1 sensitizes cells resistant to Compound K4. [Figure 99] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T3 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T3 sensitizes cells resistant to Compound K4. [Figure 100] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T5 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T5 sensitizes cells resistant to Compound K4. [Figure 101]1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T6 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T6 sensitizes cells resistant to Compound K4. [Figure 102] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T7 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T7 sensitizes cells resistant to Compound K4. [Figure 103] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T8 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T8 sensitizes cells resistant to Compound K4. [Figure 104] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising Compound T9 (a YAP / TAZ-TEAD inhibitor) and Compound K4 (a KRAS inhibitor), demonstrating that administration of Compound T9 sensitizes cells resistant to Compound K4. [Figure 105] 1 shows the percent inhibition of H358 resistant cells (KRAS G12C) after administration of a combination comprising compound T10 (a YAP / TAZ-TEAD inhibitor) and compound K4 (a KRAS inhibitor), demonstrating that administration of compound T10 sensitizes cells resistant to compound K4. DETAILED DESCRIPTION OF THE INVENTION

[0022] I. Definition Unless otherwise indicated, the following specific terms and phrases used in the description and claims are defined as follows:

[0023] The terms "moiety" and "substituent" refer to an atom or a set of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming a part of a molecule.

[0024] The term "substituted" refers to the replacement of at least one of a compound or moiety's hydrogen atoms with another substituent or moiety. Examples of such substituents include, but are not limited to, halogen, -OH, -CN, oxo, alkoxy, alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocycle. For example, the term "alkyl substituted by halogen" refers to the fact that one or more hydrogen atoms of an alkyl (defined below) have been replaced with one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).

[0025] The term "alkyl," unless otherwise specified, refers to an aliphatic, straight- or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms. For example, in certain embodiments, an alkyl has 1 to 10 carbon atoms. In certain embodiments, an alkyl has 1 to 6 carbon atoms. Alkyl groups may be independently substituted with one or more substituents described herein.

[0026] The term "alkoxy" refers to a group of the formula -O-R', where R' is an alkyl group. The alkoxy group may be optionally substituted independently with one or more substituents described herein. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0027] "Aryl," unless otherwise specified, refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 6 to 20 carbon ring atoms. For example, in certain embodiments, an aryl has 6 to 10 carbon atoms. Bicyclic aryl ring systems include fused bicycles having two fused 5-membered aryl rings (designated 5-5), fused bicycles having a 5-membered aryl ring and a fused 6-membered aryl ring (designated 5-6 and 5-6), and bicycles having two fused 6-membered aryl rings (designated 6-6). Aryl groups may be substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic and each is optionally substituted.

[0028] The term "heteroaryl," unless otherwise specified, refers to an aromatic heterocyclic monocyclic, bicyclic, or tricyclic ring system of 5 to 20 ring atoms containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. For example, in some embodiments, a monocyclic heteroaryl ring can be 5-6-membered. In some embodiments, a heteroaryl ring can contain 5 to 10 carbon atoms. Bicyclic heteroaryl ring systems include fused bicycles having two fused 5-membered heteroaryl rings (designated 5-5), fused bicycles having a 5-membered aryl ring and a fused 6-membered heteroaryl ring (designated 5-6 and 5-6), and fused bicycles having two fused 6-membered heteroaryl rings (designated 6-6). Heteroaryl groups may be optionally substituted as defined herein. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[0029] The terms "halo," "halogen," and "halide" may be used interchangeably and refer to a substituent fluoro, chloro, bromo, or iodo.

[0030] The term "haloalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms have been replaced by the same or different halogen atoms, in particular fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0031] "Cycloalkyl," unless otherwise specified, means a saturated or partially unsaturated carbocyclic moiety having a monocyclic, bicyclic (including bridged bicyclic), or tricyclic ring and having 3 to 10 carbon atoms in the ring. For example, in certain embodiments, a cycloalkyl contains 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular embodiments, a cycloalkyl contains 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and their partially unsaturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, and bicyclo[3.1.1]heptenyl. The cycloalkyl moieties may be attached in a "spirocycloakyl" fashion, such as "spirocyclopropyl": TIFF2024519845000002.tif17170 The cycloalkyl moiety may be substituted with one or more substituents.

[0032] "Heterocycle" or "heterocyclyl," unless otherwise indicated, refers to a 3-, 4-, 5-, 6-, and 7-membered monocyclic; 7-, 8-, 9-, and 10-membered bicyclic (including bridged bicyclic); or 10-, 11-, 12-, 13-, 14-, and 15-membered bicyclic saturated or partially unsaturated heterocyclic moiety having one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur in the ring, with the remaining ring atoms being carbon. For example, in certain embodiments, heterocycle or heterocyclyl refers to a 4-, 5-, 6-, or 7-membered heterocycle. In some aspects, the heterocycle is a heterocycloalkyl. When used in reference to a ring atom of a heterocycle, the nitrogen or sulfur may be in an oxidized form, and the nitrogen may be substituted with one or more groups, such as C1-C6 alkyl. A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any of the heterocycle ring atoms Each of these may be optionally substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0033] The term "fused bicyclic" refers to a ring system containing two fused rings, including bridged cycloalkyl and bridged heterocycloalkyl as defined elsewhere herein. The rings are each independently aryl, heteroaryl, cycloalkyl, and heterocycle. In some embodiments, the rings are each independently C 5-6 Aryl, 5-6 membered heteroaryl, C 3-6cycloalkyl, and 4-6 membered heterocycles. Non-limiting examples of fused bicyclic ring systems include C 5-6 Aryl-C 5-6 Aryl, C 5-6 Aryl-4 to 6-membered heteroaryl, and C 5-6 Aryl-C 5-6 Cycloalkyl is included.

[0034] Unless otherwise indicated, the term "hydrogen" or "hydro" refers to a hydrogen atom (-H) moiety and not to H2.

[0035] In the description herein, when the stereochemistry of a structure or portion of a structure is not indicated, for example, with a bold wedge or a dotted line, the structure or portion of the structure is intended to encompass all of its stereoisomers. However, in some cases where multiple chiral centers are present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry.

[0036] Unless otherwise indicated, the term "a compound of the formula" or "a compound of formula" or "compounds of the formula" or "compounds of formula" refers to any compound selected from the genus of compounds defined by that formula (including, unless otherwise specified, any pharmaceutically acceptable salt or ester of any such compound).

[0037] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, and is not biologically or otherwise undesirable. As used herein, "pharmaceutically acceptable" refers to a carrier, diluent, or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and N-acetylcysteine. Additionally, salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins.

[0038] The compounds of the present disclosure can exist in the form of pharmaceutically acceptable salts. Another embodiment provides non-pharmaceutically acceptable salts of such compounds, which may be useful as intermediates for isolating or purifying the compounds provided herein. The compounds of the present disclosure can exist in the form of pharmaceutically acceptable esters (e.g., methyl esters and ethyl esters used as prodrugs). The compounds of the present disclosure can also be solvated, for example, hydrated. Solvation can occur during the manufacturing process or as a result of, for example, the hygroscopic properties of the initial anhydrous compounds provided herein.

[0039] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or their arrangement in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Diastereomers are stereoisomers with opposite configurations of one or more chiral centers that are not enantiomers. Stereoisomers that possess one or more asymmetric centers that are non-superimposable mirror images of each other are called "enantiomers." For example, when a compound possesses an asymmetric center, a pair of enantiomers is possible if the carbon atoms are bonded to four different groups. Enantiomers can be characterized by the absolute configuration of their asymmetric center or centers and are described by the Cahn-Ingold-Prelog R- and S-ordering rules or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." In some embodiments, the compound is at least about 90% enriched by weight in a single diastereomer or enantiomer. In other embodiments, the compound is at least about 95%, 98%, or 99% enriched by weight in a single diastereomer or enantiomer.

[0040] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, positional isomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0041] The compounds of the present disclosure may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present disclosure, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present disclosure. In some cases, the stereochemistry has not been determined or has been tentatively assigned. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in the absence of stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, lacking optical activity. Enantiomers can be separated from racemic mixtures by chiral separation techniques such as supercritical fluid chromatography (SFC). While stereochemistry is established, such as from X-ray crystallography data, assignment of configurations at chiral centers in separated enantiomers is tentative.

[0042] The terms "effective amount" and "therapeutically effective amount" of a compound / combination / composition refer to an amount of a compound / combination / composition effective to achieve a desired result. For example, in some embodiments, an effective amount / therapeutically effective amount prevents, alleviates, or ameliorates symptoms of a disease or prolongs the survival of the subject being treated. Determining a (therapeutically) effective amount is within the skill of the art. The (therapeutically) effective amount or dosage of a compound, combination, and / or composition according to the present disclosure can vary within wide limits and can be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements of each particular case, including the particular compound(s), combination(s), and / or composition(s) administered, the route of administration, the condition being treated, and the patient being treated. Generally, for oral or parenteral administration to an adult weighing approximately 70 kg, a daily dosage of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded if indicated. The daily dosage can be administered as a single dose or in divided doses, or, for parenteral administration, as continuous infusion.

[0043] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable carrier, adjuvant, or vehicle," or "therapeutically inert carrier" can be used interchangeably throughout and are intended to include all substances compatible with drug administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other substances and compounds compatible with drug administration. Insofar as any conventional media or agent is incompatible with one or more of the active compounds, its use in the compositions of the present disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0044] Pharmaceutically acceptable carriers useful for preparing the compositions herein can be solid, liquid, or gaseous; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enteric-coated or other protective preparations (e.g., bound to ion exchange resins or packaging in lipid-protein vesicles), sustained-release preparations, solutions, suspensions, elixirs, aerosols, and the like. Carriers can be selected from various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions (when isotonic with blood). For example, formulations for intravenous administration include sterile aqueous solutions of one or more active ingredients, prepared by dissolving one or more solid active ingredients in water to produce an aqueous solution and sterilizing the solution. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, wheat flour, chalk, silica, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E.W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier to prepare the appropriate dosage form for proper administration to the recipient.

[0045] As used herein, the terms "subject," "patient," or "individual" refer to an animal, such as a human or a non-human mammal. In one embodiment, a subject, patient, or individual refers to a human.

[0046] In practicing the methods of the present disclosure, a (therapeutically) effective amount of a compound of the present disclosure, or any combination of compounds, combinations, and / or compositions of the present disclosure, is administered by any of the conventional and acceptable methods known in the art. Thus, the compounds, combinations, and / or compositions can be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppository or lavage), transdermally (e.g., by skin electroporation), or by inhalation (e.g., by aerosol), and in the form of solid, liquid, or gaseous preparations, including tablets and suspensions. Administration can be carried out in a single unit dosage form using continuous therapy, or in a single-dose therapy, as appropriate. Therapeutic compositions can also be in the form of oil emulsions or dispersions in combination with lipophilic salts such as pamoic acid, or in the form of biodegradable sustained-release compositions for subcutaneous or intramuscular administration.

[0047] II. Composition In one aspect, provided herein is a composition comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

[0048] YAP / TAZ-TEAD inhibitors In some embodiments, the one or more YAP / TAZ-TEAD inhibitors have Formula (I): TIFF2024519845000003.tif37170[in formula: R 1 is C(O)N(R a )(R b ), C 6-20 Aryl, 5- to 20-membered heteroaryl, 5- to 20-membered heterocyclyl, and C 1-6 alkyl, wherein R 1 C 6-20 Aryl, 5- to 20-membered heteroaryl, and 5- to 20-membered heterocyclyl are independently selected from halo, —OH, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 aryl, and R 1 C 1-6 Alkyl is a group that can be substituted with halo, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 optionally substituted with one or more substituents selected from the group consisting of aryl; R a and R b are each independently H or C 1-6 alkyl, where R a or R b C 1-6 Alkyl is a group that can be substituted with halo, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with one or more substituents selected from the group consisting of alkoxy; or R a and R b together with the atom to which they are attached form a 3- to 10-membered heterocyclyl, where the 3- to 10-membered heterocyclyl is selected from halo, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; L 1 is absent or is *-O-CH2-**, *-CH2-O-**, or -O-, where ** is R 2 represents the point of attachment to the moiety, and * represents the point of attachment to the rest of the molecule; R 2 is C 2-12 Alkyl, C 2-12 Alkenyl, or C 6-10 aryl, where R 2 C 2-12 Alkyl, C 2-12 Alkenyl, and C6-10 Aryl is independently halo, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, and C 3-10 cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-10 Cycloalkyl may independently include one or more halo, C 1-6 Haloalkyl, C 6-10 Aryl, or C 3-10 optionally substituted with cycloalkyl; R 3 and R 4 are each independently H or C 1-6 alkyl, where R 3 or R 4 C 1-6 Alkyl is a group that can be substituted with halo, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with one or more substituents selected from the group consisting of alkoxy; Or R 3 and R 4 together with the atom to which they are attached form a 3- to 10-membered heterocyclyl, where the 3- to 10-membered heterocyclyl is selected from halo, —OH, —CN, and C 1-6 and optionally substituted with one or more substituents selected from the group consisting of alkyl, C 1-6 Alkyl is a group that can be substituted with halo, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 and optionally substituted with one or more substituents selected from the group consisting of alkoxy. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0049] In some embodiments of Formula (I), the compound has the formula (IA): TIFF2024519845000004.tif38170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0050] In some embodiments of Formula (I), the compound has the formula (IB): TIFF2024519845000005.tif30170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5 H, halo, OH, cyano, and C 1-6 alkyl, wherein C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be optionally substituted with one or more substituents selected from the group consisting of alkoxy.

[0051] In some embodiments of Formula (IB), the compound has the formula (I-B1): TIFF2024519845000006.tif30170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0052] In some embodiments of formula (I), such as compounds of formula (IB) or formula (I-B1), L 1 In some embodiments of Formula (I), such as compounds of Formula (IA), Formula (IB), or Formula (I-B1), R 2 is C 6-10 aryl, where R 2 C 6-10 Aryl is one or more C 3-10 Optionally substituted with cycloalkyl, C 3-10 Cycloalkyl may be one or more halo, C 1-6 Haloalkyl, C 6-10 Aryl, or C 3-10 In some embodiments, R 2 teeth, The file is TIFF2024519845000007.tif21170.

[0053] In some embodiments of Formula (I), such as compounds of Formula (IA), Formula (IB), or Formula (I-B1), R 1 is a 5- to 20-membered heteroaryl, where R 1 The 5-20 membered heteroaryl may have one or more C 1-6 In some embodiments, R 1 is a 5-6 membered heteroaryl, where R 1 The 5-6 membered heteroaryl may have one or more C 1-6 In some embodiments, R 1 is pyrazinyl, where R 1 The pyrazinyl may have one or more C 1-6 In some embodiments, R 1 teeth, The file is TIFF2024519845000008.tif16170.

[0054] In some embodiments of Formula (I), the compound is TIFF2024519845000009.tif42170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0055] In some embodiments of Formula (I), the compound has the formula (IC): TIFF2024519845000010.tif37170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 , R 3 , and R 4 is as defined in formula (I).

[0056] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors comprise a compound of Formula (I), (IA), (IB), or (IC), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. A description of Formulas (I), (IA), (IB), and (IC) can be found in WO 2021 / 108483, which is incorporated herein by reference in its entirety. Formulas (I), (IA), (IB), and (IC) are described in WO 2021 / 108483 as formulas (I), (IA), (IB), and (IC), respectively (see, e.g., paragraphs

[0046] -

[0124] ), and these paragraphs and the description of methods for making compounds of formula (I), (IA), (IB), or (IC) and formula (I), (IA), (IB), or (IC) are incorporated herein by reference. A moiety of formula (I), (IA), (IB), or (IC), such as R 1 , R 2 , R 3 , R 4 , R 5 , and L 1 is as defined in WO 2021 / 108483, including any variations or embodiments thereof. R in formulas (I), (IA), (IB), and (IC) 1 , R 2 , R 3 , R 4 , R 5 , and L 1 are part R of International Publication No. WO 2021 / 108483, respectively. 1 , R 2 , R 3 , R 4 , R 5 , and corresponds to L.

[0057] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (I), (IA), (IB), or (IC) is Compound T1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T1 is chemically described as 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and has the following structure: TIFF2024519845000011.tif44170. A description of compound T1 and a method for making compound T1 can be found, for example, in WO 2021 / 108483, compound 27 on page 31 and example 27 on pages 140-142.

[0058] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (I), (IA), (IB), or (IC) is compound T9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T9 is chemically described as 5-(4-cyclohexylphenyl)-2-(3-methylpyrazin-2-yl)-3-[rac-(2S,3S)-3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one and has the following structure: TIFF2024519845000012.tif44170. A description of compound T9 and a method for making compound T9 can be found, for example, in WO 2021 / 108483, compound 44 on page 35 and example 41 on pages 156-158.

[0059] In some embodiments, the one or more YAP / TAZ-TEAD inhibitors have Formula (II): TIFF2024519845000013.tif25170[in formula: X 1 is N or CR 9 where each R 9 are independently H, -CN, halo, -C(O)-NH2, -N(R g )(Rh ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl, and C 1-6 alkyl; R 9 C 1-6 Alkyl is defined as one or more -OH or -N(R g )(R h ), or X 1 R 9 is R 3 and together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl is selected from one or more C 1-6 may be substituted with alkyl, provided that X 3 is CH; X 2 is N or CR 9 where each R 9 are independently H, -CN, halo, -C(O)-NH2, -N(R g )(R h ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl, and C 1-6 alkyl; R 9 C 1-6 Alkyl is defined as one or more -OH or -N(R g )(R h ) may be substituted; X 3 is N or CH, However, X 3 is N and R 5 but, When it is TIFF2024519845000014.tif23170, X 1 and X 2 at least one of is N; R 5 teeth, (i) oxiranyl or oxetanyl, where R 5The oxiranyl or oxetanyl of the formula (I) may be one or more C 1-6 may be substituted with alkyl, C 1-6 The alkyl is optionally substituted independently with one or more -C(O)-NH; L 2 is absent or selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** is R 6 indicates the point of attachment to the moiety, and * indicates the point of attachment to the rest of the molecule; or (ii)-N(R g )(CN), L 2 is absent or selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** is R 6 indicates the point of attachment to the moiety, and * indicates the point of attachment to the rest of the molecule, -N(R g )(CN), or (iii) TIFF2024519845000015.tif20170, where R c , R d , and R e are each independently H, halo, -CN, -OH, C 1-6 Alkyl, C 6-20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl; R c , R d , or R e C 1-6 The alkyl may be substituted with one or more -OH, provided that R c , R d , and R e At least two of H are L 2 is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** is R 6 indicates the point of attachment to the moiety, and * indicates the point of attachment to the rest of the molecule, TIFF2024519845000016.tif23170(iv) TIFF2024519845000017.tif15170, where R f H, halo, -CN, -OH, C 1-6 Alkyl, C 6-20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl; R f C 1-6 The alkyl may be substituted with —OH; L 2 is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH- and -C≡C-, where ** is R 6 indicates the point of attachment to the moiety, and * indicates the point of attachment to the rest of the molecule, TIFF2024519845000018.tif15170; R 6 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6-20 Aryl, C 5-13 spirocyclyl, or 5-20 membered heteroaryl, wherein: R 6 C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6-20 Aryl, C 5-13 Spirocyclyl or 5- to 20-membered heteroaryl is independently —CN, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -NO2, -N(R g )(R h ), -O(R g ), and -SF5, However, R 6 C 1-12 alkyl, C 1-12 Alkyl is independently -CN, halo, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-10 Cycloalkyl, -NO2, -N(R g )(R h ), and -O(R g When L is optionally substituted with one or two substituents selected from the group consisting of 2 is -CH=CH- or -C≡C-; R 7 -CN, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, where R 7 C 2-4 Alkenyl is —N(R g )(R h ), or R 7 is X 1 R 9 and together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl is selected from one or more C 1-6 may be substituted with alkyl, provided that X 3 is CH, or R 7 L 2 together with the carbon atoms of -CH2-O- and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl, however: (i)R 7 -CN, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, C 2-4 Alkenyl is -N(R g )(R h ), R 5 but, TIFF2024519845000019.tif23170, R 6 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, where R 6The 3- to 10-membered saturated heterocyclyl or 5- to 20-membered heteroaryl is independently selected from -CN, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -NO2, -N(R g )(R h ), and -O(R g and optionally substituted with one or two substituents independently selected from the group consisting of: L 2 is *-CH2-O-**, -CH=CH-, or -C≡C-, where ** is R 6 indicates the point of attachment to the moiety, * indicates the point of attachment to the rest of the molecule, (ii)R 7 But X 1 R 9 and together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, with the proviso that X 3 is CH, R 5 but, TIFF2024519845000020.tif23170, R 6 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, where R 6 The 3- to 10-membered saturated heterocyclyl or 5- to 20-membered heteroaryl is independently selected from -CN, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -NO2, -N(R g )(R h ), and -O(R g and optionally substituted with one or two substituents independently selected from the group consisting of: L 2 is absent or is *-CH2-O-**, -CH=CH-, or -C≡C-, where ** is R 6 indicates the point of attachment to the moiety, * indicates the point of attachment to the rest of the molecule, (iii)R 7 But, L 2together with the carbon atoms of -CH2-O- and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl, R 5 but, When the file is TIFF2024519845000021.tif23170, R 6 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently —CN, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -NO2, -N(R g )(R h ), and -O(R g ) optionally substituted with one or two substituents independently selected from the group consisting of: R 8 is H or C 1-6 alkyl, where C 1-6 The alkyl may be substituted with one or more -OH groups; R g and R h are, independently of each other and independently of each other, H, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, and 3-20 membered heteroaryl, wherein R g and R h C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-20 The aryl and 3- to 20-membered heteroaryl each independently represent C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, oxo, -CN, halo, -NO2, and -OH. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0060] In some embodiments of Formula (II), X 1 R 9 is R 7 and together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl is selected from one or more C 1-6 may be substituted with alkyl, provided that X 3 is CH.

[0061] In some embodiments of Formula (II), the compound has the formula (II-A): TIFF2024519845000022.tif30170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0062] In some embodiments of Formula (II), the compound has the formula (II-A1); TIFF2024519845000023.tif36170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0063] In some embodiments of Formula (II), such as Formula (II-A) and Formula (II-A1), R 5 teeth, TIFF2024519845000024.tif20170. In some of the above-described embodiments, R c , R d , and R e Each of is H.

[0064] In some embodiments of Formula (II), the compound is TIFF2024519845000025.tif30170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0065] In some embodiments of Formula (II), the compound has the formula (II-B): TIFF2024519845000026.tif49170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0066] In some embodiments of Formula (II-B), R 5 teeth, TIFF2024519845000027.tif20170. In some of the above-described embodiments, R c , R d , and R e Each of is H.

[0067] In some embodiments of Formula (II), the compound is TIFF2024519845000028.tif26170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0068] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors comprise a compound of Formula (II), (II-A), or (II-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. A description of Formulas (II), (II-A), and (II-B) can be found in WO 2021 / 097110, which is incorporated herein by reference in its entirety. Formulas (II), (II-A), and (II-B) are described as formulas (B-1), (IA), and (IF), respectively, in WO 2021 / 097110 (see, e.g., paragraphs

[0054] ,

[0067] , and

[0087] ), and those paragraphs and descriptions of formula (B-1), (IA), or (IF), and methods of making compounds of formula (B-1), (IA), or (IF), are incorporated herein by reference. A moiety of formula (II), (II-A), or (II-B), such as R 5 , R 6 , R 7 , R 8 , X 1 , X 2 , X 3 , and L 2 is as defined in WO 2021 / 097110, including any variations or embodiments thereof. X in formulas (II), (II-A), and (II-B) 1 , X 2 , X 3 , R 5 , R 6 , R 7 , R 8 , R 9 , L 2 , R c , R d , R e , R f , R g , and R h are parts X1, X2, X3, R1, R2, R3, R4, R5, L, R of WO 2021 / 097110. a , R b , R c , R d , R e , and R f correspond to the following:

[0069] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (II), (II-A), or (II-B) is compound T2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T2 is chemically described as N-(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acrylamide and has the following structure: TIFF2024519845000029.tif31170. A description of compound T2 and a method for making compound T2 can be found, for example, in WO 2021 / 097110, compound 33 on page 73 and example 33 on pages 245-246.

[0070] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (II), (II-A), or (II-B) is compound T3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T3 is chemically described as N-(6-methoxy-5-((E)-2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide and has the following structure: TIFF2024519845000030.tif30170. A description of compound T3 and a method for making compound T3 can be found, for example, in Compound 2 on page 68 and Example 2 on page 192 of WO 2021 / 097110.

[0071] In some embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (III): TIFF2024519845000031.tif25170[in formula: X 4 is N or CR 14 where each R 14 are independently H, -CN, halo, -C(O)-NH2, -N(R m )(R n ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl, and C1-6 alkyl; R 14 C 1-6 Alkyl is one or more —OH or —N(R m )(R n ), or X 4 R 14 is R 12 and together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl is selected from one or more C 1~6 optionally substituted with alkyl; X 5 is N or CR 14 where each R 14 are independently H, -CN, halo, -C(O)-NH2, -N(R m )(R n ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl, and C 1-6 alkyl; R 14 C 1-6 Alkyl is defined as one or more -OH or -N(R m )(R n ) may be substituted; X 6 is N or CH; R 10 teeth, (i) a 3- to 5-membered saturated heterocyclyl containing at least one ring oxygen atom, and one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii)-N(R m )(R n ), or (iii) TIFF2024519845000032.tif21170, where R i , R j , and R kare each independently H, halo, -CN, -OH, -B(OH), -C(O)-OH, -C(O)-N(R m )(R n ), -C(O)-C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heteocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; R i , R j , or R k C 1-6 The alkyl may be substituted with one or more -OH groups. TIFF2024519845000033.tif21170, or (iv) TIFF2024519845000034.tif15170, where R t is H, halo, -CN, -OH, -B(OH)2, -C(O)-OH, -C(O)-N(R m )(R n ), -C(O)-C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 The alkyl may be substituted with one or more -OH groups. TIFF2024519845000035.tif15170; L 3 is absent or selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH- and -C≡C-, where ** is R 11 indicates the point of attachment to the moiety, and * indicates the point of attachment to the rest of the molecule; R 11 is C 1-12 Alkyl, C3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; where R 11 C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 Aryl or 5-20 membered heteroaryl is independently —CN, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -NO2, -N(R m )(R n ), and -O(R m and optionally substituted with one or more substituents selected from the group consisting of: However, R 11 C 1-12 alkyl, and R 11 C 1-12 Alkyl is independently -CN, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -NO2, -N(R m )(R n ), and -O(R m ), when L 3 is -CH=CH- or -C≡C-; R 12 -CN, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, where C 2-4 Alkenyl is —N(R m )(R n ), or R 12 is X 4 R 14and together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl is selected from one or more C 1-6 may be substituted with alkyl, or R 12 L 3 *-CH2-O-** together with the carbon atoms to which they are attached form a C6 aryl or 6-membered heteroaryl; R 13 is H or C 1-6 alkyl, where R 13 C 1-6 The alkyl may be substituted with one or more -OH groups; R m and R n are, independently of each other and independently of each other, H, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 5- to 20-membered heteroaryl, wherein R m and R n C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 5- to 20-membered heteroaryl each independently represent C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, oxo, -CN, halo, -NO2, and -OH. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0072] In some embodiments of Formula (III), X 4 R 14 is R 12 and together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl is selected from one or more C 1-6 It may be substituted with alkyl.

[0073] In some embodiments of Formula (III), the compound has the formula (III-A): TIFF2024519845000036.tif31170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0074] In some of the foregoing embodiments, L 3 is not present. In some embodiments of Formula (III-A), the compound has the formula (III-A1): TIFF2024519845000037.tif31170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0075] In some embodiments, compounds of Formula (III), such as compounds of Formula (III-A1) or Formula (III-A2), R 10 teeth, TIFF2024519845000038.tif21170. In some of the above-described embodiments, R i and R j Both are H and R k is -C(O)OH.

[0076] In some embodiments of formula (III), such as compounds of formula (III-A1) or formula (III-A2), R 11 is C 6-20 aryl, where R 11 C6-20 Aryl is independently -CN, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -NO2, -N(R m )(R n ), and -O(R m In some embodiments, R 11 is C 6-20 aryl, where R 11 C 6-20 Aryl independently comprises one or more C 1-6 In some embodiments, R 11 teeth The file is TIFF2024519845000039.tif20170.

[0077] In some embodiments of Formula (III), the compound is TIFF2024519845000040.tif29170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0078] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (III), (III-A), or (III-A1) is compound T4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T4 is chemically described as 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid and has the following structure: It has TIFF2024519845000041.tif31170. A description of compound T4 and methods for making compound T4 can be found, for example, in WO 2022 / 020716, compound 3 on page 48 and example 3 on pages 164-165.

[0079] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (IV): TIFF2024519845000042.tif29170[in formula: [A] is a ligase ligand; [B] is a linker moiety; X 1 , X 2 , and X 3 are each independently N or CR 5 where each R 5 are independently H, halo, cyano, C 1-12 Alkyl, OC 1-12 Alkyl, and C 1-12 haloalkyl; L 1 is a bond or -C≡C-, -CH=CH-, or -(CH) m -wherein m is 1-6; R 1 is H, C 1-12 Alkyl, C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, C 1-12 Haloalkyl, OC 1-12 Alkyl, OC 3-10 Cycloalkyl, OC 1-12 Alkyl-C 3-10 Cycloalkyl or OC 1-12 is haloalkyl; R 2 is H, C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, or C 5-13 spirocyclyl, wherein: R 2 C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, or C 5-13Spirocyclyl may independently be one or more of oxo, cyano, halo, C 1-12 Alkyl, C 1-12 Haloalkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, NO2, N(R x )(R y ), and O(R x ), where: Each R x and R y are independently H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl and 5-20 membered heteroaryl, wherein: R x and R y Each C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-20 The aryl and 5- to 20-membered heteroaryl may independently be one or more of oxo, cyano, halo, NO, NH, hydroxy, C 1-12 Alkyl, C 1-12 Haloalkyl or OC l-12 optionally substituted with alkyl] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0080] The description of formula (IV) can be found in WO 2021 / 178339, which is incorporated herein by reference in its entirety. Formula (IV) is described as formula (I) in WO 2021 / 178339 (see, for example, paragraphs

[0057] -

[0058] ), and these paragraphs and the description of formula (I) and methods of making compounds of formula (I) are incorporated herein by reference. The moieties of formula (IV), such as A, B, R 1 , R 2 , X 1 , X 2 , X 3 , and L 1 is as defined in WO 2021 / 178339, including any variations or embodiments thereof.

[0081] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors are represented by formula (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), or (IV-F): Contains compounds from TIFF2024519845000043.tif215170, where: * in the linker portion represents the point of attachment to the ligase ligand, and ** in the linker portion represents the point of attachment to the rest of the molecule; L 2 is -(CH2) n -or-(CH2CH2O) n where n is 1 to 12; L 3 is a bond or -C≡C-, -CH=CH-, -(CH2) m -, -O-, -NH, or TIFF2024519845000044.tif15170, where L 3 The # of L 2 represents the point of attachment to L 3 * represents the attachment point to the ligase ligand; R 3a and R 3b each independently represents H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12Alkynyl, C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, C 1-12 Alkyl-C 6-20 Aryl, 3-10 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl, wherein: Each C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, C 1-12 Alkyl-C 6-20 Aryl, 3-10 membered heterocyclyl, C 6-20 The aryl or 5- to 20-membered heteroaryl is independently oxo, CN, C 1-12 Alkyl, C 1-12 Haloalkyl, Halo, NO2, N(R e )(R f ), C 1-12 Alkyl-C(O)-N(R e )(R f ), and OR e wherein each R e and R f are independently H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, and 5- to 20-membered heteroaryl, wherein each C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, C 1-12 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-20 The aryl or 5- to 20-membered heteroaryl may independently be one or more of oxo, CN, C1-12 Alkyl, C 1-12 Haloalkyl, Halo, NO2, OC l-12 may be substituted with alkyl or OH; Q 1 and Q 2 One of the groups is C=O, and Q 1 and Q 2 the other is C=O or CH2; R a , R b , R c , and R d One of them is the linker part L 3 to TIFF2024519845000045.tif8170 is a combined file and R a , R b , R c , and R d The others are each independently H, halo, C 1-12 Alkyl, C 1-12 Haloalkyl or OC 1-12 is alkyl; R e H, halo, C 1-12 Alkyl, C 1-12 Haloalkyl, OC 1-12 alkyl, or phenyl, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein [A], [B], X 1 , X 2 , X 3 , L 1 , R 1 , and R 2 are as defined in formula (IV). [A], [B], X in such embodiments of compounds of formula (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), and (IV-F) 1 , X 2 , X 3 , L 1 、 R 1 , and R 2 is [A], [B], X described for formula (IV). 1 , X 2 , X 3 , L 1 , R1 , and R 2 It is understood that the term may include:

[0082] Formulas (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), and (IV-F) are described in WO 2021 / 178339 as formulas (XII), (XIII), (II), (III), (IV), and (V), respectively (see, e.g., paragraphs

[0059] -

[0064] and

[0119] -

[0121] ), which paragraphs and descriptions of formulas (XII), (XIII), (II), (III), (IV), or (V), and methods of making compounds of formula (XII), (XIII), (II), (III), (IV), or (V), are incorporated herein by reference). The moieties of formula (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), or (IV-F), such as A, B, R a , R b , R c , R d , R e , R 3a , R 3b , R 1 , R 2 , X 1 , X 2 , X 3 , Q 1 , Q 2 , L 1 , L 2 , and L 3 is as defined in WO 2021 / 178339, including any variations or embodiments thereof.

[0083]

[0023] In some embodiments, in conjunction with the above or below embodiments, the compound of formula (IV), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), or (IV-F) is compound T5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T5 is chemically described as N-[[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl-methyl-amino]-2-oxo-ethyl]phenyl]methyl]-5-methoxy-4-[rac-(E)-2-[4-(trifluoromethyl)cyclohexyl]vinyl]pyridine-2-carboxamide and has the following structure: TIFF2024519845000046.tif50170. A description of compound T5 and methods for making compound T5 can be found, for example, in Table 1 on page 51 and Example 4 on pages 123-126 of WO 2021 / 178339.

[0084] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (V): TIFF2024519845000047.tif44170[In the formula, each X 1 , X 4 , X 5 , and X 6 are independently N or CR X and; each X 2 and X 3 are independently N or CR Y and; Each R X are independently hydrogen, halogen, nitro, -OR 3 , -SR 3 , -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , S(=O)2R 3 , -N(R 3 )2, -NR3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkylnyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R Y are independently hydrogen, halogen, nitro, -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR 3 , -SR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or a substituted or unsubstituted C1-C6 fluoroalkyl; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10 Heterocycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CN, or -S(=O)2R 4 and; Each R 2 are independently halogen, nitro, -N3, -CN, -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 3 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C3-C 10 cycloalkyl, or -NH; n is 0, 1, 2, 3, or 4. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0085] The description of formula (V) can be found in U.S. Patent Application Publication No. 2020 / 0347009, the entire contents of which are incorporated herein by reference. Formula (V) is described as formula (I) in U.S. Patent Application Publication No. 2020 / 0347009 (see, e.g., paragraphs

[0099] -

[0110] , the descriptions of which, together with the description of formula (I) and methods of making compounds of formula (I), are incorporated herein by reference). A moiety of formula (V), such as R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and n are as defined in U.S. Patent Application Publication No. 2020 / 0347009, including any variations or embodiments thereof.

[0086] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (V) is compound T6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T6 is chemically described as N-[(1R)-1-(6-amino-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide and has the following structure: TIFF2024519845000048.tif37170. A description of compound T6 and methods for making compound T6 can be found, for example, in U.S. Patent Application Publication No. 2020 / 0347009, on page 46, Compound 66, and on pages 112-115, Example 55.

[0087] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (VI): TIFF2024519845000049.tif55170[In the formula, each X 1 and X 2 are independently N and NR X , C(=O), or CR X and; each X 3 and X 4are independently N and NR X , C(=O), or CR X or X 3 and X 4 Both are independently NR X or CR X When these two R X together with the intervening atoms to which they are attached form a 5-membered heterocyclic ring; Each R X are independently hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR 3 , -SR 3 , -CN, -C(=O)R 2 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, a substituted or unsubstituted C2-C4 alkenyl, a substituted or unsubstituted C2-C4 alkynyl, a substituted or unsubstituted C3-C 10Cycloalkyl, substituted or unsubstituted C-C 10 Heterocycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, or -S(=O)2R 4 and; Each R 2 are independently -N3, -CN, -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 3 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, a substituted or unsubstituted C3-C 10 cycloalkyl, or -NH; each --- is independently a single bond or a double bond; n is 0, 1, 2, 3, or 4. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The description of formula (VI) can be found in WO 2020 / 097389, which is incorporated herein by reference in its entirety. Formula (VI) is described as formula (I) in WO 2020 / 097389 (see, e.g., paragraphs

[0070] -

[0082] ), and these paragraphs, as well as the description of formula (I) and methods of making compounds of formula (I), are incorporated herein by reference. The moiety of formula (VI), such as R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , and n are as defined in WO 2020 / 097389, including any variations or embodiments thereof.

[0088] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (VI-A): TIFF2024519845000050.tif55170[In the formula, Each R X are independently hydrogen, halogen, —OH, —NH2, —CH3, —CH2CH3, cyclopropyl, —CF3, —OCH3, —OCH2CH3, cyclopropyloxy, or —OCF3; R 1 is a substituted or unsubstituted C1-C6 alkyl, wherein, if C1-C6 alkyl is substituted, each is independently substituted with one or two substituents selected from -OH, -NH2, azetidinyl, pyridyl, and aminopyridyl; R 2 is F; R 5 is CF3; and n is 0 or 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Formula (VI-A) is described as formula (Ia) (e.g., WO 2020 / 097389, paragraphs

[0082] -

[0083] ).

[0089] (See, these paragraphs and the description of formula (Ia) and methods of making compounds of formula (Ia) are incorporated herein by reference.) A moiety of formula (VI-A), such as R 1 , R 2 , R 5 , R X , and n are as defined in WO 2020 / 097389, including any variations or embodiments thereof.

[0089] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (VI) or (VI-A) is compound T7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T7 is chemically described as N-[(1S)-1-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide and has the following structure: TIFF2024519845000051.tif30170. A description of compound T7 and a method for making compound T7 can be found, for example, in WO 2020 / 097389, page 65, compound 90, and page 195-196, example 84.

[0090] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (VII): TIFF2024519845000052.tif31170[In the formula, TIFF2024519845000053.tif14170 is a substituted or unsubstituted monocyclic 5-membered heterocyclic ring containing at least one N atom or a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one N atom; Each R Zare independently H, halogen, —CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -L 1 -Y 1 or -L 2 -L 3 -Y 2 and; m is 0, 1, 2, 3, 4 or 5; L 1 is a substituted or unsubstituted C1-C6 alkylene, a substituted or unsubstituted C2-C 10 cyclolkylene, or Substituted or unsubstituted C2-C 10 is heterocycloalkylene; Y 1 is a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L 2 is absent, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C 10 Cyclolylene or substituted or unsubstituted C-C 10 is heterocycloalkylene; L 3 are -O-, -S-, -(S=O)-, -(SO2)-, -NR 3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR 3 -, -(C=O)NR 3 -O-, -O-NR 3 (C=O)-, -NR 3 (C=O)-, -NR 3 (C=O)NR 3 -, -O(C=O)NR 3 -, -NR 3 (C=O)O-, -NR 3 (SO2)NR 3 -, -NR 3 (SO2)-,-(SO2)NR 3 -, -(SO2)NR 3 -(C=O)-, -(C=O)-NR 3 (SO2)-, -(SO2)NR 3 -(C=O)O-, -O(C=O)-NR 3 (SO2)-, -NR 3 (SO2)NR 3 -(C=O)-, -(C=O)-NR 3 (SO2)NR 3 -, -O(C=O)-NR 3 (SO2)-NR 3 - or -NR 3 (SO2)NR 3 -(C=O)O-; Each R 3 are independently H or substituted or unsubstituted C1-C6 alkyl; Y 2 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R on the same N atom 3 and Y 2together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R is NHR 1 or R 1 and; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; TIFF2024519845000054.tif15170 is substituted or unsubstituted phenyl or substituted or unsubstituted cyclohexyl; Each R 2 are independently H, halogen, -N3, -CN, -OR 4 , -SR 4 , -(SO2)R 4 , -N(R 4 )2, -CO2R 4 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or TIFF2024519845000055.tif14170; n is 0, 1, 2, 3, 4, or 5; Each R 4are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 10 Cycloalkyl, substituted or unsubstituted C-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The description of formula (VII) can be found in WO 2020 / 0354325, which is incorporated herein by reference in its entirety. Formula (VII) is described as formula (I) in WO 2020 / 0354325 (see, e.g., paragraphs

[0129] -

[0149] ), and these paragraphs and the description of formula (I) and methods for making compounds of formula (I) are incorporated herein by reference. The moieties of formula (VII), such as A, Z, R, R z , R 2 , m, and n are as defined in U.S. Patent Application Publication No. 2020 / 03543525, including any variations or embodiments thereof.

[0091] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (VII-A) or (VII-B): TIFF2024519845000056.tif73170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z, R, R Z , R 2 , n, and m are as defined in formula (VII). Z, R, R of such embodiments of compounds of formula (VII-A) and (VII-B) Z , R 2 , n, and m are Z, R, R as described for formula (VII). Z , R 2, n, and m. Formulas (VII-A) and (VII-B) are described, for example, in paragraphs

[0194] and

[0195] of U.S. Patent Application Publication No. 2020 / 0354325 as formulas (Id) and (Ie), respectively, and these paragraphs and the description of formula (Id) or (Ie) and methods of making compounds of formula (Id) or (Ie) are incorporated herein by reference. The moieties of formula (VII-A) or (VII-B), such as Z, R, R z , R 2 , m, and n are as defined in U.S. Patent Application Publication No. 2020 / 0354325, including any variations or embodiments thereof.

[0092] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (VII), (VII-A), or (VII-B) is compound T8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T8 is chemically described as N-methyl-3-(1-methylimidazol-4-yl)-4-[4-(trifluoromethyl)anilino]benzenesulfonamide and has the following structure: TIFF2024519845000057.tif55170. A description of compound T8 and a method for making compound T8 can be found, for example, in WO 2020 / 0354325, compound 121 on page 55 and example 113 on pages 157-158.

[0093] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (VIII): TIFF2024519845000058.tif43170[In the formula, Ring A is the following ring moiety: TIFF2024519845000059.tif185170(in formula R A1 H, D, C 1-6 Aliphatic, -CH2-Ar A1 or -CH2-CH2-Ar A1 represents; R A2H, D, halogen, C 1-6 Aliphatic, -CH2-Ar A2 or -CH2-CH2-Ar A2 represents; R A3 H, D, C 1-6 Aliphatic, -CH2-Ar A3 or -CH2-CH2-Ar A3 (represents represents a 5-membered aromatic heterocycle selected from the group consisting of: Z 1 is CR Z1 or N; Z 2 is CR Z2 or N; Z 3 is CR Z3 or N; where Z 1 , Z 2 and Z 3 At least two of them are not N; R 1 Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc 1 , unsubstituted or substituted straight or branched chain C 1-8 represents aliphatic; R 2 is -C(=O)-OR 2a , -C(=O)-NR 2b R 2c , -(CH2) w -C(=O)-NR 2b R 2c , -(CH2) x -NR 2d -C(=O)-R 2e , -SR 2f , -S(=O)-R 2f , -S(=O)2-R 2g, -S(=O)2-NR 2h R 2i , -S(=O)2-OH, -S(=O)(=NR 2j )-OH, -S(=O)(=NR 2j )-R 2g , S(=O)(=NR 2k )-NR 2l R 2m , F, Cl, Br, I, -CN, -(CH2) v -CN, -P(=O)(OR 2o )(OR 2p ), -(CH2) y -NR 2q R 2r , -(CH2) z -NR 2d -S(=O)2-R 2g , -C(=O)-N=S(=O)-R 2s R 2t , -C(=O)-N=S(=NR 2u )-R 2s R 2t , -B(OH)2 or Hetcycle X represents; Ar A1 , Ar A2 , Ar A3 are, independently of one another, unsubstituted or independently of one another, R A11 and / or R A12 represents phenyl which may be mono- or disubstituted by; R Z1 represents H or halogen; R Z2 represents H or halogen; or R 2 together to form the divalent radical -S(=O)2-N(H)-C(=O)-; R Z3 represents H or halogen; R 2a is H, unsubstituted or substituted C 1-8 represents an aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or carbohydrate-derived radical, or Cat; Cat represents a monovalent cation; R 2b , R 2c, R 2q , R 2r are, independently of each other, H, C 3-7 Unsubstituted or substituted C, including cycloaliphatic 1-8 or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocyclic ring having 3, 4, 5, 6, 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there are no or only one further reducing atom which is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; wherein the heterocyclic ring is Z or R 2b and R 2c One of them is -CN, -NH2, -OH, -OC 1-6 Alkyl, -S(=O)2-R 2g , Ar 2 , Hetar 2 , Cyc 2 or Hetcyc 2 and the other represents H or unsubstituted or substituted C 1-8 represents aliphatic; R 2d , R 2j , R 2k , R 2o , R 2p are, independently of each other, H, unsubstituted or substituted C 1-8 represents aliphatic; R 2e is H, halogen, unsubstituted or substituted C 1-8 represents aliphatic, heteroaryl; R 2f , R 2g are, independently of each other, unsubstituted or substituted C 1-8 represents aliphatic; R 2h , R 2i are each independently H, unsubstituted or substituted C 1-8represent aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached, form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocyclic ring having 3, 4, 5, 6, 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, there are none or only one additional ring atom that is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; R 2l , R 2m are each independently H, unsubstituted or substituted C 1-8 represent aliphatic; or together with the nitrogen atom to which they are attached, form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocyclic ring having 3, 4, 5, 6, 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, there are none or only one additional ring atom that is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; R 2s , R 2t are, independently of each other, unsubstituted or substituted C 1-8 aliphatic; or together, unsubstituted or substituted divalent C 3-6 Forming an alkylene radical; R 2u is hydrogen or unsubstituted or substituted C 1-6 represents aliphatic; Ar 1 is a monocyclic, bicyclic, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein the aryl is unsubstituted or contains substituents R, which may be the same or different. B1 , R B2 , R B3 , R B4 , R B5 , R B6 and / or B7 may be substituted with; Hetar 1is a monocyclic, bicyclic, or tricyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain substituents R, which may be the same or different. B1 , R B2 , R B3 , R B4 , R B5 , R B6 and / or R B7 may be substituted with; Cyc 1 is a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbocyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbocyclic ring is unsubstituted or has R B8 , R B9 , R B10 , R B11 , R B12 and / or R B13 the carbocyclic ring may be substituted with Ar X Ar via two adjacent ring atoms X wherein the fused carbocycle may further be unsubstituted or fused to R C1 , R C2 , R C3 , R C4 , R C5 , R C6 may be substituted with; Hetcyc 1 is a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; the heterocycle may be unsubstituted or comprise R B8 , R B9 , R B10 , R B11 , RB12 and / or R B13 may be substituted with; L 1 is -S(=O)2-, -C(=O)-, unsubstituted or substituted straight or branched C 1-6 Alkylene or C 2-6 alkenylene, in which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L 2 is an unsubstituted or substituted straight-chain or branched C 1-6 Alkylene or C 2-6 alkenylene, in which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; R A11 , R A12 are each independently a halogen or an unsubstituted or substituted straight-chain or branched C 1-6 represents aliphatic; R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 are, independently of one another, unsubstituted or substituted straight-chain or branched C 1-6 aliphatic, C 1-6 Alphatoxy (aliphatoxy), -SC 1-6 Aliphatic; halogen, -CN, -S(=O)-R b1 , S(=O)2-R b1 , -NR b2 NR b3 , Ar 2 , -CH2-Ar 2 , Hetar 2 , Cyc 2 , Hetcyc 2 and / or two adjacent R B1 , R B2 , R B3 , R B4 , R B5, R B6 and / or R B7 together, one of the alkylene carbon units is a carbonyl unit (-C(=O)-) or a divalent -OC 1-3 Alkylene radical or divalent -OC 1-3 A divalent -C optionally replaced by an alkylene-O- radical 2-4 Forming an alkylene radical; R b1 is unsubstituted or substituted C 1-8 represents aliphatic; R b2 , R b3 are each independently H, unsubstituted or substituted C 1-8 represent aliphatic; or together with the nitrogen atom to which they are attached, form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocyclic ring having 3, 4, 5, 6, 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, there are none or only one additional ring atom which is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; R B8 , R B9 , R B10 , R B11 , R B12 , R B13 are each independently a halogen, an unsubstituted or substituted C 1-6 aliphatic, C 1-6 Alphatoxy (aliphatoxy), Ar Y and / or R bonded to the same carbon atom of said carbocyclic ring or said heterocyclic ring. B8 , R B9 , R B10 , R B11 , R B12 , R B13 two of which form a divalent oxo (=O) group; and / or R bonded to the same sulfur atom of the heterocycle. B8 , R B9 , R B10 , R B11 , R B12 , R B13 Four of the four or R B8 , RB9 , R B10 , R B11 , R B12 , R B13 two of them form a divalent oxo (=O) group, thereby forming a -S(=O)- or -S(=O)2- moiety; Ar 2 is a monocyclic or bicyclic aryl having 5, 6, 7, 8, 9, 10 ring carbon atoms, wherein the aryl is unsubstituted or contains substituents R, which may be the same or different. D1 , R D2 , R D3 , R D4 and / or R D5 may be substituted with; Hetar 2 is a monocyclic or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain substituents R, which may be the same or different. D1 , R D2 , R D3 , R D4 and / or R D5 may be substituted with; Cyc 2 is a saturated or partially unsaturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle is unsubstituted or has R D6 , R D7 , R D8 , R D9 and / or R D10 the carbocyclic ring may be substituted with Ar Z or Hetar Z Ar via two adjacent ring atoms Z or Hetar Z The fused carbocycle may be further fused to R C1 , R C2 , R C3 , R C4 , R C5 , RC6 may be substituted with; Hetcyc 2 is a saturated or partially unsaturated monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, and the heterocycle may be unsubstituted or comprise R D6 , R D7 , R D8 , R D9 and / or R D10 the heterocycle may be substituted with Ar Z or Hetar Z Ar via two adjacent ring atoms Z or Hetar Z The fused heterocycle may be further fused to R C1 , R C2 , R C3 , R C4 , R C5 , R C6 may be substituted with; Ar X , Ar Z are, independently of each other, an unsubstituted or substituted benzo ring; Ar Y is unsubstituted, mono- or disubstituted phenyl; Hetar Y1 is a 5- or 6-membered monocyclic heteroaryl in which 1, 2, 3, or 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl is unsubstituted or optionally substituted with halogen, OH, C 1-4 optionally substituted with alkyl; Hetar Zis an unsubstituted or substituted 5- or 6-membered heteroaryl ring selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxaole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran; Cyc Y1 is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or may contain halogen, OH, C 1-4 optionally substituted with alkyl; Hetcyc X is a saturated, partially unsaturated or aromatic monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, where 1, 2, 3, 4 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, and the heterocycle may be unsubstituted or comprise R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 and / or R X8 and the heterocycle may be a carboxylic acid bioisostere; Hetcyc Y is a saturated, partially unsaturated or aromatic monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein 1, 2, 3, 4 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; Hetcyc Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; R C1 , R C2 , R C3 , R C4 , R C5 , R C6 are, independently of each other, unsubstituted or substituted C1-6 represents aliphatic; R D1 , R D2 , R D3 , R D4 , R D5 are, independently of each other, unsubstituted or substituted C 1-6 represents aliphatic; R D6 , R D7 , R D8 , R D9 , R D10 are, independently of each other, unsubstituted or substituted C 1-6 Aliphatic, unsubstituted or substituted C 1-6 Alphatoxy (aliphatoxy), halogen, hydroxy; Hetar Y1 , CH2-Hetar Y1 , Cyc Y1 , Hetcyc Y1 , -CH2-Hetcyc Y1 and / or R attached to the same ring atom of said carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 2-6 can form an alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical are, independently of one another, O, NH, or NC 1-4 The alkylene radical may be substituted with OH, C 1-4 Alkyl or -OC 1-4 and / or R attached to different ring atoms of said carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 1-6 can form an alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical are, independently of one another, O, NH, or NC 1-4 may be replaced by alkyl; R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 are, independently of each other, unsubstituted or substituted C 1-6 aliphatic, C 1-6 Alphatoxy, halogen, -OH, -NR 2d -S(=O)2-R 2g , Hetcyc Y , O-Hetcyc Y and / or R bonded to the same carbon atom of said heterocycle. X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 two of which form a divalent oxo (=O) group; and / or R bonded to the same sulfur atom of the heterocycle. X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 Four of the four or R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 two of form a divalent oxo (=O) group, thereby forming an -S(=O)- or -S(=O)2- moiety; Halogen is F, Cl, Br, I; v is 1 or 2; w is 1 or 2; x is 0, 1, or 2; y is 0, 1 or 2; z is 0, 1, or 2. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0094] The description of formula (VIII) can be found in WO 2021 / 224291, which is incorporated herein by reference in its entirety. Formula (VIII) is described in WO 2021 / 224291 as formula (IA) (see, for example, pages 3-12), and these paragraphs, as well as the description of formula (IA) and methods for making compounds of formula (IA), are incorporated herein by reference. The moieties of formula (VIII), such as A, Z, 1 , Z 2 , Z 3 , R 1 , and R 2 is as defined in WO 2021 / 224291, including any variations or embodiments thereof.

[0095] In some embodiments, in conjunction with the above or below embodiments, the one or more YAP / TAZ-TEAD inhibitors have formula (VIII-A): TIFF2024519845000060.tif44170[in the formula, Ring A is the following ring moiety: TIFF2024519845000061.tif185170 (in the formula, R A1 is H, C 1-6 Aliphatic, -CH2-Ar A1 or -CH2-CH2-Ar A1 (represents represents a 5-membered aromatic heterocycle selected from the group consisting of: R A2 H, halogen, C 1-6 Aliphatic, -CH2-Ar A2 or -CH2-CH2-Ar A2 represents; R A3 is H, C 1-6 Aliphatic, -CH2-Ar A3 or -CH2-CH2-Ar A3 (represents represents a 5-membered aromatic heterocycle selected from the group consisting of: Z 1 is CR Z1 or represents N; Z 2 is CR Z2 or represents N; where Z 1 and Z 2 At least one of them is not N; R 1 Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc 1 , unsubstituted or substituted straight or branched chain C 1-8 represents aliphatic; R 2 is -C(=O)-OR 2a , -C(=O)-NR 2b R 2c , -(CH2) w -C(=O)-NR 2b R 2c , -(CH2) x -NR 2d -C(=O)-R 2e , -SR 2f , -S(=O)-R 2f , -S(=O)2-R 2g , -S(=O)2-NR 2h R 2i , -S(=O)2-OH, -S(=O)(=NR 2j )-OH, -S(=O)(=NR 2j )-R 2g , S(=O)(=NR 2k )-NR 2l R 2m , F, Cl, Br, I, -CN, -(CH2) v -CN, -P(=O)(OR 2o )(OR 2p ), -(CH2) y -NR 2q R2r , -(CH2) z -NR 2d -S(=O)2-R 2g , -C(=O)-N=S(=O)-R 2s R 2t , -C(=O)-N=S(=NR 2u )-R 2s R 2t , -B(OH)2 or Hetcycle X represents; Ar A1 , Ar A2 , Ar A3 are, independently of one another, unsubstituted or independently of one another, R A11 and / or R A12 represents a phenyl mono- or disubstituted by; R Z1 represents H or halogen; R Z2 represents H or halogen; or R 2 together to form the divalent radical -S(=O)2-N(H)-C(=O)-; R 2a is H, unsubstituted or substituted C 1-8 represents an aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or carbohydrate-derived radical, or Cat; Cat represents a monovalent cation; R 2b , R 2c , R 2q , R 2r are, independently of each other, H, C 3-7 Unsubstituted or substituted C, including cycloaliphatic 1-8 or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocyclic ring having 3, 4, 5, 6, 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there are no or only one further reducing atom which is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; wherein the heterocyclic ring is Z or R 2b and R2c One of them is -CN, -NH2, -OH, -OC 1-6 Alkyl, -S(=O)2-R 2g , Ar 2 , Hetar 2 , Cyc 2 or Hetcyc 2 represents R 2b and R 2c the other is H or unsubstituted or substituted C 1-8 represents aliphatic; R 2d , R 2j , R 2k , R 2o , R 2p are, independently of each other, H, unsubstituted or substituted C 1-8 represents aliphatic; R 2e is H, halogen, unsubstituted or substituted C 1-8 represents aliphatic, heteroaryl; R 2f , R 2g are, independently of each other, unsubstituted or substituted C 1-8 represents aliphatic; R 2h , R 2i are each independently H, unsubstituted or substituted C 1-8 represent aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached, form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocyclic ring having 3, 4, 5, 6, 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, there are none or only one additional ring atom that is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; R 2l , R 2m are each independently H, unsubstituted or substituted C 1-8represent aliphatic; or together with the nitrogen atom to which they are attached, form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocyclic ring having 3, 4, 5, 6, 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, there are none or only one additional ring atom that is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; R 2s , R 2t are, independently of each other, unsubstituted or substituted C 1-8 aliphatic; or together, unsubstituted or substituted divalent C 3-6 Forming an alkylene radical; R 2u is hydrogen or unsubstituted or substituted C 1-6 represents aliphatic; Ar 1 is a monocyclic, bicyclic, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein the aryl is unsubstituted or contains substituents R, which may be the same or different. B1 , R B2 , R B3 , R B4 , R B5 , Rb6 and / or B6 and / or tricyclic aryl, wherein the aryl is unsubstituted or has the same or different substituents RB1 R B7 may be substituted with; Hetar 1 is a monocyclic, bicyclic, or tricyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain substituents R, which may be the same or different. B1 , R B2 , R B3 , R B4 , R B5 , R B6 and / or R B7may be substituted with; Cyc 1 is a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbocyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbocyclic ring is unsubstituted or has R B8 , R B9 , R B10 , R B11 R B12 and / or R B13 the carbocyclic ring may be substituted with the Ar X Ar via two adjacent ring atoms X wherein the fused carbocycle may further be unsubstituted or fused to R C1 , R C2 , R C3 , R C4 , R C5 , R C6 may be substituted with; Hetcyc 1 is a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; the heterocycle may be unsubstituted or comprise R B8 , R B9 , R B10 , R B11 , R B12 and / or R B13 may be substituted with; L 1 is -S(=O)2-, -C(=O)-, unsubstituted or substituted straight or branched C 1-6 Alkylene or C 2-6 alkenylene, in which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L 2is an unsubstituted or substituted straight-chain or branched C 1-6 Alkylene or C 2-6 alkenylene, in which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; R A11 , R A12 are each independently a halogen or an unsubstituted or substituted straight-chain or branched C 1-6 represents aliphatic; R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 are, independently of one another, unsubstituted or substituted straight-chain or branched C 1-6 aliphatic, C 1-6 Alphatoxy (aliphatoxy), -SC 1-6 Aliphatic; halogen, -CN, -S(=O)-R b1 , S(=O)2-R b1 , -NR b2 NR b3 , Ar 2 , -CH2-Ar 2 , Hetar 2 , Cyc 2 , Hetcyc 2 and / or two adjacent R B1 , R B2 , R B3 , R B4 , R B5 , R B6 and / or R B7 together, one of the alkylene carbon units is a carbonyl unit (-C(=O)-) or a divalent -OC 1-3 Alkylene radical or divalent -OC 1-3 A divalent -C optionally replaced by an alkylene-O- radical 2-4 Forming an alkylene radical; R b1 is unsubstituted or substituted C 1-8 represents aliphatic; R b2 , R b3 are each independently H, unsubstituted or substituted C 1-8 represent aliphatic; or together with the nitrogen atom to which they are attached, form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocyclic ring having 3, 4, 5, 6, 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, there are none or only one additional ring atom that is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; R B8 , R B9 , R B10 , R B11 , R B12 , R B13 are each independently a halogen, an unsubstituted or substituted C 1-6 aliphatic, C 1-6 Alphatoxy (aliphatoxy), Ar Y and / or R bonded to the same carbon atom of said carbocyclic ring or said heterocyclic ring. B8 , R B9 , R B10 , R B11 , R B12 , R B13 two of which form a divalent oxo (=O) group; and / or R B8 , R B9 , R B10 , R B11 , R B12 , R B13 or two of R bonded to the same sulfur atom of the heterocycle B8 , R B9 , R B10 , R B11 , R B12 , R B13 four of which form a divalent oxo (=O) group, thereby forming an -S(=O)- or -S(=O)2- moiety; Ar 2 is a monocyclic or bicyclic aryl having 5, 6, 7, 8, 9, 10 ring carbon atoms, wherein the aryl is unsubstituted or contains substituents R, which may be the same or different. D1 , R D2, R D3 , R D4 and / or R D5 may be substituted with; Hetar 2 is a monocyclic or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain substituents R, which may be the same or different. D1 , R D2 , R D3 , R D4 and / or R D5 may be substituted with; Cyc 2 is a saturated or partially unsaturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle is unsubstituted or has R D6 , R D7 , R D8 , R D9 and / or R D10 the carbocyclic ring may be substituted with the Ar Z or Hetar Z Ar via two adjacent ring atoms Z or Hetar Z The fused carbocycle may be further fused to R C1 , R C2 , R C3 , R C4 , R C5 , R C6 may be substituted with; Hetcyc 2 is a saturated or partially unsaturated monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, and the heterocycle may be unsubstituted or comprise R D6 , R D7 , R D8 , R D9 and / or R D10the heterocycle may be substituted with the Ar Z or Hetar Z Ar via two adjacent ring atoms Z or Hetar Z The fused heterocycle may be further fused to R C1 , R C2 , R C3 , R C4 , R C5 , R C6 may be substituted with; Ar X , Ar Z are, independently of each other, an unsubstituted or substituted benzo ring; Ar Y is unsubstituted, mono- or disubstituted phenyl; Hetar Y1 is a 5- or 6-membered monocyclic heteroaryl in which 1, 2, 3, or 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl is unsubstituted or optionally substituted with halogen, OH, C 1-4 optionally substituted with alkyl; Hetar Z is an unsubstituted or substituted 5- or 6-membered heteroaryl ring selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxaole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran; Cyc Y1 is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or may contain halogen, OH, C 1-4 optionally substituted with alkyl; Hetcyc Xis a saturated, partially unsaturated or aromatic monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, where 1, 2, 3, 4 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, and the heterocycle may be unsubstituted or comprise R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 and / or R X8 and the heterocycle may be a carboxylic acid bioisostere; Hetcyc Y is a saturated, partially unsaturated or aromatic monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein 1, 2, 3, 4 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; Hetcyc Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; R C1 , R C2 , R C3 , R C4 , R C5 , R C6 are, independently of each other, unsubstituted or substituted C 1-6 represents aliphatic; R D1 , R D2 , R D3 , R D4 , R D5 are, independently of each other, unsubstituted or substituted C 1-6 represents aliphatic; R D6 , R D7 , R D8 , R D9 , R D10 are, independently of each other, unsubstituted or substituted C 1-6 Aliphatic, unsubstituted or substituted C1-6 Alphatoxy (aliphatoxy), halogen, hydroxy; Hetar Y1 , CH2-Hetar Y1 , Cyc Y1 , Hetcyc Y1 , -CH2-Hetcyc Y1 and / or R attached to the same ring atom of said carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 2-6 It may also be an alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical are, independently of each other, O, NH, or NC. 1-4 The alkylene radical may be substituted with OH, C 1-4 Alkyl or -OC 1-4 and / or R attached to different ring atoms of said carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 1-6 and forming an alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical are, independently of one another, O, NH, or NC. 1-4 optionally substituted by alkyl; R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 are, independently of each other, unsubstituted or substituted C 1-6 aliphatic, C 1-6 Alphatoxy, halogen, -OH, -NR 2d -S(=O)2-R 2g , Hetcyc Y , O-Hetcyc Yand / or R bonded to the same carbon atom of said heterocycle. X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 two of which contain a divalent oxo (=O) group; and / or R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 or two of R bonded to the same sulfur atom of the heterocycle X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 four of which form a divalent oxo (=O) group, thereby forming a -S(=O)- or -S(=O)2- moiety; Halogen is F, Cl, Br, I; v is 1 or 2; w is 1 or 2; x is 0, 1, or 2; y is 0, 1 or 2; z is 0, 1, or 2. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0096] Formula (VIII-A) is described, for example, as formula (I) on pages 12-94 of WO 2021 / 224291, and those paragraphs and the description of formula (I) and methods for making compounds of formula (I) are incorporated herein by reference. The moieties of formula (VIII-A), such as A, Z, 1 , Z 2 , R 1 , and R 2 is as defined in WO 2021 / 224291, including any variations or embodiments thereof.

[0097] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (VIII) or (VIII-A) is compound T10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound T10 is chemically described as 2-methyl-8-[4-(trifluoromethyl)phenyl-2H,8H-pyrazolo[3,4-b]indole)-5-carboxylic acid and has the following structure: TIFF2024519845000062.tif54170. A description of compound T10 and methods for making compound T10 can be found, for example, in WO 2021 / 224291, page 198, compound 2, and page 152, examples 2-4.

[0098] In some embodiments, in conjunction with the above or below embodiments, the one or more TEAD inhibitors are: TIFF2024519845000063.tif159170TIFF2024519845000064.tif112170 or any combination thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0099] In some embodiments, in conjunction with the above or below embodiments, the one or more TEAD inhibitors comprise a TEAD palmitate pocket binding inhibitor (e.g., any one of Compound T1, Compound T2, Compound T3, Compound T4, Compound T5, Compound T6, Compound T7, Compound T8, Compound T9, or Compound T10). TEAD palmitate pocket binding inhibitors are described, for example, in Chan et al. (Nat. Chem. Biol. 2016, 12(4):282-289), Noland et al. (Structure, 2016, 24(1):179-186), and Kim et al. (Biological Sciences, 2019, 116(20):9877-9882), each of which is incorporated by reference in its entirety, particularly with respect to the TEAD palmitate pocket binding inhibitors described herein.

[0100] In some embodiments, in conjunction with the above or below embodiments, the one or more TEAD inhibitors include a covalent TEAD inhibitor (e.g., any one of Compound T2, Compound T3, or Compound T4). Covalent TEAD inhibitors are described, for example, in Karats et al. (J. Med. Chem. 2020, 63, 11972-11989), Lu et al. (Acta Pharmaceutica Sinica B, 2021, 11(10):3206-3219), Fan et al. (Biorxiv, 2022, DOI:10.1101 / 2022.05.10.491316), and Kaneda et al. (Am. J. Cancer Res., 2020, 10(12):4399-4415), each of which is incorporated herein by reference in its entirety, particularly with respect to the covalent TEAD inhibitors described herein.

[0101] KRAS inhibitors In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have the formula (KI): TIFF2024519845000065.tif32170 [wherein E1 and E2 each independently represent Nor CR 1 and J is N, NR 10 , or CR 10 and M is N, NR 13 , or CR 13 and; TIFF2024519845000066.tif3170 are the single or double bonds necessary to give all atoms their normal valence; R 1 are independently H, hydroxy, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, NH----C 1-4 Alkyl, N(C 1-4 alkyl), cyano, or halo; R 2 Ha, Halo, C 1-6 Alkyl, C 1-6Haloalkyl, OR', N(R')2, C 2-3 Alkenyl, C 2-3 Alkynyl, C 0-3 Alkylene-C 3-8 Cycloalkyl, C 0-3 Alkylene-C 2-7 Heterocycloalkyl, C 0-3 Alkylene aryl, or C 0-3 alkyleneheteroaryl, and each R' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, C 2-3 Alkenyl, C 2-3 alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 Ha, Halo, C 1-3 Alkyl, C 1-2 Haloalkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl, C 2-3 Alkenyl, C 2-3 alkynyl, aryl, or heteroaryl; R 4 teeth, TIFF2024519845000067.tif49170 Ring A is a monocyclic 4- to 7-membered ring or a bicyclic, bridged, fused, or spiro 6- to 11-membered ring; L is a bond, C 1-6 Alkylene, -OC 0-5 Alkylene, -SC 0-5 Alkylene, or -NH-C 0-5 alkylene, C 2-6 Alkylene, -OC 2-5 Alkylene, -SC 2-5 Alkylene, and NH-C 2-5 For alkylene, one carbon atom of the alkylene group can be optionally replaced with O, S, or NH; R 4’ is H, C 1-8 Alkyl, C 2-8 Alkynyl, C 1-6 Alkylene-OC 1-4 Alkyl, C 1-6 Alkylene-OH, C1-6 Haloalkyl, C 0-3 Alkylene-C 3-8 Cycloalkyl, C 0-3 Alkylene-C 2-7 Heterocycloalkyl, C 0-3 alkylenearyl, or TIFF2024519845000068.tif125170R 5 and R 6 are each independently H, halo, C 1-8 Alkyl, C 2-8 Alkynyl, C 1-6 Alkylene-OC 1-4 Alkyl, C 1-6 Alkylene-OH, C 1-6 Haloalkyl, C 1-6 Alkyleneamines, C 0-6 Alkylene amides, C 0-3 Alkylene-C(O)OH, C 0-3 Alkylene-C(O)OC 1-4 Alkyl, C 1-6 Alkylene-O-aryl, C 0-3 Alkylene-C(O)C 1-4 Alkylene-OH, C 0-3 Alkylene-C 3-8 Cycloalkyl, C 0-3 Alkylene-C 2-7 Heterocycloalkyl, C 0-3 alkylenearyl, or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1-3 alkyl or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; Q is CR 8 R 9 , C=CR 8 R 9 , C=O, C=S, or C=NR 8 and;R 8 and R 9 are each independently H, C 1-3 Alkyl, hydroxy, C 1-3Alkoxy, cyano, nitro, or C 3-6 cycloalkyl or R 8 R 9 can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R 10 is C 1-8 Alkyl, C 0-3 Alkylene aryl, C 0-3 Alkylene Heteroaryl, C 0-3 Alkylene-C 3-8 Cycloalkyl, C 0-3 Alkylene-C 2-7 Heterocycloalkyl, C 1-6 Alkoxy, OC 0-3 Alkylene aryl, OC 0-3 Alkylene heteroaryl, OC 0-3 Alkylene-C 3-8 Cycloalkyl, OC 0-3 Alkylene aryl, OC 0-3 Alkylene-C 2-7 Heterocycloalkyl, NH-C 1-8 Alkyl, N(C 1-8 alkyl)2, NH-C 0-3 Alkylene aryl, NH-C 0-3 Alkyleneheteroaryl, NH-C 0-3 Alkylene-C 3-8 Cycloalkyl, NH-C 0-3 Alkylene-C 2-7 heterocycloalkyl, halo, cyano, or C 1-6 alkyleneamine; R 13 is C 1-4 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyleneamines, and C 3-5 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or any of the foregoing, with the proviso that: (1) J is NR 10 When M is Nor CR 13 (2) M is NR 13 When J is N or CR 10 (3) J is CR 10 When M is N or NR13 (4) M is CR 13 When J is N or NR 10 is] Includes:

[0102] The description of formula (KI) can be found in U.S. Patent Application Publication No. 2018 / 0334454, which is incorporated herein by reference in its entirety. Formula (KI) is described as formula (II) in U.S. Patent Application Publication No. 2018 / 0334454 (see, e.g., paragraphs

[0033] -

[0053] ), and these paragraphs and the description of formula (II) and methods of making compounds of formula (II) are incorporated herein by reference. Moieties of formula (KI), such as J, Q, M, E, 1 , E 2 , R 2 , R 3 , and R 4 is as defined in U.S. Patent Application Publication No. 2018 / 0334454, including any variations or embodiments thereof.

[0103] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have the formula (KIA): TIFF2024519845000069.tif37170[in formula R 1 is H, halo, or -CH3; R 2 is H, halo, or -CH3; TIFF2024519845000070.tif36170b is optionally a single bond or a double bond; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic, bridged, fused, or spiro 6- to 11-membered ring; L is a bond or NR 4 and; R 4 -H, -C 1-6 Alkyl, -C 2-6 Alkynyl, C 1-6 Alkylene-OC 1-4 Alkyl, C 1-6 Alkylene-OH, C 1-6Haloalkyl, -C 1-6 Alkyleneamine, -C 0-6 Alkylene-amide, -C(O)OH, -C(O)OC 1-4 Alkyl, -C 1-6 Alkylene-O-aryl, -N=N, -C 0-3 Alkylene-C(O)C 1-4 Alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-C 2-14 Heterocycloalkyl, -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-C 2-14 is heteroaryl; R 5 H, halo,-C 1-6 Alkyl, -C 2-6 Alkynyl, -C 0-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-4 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Haloalkyl, -C 1-6 Alkyleneamine, -C 0-6 Alkylene-amide, -C(O)OH, -C(O)OC 1-4 Alkyl, -C 0-6 Alkylene-OC 6-14 Aryl, -C 0-3 Alkylene-C(O)C 1-4 Alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-C 2-14 Heterocycloalkyl, -C 0-3 -Alkylene-C 6-14 Aryl, -C 0-3 Alkylene-C 2-14 heteroaryl, or cyano; R 5a-H, -C 1-6 Alkyl, -C 2-6 Alkynyl, -C 1-6 Alkylene-OC 1-4 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Haloalkyl, -C 1-6 Alkyleneamine, -C 0-6 Alkylene-amide, -C(O)OH, -C(O)OC 1-4 Alkyl, -C 0-6 Alkylene-OC 6-14 Aryl, -C 0-3 Alkylene-C(O)C 1-4 Alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-C 2-14 Heterocycloalkyl, -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-C 2-14 heteroaryl; R 5b -H, -C 1-6 Alkyl, -C 2-6 Alkynyl, -C 1-6 Alkylene-OC 1-4 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Haloalkyl, -C 1-6 Alkyleneamine, -C 0-6 Alkylene-amide, -C(O)OH, -C(O)OC 1-4 Alkyl, -C 0-6 Alkylene-OC 6-14 Aryl, -C 0-3 Alkylene-C(O)C 1-4 Alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-C 2-14 Heterocycloalkyl, -C 0-3 Alkylene-C6-14 Aryl or -C 0-3 Alkylene-C 2-14 selected from heteroaryl; or R 5a and R 5b together represent =O or =N=N; R 6 H, halo, -C 1-6 Alkyl, -C 2-6 Alkynyl, -C 1-6 Alkylene-OC 1-4 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Haloalkyl, -C 1-6 Alkyleneamine, -C 0-6 Alkylene-amide, -C(O)OH, -C(O)OC 1-4 Alkyl, -C 0-6 Alkylene-OC 6-14 Aryl, -C 0-3 Alkylene-C(O)C 1-4 Alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-C 2-14 Heterocycloalkyl, -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-C 2-14 is heteroaryl; R 5a and R 6a can, together with the atoms to which they are attached, form a 3- to 6-membered ring optionally containing 1 or 2 heteroatoms selected from O, S, or N; or R 5a and R 6a is absent when b is a double bond; R 6a is H or -C 1-6 is alkyl; R 6b -H, -C 1-6 Alkyl, -C 2-6 Alkynyl, -C 1-6Alkylene-OC 1-4 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Haloalkyl, -C 1-6 Alkyleneamine, -C 0-6 Alkylene-amide, -C(O)OH, -C(O)OC 1-4 Alkyl, -C 0-6 Alkylene-OC 6-14 Aryl, -C 0-3 Alkylene-C(O)C 1-4 Alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-C 2-14 Heterocycloalkyl, -C 0-3 Alkylene-C 6-14 Aryl, -C 0-3 Alkylene-C 2-14 heteroaryl or cyano; or R 6a and R 6b together can represent =O; R 7 is H or C 1-8 is alkyl; R 8 H, OH, NR a R b and; where R a and R b are each independently H, halo, -C 1-6 Alkyl, -C 2-6 is alkynyl; where ring A or R 4 , R 5 , R 5a , R 5b , R 6 , R 6a , R 6b , R 7 and R 8 Either -C 1-6 Alkyl, -C 2-6 Alkynyl, -C 1-6 Alkylene-OC 1-4 Alkyl, -C1-6 Alkylene -OH, -C 1-6 Haloalkyl, -C 1-6 Alkyleneamine, -C 0-6 Alkylene-amide, -C(O)OC 1-4 Alkyl, -C 1-6 Alkylene-O-aryl, -C 0-3 Alkylene-C(O)C 1-4 Alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-C 2-14 Heterocycloalkyl, -C 0-3 Alkylene-C 6-14 Aryl or -C 0-3 Alkylene-C 2-14 Heteroaryl groups may be unsubstituted or, as permitted, may include halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -OH, or -C 1-6 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl-CN. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0104] The description of formula (KIA) can be found in U.S. Patent Application Publication No. 021 / 081212, which is incorporated herein by reference in its entirety. Formula (KI) is described in WO 2021 / 081212 as formula (I) (see, e.g., embodiment 1, paragraph

[0037] ), and these paragraphs and the description of formula (I) and methods of making compounds of formula (I) are incorporated herein by reference. The moiety of formula (KIA), e.g., R 1 , R 2 , R 3 , and R 8 is as defined in WO 2021 / 081212, including any variations or embodiments thereof.

[0105] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (KI) or (KIA) is sotorasib (Compound K1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Sotorasib is chemically described as 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and has the following structure: TIFF2024519845000071.tif62170. A description of sotorasib (Compound K1) and a method for making sotorasib can be found in U.S. Patent Application Publication No. 2018 / 0334454, the entire contents of which are incorporated herein by reference. A description of sotorasib (Compound K1) and a method for making sotorasib can be found, for example, in Example 41, pages 210-212 of U.S. Patent Application Publication No. 2018 / 0334454.

[0106] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have formula (K-II): TIFF2024519845000072.tif44170[In the formula, R1 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein; R2 is H, OH, NH2, halo, C 1-6 Alkyl, C 1-6 is selected from the group consisting of haloalkyl, cyclopropyl, and -NHR, where R is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkanoyl, C 1-6 Hydroxyalkanoyl, C 1-6 Cyanoalkyl, C 1-6 Alkylamino, -(C 1-6 alkenyl)NH(CH3)-(C 1-6 alkylenyl)N(CH3)2, and -(C 1-3alkylenyl)(3- to 7-membered heterocyclyl); R3 and R4 are each independently H, NH2, halo, C 1-6 Alkyl, C 1-6 Haloakyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio, C 1-6 Haloalkylthio, C 1-6 selected from the group consisting of alkylamino, and cyclopropyl; R5 is H, NH2, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio, C 1-6 Haloalkylthio, C 1-6 Alkylamino, and C 3-7 is selected from the group consisting of cycloalkyl, wherein at least one of R2, R3, R4, and R5 is other than H; or R2 and R3, R3 and R4, or R4 and R5, together with the atoms to which they are each attached, form a C 3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-14 aryl, or 5- to 10-membered heteroaryl; each of which is independently OH, NH, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; X is NH2, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfanyl, C 1-6 Alkylthio, C 3-7and selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; each of which is optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Carbamoylalkyl, C 1-6 Carboxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl; two geminal substituents together are selected from the group consisting of C 3-7 can form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkyl, 1-4 Y 1a C substituted with optionally substituted 4- to 10-membered heterocyclyl 1-6 Alkyl, C 1-6 C substituted with dialkylamino substituents 1-6 Alkyl, C 1-6 Dialkylaminocyclopropyl-substituted C 1-6 Alkyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 2-6 Alkynyl, C 1-6 Alkylamino, C 6-14 Aryl, C 1-6 Alkyl-substituted C 6-14 Aryl, C 1-6 Aminoalkyl, C 1-6 Carbamoylalkyl, C 1-6 Carboxyalkyl, C 1-6 Haloalkoxy, C 1-6selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl substituted with methyl, hydroxyl, and oxo; Each Y 1a independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 7-membered heterocyclyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, hydroxyl, NH2, cyano, C 1-6 Carboxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, and C 1-6 haloalkoxy; L is a bond, O, S, and N(L a ) selected from the group consisting of; L a is hydrogen and C 1-3 selected from the group consisting of alkyl; U is C(R 6a ) and; V is C(R 6b ) and; W is C(R 6c ) or N; R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1-6 Alkyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Haloalkylthio, C 2-6 Alkynyl, C 1-6 Alkylamino, C 6-14 Aryl, C 1-6 Aminoalkyl, C 1-6 Carbamoylalkyl, C 1-6Carboxyalkyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkoxy, C 1-6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0107] The description of formula (K-II) can be found in U.S. Patent Application Publication No. 2021 / 0230142, which is incorporated herein by reference in its entirety. Formula (K-II) is described as formula (I) in U.S. Patent Application Publication No. 2021 / 0230142 (see, for example, paragraphs

[0113] -

[0132] ), and these paragraphs and the description of formula (I) and methods for making compounds of formula (I) are incorporated herein by reference. The moieties of formula (K-II), such as U, V, W, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 is as defined in U.S. Patent Application Publication No. 2021 / 0230142, including any variations or embodiments thereof.

[0108] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have formula (K-II-A): TIFF2024519845000073.tif42170[In the formula, R2 is H, OH, NH2, halo, C 1-6 Alkyl, C 1-6 is selected from the group consisting of haloalkyl, cyclopropyl, and -NHR, where R is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkanoyl, C 1-6 Hydroxyalkanoyl, C 1-6 Cyanoalkyl, C 1-6 Alkylamino, -(C 1-6 alkylenyl)NH(CH3)-(C 1-6 alkylenyl)N(CH3)2, and -(C 1-3 alkylenyl)(3- to 7-membered heterocyclyl); R3 and R4 are each independently H, NH2, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio, C 1-6 Haloalkylthio, C 1-6 selected from the group consisting of alkylamino, and cyclopropyl; R5 is H, NH2, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio, C 1-6 Haloalkylthio, C 1-6 Alkylamino, and C 3-7 is selected from the group consisting of cycloalkyl, wherein at least one of R2, R3, R4, and R5 is other than H; or R2 and R3, R3 and R4, or R4 and R5, together with the atoms to which they are each attached, form a C 3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-14 aryl, or 5- to 10-membered heteroaryl; each of which is independently OH, NH, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; R7 is selected from the group consisting of H, cyano, and halo; R8 and R9 are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 is selected from the group consisting of hydroxyalkyl, cyano, and halo; 1-6Alkyl is methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or aryl sulfonate leaving group, C 1-6 Alkanoylamino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyl sulfonyl amino, C 6-12 Dialkylamino, and C 1-6 optionally substituted with one substituent selected from the group consisting of haloalkoxy; or R7 and R8 together form a triple bond with the carbon to which they are attached, or R7 and R8 together with the carbon to which they are each attached may be substituted with one or two halo substituents. 3-7 Forms a cycloalkenyl; R9 is H, C 1-6 Alkyl, C 1-6 selected from the group consisting of haloalkyl, cyano, and halo; 1~6 Alkyl is C 1-6 Alkanoylamino, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkyl sulfonyl amino, C 6-12 Dialkylamino, and C 1-6 optionally substituted with one substituent selected from the group consisting of haloalkoxy; X is NH2, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; each of which is independently OH, NH, halo, cyano, carboxy, carbamoyl, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Carbamoylalkyl, C 1-6 Carboxyalkyl, C 1-6Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 and optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyalkyl, and 4- to 7-membered heterocyclyl; wherein two geminal substituents together form C 3-7 can form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkyl, 1-4 Y 1a C substituted with optionally substituted 4- to 10-membered heterocyclyl 1-6 Alkyl, C 1-6 C substituted with dialkylamino substituents 1-6 Alkyl, C 1-6 Dialkylaminocyclopropyl-substituted C 1-6 Alkyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 2-6 Alkynyl, C 1-6 Alkylamino, C 6-14 Aryl, C 1-6 Alkyl-substituted C 6-14 Aryl, C 1-6 Aminoalkyl, C 1-6 Carbamoylalkyl, C 1-6 Carboxyalkyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, C 1-6 Dialkylamino-substituted C 3-7 Cycloalkyl, C 1-6 Haloalkoxy, C 1-6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl substituted with methyl, hydroxy, and oxo; Each Y 1a independently, halo, C 1-6Alkyl, C 1-6 Alkoxy, 3- to 7-membered heterocyclyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1-6 Carboxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, and C 1-6 haloalkoxy; L is a bond, O, S, and N(L a ) selected from the group consisting of; L a is hydrogen and C 1-3 selected from the group consisting of alkyl; U is C(R 6a ) and; V is C(R 6b ) and; W is C(R 6c ) or N; R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 C substituted with alkyl, 4- to 10-membered heterocyclyl 1-6 Alkyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Haloalkylthio, C 2-6 Alkynyl, C 1-6 Alkylamino, C 6-14 Aryl, C 1-6 Aminoalkyl, C 1-6 Carbamoylalkyl, C 1-6 Carboxyalkyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkoxy, C 1-6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0109] Formula (K-II-A) is described as Formula (II), for example, in paragraph

[0137] of U.S. Patent Application Publication No. 2021 / 0230142, and the description of formula (II) and methods for making compounds of formula (II) are incorporated herein by reference. The moieties of formula (K-II-A), such as U, V, W, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9 is as defined in U.S. Patent Application Publication No. 2021 / 0230142, including any variations or embodiments thereof.

[0110] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have formula (K-II-B) or (K-II-C): TIFF2024519845000074.tif105170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, where U, V, W, Y, R2, R3, R4, and R5 are as defined for Formula (K-II). It is understood that U, V, W, Y, R2, R3, R4, and R5 of such embodiments of compounds of Formula (K-II-B) and (K-II-C) can include U, V, W, Y, R2, R3, R4, and R5 as described for Formula (K-II). Formulae (K-II-B) and (K-II-C) are described, for example, as formulae (Ib) and (IVb) in paragraphs

[0277] and

[0285] of U.S. Patent Application Publication No. 2021 / 0230142, respectively, and these paragraphs and the description of formula (Ib) or (IVb) and methods of making compounds of formula (Ib) or (IVb) are incorporated herein by reference. The moieties of formulae (K-II-B) and (K-II-C), such as U, V, W, Y, R2 , R 3 , R 4 , and R 5 is as defined in U.S. Patent Application Publication No. 2021 / 0230142, including any variations or embodiments thereof.

[0111] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (K-II), (K-II-A), (K-II-B), or (K-II-C) is compound K2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound K2 is chemically described as 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one and has the following structure: TIFF2024519845000075.tif55170. A description of Compound K2 and methods for making Compound K2 can be found, for example, in Examples 17a and 17b on pages 130-135 of U.S. Patent Application Publication No. 2021 / 0230142.

[0112] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have formula (K-III): TIFF2024519845000076.tif54170[in formula: X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is 8 may be substituted with; Y is a bond, O, S, or NR 5 and; R 1 teeth, TIFF2024519845000077.tif13170R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, where Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl each may be selected from the group consisting of one or more R 9 may be substituted with; each Z is a C1-C4 alkylene; Each R 3 are independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl, or halogen; L is a bond, —C(O)—, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl is selected from one or more R 6 , R 7 or R 8 may be substituted with; Each R 5 are independently hydrogen or C1-C3 alkyl; R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 7 may be replaced by; Each R 7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, where Q is O or S; R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 )2, -N(R 5 )2, where C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R5 )2, or optionally substituted with heteroaryl; Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl is optionally substituted with cycloalkyl; Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R 11 is haloalkyl; R A is absent or is selected from hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2, or hydroxyalkyl; Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 )2, -NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 may be substituted with; or TIFF2024519845000078.tif5170 is a double bond and when p is two, one R B is hydrogen and R A and one R Band the carbon atom to which they are attached form a 4- to 8-membered partially saturated cycloalkyl substituted with oxo; m is zero or an integer between 1 and 2; p is 1 or 2; When TIFF2024519845000079.tif5170 is a triple bond, R A does not exist, p is equal to 1, and R B is hydroxyalkyl, or or When TIFF2024519845000080.tif5170 is a double bond, R A exists and R B does not exist and p is equal to 2, where R A is hydrogen or C1-C3 alkyl, at least one R B is deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, -ZNR 5 R 11 , -C(O)N(R 5 )2, —NHC(O)C1-C3 alkyl, —CH2NHC(O)C1-C3 alkyl, or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl; or R B When is hydrogen, R A is deuterium, cyano, halogen, haloalkyl, -C(O)N(R 5 )2, hydroxyalkyl or heteroalkyl] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0113] The description of formula (K-III) can be found in U.S. Patent Application Publication No. 2019 / 0144444, which is incorporated herein by reference in its entirety. Formula (K-III) is described as formula (II) in U.S. Patent Application Publication No. 2019 / 0144444 (see, for example, paragraphs

[0169] -

[0193] ), and these paragraphs and the description of formula (II) and methods of making compounds of formula (II) are incorporated herein by reference. The moieties of formula (K-III), such as X, Y, L, m, R 1 , R 2 , R 3 , and R 4 is as defined in U.S. Patent Application Publication No. 2019 / 0144444, including any variations or embodiments thereof.

[0114] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have formula (K-III-A): TIFF2024519845000081.tif51170 [wherein the piperazinyl ring is R 8 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 , R 3 , R 4 , R 8 , L, and m are as defined in formula (K-III). R of such an embodiment of the compound of formula (K-III-A) 1 , R 3 , R 4 , R 8 , L, and m are R as described for formula (K-III). 1 , R 3 , R 4 , R 8 It should be understood that the moieties of Formula (K-III-A), such as L, m, R, and m, may be included. Formula (K-III-A) is described, for example, as Formula (II-B) in paragraphs

[0231] -

[0241] of U.S. Patent Application Publication No. 2019 / 0144444, the disclosures of which, together with the description of Formula (II-B) and methods of making compounds of Formula (II-B), are incorporated herein by reference. 1 , R2 , R 3 , and R 4 is as defined in U.S. Patent Application Publication No. 2019 / 0144444, including any variations or embodiments thereof.

[0115] In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (K-III) or (K-III-A) is adagrasib (compound K3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Adagrasib is chemically described as 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile and has the following structure: TIFF2024519845000082.tif61170. A description of adagrasib (compound K3) and methods of making adagrasib can be found, for example, in Example 478 on pages 668-669 of U.S. Patent Application Publication No. 2019 / 0144444.

[0116] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have formula (K-IV): TIFF2024519845000083.tif30170[In the formula, A is, (a) C5-C7 cycloalkylene that is unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4 alkyl; (b) a 5- to 7-membered unsaturated heterocyclyl containing one carbon-carbon double bond and one oxygen atom as ring members, wherein the unsaturated heterocyclyl is unsubstituted or substituted with one or more, preferably 1, 2 or 3, substituents independently selected from fluoro and C1-C4 alkyl, preferably 1, 2 or 3 C1-C4 alkyl; (c) unsubstituted or 1, 2, or 3 RA2 C6-C substituted with 10 aryl; (d) A 5- to 6-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R on one or more (e.g., 1, 2, or 3) carbon atoms. A3 and the nitrogen atom, when present in a heteroaryl ring, is unsubstituted or substituted with C1-C4 alkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, C3-C6 cycloalkyl, hydroxy-C1-C4 alkyl, fluoro-C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl, N(R 9 )(R 10 )-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C4 cycloalkyl, -(CH2) p -Het py , and ib-(CH2) p -N(R 9 )(R 10 a heteroaryl ring substituted with a substituent selected from the group consisting of: (e) an 8- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atom, and 0 to 1 S(═O)2 group in the heterobicyclic ring, wherein the heteroaryl ring or heterobicyclic ring is unsubstituted or has 1, 2, 3, 4, or 5 R groups on the carbon atoms; A4 and the heterobicyclic ring may be further substituted on a carbon atom by oxo, and the nitrogen atom, when present, is unsubstituted or substituted with a substituent which is -(CO)-C1-C4 alkyl or C1-C4 alkyl, wherein said C1-C4 alkyl is selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl-oxy, Het b and NR 9 R10 and optionally substituted with one or two substituents independently selected from: Here, Het b is a 4-, 5-, or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently selected from N, O, S, SO, and SO2, and Het b is unsubstituted or substituted on carbon atoms with one or two substituents independently selected from C1-C4 alkyl, hydroxy, cyano, fluoro, C1-C4 alkoxy-hydroxy-C1-C4 alkyl, hydroxy-C1-C4 alkyl, C1-C4 alkoxy, fluoro-C1-C4 alkoxy and fluoro-C1-C4 alkyl, and Het b may be further substituted on the carbon atom by oxo, and the nitrogen atom is b when present in a heteroaryl ring or heterobicyclic ring, optionally further substituted with C1-C4 alkyl, optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy, and C1-C4 alkoxy; is selected from the group consisting of where A is a sp hybridized group to the remainder of the compound of formula (I). 2 is attached by a carbon atom on A which is where: B is B 1 and B 2 selected from the group consisting of: where B 1 is unsubstituted or contains 1, 2, 3 or 4 R Ba C is replaced by 6-10 is aryl; B 2 is a 6- to 13-membered heteroaryl containing 1, 2, or 3 nitrogen atoms; B 2 is unsubstituted or contains 1, 2, 3 or 4 R Bb is replaced by; C is selected from the group consisting of hydrogen, C-C alkyl, C-C cycloalkyl, fluoro-C-C alkyl, cyano, —CH—CN, —CH(CN)—CH, —CH—OH, —CH(OH)—CH, and halo; L is TIFF2024519845000084.tif62170, wherein n is 1, 2, or 3; R L is selected from hydrogen, methyl, ethyl, —CH—CN and —CH—OH, G* represents the point of attachment to G; G is TIFF2024519845000085.tif30170, wherein R 2 is selected from hydrogen, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and fluoro; R 3 is hydrogen; R 4 is selected from hydrogen, methyl, —CHF, —CH—OCH and —CH—N(CH); R 5 is selected from hydrogen and methyl; R 6 is hydrogen, R 7 is selected from hydrogen and methyl; where R A2 is independently, NR 9 R 10 , cyano, -(CH2) p -CN, halo, OH, hydroxy-C1-C4 alkyl, -(COOH), -(CH2) p -COOH, C1-C4 alkyl, fluoro-C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl, N(R 9 )(R 10 )-C1-C4 alkyl, N(R 9 )(R 10 )-C1-C4 alkyl-oxy, N(R 9 )(R 10)-C1-C4 alkoxy, C1-C4 alkyl-carbonyl-oxy-C1-C4 alkyl-oxy, hydroxy-C1-C4 alkyl-oxy, C1-C4 alkoxy-C1-C4 alkyl-oxy, C1-C4 alkoxy-C1-C4 alkyl-oxy-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C4 cycloalkyl, -(CH2) 1-2 -C3-C4 cycloalkyl, Het py , -(CH2) p -Het py , -C(=O)-NR 9 R 10 , -(CH2) p -C(=O)NR 9 R 10 selected from the group consisting of: where R A3 are independently oxo, NR 9 R 10 , cyano, -(CH2) p -CN, halo, OH, hydroxy-C1-C4 alkyl, -(COOH), -(CH2) p -COOH, C1-C4 alkyl, fluoro-C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl, N(R 9 )(R 10 )-C1-C4 alkyl, N(R 9 )(R 10 )-C1-C4 alkyl-oxy, N(R 9 )(R 10 )-C1-C4 alkoxy, C1-C4 alkyl-carbonyl-oxy-C1-C4 alkyl-oxy, hydroxy-C1-C4 alkyl-oxy, C1-C4 alkoxy-C1-C4 alkyl-oxy, C1-C4 alkoxy-C1-C4 alkyl-oxy-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C4 cycloalkyl, -(CH2) 1-2 -C3-C4 cycloalkyl, Het py , -(CH2) p -Het py , -C(=O)-NR 9 R 10 , -(CH2) p -C(=O)NR9 R 10 , (CH2) p -NR 9 R 10 selected from the group consisting of: where R A4 are independently cyano, COH, halo, C1-C4 alkyl, fluoro-C1-C4 alkyl, hydroxy, hydroxy-C1-C4 alkyl, hydroxy-C1-C4 alkyl-oxy, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl-oxy, NR 9 R 10 , N(R 9 )(R 10 )-C1-C4 alkyl, N(R 9 )(R 10 )-C1-C4 alkyl-oxy, -(CO)-C1-C4 alkyl, and R 9 R 10 selected from the group consisting of N-C1-C4 alkyl-oxy-(CO)-C1-C4 alkyl; where: p is 1, 2, or 3; R 9 is selected from hydrogen and C1-C4 alkyl; R 10 is selected from the group consisting of hydrogen, C1-C4 alkyl, hydroxyl-C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl, and di-C1-C4 alkyl-amino-C1-C4 alkyl; Het py is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring containing one or two heteroatoms independently selected from O, N, and S, or containing an S-oxide (SO) or S-dioxide (SO) group, said heterocyclic ring being optionally substituted on one carbon atom with oxo, said heterocyclic ring being optionally further substituted on one or more carbon atoms with one, two, or three substituents independently selected from C-C alkoxy, halo, C-C alkyl, hydroxy-C-C alkyl, and fluoro-C-C alkyl, and a nitrogen atom, when present in said heterocycle, is optionally substituted with R 10 may be further substituted with; or Het py is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, said heteroaryl ring being NR 9 R 10 , -C(=O)-NR 9 R 10 , halo, C1-C4 alkyl, hydroxy-C1-C4 alkyl, fluoro-C1-C4 alkyl, cyano, OH, and C1-C4 alkoxy; Each R Ba is independently selected from the group consisting of hydroxy, NH, C-C alkyl, and halo; Each R Bb are independently selected from the group consisting of C1-C4 alkyl, cyclopropyl, fluoro-C1-C3 alkyl, cyano, halo, NH2, and C1-C3 alkoxy. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0117] The description of formula (K-IV) can be found in WO 2021 / 124222, which is incorporated herein by reference in its entirety. Formula (K-IV) is described as formula (I) in WO 2021 / 124222 (see, for example, pages 5-13 and pages 29-32 of embodiment 1), and these paragraphs and the description of formula (I) and methods for making compounds of formula (I) are incorporated herein by reference. The moieties of formula (K-IV), such as A, B, C, L, and G, are as defined in WO 2021 / 124222, including any variations or embodiments thereof.

[0118] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have formula (K-IV-A): TIFF2024519845000086.tif38170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, where A, B, and C are as defined in Formula (K-IV). It is understood that A, B, and C of such embodiments of a compound of Formula (K-IV-A) can include A, B, and C as described for Formula (K-IV). Formula (K-IV-A) is described, for example, as Formula (Ia) in Embodiment 21 of WO 2021 / 124222, and these paragraphs and the description of methods for making compounds of Formula (Ia) and Formula (Ia) are incorporated herein by reference. Moieties of Formula (K-IV-A), such as A, B, and C, are as defined in WO 2021 / 124222, including any variations or embodiments thereof.

[0119] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors have the formula (K-IV-B) or (K-IV-C): TIFF2024519845000087.tif113170[In the formula, R B2 are independently selected from hydrogen, halo, C1-C4-alkyl, cyclopropyl and NH2; R B3 are independently selected from hydrogen, halo, cyclopropyl and C1-C4-alkyl; R B4 are independently selected from hydrogen, halo and C-C-alkyl, or R B3 and R B4 together with the atoms to which they are attached, R B3 and R B4 forms a 4- to 6-membered ring fused to the aromatic ring to which it is attached; R N is hydrogen, halo, C 1-4 Alkyl, or halo or fluoro-C 1-4 is alkyl; R ae is hydrogen and C 1-4 alkyl, wherein said alkyl is selected from the group consisting of cyano, hydroxyl, fluoro, C 1-4Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl-oxy, Het b and NR 9 R 10 optionally substituted with one or two substituents selected from: R 9 is hydrogen and C 1-4 alkyl; R 10 is hydrogen, C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl and di-C 1-4 Alkyl-amino-C 1-4 alkyl; Here, Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently selected from N, O, S, SO and SO2, wherein said heterocyclic ring Het b is unsubstituted or has a C 1-4 Alkyl, hydroxy, cyano, fluoro, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy and Fluoro-C 1-4 and the heterocyclic ring Het b may be further substituted on the carbon atom by oxo, and the nitrogen atom is b When present in 1-4 C optionally substituted with 1 to 3 substituents independently selected from alkoxy 1-4 may be further substituted with alkyl. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A and C are as defined in formula (K-IV). It is understood that A and C of such embodiments of compounds of formulas (K-IV-B) and (K-IV-C) can include A and C as described for formula (K-IV).

[0120] Formulae (K-IV-B) and (K-IV-C) are described, for example, as formulae (Ib*) and (Id*) in embodiments 39 and 41 of WO 2021 / 124222, respectively, and these paragraphs and the description of formula (Ib*) or (Id*) and methods of making compounds of formula (Ib*) or (Id*) are incorporated herein by reference. Moieties of formula (K-IV-B) or (K-IV-C), such as A, C, R B2 , R B3 , R B4 , R N , and R ae is as defined in WO 2021 / 124222, including any variations or embodiments thereof.

[0121] In some embodiments, in conjunction with the above or below embodiments, the compound of formula (K-IV), (K-IV-A), (K-IV-B), or (K-IV-C) is compound K4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Compound K4 is chemically described as 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one and has the following structure: TIFF2024519845000088.tif63170. A description of compound K4 and methods for making compound K4 can be found, for example, in Method 1 - Synthetic Scheme on pages 111 to 114 of WO 2021 / 124222.

[0122] In some embodiments, the one or more KRAS inhibitors are: TIFF2024519845000089.tif131170 or any combination thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0123] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors are: TIFF2024519845000090.tif133170 or any combination thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0124] In some embodiments, the one or more KRAS inhibitors are: TIFF2024519845000091.tif64170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more KRAS inhibitors comprise sotorasib, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0125] In some embodiments, the one or more KRAS inhibitors are: TIFF2024519845000092.tif56170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more KRAS inhibitors comprise adagrasib, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0126] In some embodiments, the one or more KRAS inhibitors are: TIFF2024519845000093.tif53170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0127] In some embodiments, the one or more KRAS inhibitors are: TIFF2024519845000094.tif61170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0128] In some embodiments, in conjunction with the above or below embodiments, the one or more KRAS inhibitors include a G12C KRAS inhibitor (e.g., any one of compound K1, compound K2, compound K3, and compound K4). G12C KRAS inhibitors are described, for example, in Hallin et al. (Cancer Discov, 2020, 10(1):54-71), Skoulidis et al. (N. Engl. J. Med., 2021, 384(25):2371-2381), and Hong et al. (N. Engl. J. Med., 2020, 383(13):1207-1217), each of which is incorporated herein by reference in its entirety, particularly with respect to the G12C KRAS inhibitors described herein.

[0129] combination: Provided herein are compositions, methods, and kits comprising one or more TEAD inhibitors (e.g., compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or any variation or embodiment thereof) and one or more KRAS inhibitors (e.g., compounds of Formula (KI), (K-II), (K-III), or (K-IV), or any variation or embodiment thereof). Each and every combination of a TEAD inhibitor and a KRAS inhibitor is intended to be the same when each and every combination is specifically and individually listed. Thus, for example, combinations of: (1) a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or any variation or embodiment thereof, with (2) a compound of formula (KI), (K-II), (K-III), or (K-IV), or any variation or embodiment thereof, are contemplated herein.

[0130] Also provided herein are compositions, methods, and kits comprising one or more TEAD inhibitors (e.g., a TEAD palmitate pocket binding inhibitor, a covalent TEAD inhibitor, or a compound of Formula (I)) and one or more KRAS inhibitors (e.g., a G12C KRAS inhibitor, or a compound of Formula (K-II)). Each and every combination of a TEAD inhibitor and a KRAS inhibitor is intended to be the same when each and every combination is specifically and individually listed. Thus, for example, any combination of: (1) a TEAD palmitate pocket binding inhibitor (e.g., Compound T1, Compound T2, Compound T3, Compound T4, Compound T5, Compound T6, Compound T7, Compound T8, Compound T9, or Compound T10) or a covalent TEAD inhibitor (e.g., Compound T2, Compound T3, or Compound T4) with (2) a G12C KRAS inhibitor (e.g., Compound K1, Compound K2, Compound K3, or Compound K4) is contemplated.

[0131] In some embodiments, the one or more TEAD inhibitors comprise a TEAD palmitate pocket binding inhibitor and the one or more KRAS inhibitors comprise a G12C KRAS inhibitor, hi some embodiments, the one or more TEAD inhibitors comprise a covalent TEAD inhibitor and the one or more KRAS inhibitors comprise a G12C KRAS inhibitor.

[0132] In some embodiments, the one or more TEAD inhibitors comprise a compound of Formula (I), (IA), (IB), (I-B1), or (IC) (e.g., compound T1 or T9), and the one or more KRAS inhibitors comprise a compound of Formula (KI), (K-II), (K-III), or (K-IV). In some embodiments, the one or more TEAD inhibitors comprise a compound of Formula (II), (II-A), (II-A1), or (II-B) (e.g., compound T2 or T3), and the one or more KRAS inhibitors comprise a compound of Formula (KI), (K-II), (K-III), or (K-IV). In some embodiments, one or more TEAD inhibitors comprise a compound of Formula (III), (III-A), or (III-A1) (e.g., compound T4), and one or more KRAS inhibitors comprise Formula (KI), (K-II), (K-III), or (K-IV). In some embodiments, one or more TEAD inhibitors comprise a compound of Formula (IV), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), or (IV-F) (e.g., compound T5), and one or more KRAS inhibitors comprise Formula (KI), (K-II), (K-III), or (K-IV). In some embodiments, one or more TEAD inhibitors comprise a compound of Formula (V) (e.g., compound T6), and one or more KRAS inhibitors comprise Formula (KI), (K-II), (K-III), or (K-IV). In some embodiments, one or more TEAD inhibitors comprise a compound of Formula (VI) or (VI-A) (e.g., compound T7), and one or more KRAS inhibitors comprise Formula (KI), (K-II), (K-III), or (K-IV). In some embodiments, one or more TEAD inhibitors comprise a compound of Formula (VII), (VII-A), or (VII-B) (e.g., compound T8), and one or more KRAS inhibitors comprise Formula (KI), (K-II), (K-III), or (K-IV). In some embodiments, one or more TEAD inhibitors comprise a compound of Formula (VIII) or (VIII-A) (e.g., compound T10), and one or more KRAS inhibitors comprise Formula (KI), (K-II), (K-III), or (K-IV).

[0133] In some embodiments, the one or more TEAD inhibitors comprise a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), and the one or more KRAS inhibitors comprise a compound of Formula (KI) or (KIA) (e.g., compound K1). In some embodiments, the one or more TEAD inhibitors comprise a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), and the one or more KRAS inhibitors comprise a compound of Formula (K-II), (K-II-A), (K-II-B), or (K-II-C) (e.g., compound K2). In some embodiments, the one or more TEAD inhibitors comprise a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), and the one or more KRAS inhibitors comprise a compound of Formula (K-III) or (K-III-A) (e.g., compound K3). In some embodiments, the one or more TEAD inhibitors comprise a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), and the one or more KRAS inhibitors comprise a compound of Formula (K-IV), (K-IV-A), (K-IV-B), or (K-IV-C) (e.g., compound K4).

[0134] In some embodiments, a composition, method, or kit described herein includes compound T1 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T2 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T3 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T4 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T5 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T6 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T7 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T8 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T9 and compound K1. In some embodiments, a composition, method, or kit described herein includes compound T10 and compound K1.

[0135] In some embodiments, a composition, method, or kit described herein includes compound T1 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T2 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T3 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T4 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T5 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T6 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T7 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T8 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T9 and compound K2. In some embodiments, a composition, method, or kit described herein includes compound T10 and compound K2.

[0136] In some embodiments, the compositions, methods, or kits described herein include compound T1 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T2 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T3 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T4 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T5 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T6 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T7 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T8 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T9 and compound K3. In some embodiments, the compositions, methods, or kits described herein include compound T10 and compound K3.

[0137] In some embodiments, the compositions, methods, or kits described herein include compound T1 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T2 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T3 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T4 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T5 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T6 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T7 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T8 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T9 and compound K4. In some embodiments, the compositions, methods, or kits described herein include compound T10 and compound K4.

[0138] In some embodiments, provided herein are compositions comprising: (i) one or more YAP / TAZ-TEAD inhibitors, including a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (ii) one or more KRAS inhibitors. In some embodiments, provided herein are compositions comprising: (i) one or more YAP / TAZ-TEAD inhibitors, including a compound of Formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (ii) one or more KRAS inhibitors. In some embodiments, provided herein are compositions comprising: (i) one or more YAP / TAZ-TEAD inhibitors, including a compound of Formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (ii) one or more KRAS inhibitors. In some embodiments, provided herein are compositions comprising: (i) one or more YAP / TAZ-TEAD inhibitors, including compounds of Formula (I), Formula (II), or Formula (III), or any variation or embodiment thereof, or any combination of the foregoing; and (ii) one or more KRAS inhibitors.

[0139] In some embodiments, provided herein are methods for treating psoriasis comprising: (i) TIFF2024519845000095.tif76170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (ii) TIFF2024519845000096.tif125170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0140] In some embodiments, provided herein are methods for treating psoriasis comprising: (i) TIFF2024519845000097.tif152170TIFF2024519845000098.tif112170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (ii) TIFF2024519845000099.tif133170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0141] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000100.tif42170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000101.tif64170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0142] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000102.tif42170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000103.tif53170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0143] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000104.tif42170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000105.tif56170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0144] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000106.tif30170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000107.tif64170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0145] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000108.tif30170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000109.tif53170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0146] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000110.tif30170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000111.tif56170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0147] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000112.tif26170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000113.tif64170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0148] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000114.tif26170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000115.tif53170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0149] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000116.tif26170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000117.tif56170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0150] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000118.tif29170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000119.tif64170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0151] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000120.tif29170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000121.tif53170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0152] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: TIFF2024519845000122.tif29170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and TIFF2024519845000123.tif56170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0153] In some embodiments, the YAP / TAZ-TEAD inhibitor is selected from the group consisting of compounds T1, T2, T3, and T4, or stereoisomers or tautomers thereof, or a pharmaceutically acceptable salt of any of the foregoing, as listed in Table 1. In some embodiments, the one or more KRAS inhibitors are selected from the group consisting of compounds K1, K2, and K3, or stereoisomers or tautomers thereof, as listed in Table 1, or a pharmaceutically acceptable salt of any of the foregoing.

[0154] In some embodiments, the YAP / TAZ-TEAD inhibitor is selected from the group consisting of compounds T1, T2, T3, T4, T5, T6, T7, T8, T9, and T10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, as listed in Table 1. In some embodiments, the one or more KRAS inhibitors are selected from the group consisting of compounds K1, K2, K3, and K4, or a stereoisomer or tautomer thereof, as listed in Table 1, or a pharmaceutically acceptable salt of any of the foregoing. Table 1 TIFF2024519845000124.tif232170TIFF2024519845000125.tif206170TIFF2024519845000126.tif249170

[0155] In some embodiments, the YAP / TAZ-TEAD inhibitor is 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; N-(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acrylamide; N-(6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide; 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid; N-(3-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3-methyl-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)benzyl)-5-methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)picolinamide; N-(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide; N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide; N-methyl-3-(1-methylimidazol-4-yl)-4-[4-(trifluoromethyl)anilino]benzenesulfonamide; 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; and 2-methyl-8-[4-(trifluoromethyl)phenyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is selected from the group consisting of:

[0156] In some embodiments, the one or more KRAS inhibitors are: 4-(4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; 2-(4-(7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile; 1-(4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one; and 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is selected from the group consisting of:

[0157] Further provided herein are, where appropriate, all stereoisomers of the TEAD inhibitors and KRAS inhibitors set forth herein, including geometric isomers (e.g., cis / trans or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio, including racemic mixtures.

[0158] In some embodiments, the TEAD inhibitors provided herein, e.g., compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or any variation or embodiment thereof, are isotopically labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically labeled (e.g., radiolabeled) compounds are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into the TEAD inhibitors provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, including, but not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively. 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Some isotopically labeled TEAD inhibitor compounds, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, the TEAD inhibitors provided herein can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0159] For each of the TEAD inhibitors described herein, e.g., compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or any variation or embodiment thereof, a heavier isotope, e.g., deuterium, i.e., 2Substitution with H may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Any hydrogen (H) present in any of the compounds disclosed herein may be substituted with a methyl group. 1 H) atoms and deuterium ( 2 It is understood that any hydrogen atom may be replaced by an equal number of deuterium atoms in any given compound provided herein.

[0160] With respect to each of the TEAD inhibitors described herein, e.g., compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or any variation or embodiment thereof, a positron-emitting isotope, e.g., 11 C. 18 F, 15 O and 13 Substitution at N may be useful in positron emission topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds may generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0161] In addition to salt forms, the present disclosure provides prodrug forms of TEAD inhibitors, such as compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or any variation or embodiment thereof. As used herein, the term "prodrug" refers to a compound that readily undergoes chemical changes under physiological conditions to provide a TEAD inhibitor of the present disclosure. Furthermore, prodrugs can be converted to a TEAD inhibitor of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to a TEAD inhibitor of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0162] Prodrugs of the TEAD inhibitors provided herein may include a phosphate, phosphate ester, alkyl phosphate, alkyl phosphate ester, acyl ether, or other prodrug moiety as described below. In some embodiments, the prodrug moiety is: TIFF2024519845000127.tif60170

[0163] Additional types of prodrugs of the TEAD inhibitors provided herein are also encompassed, for example, an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, covalently bonded to a free amino, hydroxy, or carboxylic acid group of a compound of the disclosure through an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, commonly represented by their three-letter symbols, and also phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosin, isodemosin, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

[0164] Additional types of prodrugs of the TEAD inhibitors provided herein are also encompassed. For example, free carboxyl groups of the disclosed compounds can be derivatized as amides or alkyl esters. As another example, TEAD inhibitors of the disclosed compounds containing free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group to groups such as, but not limited to, phosphate esters, hemisuccinates, dimethylaminoacetates, or phosphoryloxymethyloxycarbonyl groups, as reviewed in Fleisher, D. et al. (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters, and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also encompassed, where the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include prodrugs in which the hydrogen atom of the alcohol group is replaced with a (C 1-6 ) alkanoyloxymethyl, 1-((C 16 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkanoyl, alpha-amino (C 1-4)alkanoyl, arylacyl, and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl groups, where each alpha-aminoacyl group independently represents a naturally occurring L-amino acid, P(O)(OH), -P(O)(O(C 1-6 ) alkyl) 2 or glycosyl (a group resulting from removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0165] For further examples of prodrug derivatives that may be suitable for the TEAD inhibitors provided herein, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. See Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984).

[0166] Additionally, the present disclosure provides metabolites of the disclosed TEAD inhibitors, e.g., compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or any variation or embodiment thereof. As used herein, "metabolite" refers to a product produced through metabolism in the body of a particular compound or salt thereof. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of an administered compound. Metabolites typically include radiolabeled (e.g., methyl) TEAD inhibitors of the present disclosure. 14 C or 3 Identification of metabolites is accomplished by preparing a TEAD inhibitor (H) isotope, parenterally administering it to animals such as rats, mice, guinea pigs, monkeys, or humans at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding to epitopes surviving in the metabolites). The structures of the metabolites are determined by conventional methods, such as MS, LC / MS, or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites, unless otherwise observed in vivo, are useful in diagnostic assays for therapeutic dosing of the disclosed TEAD inhibitors.

[0167] Some compounds of the present disclosure can exist in unsolvated forms and solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present disclosure. Some compounds of the present disclosure can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0168] III. Pharmaceutical Compositions and Administration Further disclosed are pharmaceutical compositions comprising (i) one or more YAP / TAZ-TEAD inhibitors; (ii) one or more KRAS inhibitors; and (iii) one or more therapeutically inert carriers. The pharmaceutical compositions may comprise any of the YAP / TAZ-TEAD inhibitors and any of the KRAS inhibitors described elsewhere herein. Another aspect comprises (i) one or more YAP / TAZ-TEAD inhibitors; (ii) one or more KRAS inhibitors; and (iii) one or more pharmaceutically acceptable carriers. In one embodiment, disclosed are pharmaceutical compositions comprising (i) one or more YAP / TAZ-TEAD inhibitors; (ii) one or more KRAS inhibitors; and (iii) one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In another embodiment, the composition comprises one or more YAP / TAZ-TEAD inhibitors in an amount effective to measurably disrupt YAP:TEAD protein-protein interaction. In another embodiment, the composition comprises one or more KRAS inhibitors in an amount effective to measurably disrupt the activity of the oncogenic KRAS gene. In some embodiments, the composition is formulated for administration to a patient in need thereof. In another embodiment, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a composition comprising: (i) one or more YAP / TAZ-TEAD inhibitors; (ii) one or more KRAS inhibitors; and (iii) one or more pharmaceutically acceptable carriers, diluents, and / or additives. In some of the foregoing embodiments, the one or more YAP / TAZ-TEAD inhibitors comprise a compound of Formula (I), Formula (II), or Formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of the foregoing, or any combination thereof. In some embodiments, the one or more YAP / TAZ-TEAD inhibitors comprise one or more of compounds T1, T2, T3, and T4, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof. In some embodiments, the one or more KRAS inhibitors include one or more of compounds K1, K2, and K3, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.In some embodiments, the one or more KRAS inhibitors comprise sotorasib, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more KRAS inhibitors comprise adagrasib, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0169] In some of the foregoing embodiments, the one or more YAP / TAZ-TEAD inhibitors comprise a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof. In some embodiments, the one or more YAP / TAZ-TEAD inhibitors comprise one or more of compounds T1, T2, T3, T4, T5, T6, T7, T8, T9, and T10, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof. In some embodiments, the one or more KRAS inhibitors comprise one or more of compounds K1, K2, K3, and K4, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof. In some embodiments, the one or more KRAS inhibitors comprise sotorasib, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more KRAS inhibitors comprise adagrasib, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0170] Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, water, partial glyceride mixtures of salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0171] The compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, bucally, sublingually, vaginally, intraperitoneally, pulmonary, intradermally, epidurally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0172] In one embodiment, the compositions disclosed herein are formulated as solid dosage forms for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, solid oral dosage forms comprising the compositions described herein contain (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate; (ii) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (iii) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or acacia; (iv) a humectant, such as glycerol; (v) a disintegrant, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates, or sodium carbonate; (vi) a solution retarder. (vii) an absorption enhancer, such as a quaternary ammonium salt; (viii) a wetting agent, such as cetyl alcohol or glycerol monostearate; (ix) an absorbent, such as kaolin or bentonite clay; and (x) a lubricant, such as one or more of talc, calcium stearate, magnesium stearate, polyethylene glycol, or sodium lauryl sulfate. In some embodiments, the solid oral dosage form is formulated as a capsule, tablet, or pill. In some embodiments, the solid oral dosage form further comprises a buffering agent. In some embodiments, such compositions for solid oral dosage forms may be formulated as a filler in soft and hard-filled gelatin capsules containing one or more additives, such as lactose or sugared milk, and polyethylene glycol, etc.

[0173] In some embodiments, the tablets, dragees, capsules, pills, and granules of the compositions described herein comprise a coating or shell, such as an enteric coating. They may optionally contain opacifying agents and may be of a composition that they release one or more active ingredients only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions include polymeric substances and waxes, which may be used as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or sugar milk and high molecular weight polyethylene glycols.

[0174] In another embodiment, the composition comprises a liquid dosage formulation comprising the composition described herein for oral administration, optionally further comprising one or more pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In some embodiments, the liquid dosage form optionally further comprises one or more of an inert diluent, such as water or other solvent, a solubilizer, and an emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol or fatty acid esters of sorbitan, and mixtures thereof. In some embodiments, the liquid oral composition optionally further comprises one or more adjuvants, such as wetting agents, suspending agents, sweeteners, flavoring agents, and fragrances.

[0175] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally administrable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic aqueous sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating, fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0176] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0177] To prolong the effect of the compositions described herein, it is often desirable to slow the absorption of the components from the composition from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the compound depends on its rate of dissolution, which, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0178] In some embodiments, compositions for rectal or vaginal administration are formulated as suppositories, e.g., which are solid at ordinary temperatures but liquid at body temperature and thus melt in the rectum or vaginal cavity and release the compounds described herein, which can be prepared by mixing a composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax.

[0179] Exemplary dosage forms for topical or transdermal administration of the compositions described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The compositions are mixed under sterile conditions with a pharmaceutically acceptable carrier and, optionally, a preservative or buffer. Additional exemplary formulations include ophthalmic formulations, ear drops, eye drops, and transdermal patches. Transdermal dosage forms can be made by dissolving or suspending the composition in a vehicle such as ethanol or dimethyl sulfoxide. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0180] Nasal aerosol or inhalation formulations of the compositions described herein can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other common solubilizing or dispersing agents.

[0181] The specific administration and treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, rate of excretion, combination formulation, the judgment of the treating physician, and the severity of the particular disease being treated. The amounts of the compositions described herein provided will also depend on the particular compounds in the composition.

[0182] In one embodiment, the therapeutically effective amount per dose of a parenterally administered combination or composition of the present disclosure ranges from about 0.01-100 mg / kg of patient body weight per day, alternatively about 0.1 to 20 mg / kg, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 5 to about 500 mg of a compound of the present disclosure.

[0183] In one embodiment, a therapeutically effective amount of a combination or composition of the present disclosure is about 5mg-600mg, 5mg-500mg, 5mg-400mg, 5mg-300mg, 5mg-250mg, 5mg-200mg, 5mg-150mg, 5mg-100mg, 5mg-50mg, 5mg-25mg, 25mg-600mg, 25mg-500mg, 25mg-400mg, 25mg-300mg, 25mg-250mg, 25mg-200mg, 25mg-150mg, 25mg-100mg, 25mg-50mg, 50mg-600mg, 50mg-500mg, 50mg-400mg, 50mg-300mg, 50mg-250mg, 50mg-200mg, 50mg-150mg, or 50mg-100mg In another embodiment, a therapeutically effective amount of a combination or composition of the present disclosure is administered in an amount of about 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg.

[0184] In some embodiments of the methods of treatment provided herein, one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered simultaneously. In some embodiments in which one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered simultaneously, one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered in a single composition. By way of illustration and not limitation, in one embodiment, one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered together in a single tablet. In some embodiments in which one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered simultaneously, one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered in separate compositions. By way of illustration and not limitation, in one embodiment, one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered simultaneously in separate tablets.

[0185] In some embodiments of the methods of treatment provided herein, the one or more YAP / TAZ-TEAD inhibitors and the one or more KRAS inhibitors are administered sequentially. In some embodiments, the one or more YAP / TAZ-TEAD inhibitors are administered before the one or more KRAS inhibitors. In some embodiments, the one or more KRAS inhibitors are administered before the one or more YAP / TAZ-TEAD inhibitors. In some embodiments, the sequential administration is separated by minutes, hours, days, or weeks.

[0186] IV. Treatment Methods and Indications In some embodiments, certain compounds present in the combinations and compositions described herein are inhibitors of the YAP:TEAD protein-protein interaction ("YAP:TEAD inhibitors") that bind to TEAD and disrupt the YAP:TEAD protein-protein interaction. In embodiments, certain disclosed compounds are useful for the treatment of cancer, including cancers characterized by solid tumors, through their ability to inhibit the YAP:TEAD protein-protein interaction. The compounds present in the combinations and compositions of the present disclosure are small molecule YAP:TEAD inhibitors. Small molecule YAP:TEAD inhibitors are useful, for example, for the diagnosis or treatment of cancer, including, but not limited to, lung cancer, breast cancer, head and neck cancer, colon cancer, ovarian cancer, liver cancer, brain cancer, and prostate cancer, mesothelioma, sarcoma, and / or leukemia. In other embodiments, small molecule YAP:TEAD inhibitors are useful for the diagnosis or treatment of cancer characterized by solid tumors, including, but not limited to, lung cancer, liver cancer, ovarian cancer, breast cancer, and / or squamous cell carcinoma. In some embodiments, the solid tumor has YAP / TAZ amplification or Nf2 deletion / mutation.

[0187] In some embodiments, certain compounds disclosed herein are inhibitors of the oncogenic Ras gene, for example, inhibitors of KRAS.

[0188] In some embodiments, the disclosed compounds, and any combination thereof, are for use as therapeutically active agents.

[0189] In some embodiments, the disclosed compounds, and any combination thereof, are for the therapeutic and / or prophylactic treatment of cancer.

[0190] In some embodiments, the disclosed compounds, and any combination thereof, are for the preparation of a medicament for the therapeutic treatment of cancer.

[0191] In some embodiments, the disclosed compounds, and any combination thereof, are for use in the therapeutic treatment of cancer.

[0192] The present disclosure is directed to a method for the therapeutic treatment of cancer in a subject, the method comprising administering to the subject an effective amount of any of the compositions described elsewhere herein.

[0193] In some embodiments, provided are methods for modulating YAP / TAZ-TEAD activity, or KRAS activity, or both, in a cell, the methods comprising administering to the cell an effective amount of a combination comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

[0194] In some embodiments, provided are methods for inhibiting YAP / TAZ-TEAD activity, or KRAS activity, or both, in a cell, the methods comprising administering to the cell an effective amount of a combination, comprising a combination comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

[0195] In some embodiments, provided are methods of sensitizing (or re-sensitizing) cells that are resistant to KRAS inhibitors, the methods comprising administering to the cells an effective amount of a combination comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors. In some embodiments, the cells have always been resistant to the KRAS inhibitor. In some embodiments, the cells have acquired resistance to the KRAS inhibitor over time.

[0196] In some embodiments, provided are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject an effective amount of a combination comprising: (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

[0197] In some embodiments of the foregoing, the described methods utilize combinations or compositions described elsewhere herein. In some embodiments of the foregoing methods, the one or more YAP / TAZ-TEAD inhibitors comprise a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or any variation or embodiment thereof (e.g., including a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof), or any combination of the foregoing.

[0198] In some embodiments, the one or more YAP / TAZ-TEAD inhibitors are: TIFF2024519845000128.tif76170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0199] In some embodiments, the one or more KRAS inhibitors are: TIFF2024519845000129.tif125170, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more KRAS inhibitors comprise sotorasib, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more KRAS inhibitors comprise adagrasib, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0200] In some embodiments, the cancer is a solid tumor.

[0201] In some embodiments, the cancer is associated with YAP, TAZ, TEAD, and / or YAP:TEAD protein-protein interactions.

[0202] Embodiments of the present disclosure provide methods for inhibiting Ras-mediated cell signaling, comprising contacting cells with a therapeutically effective amount of one or more combinations or compositions disclosed herein. Inhibition of Ras-mediated signaling can be assessed and demonstrated by a variety of methods known in the art. Non-limiting examples include demonstrating (a) a decrease in Ras GTPase activity; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in GTP Koff or a decrease in GDP Koff; (d) a decrease in the levels of signaling molecules downstream of the Ras pathway, such as a decrease in pMEK levels; and / or (e) a decrease in binding of the Ras complex to downstream signaling molecules, including, but not limited to, Raf. Kits and commercially available assays can be used to determine one or more of the above.

[0203] Embodiments also provide methods of treating disease states, including but not limited to conditions associated with G12C K-Ras mutations, G12C H-Ras mutations, and / or G12C N-Ras mutations (e.g., cancer), using the combinations or compositions of the present disclosure. In some embodiments, the cancer is associated with a Ras mutation. In some embodiments, the cancer is associated with a KRas mutation. In some embodiments, the cancer is associated with a KRAS G12C mutation.

[0204] In some embodiments, the present disclosure provides a method of treating a disorder in a subject in need thereof, the method comprising determining whether the subject has a K-Ras, H-Ras, or N-Ras G12C mutation, and administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, if the subject is determined to have a K-Ras, H-Ras, or N-Ras G12C mutation.

[0205] K-Ras, H-Ras, or N-Ras G12C mutations have also been identified in hematological tumors (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, some embodiments are directed to the administration of the disclosed combinations or compositions of the present disclosure (e.g., in the form of a pharmaceutical composition) to patients in need of treatment for hematological tumors. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the combinations and compositions disclosed herein can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the disclosed combinations and compositions are useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0206] Determining whether a tumor or cancer contains a G12C K-Ras, H-Ras, or N-Ras mutation can be performed by evaluating the nucleotide sequence encoding the K-Ras, H-Ras, or N-Ras protein, by evaluating the amino acid sequence of the K-Ras, H-Ras, or N-Ras protein, or by evaluating the characteristics of a predicted K-Ras, H-Ras, or N-Ras mutant protein. The sequences of wild-type human K-Ras (e.g., accession number NP203524), H-Ras (e.g., accession number NP001123914), and N-Ras (e.g., accession number NP002515) are known in the art.

[0207] Methods for detecting mutations in K-Ras, H-Ras, or N-Ras nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for G12C K-Ras, H-Ras, or N-Ras mutations by real-time PCR. Real-time PCR uses a fluorescent probe specific for the K-Ras, H-Ras, or N-Ras G12C mutation. If the mutation is present, the probe binds and fluorescence is detected. In some embodiments, K-Ras, H-Ras, or N-Ras G12C mutations are identified using direct sequencing of specific regions within the K-Ras, H-Ras, or N-Ras gene (e.g., exon 2 and / or exon 3). This technique will identify all possible mutations within the sequenced region.

[0208] Methods for detecting mutations in K-Ras, H-Ras, or N-Ras proteins are known to those of skill in the art. These methods include, but are not limited to, detecting K-Ras, H-Ras, or N-Ras mutations using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing. Methods for determining whether a tumor or cancer contains a G12C K-Ras, H-Ras, or N-Ras mutation can use a variety of samples. In some embodiments, the sample is obtained from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0209]

[0010] Embodiments also relate to methods of treating a hyperproliferative disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of the combinations and compositions of the present disclosure. In some embodiments, the methods are directed to treating a hyperproliferative disorder, including acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid rhabdomyosarcoma-like tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid leukemia (CRL), and leukemia-associated leukemia (LEU). Myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, uterine cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, Pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lobular intraepithelial carcinoma (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasia, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasia, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, oropharynx for the treatment of cancers such as ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, sarcoma of soft tissue, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, abnormal cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, the methods relate to the treatment of non-cancerous hyperproliferative disorders such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or benign prostatic hyperplasia (BPH).

[0210] In certain embodiments, the present disclosure relates to a method for treating lung cancer, the method comprising administering a therapeutically effective amount of a combination or composition of the present disclosure to a subject in need thereof. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenocarcinoma, carcinoid tumor, and undifferentiated carcinoma.

[0211] In some embodiments, the present disclosure provides methods of inhibiting the activity of K-Ras, H-Ras, or N-Ras G12C in a cell by contacting the cell with a combination or composition of the present disclosure in an amount sufficient to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the cell. In some embodiments, the present disclosure provides methods of inhibiting the activity of K-Ras, H-Ras, or N-Ras G12C in a tissue by contacting the tissue with a combination or composition of the present disclosure in an amount sufficient to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the tissue. In some embodiments, the present disclosure provides methods of inhibiting the activity of K-Ras, H-Ras, or N-Ras G12C in an organism by contacting the organism with a combination or composition of the present disclosure in an amount sufficient to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the organism. In some embodiments, the present disclosure provides methods of inhibiting the activity of K-Ras, H-Ras, or N-Ras G12C in an animal by contacting the animal with a combination or composition of the present disclosure in an amount sufficient to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the animal. In some embodiments, the present disclosure provides methods of inhibiting the activity of K-Ras, H-Ras, or N-Ras G12C in a mammal by contacting the mammal with a combination or composition of the present disclosure in an amount sufficient to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the mammal. In some embodiments, the present disclosure provides methods of inhibiting the activity of K-Ras, H-Ras, or N-Ras G12C in a human by contacting the human with a combination or composition of the present disclosure in an amount sufficient to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the human. In other embodiments, the present disclosure provides methods of treating a disease mediated by the activity of K-Ras, H-Ras, or N-Ras G12C in a subject in need of such treatment.

[0212] In some embodiments, the present disclosure provides a method of treating cancer, comprising administering a therapeutically effective amount of a combination or composition of the present disclosure to an individual in need thereof. In some embodiments, the individual is human. In some embodiments, administration is via the oral route. In some embodiments, administration is via injection. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma.

[0213] In some embodiments, the present disclosure provides a method for regulating the activity of a mutant protein selected from the group consisting of K-Ras G12C, H-Ras G12C, and N-Ras G12C, the method comprising reacting the mutant protein with a combination or composition of the present disclosure.

[0214] In some embodiments, the present disclosure provides a method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a combination or composition of the present disclosure, hi some embodiments, the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0215] In some embodiments, the present disclosure provides a method for treating a disorder mediated by a mutation selected from the group consisting of K-Ras G12C, H-Ras G12C, and N-Ras G12C in an individual in need of such treatment, the method comprising determining whether the individual has the mutation and, if the individual is determined to have the mutation, administering to the individual a therapeutically effective amount of a combination or composition of the present disclosure. In some embodiments, the disorder is mediated by a K-Ras G12C mutation. In some embodiments, the disease is cancer. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma.

[0216] In some embodiments, the present disclosure provides a method for preparing a labeled K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant protein, the method comprising reacting a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant protein with a combination or composition of the present disclosure to obtain the labeled K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant protein.

[0217] In some embodiments, the present disclosure provides a method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a combination or composition of the present disclosure.

[0218] In some embodiments, the disclosure provides use of a combination or composition of the disclosure in the manufacture of a medicament for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is mediated by an H-Ras G12C mutation. In some embodiments, the cancer is mediated by an N-Ras G12C mutation. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0219] In some embodiments, the present disclosure provides a combination or composition of the present disclosure for use in a method of treatment of the human or animal body by therapy. In some embodiments, the present disclosure provides a combination or composition of the present disclosure for use in a method of treating cancer. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is mediated by an H-Ras G12C mutation. In some embodiments, the cancer is mediated by an N-Ras G12C mutation. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in a method of inhibiting tumor metastasis.

[0220] Further provided herein is a method for treating lung cancer in a patient, comprising administering a therapeutically effective amount of a combination or composition described herein to a patient with lung cancer. In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC). The NSCLC can be, for example, adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenocarcinoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. The methods provided herein include administering a compound as a first line of therapy. In one embodiment, the lung cancer comprises a G12C KRas mutation.

[0221] Also provided is a method of treating pancreatic cancer in a patient having pancreatic cancer, the method comprising administering to the patient a therapeutically effective amount of a combination or composition described herein. In one embodiment, the patient has previously been treated with radiation and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is stage 0, stage I, or stage II. In another embodiment, the pancreatic cancer is stage III or stage IV. In one embodiment, the pancreatic cancer comprises a KRas mutation.

[0222] Further provided herein is a method of treating colon cancer in a patient having colon cancer, the method comprising administering to the patient a therapeutically effective amount of a combination or composition described herein. In one embodiment, the colon cancer is stage I or stage II. In another embodiment, the colon cancer is stage III or stage IV. In one embodiment, the colon cancer comprises a G12C KRas mutation.

[0223] Further provided herein is a method for treating tumor-independent G12C mutant KRas-mediated cancer. In one embodiment of such a method, the method comprises: a. Determining the presence or absence of the KRas G12C mutation in samples taken from patients diagnosed with suspected cancer; and b. administering to the patient a therapeutically effective amount of a combination or composition described herein. Includes:

[0224] In one embodiment of such a method, the patient is diagnosed with a cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before the administration of any therapy. In another such embodiment, the sample is taken before the administration of a compound of a pharmaceutically acceptable salt thereof described herein and after the administration of another chemotherapeutic agent. In another embodiment of such a method, the compound described herein or a pharmaceutically acceptable salt thereof is administered as provided herein (e.g., orally).

[0225] In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In other such embodiments, the cancer is NSCLC mediated by KRAS G12C mutation, adenocarcinoma, lung squamous cell carcinoma, large cell lung carcinoma, or SCLC.

[0226] In some embodiments, the cancer is cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, sebaceous cyst, and teratoma; lung: lung carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (adenocarcinoma, lymphoma, leiomyosarcoma), pancreas (ductal carcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (carcinoma, lymphoma, carcinoma, gallbladder ... Tinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, sebaceous cyst, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, malignant teratoma, choriocarcinoma, sarcoma, interstitial i-cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, sebaceous cyst); liver: hepatocellular carcinoma, cholangiocarcinoma, pulmonary blastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder Cancer, ampullary carcinoma, bile duct carcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor Chordoma, osteocytoma (osteochondral exostosis), benign chondroma, chondroblastoma, chondroblastoma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningitis (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, bacteriomatosis (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, undifferentiated cancers of the genital tract, granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), female vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);Skin: selected from the group consisting of malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo (dysplastic nevi), sebaceous cyst, hemangioma, dermatofibroma, keloid, and psoriasis; and adrenal gland: neuroblastoma.

[0227] Breast cancer The combinations and compositions of the present disclosure can be administered alone or can be used in combination therapy for the treatment of breast cancer. For example, the combination therapy includes administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent (e.g., 1, 2, 3, 4, 5, or 6 additional therapeutic agents) for the treatment of breast cancer.

[0228] The standard of care for breast cancer is determined by both disease (tumor, stage, pace of disease, etc.) and patient characteristics (age, biomarker expression, and intrinsic phenotype). General guidance regarding treatment options is provided in NCCN guidelines (e.g., NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, version 2.2016, National Comprehensive Cancer Network, 2016, pp. 1-202) and ESMO guidelines (e.g., Senkus, E., et al. Primary Breast Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2015;26(Suppl. 5):v8-v30; and Cardoso F., et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2012;23(Suppl. 7):vii11-vii19.).

[0229] In some embodiments, the combinations and compositions of the present disclosure are for use in combination therapy for the treatment of breast cancer in combination with one or more other therapeutic agents. In further embodiments, the combinations and compositions of the present disclosure are for use in combination therapy for the treatment of early stage breast cancer or locally advanced breast cancer. In further embodiments, the combinations and compositions of the present disclosure are for use in combination therapy for the treatment of advanced breast cancer or metastatic breast cancer.

[0230] In particular, the combinations and compositions of the present disclosure can be used alone or in combination with standard treatment options for breast cancer, which generally include surgery, systemic chemotherapy (pre- or post-operative), and / or radiation therapy. Depending on tumor and patient characteristics, systemic chemotherapy can be administered as adjuvant (post-operative) therapy or as neoadjuvant (pre-operative) therapy.

[0231] Thus, in one embodiment, the combination therapy comprises administering the combinations and compositions of the present disclosure and administering at least one additional therapeutic agent such as doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, methotrexate, and / or 5-fluorouracil.

[0232] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering doxorubicin and cyclophosphamide (AC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering docetaxel, doxorubicin, and cyclophosphamide (TAC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering cyclophosphamide, methotrexate, and 5-fluorouracil (CMF chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering epirubicin and cyclophosphamide (EC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering 5-fluorouracil, epirubicin, and cyclophosphamide (FEC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a taxane, particularly docetaxel or paclitaxel.

[0233] In one embodiment, when the combination or composition of the present disclosure is for use in treating metastatic breast cancer, the combination therapy comprises administering a combination or composition of the present disclosure and at least one additional therapeutic agent, such as doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, carboplatin, cisplatin, docetaxel, paclitaxel, albumin-bound paclitaxel, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepilone, methotrexate, and / or 5-fluorouracil (5-FU). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering docetaxel and capecitabine for use in treating metastatic breast cancer. In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering gemcitabine and paclitaxel for use in treating metastatic breast cancer.

[0234] Breast cancer - hormone receptor positive (ER+ and / or PR+) In a further aspect, the present disclosure provides a method for treating hormone receptor positive (HR+) breast cancer (also called estrogen receptor positive (ER+) breast cancer or estrogen receptor positive and / or progesterone receptor positive (PR+) breast cancer) by administering an effective amount of a combination or composition of the present disclosure. In a further aspect of this embodiment, the breast cancer is early stage or locally advanced hormone receptor positive (HR+) breast cancer, also called early stage or locally advanced ER+ breast cancer. In a further aspect, the breast cancer is advanced hormone receptor positive (HR+) breast cancer or metastatic hormone receptor positive (HR+) breast cancer, also called advanced ER+ breast cancer or metastatic ER+ breast cancer.

[0235] In some aspects, the combination or composition is for use in combination therapy for the treatment of hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer. In a further aspect, the combination or composition is for use in combination therapy for the treatment of early stage or locally advanced hormone receptor positive (HR+) breast cancer, also referred to as early stage or locally advanced ER+ breast cancer. In a further aspect of this embodiment, the combination or composition is for use in combination therapy for the treatment of advanced hormone receptor positive (HR+) breast cancer or metastatic hormone receptor positive (HR+) breast cancer, also referred to as advanced ER+ breast cancer or metastatic ER+ breast cancer. In one embodiment, the method comprises administering to an individual with hormone receptor positive (HR) breast cancer or estrogen receptor positive (ER+) breast cancer an effective amount of a combination and compound of the present disclosure in combination with one or more other therapeutic agents.

[0236] In particular, the combinations or compositions of the present disclosure can be used alone or in combination with standard treatment options for hormone receptor positive (HR+) or estrogen receptor positive (ER+) breast cancer, which generally include surgery, systemic chemotherapy (pre- or post-operative), and / or radiation therapy. Depending on tumor and patient characteristics, systemic chemotherapy can be administered as adjuvant (post-operative) therapy or as neoadjuvant (pre-operative) therapy.

[0237] In one embodiment, the combination or composition of the present disclosure is for use in treating hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer in combination with endocrine therapy. In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering tamoxifen. In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an aromatase inhibitor, such as anastrozole, letrozole, or exemestane, for use in treating hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer. In one embodiment, the combination therapy comprises administering the combinations and compounds of the present disclosure and administering at least one additional therapeutic agent, such as anastrozole, letrozole, exemestane and everolimus, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxemesterone, and / or ethinyl estradiol for use in the treatment of hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer.

[0238] In one embodiment, the combination or composition of the present disclosure is for use in the treatment of hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer in combination with one or more chemotherapeutic agents. In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent such as doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, methotrexate, and / or 5-fluorouracil for use in the treatment of hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer.

[0239] In one aspect, the combination or composition of the present disclosure is for use in combination with doxorubicin and cyclophosphamide (AC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering docetaxel, doxorubicin, and cyclophosphamide (TAC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering cyclophosphamide, methotrexate, and 5-fluorouracil (CMF chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering epirubicin and cyclophosphamide (EC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering 5-fluorouracil, epirubicin, and cyclophosphamide (FEC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC chemotherapy). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a taxane, such as docetaxel or paclitaxel.

[0240] In one embodiment, the compounds of the present disclosure are for use in the treatment of metastatic breast cancer. In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, carboplatin, cisplatin, docetaxel, paclitaxel, albumin-bound paclitaxel, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepilone, methotrexate, and 5-fluorouracil (5-FU) for use in the treatment of metastatic breast cancer. In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering docetaxel and capecitabine for use in the treatment of metastatic breast cancer. In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering gemcitabine and paclitaxel for use in the treatment of metastatic breast cancer.

[0241] Breast cancer - HER2+ In a further aspect, the present disclosure provides a method for treating Her2+ positive breast cancer by administering an effective amount of a combination or composition of the present disclosure. In a further aspect of the embodiment, the breast cancer is early stage or locally advanced Her2+ positive breast cancer, also referred to as early stage or locally advanced Her2+ positive breast cancer. In a further aspect, the breast cancer is advanced breast cancer, also referred to as advanced Her2+ positive breast cancer or metastatic ER+ breast cancer.

[0242] In some aspects, the combination or composition is for use in combination therapy for the treatment of Her2+ positive breast cancer. In a further aspect, the combination or composition is for use in combination therapy for the treatment of early stage or locally advanced Her2+ positive breast cancer, also referred to as early stage or locally advanced Her2+ positive breast cancer. In a further aspect of this embodiment, the combination or composition is for use in combination therapy for the treatment of advanced Her2+ positive breast cancer, also referred to as advanced Her2+ positive breast cancer or metastatic ER+ breast cancer. In one embodiment, a method comprises administering to an individual with Her2+ positive breast cancer an effective amount of a combination or composition of the present disclosure in combination with one or more other therapeutic agents.

[0243] In particular, the compounds of the present disclosure can be used alone or in combination with standard treatment options for Her2+ positive breast cancer, which generally include surgery, systemic chemotherapy (pre- or post-operative), and / or radiation therapy. Depending on tumor and patient characteristics, systemic chemotherapy can be administered as adjuvant (post-operative) therapy or as neoadjuvant (pre-operative) therapy.

[0244] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a Her2 antibody to treat Her2+ positive breast cancer. In one aspect, the combination therapy comprises administering a combination or composition of the present disclosure and administering trastuzumab or pertuzumab to treat Her2+ positive breast cancer. In another aspect, the combination therapy comprises administering a combination or composition of the present disclosure and administering chemotherapy to treat Her2+ positive breast cancer. In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering doxorubicin and cyclophosphamide, followed by trastuzumab, to treat Her2+ positive breast cancer. In a further embodiment, the combination or composition of the present disclosure is for use in the treatment of Her2+ positive breast cancer in combination with chemotherapy followed by a taxane and trastuzumab to treat Her2+ positive breast cancer. In another aspect, the combination or composition of the present disclosure is for use in the treatment of Her2+ positive breast cancer in combination with trastuzumab (Herceptin) and pertuzumab (Perjeta) for the treatment of Her2+ positive breast cancer.

[0245] In another embodiment, the combination or composition of the present disclosure is used in combination with docetaxel, carboplatin, and trastuzumab (TCH chemotherapy). In a further embodiment, the compound of the present disclosure is administered in combination with docetaxel, carboplatin, trastuzumab, and pertuzumab. In a further embodiment, the combination or composition of the present disclosure is administered in combination with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC chemotherapy), and pertuzumab, trastuzumab, and docetaxel or paclitaxel. In another embodiment, the combination or composition of the present disclosure is used in combination with paclitaxel and trastuzumab. In a further embodiment, the combination or composition of the present disclosure is administered in combination with pertuzumab, trastuzumab, and paclitaxel or docetaxel.

[0246] The combination or composition of the present disclosure, when it is for use in the treatment of metastatic Her2+ positive breast cancer, can also be used in combination with one or more chemotherapeutic agents selected from the group consisting of doxorubicin (A) (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (E) (Ellence), cyclophosphamide (C) (Cytoxan), carboplatin (Platinol), cisplatin (Paraplatin), docetaxel (T) (Taxotere), paclitaxel (Taxol), albumin-bound paclitaxel (Abraxane), capecitabine (Xeloda), gemcitabine (Cynzar), vinorelbine (Navelbine), eribulin (Halaven), and ixabepilone (Ixempra). In one embodiment, the combination or composition of the disclosure is for use in the treatment of metastatic Her2+ positive breast cancer in combination with trastuzumab emtansine (T-DM1).

[0247] In certain embodiments, the combination or composition of the present disclosure is for use in treating metastatic Her2+ positive breast cancer in combination with trastuzumab and pertuzumab and a taxane. In one embodiment, the taxane is docetaxel. In another embodiment, the taxane is paclitaxel.

[0248] Breast Cancer - Triple Negative The combinations or compositions of the present disclosure can be used alone or in combination with standard treatment options for triple-negative breast cancer (TNBC), which generally include surgery, systemic chemotherapy (pre- or post-operative), and / or radiation therapy.

[0249] The standard of care for TNBC is determined by both disease (stage, pace, etc.) and patient (age, comorbidities, symptoms, etc.) characteristics. General guidance regarding treatment options is provided in the NCCN guidelines (e.g., NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, version 2.2016, National Comprehensive Cancer Network, 2016, pp. 1-202) and the ESMO guidelines (e.g., Senkus, E., et al. Primary Breast Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2015;26(Suppl. 5):v8-v30; and Cardoso F., et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2012;23(Suppl. 7):vii11-vii19.). See also Rodler, E, et al. Breast Disease. 2010 / 2011;32:99-122.

[0250] Metastatic TNBC Systemic chemotherapy is the standard of care for patients with metastatic TNBC, but no standard regimen or protocol exists. Single-agent cytotoxic chemotherapy agents listed in Table 2 are typically considered the first-line options for patients with metastatic TNBC; however, combination chemotherapy regimens, such as those listed in Table 3, may be used, for example, in the setting of aggressive disease and visceral involvement. Further details on available chemotherapy combinations are provided below in the section on early-stage and locally advanced treatment options. Treatment may involve the sequential use of different single-agent therapies. Appropriate palliative surgery and radiation may be utilized to manage local complications.

[0251] The methods provided herein include administering to a patient with metastatic TNBC a combination or composition of the present disclosure in combination with one of the single agent chemotherapeutic agents listed in Table 2, or in combination with the sequential use of different chemotherapeutic agents listed in Table 2. Such methods can optionally be combined with surgery and / or radiation therapy. Table 2: Single-agent chemotherapy regimens TIFF2024519845000130.tif114170

[0252] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an anthracycline, such as doxorubicin, pegylated liposomal doxorubicin, or epirubicin.

[0253] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a taxane, such as paclitaxel, docetaxel, or albumin-bound paclitaxel (eg, nab-paclitaxel).

[0254] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an antimetabolite, including, for example, capecitabine or gemcitabine.

[0255] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a non-taxane microtubule inhibitor such as vinorelbine, eribulin, or ixabepilone.

[0256] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a platinum compound, such as carboplatin or cisplatin.

[0257] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an alkylating agent, such as cyclophosphamide.

[0258] In some embodiments, the combination or composition of the present disclosure is administered with a combination of chemotherapeutic agents summarized in Table 3 below.

[0259] Further guidance for treating metastatic TNBC is provided in Jones SE, et al. J Clin Concol. 2006;24:5381-5387; Heemskerk-Gerritsen BAM, et al. Ann Surg. Oncol. 2007;14:3335-3344; and Kell MR, et al. MBJ. 2007;334:437-438.

[0260] Early and locally advanced TNBC Patients with early, potentially resectable locally advanced TNBC (i.e., no distant metastatic disease) are managed with locoregional therapy (surgical resection with or without radiation therapy) with or without systemic chemotherapy.

[0261] Surgical treatment can be breast-conserving (e.g., lumpectomy, which focuses on removing the primary tumor at the margins) or more extensive (e.g., mastectomy, which aims to completely remove all breast tissue). Radiation therapy is typically administered postoperatively to the breast / chest wall and / or regional lymph nodes with the goal of killing any microscopic cancer cells remaining after surgery. In breast-conserving surgery, radiation is administered to the remaining breast tissue and sometimes to the regional lymph nodes (including the axillary lymph nodes). Radiation may also be administered in the case of mastectomy if factors predicting a higher risk of local recurrence are present.

[0262] In one embodiment, the combination or composition of the present disclosure is administered in conjunction with surgical treatment as neoadjuvant or adjuvant therapy. In another embodiment, the combination or composition of the present disclosure is administered before or after radiation therapy. In yet another embodiment, the combination or composition of the present disclosure is administered in combination with surgical treatment and radiation therapy.

[0263] Depending on tumor and patient characteristics, chemotherapy may be administered in an adjuvant (post-operative) or neoadjuvant (pre-operative) setting. Examples of adjuvant / neoadjuvant chemotherapy regimens used to treat TNBC recommended by current guidelines are shown in Table 3. The combinations or compositions of the present disclosure can be combined with any of the regimens shown in Table 3. Table 3: Combination chemotherapy regimens TIFF2024519845000131.tif213170

[0264] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and an anthracycline and an alkylating agent, optionally followed by a taxane. In one such embodiment, the combination or composition of the present disclosure is administered with doxorubicin and cyclophosphamide, followed by a taxane (e.g., docetaxel or paclitaxel), a chemotherapy regimen designated AC→T.

[0265] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an anthracycline and an alkylating agent. For example, in one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering doxorubicin or liposomal doxorubicin and cyclophosphamide (referred to as AC). In another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering epirubicin and cyclophosphamide, a chemotherapy regimen referred to as EC.

[0266] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a taxane, an anthracycline, and an alkylating agent. For example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel, doxorubicin, and cyclophosphamide, a chemotherapy regimen called TAC.

[0267] In another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a taxane and an alkylating agent. In one such embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering docetaxel and cyclophosphamide, a chemotherapy regimen referred to as TC.

[0268] In another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a taxane and an alkylating agent. For example, in one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering docetaxel and cyclophosphamide, a chemotherapy regimen designated TC.

[0269] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an alkylating agent, methotrexate, and an antimetabolite. As an example, in one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an alkylating agent, methotrexate, and an antimetabolite. In one such embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a chemotherapy regimen called CMF, which consists of cyclophosphamide, methotrexate, and fluorouracil.

[0270] In another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an antimetabolite, an anthracycline, and an alkylating agent. In one such embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering fluorouracil, doxorubicin, and cyclophosphamide, a chemotherapy regimen called FAC. In another such embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering fluorouracil, epirubicin, and cyclophosphamide, a chemotherapy regimen called FEC.

[0271] In another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and an antimetabolite, an anthracycline, and an alkylating agent, followed by a taxane. As an example, in one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and fluorouracil, epirubicin, and cyclophosphamide, followed by docetaxel or paclitaxel (a chemotherapy regimen called FEC (or CEF)→T). In another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and fluorouracil, doxorubicin, and cyclophosphamide, followed by paclitaxel, a chemotherapy regimen called FAC→T.

[0272] In yet another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a taxane and an antimetabolite. As an example, in one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering docetaxel and capecitabine. In another example, the combination therapy comprises administering a combination or composition of the present disclosure and administering paclitaxel and gemcitabine, a chemotherapy regimen called GT.

[0273] In one embodiment, the combination therapy comprises administering a combination or compound of the present disclosure and administering an antimetabolite and a platinum compound. For example, in one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering gemcitabine and carboplatin.

[0274] In another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering an antimetabolite and a non-taxane microtubule inhibitor. In one such embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering capecitabine and vinorelbine. In another such embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering gemcitabine and vinorelbine.

[0275] In another embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a taxane and a VEGF inhibitor (e.g., an anti-VEGF antibody). For example, in one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering paclitaxel and bevacizumab.

[0276] Further guidance for treating early locally advanced TNBC is provided in Solin LJ., Clin Br Cancer. 2009;9:96-100; Freedman GM,et al. Cancer. 2009;115:946-951; Heemskerk-Gerritsen BAM,et al. Ann Surg Oncol. 2007;14:3335-3344; and Kell MR,et al. MBJ. 2007;334:437-438.

[0277] Non-small cell lung cancer (NSCLC) The combinations or compositions of the present disclosure can be administered alone or can be used in combination therapy, for example, a combination therapy comprising administering a combination or composition of the present disclosure and at least one additional therapeutic agent (e.g., one, two, three, four, five, or six additional therapeutic agents).

[0278] In some embodiments, the combination or composition is for use in combination therapy for the treatment of non-small cell lung cancer NSCLC, e.g., squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, or a combination thereof.

[0279] In one embodiment, the NSCLC is associated with a KRas mutation. In one embodiment, the NSCLC is associated with a KRAS G12C mutation.

[0280] In one embodiment, the NSCLC is in latent stage 0, I, II, III, or IV.

[0281] In one embodiment, the NSLCL is in latent stage, stage 0, IA, IB, IIA, IIB, IIIA, IIIB, or IV.

[0282] The present disclosure is directed to the use of the disclosed combinations or compositions for adjuvant or neoadjuvant therapy.

[0283] The present disclosure is directed to the use of the disclosed combinations or compositions for first-line, second-line, or third-line treatment.

[0284] The present disclosure is directed to the use of the disclosed combinations or compositions for monotherapy.

[0285] The present disclosure is directed to the use of the disclosed combinations or compositions for the treatment of stage IV disease or recurrent disease.

[0286] The present disclosure is directed to the use of the disclosed combinations or compositions for treatment in combination with surgery, radiation therapy, or a combination thereof.

[0287] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent such as cisplatin, carboplatin, paclitaxel, paclitaxel protein-bound, docetaxel, gemcitabine, vinorelbine, etoposide, nintedanib, vinblastine, and / or pemetrexed.

[0288] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent such as afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, and / or onartuzumab.

[0289] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent, such as afatinib, crizotinib, erlotinib hydrochloride, and / or gefitinib.

[0290] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering a checkpoint inhibitor such as pembrolizumab, atezolizumab, and / or nivolumab.

[0291] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent such as cisplatin, carboplatin, paclitaxel, paclitaxel protein-bound, docetaxel, gemcitabine, vinorelbine, etoposide, nintedanib, vinblastine, pemetrexed, afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, necitumumab, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, onartuzumab, pembrolizumab, atezolizumab, and / or nivolumab.

[0292] Small cell lung cancer (SCLC) The combinations or compositions of the present disclosure can be administered alone or can be used in combination therapy, for example, a combination therapy comprising administering a combination or composition of the present disclosure and at least one additional therapeutic agent (e.g., one, two, three, four, five, or six additional therapeutic agents).

[0293] In some embodiments, the combination or composition is for use in combination therapy for the treatment of small cell lung cancer (SCLC).

[0294] In one embodiment, the SCLC is small cell carcinoma (oat cell carcinoma), mixed small cell / large cell carcinoma, or combined small cell carcinoma.

[0295] In one embodiment, the SCLC is in latent stage 0, I, II, III, or IV.

[0296] In one embodiment, the SCLC is in latent stage, stage 0, stage IA, stage IB, stage IIA, stage IIB, II stage IA, stage IIIB, or stage IV.

[0297] In one embodiment, the SLCL is in stages I-III (extreme stage).

[0298] The present disclosure is directed to the use of the disclosed combinations or compositions for first line treatment of Stage IV (extensive) disease.

[0299] The present disclosure is directed to the use of the disclosed combinations or compositions for second line treatment of Stage IV (relapsed or refractory disease).

[0300] The present disclosure is directed to the use of the disclosed combinations or compositions for third line treatment of Stage IV (relapsed or refractory disease).

[0301] In one embodiment, the combination or composition of the present disclosure is administered with one or more additional therapeutic agents selected from etoposide, platinum compounds, irinotecan, topotecan, vinca alkaloids, alkylating agents, doxorubicin, taxanes, and gemcitabine. In another embodiment, the platinum compound is cisplatin or carboplatin. In another embodiment, the vinca alkaloid is vinblastine, vincristine, or vinorelbine. In another embodiment, the alkylating agent is cyclophosphamide or ifosfamide. In another embodiment, the taxane is docetaxel or paclitaxel.

[0302] ovarian cancer In a further aspect, the present disclosure provides a method for treating ovarian cancer (e.g., epithelial ovarian cancer (EOC), ovarian germ cell tumor, or ovarian stromal tumor) by administering an effective amount of a combination or composition of the present disclosure. In a further aspect of this embodiment, the ovarian cancer is epithelial ovarian cancer (EOC). In a further aspect of this embodiment, the ovarian cancer is ovarian germ cell tumor. In a further aspect of this embodiment, the ovarian cancer is ovarian stromal cell tumor. In one embodiment, the method comprises administering to an individual with ovarian cancer an effective amount of a combination or composition of the present disclosure.

[0303] The combinations or compositions of the present disclosure can be administered alone or in combination therapy to treat ovarian cancer, for example, combination therapy includes administering a combination or composition of the present disclosure and at least one additional therapeutic agent (e.g., 1, 2, 3, 4, 5, or 6 additional therapeutic agents).

[0304] In some aspects, the combination or composition is for use in combination therapy for the treatment of ovarian cancer (e.g., epithelial ovarian cancer (EOC), ovarian germ cell tumor, or ovarian stromal tumor). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent, such as a platinum compound (e.g., carboplatin, cisplatin, less frequently oxaliplatin or iproplatin), and / or a taxane (e.g., paclitaxel or docetaxel, or albumin-bound paclitaxel (nab-paclitaxel)). In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering carboplatin and a taxane (e.g., paclitaxel or docetaxel, or albumin-bound paclitaxel (nab-paclitaxel)).

[0305] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent such as albumin-bound paclitaxel (nab-paclitaxel), altretamine, capecitabine, cyclophosphamide, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan, vinorelbine, bevacizumab, platinum compounds (e.g., carboplatin, cisplatin, oxaliplatin, or iproplatin), and / or taxanes (e.g., paclitaxel or docetaxel, or albumin-bound paclitaxel (nab-paclitaxel)).

[0306] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering bevacizumab and a taxane (e.g., paclitaxel or docetaxel, or albumin-bound paclitaxel (nab-paclitaxel)).

[0307] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering at least one additional therapeutic agent, such as cisplatin, etoposide, and / or bleomycin.

[0308] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering cisplatin (Platinol), etoposide, and bleomycin (PEB (or BEP)).

[0309] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering paclitaxel (Taxol), ifosfamide, and cisplatin (TIP).

[0310] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering vinblastine, ifosfamide, and cisplatin (VeIP).

[0311] In one embodiment, the combination therapy comprises administering a combination or composition of the present disclosure and administering etoposide (VP-16), ifosfamide, and cisplatin (VIP).

[0312] Any of the methods detailed herein, e.g., methods of treating cancer, in some embodiments, include the use of a combination of a TEAD inhibitor and a KRAS inhibitor provided herein, e.g., any of the combinations of a TEAD inhibitor and a KRAS inhibitor provided under the heading "Combinations." For example, in some embodiments, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a TEAD inhibitor (e.g., a TEAD palmitate pocket binding inhibitor, a covalent TEAD inhibitor, a compound of Formula (I), etc.) and an effective amount of a KRAS inhibitor (e.g., a G12C KRAS inhibitor, a compound of Formula (K-II), etc.). In some embodiments, the method comprises administering to the subject an effective amount of a TEAD palmitate pocket binding inhibitor and an effective amount of a KRAS inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of a covalent TEAD inhibitor and an effective amount of a KRAS inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of a compound of Formula (I) and an effective amount of a KRAS inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of a TEAD palmitate pocket binding inhibitor and an effective amount of a G12C KRAS inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of a covalent TEAD inhibitor and an effective amount of a G12C KRAS inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of a compound of Formula (I) and an effective amount of a G12C KRAS inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of a TEAD palmitate pocket binding inhibitor and an effective amount of a compound of Formula (K-II). In some embodiments, the method comprises administering to the subject an effective amount of a covalent TEAD inhibitor and an effective amount of a compound of Formula (K-II). In some embodiments, the method comprises administering to the subject an effective amount of a compound of Formula (I) and an effective amount of a compound of Formula (K-II).

[0313] V. Kit In some embodiments, provided herein is a kit comprising: (i) an effective amount of a combination comprising one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors; and (ii) instructions for administering the combination to treat cancer in a subject in need thereof. The kit can include an effective amount of any of the compositions or combinations described elsewhere herein. In some embodiments, the one or more YAP / TAZ-TEAD inhibitors comprise a compound of Formula (I), (II), or (III), or any variation or emb...

Claims

**Claim 1** [1] (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors A combination comprising [2] (i) one or more YAP / TAZ-TEAD inhibitors, or [3] (ii) one or more KRAS inhibitors Comprising An agent for regulating YAP / TAZ-TEAD activity, or KRAS activity, or both in cells, wherein An effective amount of a combination comprising (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors is administered to the cells **Claim 2** [1] (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors A combination comprising [2] (i) one or more YAP / TAZ-TEAD inhibitors, or [3] (ii) one or more KRAS inhibitors Comprising An agent for inhibiting YAP / TAZ-TEAD activity, or KRAS activity, or both in cells, wherein An effective amount of a combination comprising (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors is administered to the cells **Claim 3** [1] (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors A combination comprising [2] (i) one or more YAP / TAZ-TEAD inhibitors, or [3] (ii) one or more KRAS inhibitors Comprising YAP / TAZ-TEAD activity, or KRAS activity, or both in cells A medicament for treating cancer in a subject in need of cancer treatment, wherein An effective amount of a combination comprising (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors is administered to the subject **Claim 4** The medicament according to claim 3, wherein the cancer is selected from the group consisting of blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, and lung cancer **Claim 5** The medicament according to claim 3, wherein the cancer is lung cancer **Claim 6** The medicament according to claim 5, wherein the lung cancer is non-small cell lung cancer **Claim 7** The one or more YAP / TAZ-TEAD inhibitors are A compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing A compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; A compound of formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; A compound of formula (IV), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; A compound of formula (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; A compound of formula (VI), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; A compound of formula (VII), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; or A compound of formula (VIII), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof The agent or medicament according to any one of claims 1 to 6, comprising

8. The agent or medicament according to claim 7, wherein one or more YAP / TAZ - TEAD inhibitors comprise a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

9. One or more YAP / TAZ - TEAD inhibitors or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the agent or medicament according to claim 8.

10. The agent or medicament according to claim 7, wherein one or more YAP / TAZ - TEAD inhibitors comprise a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

11. One or more YAP / TAZ - TEAD inhibitors or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the agent or medicament according to claim 10.

12. One or more YAP / TAZ - TEAD inhibitors or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the agent or medicament according to claim 10.

13. The agent or medicament according to claim 7, wherein one or more YAP / TAZ - TEAD inhibitors comprise a compound of formula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

14. One or more YAP / TAZ - TEAD inhibitors 、or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the agent or medicament according to claim 13.

15. The agent or medicament according to claim 7, wherein one or more YAP / TAZ-TEAD inhibitors comprise a compound of formula (IV), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

16. One or more YAP / TAZ-TEAD inhibitors 、or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the agent or medicament according to claim 15.

17. The agent or medicament according to claim 7, wherein one or more YAP / TAZ-TEAD inhibitors comprise a compound of formula (V), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

18. One or more YAP / TAZ-TEAD inhibitors 、or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the agent or medicament according to claim 17.

19. The agent or medicament according to claim 7, wherein one or more YAP / TAZ-TEAD inhibitors comprise a compound of formula (VI), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

20. One or more YAP / TAZ-TEAD inhibitors 、or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the agent or medicament according to claim 19.

21. The agent or medicament according to claim 7, wherein one or more YAP / TAZ-TEAD inhibitors comprise a compound of formula (VII), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

22. One or more YAP / TAZ-TEAD inhibitors 、or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the agent or medicament according to claim 21.

23. The agent or medicament according to claim 7, wherein one or more YAP / TAZ-TEAD inhibitors comprise a compound of formula (VIII), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

24. One or more YAP / TAZ-TEAD inhibitors The agent or medicament according to claim 23, comprising an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

25. The agent or medicament according to any one of claims 1 to 6, wherein one or more KRAS inhibitors comprise one or more inhibitors of the KRAS G12C variant.

26. One or more KRAS inhibitors are a compound of formula (K-I), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; a compound of formula (K-II), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; a compound of formula (K-III), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; or a compound of formula (K-IV), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof The agent or medicament according to any one of claims 1 to 6.

27. The agent or medicament according to claim 26, wherein one or more KRAS inhibitors comprise a compound of formula (K-I), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

28. One or more KRAS inhibitors are The agent or medicament according to claim 27, comprising an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

29. The agent or medicament according to claim 26, wherein one or more KRAS inhibitors comprise a compound of formula (K-II), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

30. One or more KRAS inhibitors are The agent or medicament according to claim 29, comprising an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

31. The agent or medicament according to claim 26, wherein one or more KRAS inhibitors comprise a compound of formula (K-III), or an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

32. One or more KRAS inhibitors are The agent or medicament according to claim 31, comprising an isomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

33. The agent or medicament according to claim 26, wherein one or more KRAS inhibitors comprise a compound of formula (K-IV), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

34. One or more KRAS inhibitors are The agent or medicament according to claim 33, which comprises, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

35. The agent or medicament according to any one of claims 1 to 6, wherein the combination further comprises one or more pharmaceutically acceptable additives.

36. The agent or medicament according to any one of claims 1 to 6, wherein one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered simultaneously.

37. The agent or medicament according to any one of claims 1 to 6, wherein one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors are administered sequentially.

38. A composition comprising (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

39. The composition according to claim 38, wherein one or more YAP / TAZ-TEAD inhibitors comprise a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

40. The composition according to claim 38, wherein one or more KRAS inhibitors comprise one or more inhibitors of the KRAS G12C variant.

41. The composition according to claim 38, wherein one or more KRAS inhibitors comprise a compound of formula (K-I), (K-II), (K-III), or (K-IV), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

42. The composition according to claim 38, which further comprises one or more pharmaceutically acceptable additives.

43. A kit comprising (i) an effective amount of a combination comprising one or more YAP / TAZ-TEAD inhibitors and one or more KRAS inhibitors; and (ii) instructions for administering the combination to treat cancer in a subject in need of treatment for cancer.

44. The kit according to claim 43, wherein the cancer is selected from the group consisting of blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, and lung cancer.

45. The kit according to claim 43, wherein the cancer is lung cancer.

46. The kit according to claim 45, wherein the lung cancer is non-small cell lung cancer.

47. The kit according to any one of claims 43 to 46, wherein the one or more YAP / TAZ-TEAD inhibitors comprise a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

48. The kit according to any one of claims 43 to 46, wherein the one or more KRAS inhibitors comprise one or more inhibitors of the KRAS G12C variant.

49. The kit according to any one of claims 43 to 46, wherein the one or more KRAS inhibitors comprise a compound of formula (K-I), (K-II), (K-III), or (K-IV), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

50. The kit according to any one of claims 43 to 46, wherein the combination further comprises one or more pharmaceutically acceptable additives.

51. The kit according to any one of claims 43 to 46, wherein the one or more YAP / TAZ-TEAD inhibitors and the one or more KRAS inhibitors are administered simultaneously.

52. The kit according to claim 51, wherein the one or more YAP / TAZ-TEAD inhibitors and the one or more KRAS inhibitors are formulated together in a single composition.

53. The kit according to claim 51, wherein the one or more YAP / TAZ-TEAD inhibitors and the one or more KRAS inhibitors are formulated in separate compositions.

54. The kit according to any one of claims 43 to 46, wherein the one or more YAP / TAZ-TEAD inhibitors and the one or more KRAS inhibitors are administered sequentially.

55. Use of the composition according to any one of claims 38 to 42 in the manufacture of a medicament for use in the treatment of cancer.

56. The use according to claim 55, wherein the cancer is selected from the group consisting of blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, and lung cancer.

57. The use according to claim 55, wherein the cancer is lung cancer.

58. The use according to claim 57, wherein the lung cancer is non-small cell lung cancer.

59. The composition according to any one of claims 38 to 42, for use in the treatment of cancer.

60. The composition according to claim 59, wherein the cancer is selected from the group consisting of blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, and lung cancer.

61. The composition according to claim 60, wherein the cancer is lung cancer.

62. The composition according to claim 61, wherein the lung cancer is non-small cell lung cancer.

63. A process for preparing a composition comprising (i) one or more YAP / TAZ-TEAD inhibitors; and (ii) one or more KRAS inhibitors.

64. A composition prepared by the process according to claim 63.

65. [1] One or more YAP-TAZ-TEAD inhibitors selected from the group consisting of or its stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing; and One or more KRAS inhibitors selected from the group consisting of or its stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing A combination comprising [2] (i), or [3] (ii) Comprising A medicament for treating cancer in a subject in need thereof, wherein an effective amount of the combination comprising (i) and (ii) is administered to the subject.

66. One or more YAP-TAZ-TEAD inhibitors selected from the group consisting of or its stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing; and One or more KRAS inhibitors selected from the group consisting of or its stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing A composition comprising

67. One or more YAP-TAZ-TEAD inhibitors selected from the group consisting of or its stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing; One or more KRAS inhibitors selected from the group consisting of or its stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing; and Instructions for administering a combination for treating cancer in a subject in need of cancer treatment A kit comprising the same. [

68. ] A medicament for treating cancer in a subject in need of cancer treatment, comprising a TEAD inhibitor and / or a KRAS inhibitor, wherein an effective amount of a TEAD inhibitor and an effective amount of a KRAS inhibitor are administered to the subject, the TEAD inhibitor is a TEAD palmitate pocket binding inhibitor or a covalent TEAD inhibitor; and the KRAS inhibitor is a G12C KRAS inhibitor, the medicament.

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