Methods of treating a ras related disease or disorder

Abstract

The present disclosure features methods of treating RAS disorders using a safe and effective dose of Compound (A) or a pharmaceutically acceptable salt thereof. The disclosure also features methods of treating RAS disorders comprising combination therapies comprising Compound (A) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480052559.0 (22) Application Date 2024.07.12 (30) Priority Data 63 / 526781 2023.07.14 US 63 / 618731 2024.01.08 US (85) PCT International Application Entering National Phase Date 2026.02.10 (86) PCT International Application Application Data PCT / US2024 / 037809 2024.07.12 (87) PCT International Application Publication Data WO2025 / 019318 EN 2025.01.23 (71) Applicant: Ruixin Pharmaceutical Company, Address: California, USA (72) Inventors: Jiang Liangliang, B. Maldonato, Z. Salman, M. Singh, Wang Zhengping, S.S. Zhang, W.C. Gustafson (74) Patent Agency: China Patent Agency (Hong Kong) Limited, 72001 Patent Attorneys: Guo Hui, Cai Xiaohan (51) Int.Cl. A61K 31 / 395 (2006.01) A61K 31 / 404 (2006.01) A61K 31 / 426 (2006.01) C07D 417 / 14 (2006.01) C07D 471 / 22 (2006.01) A61K 31 / 33 (2006.01) (54) Invention Title: Method for Treating RAS-Related Diseases or Conditions (57) Abstract: This disclosure is characterized by a method for treating RAS conditions using a safe and effective dose of compound (A) or a pharmaceutically acceptable salt thereof. This disclosure is also characterized by a method for treating RAS conditions comprising a combination therapy comprising compound (A) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent. Claims: 3 pages Description: 82 pages Drawings: 12 pages CN 121693329 A 2026.03.17 CN 1 21 69 33 29 A 1. A method for treating cancer in a human subject in need, the method comprising orally administering 10 mg to 500 mg of compound A to the subject daily: Compound A or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein the method comprises administering 120 mg to 500 mg of compound A to the subject. 3. The method of claim 1, wherein the method comprises administering 160 mg to 500 mg of compound A to the subject. 4. The method of claim 1, wherein the method comprises administering 250 mg to 500 mg of compound A to the subject. 5. The method of claim 1, wherein the method comprises administering 300 mg of compound A to the subject.6. The method of claim 1, wherein the method comprises administering 400 mg to 500 mg of compound A to the subject. 7. The method of claim 1 or claim 2, wherein the method comprises administering 120 mg of compound A to the subject. 8. The method of any one of claims 1 to 3, wherein the method comprises administering 160 mg of compound A to the subject. 9. The method of any one of claims 1 to 3, wherein the method comprises administering 200 mg of compound A to the subject. 10. The method of any one of claims 1 to 4, wherein the method comprises administering 250 mg of compound A to the subject. 11. The method of any one of claims 1 to 5, wherein the method comprises administering 300 mg of compound A to the subject. 12. The method of any one of claims 1 to 5, wherein the method comprises administering 350 mg of compound A to the subject. 13. The method of any one of claims 1 to 6, wherein the method comprises administering 400 mg of compound A to the subject. 14. The method of any one of claims 1 to 6, wherein the method comprises administering 450 mg of compound A to the subject. 15. The method of any one of claims 1 to 6, wherein the method comprises administering 500 mg of compound A to the subject. 16. The method of any one of claims 1 to 15, wherein compound A is administered to the subject once daily. 17. The method of any one of claims 1 to 16, wherein compound A is administered once, twice, three times, four times, five times, six times, or seven times per week. 18. The method of any one of claims 1 to 17, wherein compound A is administered to the subject for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months. 19. The method of any one of claims 1 to 18, wherein compound A is administered in treatment cycles and each treatment cycle is 7 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. 20. The method of claim 19, wherein the subject undergoes one, two, three, or more treatment cycles. 21. The method of any one of claims 1 to 20, wherein the cancer comprises a RAS mutation.22. The method of claim 21, wherein the RAS mutation is at position 12, 13, or 61. 23. The method of claim 22, wherein the RAS mutation is a mutation selected from the group consisting of: G12C, G12D, G12V, G12R, G12A, G12S, G13C, G13D, and Q61H. 24. The method of any one of claims 1 to 23, wherein the cancer is pancreatic cancer. 25. The method of claim 24, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). 26. The method of any one of claims 1 to 23, wherein the cancer is lung cancer. 27. The method of claim 26, wherein the lung cancer is non-small cell lung cancer (NSCLC). 28. The method of any one of claims 1 to 23, wherein the cancer is colorectal cancer. 29. The method or use of any one of claims 1 to 6, wherein the method further comprises administering additional anticancer therapy. 30. A method of treating pancreatic ductal adenocarcinoma (PDAC) in a human subject of need, the method comprising orally administering 120 mg to 500 mg of compound A: compound A or a pharmaceutically acceptable salt thereof to the subject daily. Claims 2 / 3 pages 3 CN 121693329 A 31. The method of claim 30, wherein the subject has previously received at least one cancer therapy. 32. The method of claim 30 or 31, wherein the subject has locally advanced or metastatic PDAC. 33. The method of any one of claims 30 to 32, wherein the PDAC comprises wild-type RAS or a RAS mutation at position 12, 13, or 61, or a combination thereof. 34. A method of treating non-small cell lung cancer (NSCLC) in a human subject of need, the method comprising orally administering 120 mg to 500 mg of compound A: compound A or a pharmaceutically acceptable salt thereof to the subject daily. 35. The method of claim 34, wherein the subject has previously received at least one cancer therapy. 36. The method of claim 34 or 35, wherein the subject has locally advanced or metastatic NSCLC. 37. The method of any one of claims 34 to 36, wherein the NSCLC comprises wild-type RAS or a RAS mutation at position 12, 13, or 61, or a combination thereof. Claims 3 / 3 Page 4 CN 121693329 A Method for treating RAS-related diseases or conditions Background Art

[0001] Most small molecule drugs modulate the function of a target protein by binding to a functionally important pocket on the protein.Activity is what makes it work. For example, cholesterol-lowering drugs called statins bind to the active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. The fact that many such drug / target interaction pairs are known may mislead some into believing that small molecule regulators can be discovered for most (if not all) proteins with a reasonable amount of time, effort, and resources. But this is far from the case. Currently, it is estimated that only about 10% of all human proteins are suitable targets for small molecules. The remaining 90% are currently considered difficult to cure or treat with the aforementioned small molecule drugs. These targets are often referred to as “undruggable.” These undruggable targets comprise a large and largely unexplored library of medically important human proteins. Therefore, there is great interest in discovering new molecular modalities that can regulate the function of these undruggable targets.

[0002] It has been well established in the literature that RAS proteins (KRAS, HRAS, and NRAS) play a vital role in a variety of human cancers and are therefore suitable targets for anticancer therapies. In fact, approximately 30% of all human cancers in the United States are caused by mutations in the RAS protein, many of which are fatal. RAS protein dysregulation caused by activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations in RAS are frequently found in human cancers. For example, an activating mutation at codon 12 in the RAS protein significantly biases the RAS mutant protein population towards the "on" (GTP-binding) state (RAS(ON)) by inhibiting GTPase activator protein (GAP) dependence and intrinsic GTP hydrolysis rate, leading to oncogenic MAPK signaling. Notably, RAS exhibits a picomolar affinity for GTP, allowing it to be activated even in low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13C) and 61 (e.g., Q61K) in RAS also contribute to oncogenic activity in some cancers.

[0003] In normal cells, RAS proteins play a crucial role in regulating cell growth, differentiation, and survival. They act as molecular switches, transmitting signals from cell surface receptors to intracellular pathways that control key cellular processes. Genetic studies have shown that complete deletion of the RAS gene is lethal in mouse models and leads to a lack of cell proliferation in vitro (Drosten et al., Oncogene 33, 2857–2865 (2014); Drosten et al., EMBO J. 29, 1091–1104 (2010)). Furthermore, conditional knockout of KRAS in adult bone marrow has been shown to induce significant hematopoietic defects, including splenomegaly, enlarged neutrophil compartments, and reduced B cell numbers (Zhang et al., Stem Cells;34(7):1859-71 (2016)). Targeting the mutant form of RAS, rather than wild-type RAS, has become a strategy for treating RAS-mutant cancers because it is specifically involved in oncogenic signaling. Despite extensive drug discovery efforts targeting RAS over the past few decades, only two agents targeting the KRAS G12C mutant (sotorasib and adagrasib) have been approved in the United States. By developing inhibitors that selectively target mutant RAS isotypes, researchers aim to disrupt the abnormal signaling pathways that drive tumor growth while minimizing interference with the essential functions of wild-type RAS in normal cells. Moore et al. (Nat Rev Drug Discov. 19(8): 533-552 (2020)) presented evidence against the feasibility of pan-RAS inhibitors, partly through the discovery of compound 3144. While this compound can bind to KRAS-G13D and wild-type KRAS, NRAS, and HRAS, it exhibits toxicity and off-target activity. These results highlight the challenges of developing pan-RAS inhibitors, as wild-type RAS is essential for normal cell signaling and thus causes tolerance issues. See also Hofmann et al., Cancer Discov. 12(4): 924-937 (2022), who argue that, “By contrast, pan-KRAS drugs and pan-RAS drugs face the unresolved issue of tolerance based on the inhibition of wild-type (K)RAS… Therefore, pan-RAS inhibitors are highly likely to exhibit significantly higher toxicity levels than KRAS isotype-specific inhibitors.” Summary of the Invention

[0004] This invention provides a method for treating RAS protein-related conditions using compound A or a pharmaceutically acceptable salt thereof, said compound A or a pharmaceutically acceptable salt thereof being a RAS inhibitor.

[0005]

[0006] Compound A

[0007] In one aspect, this disclosure features a method for treating RAS protein-related conditions in human subjects of need. The method includes the following steps: administering orally to the subject daily at doses ranging from 10 mg to 500 mg (e.g., 20 mg to 500 mg, 40 mg to 500 mg, 80 mg to 500 mg, 120 mg to 500 mg, 160 mg to 500 mg, 200 mg to 500 mg, 220 mg to 500 mg, 250 mg to 500 mg, 300 mg to 500 mg, 350 mg to 500 mg, 400 mg to 500 mg, 450 mg to 500 mg, 10 mg to 400 mg, 20 mg to 400 mg, 40 mg to 400 mg, 40 mg to 500 mg, 10 mg to 400 mg, 20 mg to 400 mg, 40 mg to 500 mg).mg to 400 mg, 80 mg to 400 mg, 120 mg to 400 mg, 160 mg to 400 mg, 200 mg to 400 mg, 220 mg to 400 mg, 250 mg to 400 mg, 300 mg to 400 mg, 350 mg to 400 mg, 10 mg to 300 mg, 20 mg to 300 mg, 40 mg to 300 mg, 80 mg to 300 mg, 120 mg to 300 mg, 160 mg to 300 mg, 200 mg to 300 mg, 220 mg to 300 mg, 250 mg to 300 mg, 10 mg to 250 mg, 20 mg to 250 mg, 40 mg to 250 mg, 80 mg to 250 mg, 120 mg to 250 mg, 160 mg to 250 mg, 10 mg to 220 mg, 20 mg to 220 mg Compound A is present in the following amounts: mg, 40 mg to 220 mg, 80 mg to 220 mg, 120 mg to 220 mg, 160 mg to 220 mg, 10 mg to 200 mg, 20 mg to 200 mg, 40 mg to 200 mg, 80 mg to 200 mg, 120 mg to 200 mg, 160 mg to 200 mg, 10 mg to 160 mg, 20 mg to 160 mg, 40 mg to 160 mg, 80 mg to 160 mg, 120 mg to 160 mg, 10 mg to 120 mg, 20 mg to 120 mg, 40 mg to 120 mg, 80 mg to 120 mg, 10 mg to 80 mg, 20 mg to 80 mg, 40 mg to 80 mg, 10 mg to 40 mg, 20 mg to 40 mg, or 10 mg to 20 mg.

[0008] In some embodiments, the method includes administering to a subject 20 mg to 500 mg (e.g., 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg).Compound A is administered in doses of 40 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg. In some embodiments, the method includes administering 40 mg to 500 mg of compound A to the subject. In some embodiments, the method includes administering 80 mg to 500 mg of compound A to the subject. In some embodiments, the method includes administering 120 mg to 500 mg of compound A to the subject. In some embodiments, the method includes administering 160 mg to 500 mg of compound A to the subject. In some embodiments, the method includes administering 200 mg to 500 mg of compound A to the subject. In some embodiments, the method includes administering 220 mg to 500 mg of compound A to the subject. In some embodiments, the method includes administering 250 mg to 500 mg of compound A to the subject. In some embodiments, the method includes administering 300 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 350 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 400 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 450 mg to 500 mg of compound A to a subject.

[0009] In some embodiments, the method includes administering 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A to a subject.

[0010] In some embodiments, the method includes administering 10 mg to 250 mg of compound A to a subject. In some embodiments, the method includes administering 20 mg to 250 mg of compound A to a subject. In some embodiments, the method includes administering 40 mg to 250 mg of compound A to a subject. In some embodiments, the method includes administering 80 mg to 250 mg of compound A to a subject. In some embodiments, the method includes administering 120 mg to 250 mg of compound A to a subject. In some embodiments, the method includes administering 160 mg to 250 mg of compound A to a subject. In some embodiments, the method includes administering 220 mg to 250 mg of compound A to a subject.

[0011] In some embodiments, the method includes administering 10 mg to 220 mg of compound A to a subject. In some embodiments, the method includes administering 20 mg to a subject.Compound A is administered in doses of 40 mg to 220 mg. In some embodiments, the method includes administering 40 mg to 220 mg of compound A to the subject. In some embodiments, the method includes administering 80 mg to 220 mg of compound A to the subject. In some embodiments, the method includes administering 120 mg to 220 mg of compound A to the subject. In some embodiments, the method includes administering 160 mg to 220 mg of compound A to the subject. In some embodiments, the method includes administering 200 mg to 220 mg of compound A to the subject.

[0012] In some embodiments, the method includes administering 10 mg to 200 mg of compound A to the subject. In some embodiments, the method includes administering 20 mg to 200 mg of compound A to the subject. In some embodiments, the method includes administering 40 mg to 200 mg of compound A to the subject. In some embodiments, the method includes administering 80 mg to 200 mg of compound A to the subject. In some embodiments, the method includes administering 120 mg to 200 mg of compound A to the subject. In some embodiments, the method includes administering 160 mg to 200 mg of compound A to the subject.

[0013] In some embodiments, the method includes administering 10 mg to 160 mg of compound A to the subject. In some embodiments, the method includes administering 20 mg to 160 mg of compound A to the subject. In some embodiments, the method includes administering 40 mg to 160 mg of compound A to the subject. In some embodiments, the method includes administering 80 mg to 160 mg of compound A to the subject. In some embodiments, the method includes administering 120 mg to 160 mg of compound A to the subject.

[0014] In some embodiments, the method includes administering 10 mg to 120 mg of compound A to the subject. In some embodiments, the method includes administering 20 mg to 120 mg of compound A to the subject. In some embodiments, the method includes administering 40 mg to 120 mg of compound A to the subject. In some embodiments, the method includes administering 80 mg to 120 mg of compound A to the subject.

[0015] In some embodiments, the method includes administering 10 mg to 80 mg of compound A to a subject. In some embodiments, as described on page 3 / 82 of CN 121693329 A, the method includes administering 20 mg to 80 mg of compound A to a subject. In some embodiments, the method includes administering 40 mg to 80 mg of compound A to a subject.

[0016] In some embodiments, the method includes administering 10 mg to 40 mg of compound A to a subject. In some embodiments, the method includes administering 20 mg to 40 mg of compound A to a subject. In some embodiments, the method includes administering 10 mg to 20 mg of compound A to a subject.

[0017] In some embodiments, the method includes administering 10 mg of compound A to a subject. In some embodiments, the method includes administering 20 mg of compound A to a subject. In some embodiments, the method includes administering 40 mg of compound A to a subject. In some embodiments, the method includes administering 80 mg of compound A to a subject. In some embodiments, the method includes administering 120 mg of compound A to a subject. In some embodiments, the method includes administering 160 mg of compound A to a subject. In some embodiments, the method includes administering 200 mg of compound A to a subject. In some embodiments, the method includes administering 220 mg of compound A to a subject. In some embodiments, the method includes administering 225 mg of compound A to a subject. In some embodiments, the method includes administering 250 mg of compound A to a subject. In some embodiments, the method includes administering 275 mg of compound A to a subject. In some embodiments, the method includes administering 300 mg of compound A to a subject. In some embodiments, the method includes administering 325 mg of compound A to a subject. In some embodiments, the method includes administering 350 mg of compound A to a subject. In some embodiments, the method includes administering 375 mg of compound A to a subject. In some embodiments, the method includes administering 400 mg of compound A to a subject. In some embodiments, the method includes administering 450 mg of compound A to a subject. In some embodiments, the method includes administering 500 mg of compound A to a subject.

[0018] In some embodiments, compound A is administered to the subject once daily.

[0019] In some embodiments, RAS protein-related disease is RAS lesion.

[0020] In some embodiments, RAS protein-related disease is cancer. In some embodiments, cancer includes RAS mutation. In some embodiments, cancer includes wild-type RAS. In some embodiments, the RAS mutation is at position 12, 13, or 61. In some embodiments, the RAS mutation is located at position 12. In some embodiments, the RAS mutation is a mutation selected from the group consisting of: G12C, G12D, G12V, G12R, G13C, G13D, and Q61H, or any combination thereof. In some embodiments...In this embodiment, the RAS mutation is selected from the group consisting of G12D, G12V, and G12R. In some embodiments, the RAS mutation is selected from the group consisting of G12D and G12V. In some embodiments, the cancer includes RAS amplification. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the method further includes administering additional anticancer therapy. In some embodiments, the additional anticancer therapy is an EGFR inhibitor, a second RAS inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. In some embodiments, the additional anticancer therapy comprises an SHP2 inhibitor and a PD-L1 inhibitor. In some embodiments, the additional therapy comprises a second RAS inhibitor and a PD-L1 inhibitor. In some embodiments, the second RAS inhibitor is a KRASG12C inhibitor. In some embodiments, the second RAS inhibitor is a KRASG12C(ON) inhibitor. In some embodiments, the second RAS inhibitor is a KRASG12C(OFF) inhibitor.

[0021] Specifically, it is contemplated that any limitations discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention. Specification 4 / 82 pages 8 CN 121693329 A Brief Description of the Drawings

[0022] Figure 1 illustrates the Phase 1 study design of compound A.

[0023] Figure 2A illustrates patient demographics and baseline characteristics, including KRAS mutation type, of patients enrolled in the Phase 1 study of compound A as of September 11, 2023.

[0024] Figure 2B shows the demographic information and baseline characteristics of NSCLC and PDAC patients enrolled in the Phase 1 study of compound A as of October 12, 2023.

[0025] Figure 3 graphically depicts the mean steady-state blood PK characteristics and individual steady-state blood AUC. Exposure showed a dose-dependent increase and reached levels predicting tumor regression.

[0026] Figure 4 is a waterfall plot showing the best response in KRASG12X NSCLC.

[0027] Figure 5 is a waterfall plot showing the best response in KRASG12X PDAC.

[0028] Figure 6 shows a significant decrease in the frequency of KRAS variant alleles in ctDNA across multiple tumor types, indicating antitumor activity. Lines within box plots indicate medians; maximum or minimum values ​​must be indicated (up to ±1.5 x interquartile range). Circles indicate data points >1.5 times the interquartile range; KRASG12XVAF was measured by the Guardant Health ctDNA test from day 1 of cycle 1 (pre-treatment) to day 1 of cycle 2 or day 1 of cycle 3 (during treatment). ctDNA, circulating tumor DNA; VAF, variant allele frequency.

[0029] Figure 7 shows baseline and treatment-in (C7D1) scans of target lesions in patients with KRASG12DNSCLC.

[0030] Figure 8 shows baseline and treatment-in (C13D1) scans of target lesions in patients with KRASG12DPDAC.

[0031] Figure 9 shows baseline and in-treatment (C7D1 and C19D1) scans of target lesions in patients with KRASG12V ovarian cancer.

[0032] Figure 10 shows baseline and in-treatment (week 6) scans of target lesions in patients with KRASG12V NSCLC.

[0033] Figure 11 shows baseline and in-treatment (week 12) scans of target lesions in patients with KRASG12RPDAC.

[0034] Figure 12 shows the preclinical validation of the combination of compound A with RMC-6291. The RAS(ON) inhibitor dual was evaluated across seven models, including five models identified as resistant to RMC-6291 monotherapy. Detailed Description

[0035] Compound A is a RAS inhibitor, and more specifically, a multiselective, ternary complex inhibitor of RAS(ON) that is selective for the active GTP binding status of mutant and wild-type variants of the typical RAS isotype. Compound A binds to cyclophilic protein A, which is highly expressed in normal tissues and tumors, to produce a binary complex that effectively binds to RAS(ON) to form a ternary complex, blocking downstream RAS signaling. Jiang et al., Canc Discov 14:1-24 (2024).

[0036] Definitions

[0037] In this application, unless the context clearly indicates otherwise, (i) the term “a” means “one or more”; (ii) the term “or” is used to mean “and / or” unless explicitly indicated that the term refers to an alternative that is unique or that the alternatives are mutually exclusive, however, the definition supported by this disclosure refers to a unique alternative and “and / or”; (iii) the terms “comprising” and “including” should be understood to encompass the listed components or steps, whether presented alone or in conjunction with oneOr a combination of multiple additional components or steps; and (iv) when a range is provided, the endpoints are included.

[0038] As used herein, the term “about” is used to indicate that a value includes the standard deviation of the error specification of the apparatus or method used to determine the value (page 5 / 82, CN 121693329 A). In some embodiments, the term “about” refers to a range of values ​​along any direction (greater or less than) within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or lower of the value, unless otherwise specified or otherwise apparent from the context (e.g., when the number would exceed 100% of the possible value).

[0039] It should be noted that, unless otherwise indicated, when a range or quantity is provided in the disclosure herein, each range endpoint or specific quantity + / - 5% is included. For example, a compound A in the range of 10 mg to 500 mg should be understood to cover 10 + / - 5% mg to 500 + / - 5% mg, such as 9.5 mg to 525 mg of compound A.

[0040] As used herein, the term “administration” means administering a composition comprising compound A to a subject or system. Administration also includes administering to a subject a prodrug derivative or analog or a pharmaceutically acceptable salt that can form an equivalent amount of the active compound in the subject's body. Administration to animal subjects (e.g., to humans) can be performed via any suitable route. For example, in some embodiments, administration can be via bronchial (including bronchial infusion), buccal, intestinal, intradermal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, mucosal, nasal, oral, rectal, subcutaneous, sublingual, surface, tracheal (including intratracheal infusion), percutaneous, vaginal, or vitreous administration. In some embodiments, the composition comprising compound A is administered orally.

[0041] The term "combination therapy" refers to a treatment method comprising administering to a subject, as part of a treatment regimen, at least two active therapeutic agents in the form of one or more pharmaceutical compositions. For example, combination therapy may include the administration of a single pharmaceutical composition comprising at least two therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Combination therapy may include the administration of two or more pharmaceutical compositions, each comprising one or more therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. The two or more agents may optionally be administered simultaneously (in the form of a single or separate composition) or sequentially (in the form of separate compositions). The therapeutic agents may be administered in an effective amount. The therapeutic agents may be administered in a therapeutically effective amount. In some embodimentsIn this regimen, the effective amount of one or more therapeutic agents used in combination therapy may be lower than the therapeutic amount of the same therapeutic agent used as a monotherapy, for example, due to the additive or synergistic effect of the combination of two or more therapeutic agents.

[0042] As used herein, the term “dosage form” refers to a physically discrete unit of a compound (e.g., compound A) to be administered to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such an amount is an amount (or a whole portion thereof) of a unit dose suitable for administration according to a dosing regimen that is determined to be associated with a desired or beneficial outcome when administered to a relevant population (i.e., according to a treatment dosing regimen). Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0043] As used herein, the term “dosing regimen” refers to a set of unit doses (typically more than one unit dose) administered individually to a subject, said unit doses typically spaced at intervals. In some embodiments, a given therapeutic compound (e.g., compound A) has a recommended dosing regimen that may involve one or more doses. In some embodiments, the dosing regimen includes multiple doses, each dose being spaced apart by an equal period of time; in some embodiments, the dosing regimen includes multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses within the dosing regimen are amounts of the same unit dose. In some embodiments, the different doses within the dosing regimen are different amounts. In some embodiments, the dosing regimen includes a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose different from the first dose. In some embodiments, the dosing regimen includes a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose identical to the first dose. In some embodiments, the dosing regimen, when administered to a relevant population, is associated with a desired or beneficial outcome (i.e., a therapeutic dosing regimen). Specification 6 / 82 pages 10 CN 121693329 A

[0044] Unless otherwise indicated, the term “symptom” is used in this disclosure to mean the terms disease, ailment, or illness, and is used interchangeably with these terms.

[0045] The terms “inhibition,” “blocking,” and “curbing” are used interchangeably to refer to any statistically significant reduction in biological activity, including complete blockage of activity. As used herein, the term “inhibitor” refers to a compound that prevents a biomolecule (e.g., a protein, nucleic acid) from completing or initiating a reaction. Inhibitors can inhibit reactions in, for example, competitive, non-competitive, or non-competitive ways. Regarding their binding mechanism, inhibitors can be irreversible or reversible. Exemplary inhibitors include (but...)This includes, but is not limited to, nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimics, peptides, peptide mimics, antibodies, small molecules, chemicals, analogs of enzyme binding sites, receptors, or other proteins. In some embodiments, the inhibitor is a small molecule, such as a low molecular weight organic compound, for example, an organic compound with a molecular weight (MW) of less than 1200 Daltons (Da). In some embodiments, the MW is less than 1100 Da. In some embodiments, the MW is less than 1000 Da. In some embodiments, the MW is less than 900 Da. In some embodiments, the small molecule MW ranges between 800 Da and 1200 Da. Small molecule inhibitors include cyclic and acyclic compounds. Small molecule inhibitors include natural products, their derivatives, and analogs. Small molecule inhibitors may include covalently cross-linked groups capable of, for example, forming covalent cross-links with the amino acid side chains of the target protein.

[0046] As used herein, “patient” and “subject” are used interchangeably and refer to a mammal in need of diagnosis, prognosis, or therapy. Mammal subjects include, but are not limited to, humans, livestock, farm animals, sporting animals, and zoo animals, including, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, and cattle. In some embodiments, the subject has been diagnosed with cancer. In some embodiments, the subject is a person with a tumor (e.g., cancer) who has been diagnosed with a need for treatment of the tumor (e.g., cancer).

[0047] As used herein, the term "pharmaceutical composition" refers to a compound formulated with a pharmaceutically acceptable excipient, such as compound A disclosed herein, or a pharmaceutically acceptable salt thereof.

[0048] As used herein, "pharmaceuticalally acceptable excipient" refers to any inactive ingredient (e.g., a medium capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in the subject. Typical excipients include, for example: anti-adhesion agents, antioxidants, adhesives, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavoring agents, fragrances, flow enhancers, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, croscarmellose, citric acid, croscarmellose, cysteine, ethyl cellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, etc.Propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn starch), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. A variety of agents and materials that can be used as excipients are well known to those skilled in the art. See, for example, Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0049] As used herein, the term “pharmaceuticalally acceptable salt” means a salt of a compound described herein that, to the extent of reasonable medical judgment, is suitable for use in contact with tissues of humans and other animals without excessive toxicity, irritation, anaphylactic reactions, etc., and is commensurate with a reasonable benefit / risk ratio as stated on page 7 / 82 of the specification, CN 121693329 A. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:119, 1977; and Pharmaceutical Salts: Properties, Selection, and Use, (edited by P.H. Stahl and C.G. Wermuth), Wiley VCH, 2008. The salt may be prepared in situ during the final isolation and purification of the compound described herein, or may be prepared alone by reacting a free basic group with a suitable organic acid.

[0050] The terms “RAS inhibitor” and “RAS inhibitor” are used interchangeably and refer to any inhibitor that targets (i.e., selectively binds to or inhibits) the RAS protein.

[0051] As used herein, the terms “RAS(ON) multiselective inhibitor,” “RAS multi-inhibitor,” and “RAS multi-(ON) inhibitor” are also used."RAS(ON) inhibitor" or "RAS(ON) inhibitor" refers to a RAS inhibitor of at least three RAS isotypes, including wild-type and / or variants having a missense mutation at one of the following positions: 12, 13, 59, 61, or 146. In some embodiments, a RAS(ON) multiselective inhibitor refers to a RAS inhibitor of at least three RAS variants having a missense mutation at one of the following positions: 12, 13, and 61.

[0052] As used herein, the term "RAS(ON) inhibitor" refers to a target (i.e., selectively binds to or inhibits) RAS. Inhibitors of the GTP-binding active state of RAS (e.g., selectively more so than the GDP-binding inactive state of RAS). Inhibition of the GTP-binding active state of RAS includes, for example, inhibiting oncogenic signaling from the GTP-binding active state of RAS. In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the GTP-binding active state of RAS. In some embodiments, the RAS(ON) inhibitor may also bind to or inhibit the GDP-binding inactive state of RAS (e.g., with an affinity or inhibition constant lower than that for the GTP-binding active state of RAS). In some embodiments, the RAS(ON) inhibitors used in this disclosure may form a high-affinity three-component complex or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., RAS) and a widely expressed cytosolic chaperone protein (presenting protein) (e.g., cyclophilin A). More specifically, in some embodiments, the RAS inhibitors described herein drive the interaction between the RAS protein and the widely expressed cytosolic chaperone protein cyclophilin A. (CYPA) form high-affinity ternary complexes or conjugates to induce new binding pockets in the RAS.

[0053] As used herein, the term “RAS(OFF) inhibitor” refers to an inhibitor that targets (i.e. selectively binds to or inhibits) the GDP-binding inactive state of the RAS (e.g., selectively over the GTP-binding inactive state of the RAS).

[0054] The terms “RAS pathway” and “RAS / MAPK pathway” are used interchangeably herein, referring to the signal transduction cascade downstream of various cell surface growth factor receptors, in which activation of the RAS (and its various isoforms and alloforms) is a central event driving a variety of cellular effector events that determine cell proliferation, activation, differentiation, mobilization, and other functional properties. SHP2 transmits positive signals from growth factor receptors to the RAS activation / deactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs, such as SOS1), which load GTP onto the RAS to produce functionally active GTP-binding RAS and GTP.Accelerating proteins (GAPs, such as NF1) promote the termination of signals by converting GTP into GDP. GTP-binding RAS generated by this cycle delivers the necessary positive signal to a series of serine / threonine kinases (including RAF and MAP kinases), from which additional signals are emitted for various cellular effector functions.

[0055] A “therapeutic agent” is any substance, such as a compound or composition, capable of treating a disease or condition. In some embodiments, therapeutic agents available for the purposes of this disclosure include RAS inhibitors and cancer chemotherapy agents. Many of these therapeutic agents are known in the art and disclosed herein.

[0056] The term “therapeuticly effective amount” means an amount sufficient to treat a disease, condition, or disorder when administered according to a therapeutic dosing regimen to a population suffering from or susceptible to such a disease, condition, or disorder. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity of one or more symptoms of the disease, condition, or disorder or delays its onset. The general description of this art, 8 / 82 pages, 12 CN 121693329 A, indicates that those skilled in the art will understand that the term "therapeuticly effective amount" does not actually require successful treatment in a particular individual. In fact, a therapeutically effective amount can be the amount that provides a specific desired pharmacological response in a substantial number of subjects when administered to a patient requiring the treatment. It is particularly important to understand that a particular subject can actually be "therapeuticly effective" and "refractory." In some embodiments, references to a therapeutically effective amount may refer to an amount measured in one or more specific tissues (e.g., tissues affected by a disease, condition, or ailment) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount may be formulated as a single dose or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated as multiple doses, for example, as part of a dosing regimen, or administered in multiple doses.

[0057] The term “treatment” (and “treat” or “treating”) in its broadest sense refers to any application of a substance (e.g., compound A) that partially or completely relieves, improves, reduces, or inhibits one or more symptoms, features, or causes of a particular disease, condition, or disorder; delays its onset; reduces its severity; or reduces its occurrence. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, condition, or disorder, or to a subject who exhibits only early signs of the disease, condition, or disorder. Alternatively or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or more identified signs of the relevant disease, condition, or disorder. In some embodiments, treatment may be used to a subject who has been diagnosed with the relevant disease, condition, or disorder. In some embodiments,Treatment may be used for subjects known to have one or more susceptibility factors that are statistically associated with an increased risk of developing a disease, condition, or disorder. In any treatment described herein, the patient or subject may require such treatment.

[0058] Treatment Methods

[0059] Generally, this disclosure is characterized by a method of treating a human subject with a RAS protein-related condition, the method comprising administering (e.g., orally) 10 mg to 500 mg of compound A daily:

[0060]

[0061] Compound A (also known as RMC-6236 or RM-031).

[0062] Compound A may be present in conformational stereoisomers, such as transisomers. Pharmaceutically acceptable salts of compound A are also covered, as well as solvates, hydrates, and polymorphs. See, for example, WO 2022 / 060836 and PCT / US2024 / 024294, which are incorporated herein by reference in their entirety. Compound A may be prepared as generally described in WO 2021 / 091956 or specifically described in WO 2022 / 060836 or PCT / US2024 / 024247, each of which is incorporated herein by reference in its entirety.

[0063] Compound A may be present in a pharmaceutically acceptable isotopically labeled form, wherein one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than those commonly found in nature. Examples of isotopes that may be incorporated into Compound A include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, and 18O, respectively. These radiolabeled compounds may be used to help determine or measure the effectiveness of Compound A by characterizing, for example, the site of action or mode of action. Certain isotopic labeling schemes of compound A, such as those incorporating radioisotopes, can be used for drug and / or substrate tissue distribution studies. Radioisotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly useful for this purpose because they are readily incorporated and readily detectable. Non-limiting examples of such incorporations can be found, for example, in WO 2022 / 060836.

[0064] Substitution with heavier isotopes, such as deuterium (i.e., 2H), can provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life or reduced dose requirement. Substitution with positron emission isotopes (e.g., 11C, 15O, and 13N) can be used for positron emission morphology (PET) studies.

[0065] A method of treating a subject with cancer is also provided, the method comprising administering a therapeutically effective amount of compound A to the subject. Cancers may be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloid leukemia, etc.Multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, ovarian cancer, or squamous cell carcinoma of the lung. In some embodiments, the cancer contains wild-type RAS. In some embodiments, the cancer contains RAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G12R, KRAS G12A, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61R, KRAS Q61K, or KRAS Q61L, or combinations thereof. In some embodiments, the cancer contains RAS mutations, such as NRAS G12D, NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS Q61H, or NRAS Q61P, or combinations thereof. Other RAS mutations are described herein.

[0066] A method for treating RAS protein-related disorders in a subject of need is also provided, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof.

[0067] A method for treating RAS lesions in a subject of need is also provided, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments of any of the methods described herein, the method includes administering 10 mg to 500 mg of compound A (e.g., 20 mg to 500 mg, 40 mg to 500 mg, 80 mg to 500 mg, 120 mg to 500 mg, 160 mg to 500 mg, 200 mg to 500 mg, 220 mg to 500 mg, 250 mg to 500 mg, 300 mg to 500 mg, 350 mg to 500 mg, 400 mg to 500 mg, 450 mg to 500 mg, 10 mg to 450 mg, 20 mg to 450 mg, 40 mg to 450 mg, 80 mg to 450 mg, 120 mg to 450 mg, 160 mg to 450 mg, 200 mg to 450 mg, 220 mg to 450 mg, 250 mg to 450 mg, 300 mg to 45 ...0 mg to 450 mg, 220 mg to 450 mg, 250 mg to 450 mg, 300 mg to 450 mg, 10 mg to 450 mg, 200 mg to 450 mg, 220 mg to 450 mg, 25 mg to 450 mg, 350 mg to 450 mg, 10 mg to 400 mg, 20 mg to 400 mg, 40 mg to 400 mg, 80 mg to 400 mg, 120 mg to 400 mg, 160 mg to 400 mg, 200 mg to 400 mg, 220 mg to 400 mg, 250 mg to 400 mg, 300 mg to 400 mg, 350 mg to 400 mg, 10 mg to 350 mg, 20mg to 350 mg, 40 mg to 350 mg, 80 mg to 350 mg, 120 mg to 350 mg, 160 mg to 350 mg, 200 mg to 350 mg, 220 mg to 300 mg, 250 mg to 300 mg, 10 mg to 300 mg, 20 mg to 300 mg, 40 mg to 300 mg, 80 mg to 300 mg, 120 mg to 300 mg, 160 mg to 300 mg, 200 mg to 300 mg, 220 mg to 300 mg, 250 mg to 300 mg, 10 mg to 250 mg, 20 mg to 250 mg, 40 mg to 250 mg, 80 mg to 250 mg, 120 mg to 250 mg, 160 mg to 250 mg, 220 mg to 250 mg, 10 mg to 220 mg, 20 mg to 220 mg mg, 40 mg to 220 mg, 80 mg to 220 mg, 120 mg to 220 mg, 160 mg to 220 mg, 200 mg to 220 mg, 10 mg to 160 mg, 20 mg to 160 mg, 40 mg to 160 mg, 80 mg to 160 mg, 120 mg to 160 mg, 10 mg to 120 mg, 20 mg to 120 mg, 40 mg to 120 mg, 80 mg to 120 mg, 10 mg to 80 mg, 20 mg to 80 mg, 40 mg to 80 mg, 10 mg to 40 mg, 20 mg to 40 mg or 10 mg to 20 mg).

[0069] In some embodiments, the method includes administering 20 mg to 500 mg daily to a subject in need of the product information, page 10 / 82, 14 CN 121693329 A, compound A. In some embodiments, the method includes administering 40 mg to 500 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg to 500 mg of compound A to a subject daily. In some embodiments, the method includes administering 120 mg to 500 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 160 mg to 500 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 200 mg to 500 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 220 mg to 500 mg of compound A to a subject in need daily.In some embodiments, the method includes administering 250 mg to 500 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 300 mg to 500 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 350 mg to 500 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 400 mg to 500 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 450 mg to 500 mg of compound A to a subject in need daily.

[0070] In some embodiments, the method includes administering 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A to a subject in need daily.

[0071] In some embodiments, the method includes administering 10 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 20 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 40 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 120 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 160 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 200 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 220 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 250 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 300 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 350 mg to 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 400 mg to 450 mg of compound A to a subject in need daily.

[0072] In some embodiments, the method includes administering 10 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 20 mg to 400 mg of compound A to a subject in need daily.Compound A. In some embodiments, the method includes administering 40 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 120 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 160 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 200 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 220 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 250 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 300 mg to 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 350 mg to 400 mg of compound A to a subject in need daily.

[0073] In some embodiments, the method includes administering 10 mg to 350 mg of compound A (see page 11 / 82 of CN 121693329 A) to a subject in need daily. In some embodiments, the method includes administering 20 mg to 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 40 mg to 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg to 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 120 mg to 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 160 mg to 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 200 mg to 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 220 mg to 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 250 mg to 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 300 mg to 350 mg of compound A to a subject in need daily.

[0074] In some embodiments, the method includes administering 10 mg to 300 mg of compound A to a subject in need daily.Compound A. In some embodiments, the method includes administering 20 mg to 300 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 40 mg to 300 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg to 300 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 120 mg to 300 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 160 mg to 300 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 200 mg to 300 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 220 mg to 300 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 250 mg to 300 mg of compound A to a subject in need daily.

[0075] In some embodiments, the method includes administering 10 mg to 250 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 20 mg to 250 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 40 mg to 250 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg to 250 mg of compound A to a subject. In some embodiments, the method includes administering 120 mg to 250 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 160 mg to 250 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 200 mg to 250 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 220 mg to 250 mg of compound A to a subject in need daily.

[0076] In some embodiments, the method includes administering 10 mg to 220 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 20 mg to 220 mg of compound A daily to a subject in need. In some embodiments, the method includes administering 40 mg to 220 mg of compound A daily to a subject in need. In some embodiments, the method includes administering 80 mg to 220 mg of compound A to a subject. In some embodiments, the method includes administering 120 mg to 220 mg of compound A daily to a subject in need.In some embodiments, the method includes administering 160 mg to 220 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 200 mg to 220 mg of compound A to a subject in need daily.

[0077] In some embodiments, the method includes administering 10 mg to 200 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 20 mg to 200 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 40 mg to 200 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg to 200 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 120 mg to 200 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 160 mg to 200 mg of compound A to a subject in need daily.

[0078] In some embodiments, the method includes administering 10 mg to 160 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 20 mg to 160 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 40 mg to 160 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg to 160 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 120 mg to 160 mg of compound A to a subject in need daily.

[0079] In some embodiments, the method includes administering 10 mg to 120 mg of compound A to a subject. In some embodiments, the method includes administering 20 mg to 120 mg of compound A to a subject. In some embodiments, the method includes administering 40 mg to 120 mg of compound A to a subject. In some embodiments, the method includes administering 80 mg to 120 mg of compound A to a subject.

[0080] In some embodiments, the method includes administering 10 mg to 80 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 20 mg to 80 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 40 mg to 80 mg of compound A to a subject in need daily.

[0081] In some embodiments, the method includes administering 10 mg to 40 mg of compound A to a subject in need daily.In some embodiments, the method includes administering 20 mg to 40 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 10 mg to 20 mg of compound A to a subject in need daily.

[0082] In some embodiments, the method includes administering 10 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 20 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 40 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 80 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 120 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 160 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 200 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 220 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 250 mg of compound A to a subject. In some embodiments, the method includes administering 300 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 350 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 400 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 450 mg of compound A to a subject in need daily. In some embodiments, the method includes administering 500 mg of compound A to a subject in need daily.

[0083] In many embodiments, compound A is administered once daily. In many embodiments, compound A is administered in separate daily doses, such as twice, three, four, five, six, or more times a day.

[0084] In some embodiments of the method disclosed herein, compound A is administered orally to a subject once daily (QD) at the disclosed dose.

[0085] In some embodiments of the methods disclosed herein, compound A is orally administered to a subject at the disclosed dose at least twice daily (BID) to page 13 / 82 of the specification, CN 121693329 A.

[0086] In several embodiments, compound A is administered once, twice, three times, four times, five times, six times, or seven times per week. In several embodiments, compound A is administered seven days per week. In several embodiments, compound A is administered six days per week. For example, inCompound A is applied on days 1, 2, 3, 4, 5, and 6 of every 7 days. In several embodiments, compound A is applied 5 days a week. For example, compound A is applied on days 1, 2, 3, 4, and 5 of every 7 days. In several embodiments, compound A is applied 4 days a week. For example, compound A is applied on days 1, 2, 3, and 4 of every 7 days. In several embodiments, compound A is applied 3 days a week. For example, compound A is applied on days 1, 2, and 3 of every 7 days. In several embodiments, compound A is applied 2 days a week. For example, compound A is applied on days 1 and 2 of every 7 days.

[0087] In several embodiments, compound A is administered to the subject for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, for example, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, or longer. In several embodiments, compound A is administered to the subject for at least 1 month. In several embodiments, compound A is administered to the subject for at least 3 months. In several embodiments, compound A is administered to the subject for at least 6 months. In several embodiments, compound A is administered to the subject for at least 8 months. In several embodiments, compound A is administered to the subject for at least 10 months. In several embodiments, compound A is administered to the subject for at least 12 months.

[0088] In some embodiments, compound A is administered in treatment cycles. In some embodiments, the treatment period is 7 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In many embodiments, the subject experiences 1, 2, 3, or more treatment periods. In some embodiments, the subject experiences at least 3, 5, 8, 10, 15, 20, 25, or more treatment periods.

[0089] As known to those skilled in the art, after a subject has taken compound A for an appropriate period of time, the response rate or outcome of the subject administered compound A in the methods disclosed herein can be measured in various ways.

[0090] For example, by the Response Evaluation Criteria in Solid Tumors (RECIST).As determined by protocol 1.1 (Eisenhauer et al., 2009), a subject may respond to therapy, as measured by at least stable disease (SD). RECIST v1.1 is discussed in detail in the examples below. At least stable disease is stable disease that has shown a partial response (PR) or a complete response (CR) (i.e., “at least SD” = SD + PR + CR, often referred to as disease control). In several embodiments, stable disease does not have a reduction sufficient to qualify for a partial response (PR) nor an increase sufficient to qualify for disease progression (PD). In several embodiments, the patient exhibits at least a partial response (i.e., “at least PR” = PR + CR, often referred to as an objective response).

[0091] Response can be measured by one or more of the following: tumor size reduction, tumor growth inhibition or reduction, reduction of target or tumor lesions, time to progression delay, no new tumors or lesions, reduced new tumor formation, increased survival or progression-free survival (PFS), and no metastases. In several implementations, the progression of a patient’s disease can be assessed by measuring tumor size, the presence or formation of new tumors or lesions, using computed tomography (CT) scans, positron emission tomography (PET) scans, magnetic resonance imaging (MRI) scans, X-rays, ultrasound, or some combination thereof to evaluate the patient.

[0092] Several criteria and definitions disclosed in the literature can be used to determine the effect of one or more treatments on the tumor of a subject with cancer. Based on these criteria, a tumor is defined as “responsive,” “stable,” or “progressive,” respectively, when it improves, remains unchanged, or worsens during treatment. The amount of tumor in an individual is called “tumor burden,” which can be measured as the number, volume, and / or weight of tumors.

[0093] Examples of commonly used guidelines disclosed in the literature include the Responsive Evaluation Criteria in Solid Tumors (RECIST), the Modified Response Evaluation Criteria in Solid Tumors (mRECIST), the PET Response Criteria in Solid Tumors (PERCIST), the Choi criteria, the Lugano response criteria, the European Association for the Study of the Liver (EASL) criteria, the Response Evaluation Criteria in the Cancer of the Liver (RECICL), and the WHO Tumor Response Criteria.

[0094] As used herein, “progression-free survival” or “PFS” is the time from treatment to the date of first confirmed disease progression, according to RECIST 1.1 guidelines. In several embodiments, patients exhibit at least 1 month of PFS. In several embodiments, patients exhibit at least 3 months of PFS. In some embodiments, patients exhibit at least 6 months of PFS.

[0095] “RECIST” should be interpreted as an acronym for “Responsiveness Assessment Criteria for Solid Tumors” and is a set of published rules defining when a cancer patient improves (“response”), remains unchanged (“stable”), or worsens (“progression”) during treatment. Responses defined by RECIST guidelines are published, for example, Journal of the National Cancer Institute, Vol. 92, No. 3, February 2, 2000, and RECIST guidelines may include other sets of similar published definitions and rules. Those skilled in the art will understand that definitions conforming to RECIST guidelines as used herein include, for example, “partial response (PR)”, “complete response (CR)”, “stable disease (SD)”, and “progressive disease (PD)”.

[0096] As used herein, “survival” means that the subject remains alive and includes overall survival and progression-free survival.

[0097] As used herein, “tumor reduction” means reducing the size, volume, or weight of a tumor, reducing the number of metastases, reducing the size or weight of metastases, or a combination thereof. In some embodiments, metastases are skin or subcutaneous. Thus, in some embodiments, for example relative to a control drug in subjects with the same genotype, administration of an immune checkpoint inhibitor reduces the size or volume of the tumor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In some embodiments, such as relative to a control drug in subjects with the same genotype, administration of compound A or a combination therapy comprising it reduces tumor weight by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In some embodiments, such as relative to a control drug in subjects with the same genotype, administration of compound A or a combination therapy comprising it reduces the size or volume of metastases by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, or at least about 90%.At least about 95%, at least about 98%, or at least about 99%. In some embodiments, for example, relative to a control drug in subjects with the same genotype, administration of a RAS(ON) inhibitor therapy or a combination therapy comprising thereof reduces the number of metastases by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In some embodiments, combinations achieve these effects.

[0098] In some embodiments, a biological sample obtained from the subject is used to determine the response to treatment with compound A. As used herein, the term "biological sample" means any sample obtained from the subject. Biological samples may be obtained from the subject before or after diagnosis, before or after treatment or therapy, at one or more time points during which no treatment or therapy is present, or may be collected from healthy subjects. Biological samples may be tissue samples or fluid samples. In some embodiments, the biological sample includes tissue samples, biopsy samples, tumor aspirates, bone marrow aspirates, or blood samples (or portions thereof, such as blood or serum). In some embodiments, the biological sample includes tumor cells or cancer cells, such as circulating tumor cells present in a fluid sample (e.g., blood or a portion thereof). In some embodiments, the biological sample includes cell-free nucleic acids present in a fluid sample (e.g., blood or a portion thereof). In one embodiment, the biological sample comprises a cell lysis product (or a portion of the lysis product) or a cell extract; or a solution containing one or more molecules derived from cells or cellular material (e.g., peptides or nucleic acids). The cell lysis product may include protein, nuclear, and / or mitochondrial portions. In some embodiments, the cell lysis product includes a cytosol portion. In some embodiments, the cell lysis product includes a nuclear / mitochondrial portion and a cytosol portion.

[0099] The source of the biological sample may be solid tissue from fresh, frozen, and / or preserved organ, tissue, biopsy, or aspirate samples; blood or any blood component; body fluids, such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; or cells from any time during the subject's pregnancy or development. The biological sample may contain compounds that do not naturally mix with tissues in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, etc. The biological sample may be preserved as a frozen sample or a formaldehyde or paraformaldehyde-fixed paraffin-embedded (FFPE) tissue preparation. For example, the sample may be embedded in a matrix, such as an FFPE block or a frozen sample. However, other tissue and sample types are applicable herein. In one embodiment, other tissue and sample types may be fresh frozen tissue, washing solution, or cell clumps, etc. The biological sample may be a tumor sample containing cells from…Nucleic acid molecules of tumors or cancer. A biological sample is a tumor sample, which can be DNA, such as genomic DNA, or cDNA derived from RNA. In one embodiment, the tumor nucleic acid sample is purified or isolated (e.g., removed from its native state). In one embodiment, the sample is tissue (e.g., tumor biopsy), CTC, or cell-free nucleic acid.

[0100] In some embodiments, tumor samples are isolated from human subjects. In some embodiments, tumor biopsies embedded in paraffin are analyzed. In one embodiment, the sample can be a fresh frozen tissue sample. In some embodiments, the sample is a bodily fluid obtained from a subject. The bodily fluid can be blood or a portion thereof (specifically, serum, plasma), urine, saliva, sputum, or cerebrospinal fluid (CSF). The sample may contain cells as well as nucleic acids of extracellular origin. Extracellular origin can be cell-free nucleic acids and / or exosomes. The methods described herein (including RT-PCR methods) are sensitive, accurate, and multianalyte-capable for use with paraffin-embedded samples. See, for example, Cronin et al., Am. J Pathol. 164(1):35-42 (2004).

[0101] Additional means for evaluating the response are described in detail in the examples below and are generally applicable to the methods disclosed herein.

[0102] In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject an amount of compound A described herein. Thus, one embodiment of this disclosure provides a method of treating a subject in need by administering a pharmaceutical composition containing an amount of compound A described herein and a pharmaceutically acceptable excipient, and a method of preparing such a composition using compound A.

[0103] In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including forms suitable for: oral administration, such as drenching (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets intended for buccal, sublingual, and systemic absorption), pills, powders, granules, pastes for application to the tongue; parenteral administration, such as via subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; surface administration, such as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or mouth; intravaginal or rectal administration, such as pessaries, creams, or foams; sublingual; ocular; transdermal; or via the nose, lungs, and other mucosal surfaces.

[0104] For use as a treatment of a subject, compound A may be formulated as a pharmaceutical composition. Depending on the subject to be treated, the mode of administration, and the type of treatment desired, such as prevention, treatment, or therapy, compound A is formulated in a manner consistent with these parameters. A compilation of these technologies can be found in Remington: The Science and Practice of Pharmacy, 21 Specification 16 / 82 pages 20 CN 121693329 A edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. Boylan, 1988–1999, Marcel Dekker, New York, each incorporated herein by reference.

[0105] The compositions may be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical compositions of the present invention may contain about 0.1% to about 99%, about 5% to about 90% or about 1% to about 20% of compound A by weight or volume. In some embodiments, compound A may be present in an amount totaling 1% to 95% by weight of the total weight of the composition (e.g., the pharmaceutical composition).

[0106] The composition may be provided in dosage forms suitable for administration as follows: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, sac-like, intraurethral, ​​intrathecal, epidural, ocular, or by injection, inhalation, or direct contact with the mucous membranes of the nose, genitourinary, genital, or oral cavity. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, solutions, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoresis delivery, or aerosols. The composition may be formulated according to conventional pharmaceutical practice.

[0107] The formulation may be prepared in a manner suitable for systemic or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or those prepared for transdermal, transmucosal, or oral administration. Formulations will generally include diluents, and in some cases, adjuvants, buffers, preservatives, etc. The compound or a pharmaceutically acceptable salt thereof may also be administered as a liposome composition or as a microemulsion.

[0108] For injection, formulations may be prepared in conventional forms, such as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or as emulsions. Suitable excipients include, for example, water, physiological saline, dextran, glycerol, etc. These compositions may also contain amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, etc.

[0109] Various sustained-release drug delivery systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0110] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, percutaneous patches, transmucosal delivery, and intranasal administration.Administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. It will be understood in the art that suitable forms include syrups, capsules, and tablets. In one embodiment, a therapeutically effective amount of compound A is administered orally in the form of tablets or multiple tablets.

[0111] Compound A as described herein can be formulated in a variety of ways known in the art. For example, the first and second doses in a combination therapy can be formulated together or separately. Other modes of combination therapy are also described herein.

[0112] The individual or separately formulated doses can be packaged together in a kit form. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, suppositories and liquid in a vial, two topical creams, etc. The kit may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstitution of the powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit dose kit may contain instructions for the preparation and administration of the composition. The cassette may be manufactured as a single-use unit dose for one subject, or for multiple uses for a specific subject (at a constant dose, or where the potency of a single compound or its pharmaceutically acceptable salt may vary with the progression of treatment); or the cassette may contain multiple doses suitable for administration to multiple subjects (“integral package”). The cassette assembly may be assembled in a carton, blister pack, bottle, tube, etc.

[0113] Formulations for oral use include tablets containing a mixture of the active ingredient and a non-toxic, pharmaceutically acceptable excipient. These excipients can be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulation agents (e.g., cellulose derivatives, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methyl cellulose, optionally substituted hydroxypropyl methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-adhesion agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0114] Two or more compounds may be mixed together in tablets, capsules, or other media, or may be separated. In one example, the first compound is contained on the inside of the tablet, and the second compound on the outside, thereby allowing the majority of the second compound to be released before the first compound is released.

[0115] Oral formulations may also be provided in the form of chewable tablets or hard gelatin capsules, wherein compound A is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or in the form of soft gelatin capsules, wherein compound A is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and fine pellets may be prepared using the ingredients mentioned above for tablets and capsules in a conventional manner, using, for example, a mixer, a fluid bed apparatus, or a spray drying device.

[0116] Dissolution or diffusion-controlled release may be achieved by appropriately coating the compound into tablets, capsules, fine pellets, or granules, or by incorporating compound A into a suitable matrix. Controlled-release coatings may include one or more of the coating substances mentioned above, or such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethyl methacrylate, methacrylate hydrogel, 1,3-butanediol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methyl cellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0117] Liquid forms of compounds A or their compositions that can be incorporated into the oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical mediators.

[0118] In some embodiments, the pharmaceutical composition may also contain additional compounds having antiproliferative activity. Depending on the administration modality, the compound or a pharmaceutically acceptable salt thereof will be formulated into a suitable composition for easy delivery. Each compound or pharmaceutically acceptable salt thereof in the combination therapy may be formulated in a variety of ways known in the art. For example, the first and second doses in the combination therapy may be formulated together or separately. Ideally, the first and second doses are formulated together for simultaneous or near-simultaneous administration of the agents.

[0119] It should be understood that compound A and its pharmaceutical compositions may be formulated and used in combination therapy, i.e., compound A and its pharmaceutical compositions may be formulated together with one or more other desired therapeutic agents or medical procedures or administered concurrently with, before, or after the administration of such one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutic agents or procedures) used in a combination regimen should take into account the compatibility of the required therapeutic agents or procedures with the desired therapeutic effect to be achieved. It will also be understood that...The therapies used may achieve the desired effect for the same condition, or they may achieve different effects (e.g., control any adverse effects).

[0120] As described herein, each drug in the combination therapy may be administered independently once to four times daily for one day to one year, or even for the subject's lifetime. Long-term, chronic administration may be indicated. Specification 18 / 82 pages 22 CN 121693329 A

[0121] In some embodiments, this disclosure provides a method for treating a disease or condition characterized by abnormal RAS activity caused by a RAS mutant. In some embodiments, the disease or condition is a RAS lesion. In some embodiments, the disease or condition is cancer.

[0122] Thus, a method for treating a subject with a RAS lesion in need is also provided, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutical composition comprising such a compound. RAS lesions are a group of inherited conditions caused by mutations in genes associated with the RAS / MAPK signaling pathway. RAS lesions are characterized by a range of clinical features and can affect multiple organ systems, including the cardiovascular, musculoskeletal, nervous, and cutaneous systems.

[0123] In some embodiments, the method includes treating RAS lesions selected from Noonan syndrome, Costello syndrome, cardiofacial skin syndrome, neurofibromatosis type 1, and Legius syndrome. Although each RAS lesion has unique features, they share certain similarities, such as facial deformities, cardiac abnormalities, developmental delays, and an increased risk of certain cancers.

[0124] RAS lesions are typically diagnosed through a combination of clinical evaluation, genetic testing, and imaging studies. Treatment and management of RAS lesions depend on the specific type and severity of the condition but may include pharmacological treatment, surgery, and supportive therapies, such as physical and occupational therapies.

[0125] Illegible non-cancerous indications related to RAS are summarized in Table 1.

[0126] Table 1: Exemplary RAS-related non-cancerous indications

[0127]

[0128] A method of treating a subject with cancer is also provided, the method comprising administering to the subject an amount of compound A as disclosed herein or a pharmaceutical composition comprising such compounds. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary site, endometrial cancer, esophageal and gastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal cancer, uterine cancer, etc. (Instructions for use 19 / 82 pages 23 CN)121693329 A Endometrial cancer or melanoma. A method of treating a subject with RAS protein-related conditions is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0129] As used herein, the terms “cancer” or “tumor” refer to cells exhibiting typical characteristics of cancerous cells (e.g., uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rates, and certain characteristic morphological features). Cancer cells typically present as tumors, but such cells may exist alone in an animal or may be non-tumorigenic, such as leukemia cells. Cancers include (but are not limited to) B-cell malignancies, such as multiple myeloma; heavy chain diseases, such as alpha chain disease, gamma chain disease, and μ chain disease; benign monoclonal gammopathy; and immune cell amyloidosis, skin cancer, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, bladder cancer, brain cancer or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, oral or pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, bile duct cancer, small intestine or appendix cancer, salivary gland cancer, thyroid cancer, adrenal cancer, osteosarcoma, chondrosarcoma, and blood tissue cancers. Other non-limiting examples of cancer types suitable for the methods covered in this disclosure include human sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelioid sarcoma, epithelioid sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, liver cancer, choriocarcinoma, seminoma, embryonal carcinoma, and Wilms' tumor. Tumors, cervical cancer, bone cancer, brain tumors, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemia, such as acute lymphoblastic leukemia and acute myeloid leukemia (myeloblastic leukemia, promyelocytic leukemia, granulocytic leukemia, monocytic leukemia, and erythroleukemia); chronic leukemia (chronic myeloid (granulocytic) leukemia and chronic lymphocytic leukemia); as well as polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple leukemia, etc.Multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease. In some embodiments, the cancer is an epithelial cancer, such as, but not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer, gynecological cancer, kidney cancer, laryngeal cancer, lung cancer, oral cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer. In other embodiments, the cancer is breast cancer, prostate cancer, lung cancer, or colon cancer. In other embodiments, the epithelial cancer is non-small cell lung cancer, non-papillary renal cell carcinoma, cervical cancer, ovarian cancer (e.g., serous ovarian cancer), or breast cancer.

[0130] In some embodiments, compound A, pharmaceutical compositions comprising compound A or its salts, and the methods provided herein can be used to treat a wide range of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, the treatable cancers and the methods of the present invention include, but are not limited to, the following types of tumors: astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. Other cancers include, for example:

[0131] Cardiac cancers, such as: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma;

[0132] Lung cancers, such as: bronchial cancers (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

[0133] Gastrointestinal cancers, such as: esophageal cancers (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancers (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancers (ductal adenocarcinoma, islet tumor, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide, 20 / 82 pages, 24 CN 121693329 A) Cancers of the following types of organs, such as: tumors, small intestinal cancers (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas), colorectal cancers (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyomas);

[0134] urogenital tract cancers, such as: renal cancer (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethral cancers (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminomas, teratomas, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma);

[0135] liver cancers, such as: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0136] Biliary tract cancer, such as gallbladder cancer, ampullary cancer, and bile duct cancer;

[0137] Bone cancer, such as: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma and giant cell tumor;

[0138] Cancers of the nervous system, such as: skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, ... Germ cell tumors (pineal gland tumors), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma);

[0139] Gynecological cancers, such as: uterine cancer (endometrial cancer, uterine cancer, endometrial cancer), cervical cancer (cervical cancer, pretumoral cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube cancer);

[0140] Cancers of the hematopoietic system, such as: blood cancers (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders (e.g., myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0141] skin cancers, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and

[0142] adrenal cancers, such as: neuroblastoma.

[0143] In some embodiments, the RAS protein is wild-type (RASWT). Therefore, in some embodiments, compound A This invention can be used in methods for treating patients with cancers containing RASWT (e.g., KRASWT, HRASWT, or NRASWT). In some embodiments, the RAS protein is amplified (e.g., KRASamp). Therefore, in some embodiments, the compounds of the present invention are used in methods for treating patients with cancers containing RASamp (KRASamp, HRASamp, or NRASamp). In some embodiments...In this context, cancer includes RAS mutations, such as the RAS mutations described herein. In some embodiments, the mutation is selected from:

[0144] (a) the following K-RAS mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof;

[0145] (b) the following H-RAS mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R, and combinations thereof; and specification page 21 / 82, 25 CN 121693329 A

[0146] (c) the following N-RAS mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof;

[0147] or any combination of the foregoing mutants. In some embodiments, the cancer comprises a RAS mutation selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two RAS mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit more than one RAS mutant. For example, the compound can inhibit both KRAS G12D and KRAS G12C. In some embodiments, the compound can inhibit both KRAS G12V and KRAS G12C. In some embodiments, the compound can inhibit both KRAS G12C and KRAS G13C. In some embodiments, the compound can inhibit both KRAS G12D and KRAS G12V. In some embodiments, the compound can inhibit both KRAS G12V and K-RAS G12S. In some embodiments, the mutation is selected from the group consisting of KRAS, NRAS, or HRAS.The G12A, G12C, G12D, G12E, G12F, G12H, G12I, G12K, G12L, G12M, G12N, G12P, G12Q, G12R, G12S, G12T, G12V, G12W, and G12Y, or combinations thereof, of KRAS, NRAS, or HRAS. In some embodiments, the mutation is selected from the group consisting of G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y, or combinations thereof, of KRAS, NRAS, or HRAS. In some embodiments, the compound inhibits wild-type KRAS, wild-type HRAS, or wild-type NRAS, and optionally also inhibits mutant RAS proteins containing mutations as described herein. In some embodiments, the cancer is non-small cell lung cancer and the RAS mutation includes a KRAS mutation, such as KRAS G12C. In some embodiments, the cancer is colorectal cancer and the RAS mutation includes a KRAS mutation, such as KRAS G12C. In some embodiments, the cancer is pancreatic cancer and the RAS mutation includes an NRAS mutation, such as NRAS G12D. In some embodiments, the cancer is non-small cell lung cancer and the RAS protein is KRASamp.

[0148] Additionally, in some embodiments, the cancer includes a KRAS mutation selected from the group consisting of: G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer includes an N-RAS mutation selected from the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer includes an HRAS mutation selected from the group consisting of: Q61H and Q61L. In some embodiments, the cancer comprises RAS mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two RAS mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit more than one RAS mutant. For example, the compound may inhibit both K-RAS G12C and K-RAS G13C. The compound may inhibit both NRAS G12C and K-RAS G12C. In some embodiments, the compound may inhibit both KRAS G12C and KRAS G12D. In some embodiments, the compound may inhibit both KRAS G12V and KRAS G12C. In some implementations, the compound can inhibit KRAS G12V and KRASBoth G12S and G12S. In some embodiments, in addition to one or more additional RAS mutations, the compounds of the present invention inhibit RASWT (e.g., K, H, or NRASWT and KRAS G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K, H, or NRASWT and H-RAS Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, G12S, G12V, G12D, G12C, K117N, G12S, G12D, G12V, G12D ... A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K, H or NRASWT and NRAS Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T). In some embodiments, in addition to one or more additional RAS mutations, the compounds of the present invention inhibit RASamp (e.g., K, H, or NRASamp and K-RAS G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H, or NRASamp and H-RAS) Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K, H or NRASamp and N-RAS Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T).

[0149] In some embodiments, compound A prevents reactivation of the RAS pathway (e.g., receptor tyrosine kinase activation), clinically reported as a resistance mechanism to mutant-specific RAS(OFF) inhibitors (e.g., KRAS(OFF) inhibitors, such as KRASG12C(OFF) inhibitors). In some embodiments, compound A inhibits RAS with one or more switch II binding pocket mutations and / or RAS secondary site mutations.

[0150] Methods for detecting RAS mutations are known in the art. Such methods include (but are not limited to) direct sequencing and methods utilizing highly sensitive diagnostic assays (with CE-IVD markers), such as those described in Domagala et al., Pol J Pathol 3: 145-164 (2012) (which is incorporated herein by reference in its entirety), including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See also, for example, WO 2020 / 106640.

[0151] In some embodiments, the cancer is non-small cell lung cancer and the RAS mutation includes a KRAS mutation, such as KRAS G12C, KRAS G12V, or KRAS G12D. In some embodiments, the cancer is colorectal cancer and the RAS mutation includes a KRAS mutation, such as KRAS G12C, KRAS G12V, or KRAS G12D. In some embodiments, the cancer is pancreatic cancer and the RAS mutation includes a KRAS mutation, such as KRAS G12D or KRAS G12V. In some embodiments, the cancer is pancreatic cancer and the RAS mutation includes an NRAS mutation, such as NRAS G12D. In some embodiments, the cancer is melanoma and the RAS mutation includes an NRAS mutation, such as NRAS Q61R or NRAS Q61K. In some embodiments, the cancer is non-small cell lung cancer and the RAS protein is KRASamp. In any of the foregoing, if not specified, the compound may also inhibit RASWT (e.g., K, H, or NRASWT) or RASamp (e.g., K, H, or NRASamp).

[0152] In some embodiments, the cancer comprises a RAS mutation and STK11LOF, KEAP1, EPHA5, or NF1 mutations, or combinations thereof. In some embodiments, the cancer is non-small cell lung cancer and comprises a KRAS G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a KRAS G12C mutation, an STK11LOF mutation, and a KEAP1 mutation. In some embodiments...In some embodiments, the cancer is non-small cell lung cancer and contains both KRAS G12C and STK11LOF mutations. In some embodiments, the cancer is non-small cell lung cancer and contains both KRAS G12C and STK11LOF mutations. In some embodiments, the cancer contains KRAS G13C mutations and STK11LOF, KEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and contains a KRAS G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and contains a KRAS G12V mutation. In some embodiments, the cancer is colorectal cancer and contains a KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer and contains a KRAS G12D mutation. In some embodiments, the cancer is pancreatic cancer and contains a KRAS G12V mutation. In some embodiments, the cancer is endometrial cancer and contains a KRAS G12C mutation. In some embodiments, the cancer is gastric cancer and contains a KRAS G12C mutation. In any of the foregoing, the compound may also inhibit RASWT (e.g., K, H, or NRASWT) or RASamp (e.g., K, H, or NRASamp).

[0153] In some embodiments, the subject treated with compound A in the disclosed method is a subject who has previously undergone at least one or more systemic cancer therapies (e.g., compound A is a second- or third-line therapy). In some embodiments, the subject treated with compound A in the disclosed method is a subject whose disease has progressed after at least one prior systemic cancer therapy (i.e., compound A is a second-line therapy). In some embodiments, the subject treated with compound A in the disclosed method is a subject whose disease has progressed after at least two prior systemic cancer therapies (i.e., compound A is a third-line therapy). The prior systemic cancer therapy can be any therapy approved by a regulatory agency (e.g., the FDA or EMA) as a treatment given according to the type and stage of cancer. In some cases, the prior systemic cancer therapy is a cancer therapy that has not yet been approved by a regulatory agency but is currently undergoing clinical trials. If the subject has previously received systemic cancer therapy, in some cases, the subject has not experienced any systemic cancer therapy for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months prior to initiating treatment with compound A as disclosed herein.

[0154] In several embodiments, this disclosure provides a method of treating a subject's cancer, the method comprising administering to the subject a composition comprising an amount of compound A disclosed herein or a combination of compounds described herein, wherein the subject has one or more tumors that are resistant to or unresponsive to treatment. In several embodiments, the subjectThe patient has one or more tumors that are resistant to or unresponsive to one or more treatments selected from the group consisting of: surgery, radiation, chemotherapy, biologics, small molecules, cell-based therapies, hormone therapy, and immunotherapy. In several embodiments, the treatment is a standard of care therapy, a first-line therapy, a second-line therapy, or a third-line therapy. In several embodiments, the subject has one or more tumors that have progressed during one or more treatments, wherein said treatment is a standard of care therapy, a first-line therapy, a second-line therapy, or a third-line therapy.

[0155] First-line therapy is defined as treatment administered to a subject with cancer who has not received any prior treatment. Second-line therapy is defined as treatment administered to a subject with cancer who has received prior first-line therapy but has experienced disease progression during first-line therapy. Third-line therapy is defined as treatment administered to a subject with cancer who has received prior first-line and second-line therapy but has experienced disease progression during second-line therapy. Each specific type of cancer has first-line, second-line, and third-line therapies. First-line, second-line, and third-line therapies for cancer types are known in the art. Additionally, FDA-approved drug labels will indicate whether a particular drug is approved as a first-line, second-line, or third-line therapy.

[0156] In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject a composition comprising a combination of compounds A disclosed herein or compounds described herein, wherein the subject is intolerant to standard care, first-line therapy, second-line therapy, or third-line therapy. In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject compound A or a combination therapy comprising compound A, wherein the subject has experienced tumor recurrence following surgical resection of a primary tumor. In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject a composition comprising a combination of compounds A disclosed herein or compounds described herein, wherein the subject has a tumor that cannot be surgically removed. In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject a composition comprising a combination of compounds A disclosed herein or compounds described herein, wherein the subject has no available treatment options.

[0157] In some embodiments, the cancer includes a RAS mutation and the cancer is resistant to treatment using RAS(OFF), such as a KRAS(OFF) inhibitor, such as a KRASG12C(OFF) inhibitor. As used herein, the term "resistance to treatment" refers to treatment of a condition with a therapeutic agent ineffective, or where the therapeutic agent was previously effective but has become less effective over time. Resistance to treatment includes acquired and / or adaptive resistance to treatment, which refers to resistance to treatment in the course of treatment administered to a subject.Treatment efficacy decreases over time. Acquired resistance to treatment may be caused by mutations in the acquired target protein that render the treatment ineffective or less effective. Therefore, resistance to treatment may persist even after the administration of the therapeutic agent is discontinued. Specifically, cancer may be resistant to treatment using RAS(OFF) inhibitors, which reduces the efficacy of the RAS(OFF) inhibitors. Measurement of reduced treatment efficacy will depend on the condition being treated, and such methods are known to those skilled in the art. For example, the efficacy of cancer treatment can be measured by disease progression. Effective treatment slows or stops disease progression. Cancer resistant to therapeutic agents (e.g., RAS(OFF) inhibitors) may not slow or stop disease progression.

[0158] In some embodiments, a dose of compound A may optionally be administered to the subject with food (e.g., a standardized high-fat, high-calorie diet) or in a fasting state (no food or liquids other than water, >10 hours). In one embodiment, a dose of compound A may be administered with or without food.

[0159] Adverse events (AEs) are monitored in subjects receiving treatment during the course of therapy. Treatment-related AEs are AEs related to the treatment drug. Treatment-occurring AEs are AEs that were not present in the subject before the start of treatment but appeared after treatment. In some cases, treatment-occurring AEs are unrelated to or suspected to be unrelated to the treatment itself. AEs are characterized by one of five grades: Grade 1 is a mild AE; Grade 2 is a moderate AE; Grade 3 is a severe AE; Grade 4 is a life-threatening or disabling AE; and Grade 5 is death related to the AE. In some cases, subjects do not exhibit any treatment-related Grade 3 AEs. In some cases, subjects do not exhibit any Grade 3 AEs. In some cases, subjects do not exhibit any treatment-related Grade 4 AEs. In some cases, subjects do not exhibit any Grade 4 AEs. In various cases, subjects do not exhibit treatment-related Grade 3 or Grade 4 AEs at least one month or at least three months after administration of compound A.

[0160] In various cases, subjects treated with compound A in the methods disclosed herein do not exhibit any dose-limiting toxicities (DLTs) at the administered dose. DLT is any adverse event (AE) that occurs during the first treatment cycle (day 1 to day 21) of compound A and meets the criteria listed below, wherein a relationship with the drug cannot be ruled out.

[0161] In various cases, subjects of the disclosed methods exhibit a response to the therapy. In some cases, subjects exhibit at least a stable disease (SD) due to administration of compound A. In some cases, subjects exhibit at least a partial response (PR) due to administration of compound A. Subject responses are assessed according to the criteria defined in RECIST 1.1, for example, asAs discussed in Eisenhauer et al., Eur J Cancer, 45:228-247 (2009). Complete response (CR) is the disappearance of all target lesions and a reduction in the short axis of any pathological lymph nodes to less than 10 mm. Partial response (PR) is a reduction in the total diameter of target lesions by at least 30% with reference to the baseline total diameter. Disease progression is an increase in the total diameter of target lesions by at least 20% with reference to the minimum total in the study (including the baseline total, if it is the minimum in the study), and an absolute increase of at least 5 mm in addition to a 20% relative increase. Stable disease has neither a reduction sufficient to qualify for PR nor an increase sufficient to qualify for PD. Controlled disease status refers to a patient who may alternate between exhibiting stable disease and partial response. Tumor size can be measured by radiographic scanning.

[0162] Combination Therapy

[0163] This document provides compositions comprising compound A and one or more therapeutic agents for the treatment of RAS-related diseases or conditions. In some embodiments, the compositions of this disclosure comprise two or more RAS(ON) inhibitor therapies (e.g., compound A plus RMC-6291). In some embodiments, the compositions of this disclosure comprise a RAS(ON) inhibitor therapy and an additional therapeutic agent. In some embodiments, the compositions of this disclosure comprise a RAS(ON) inhibitor therapy and two additional therapeutic agents. In some embodiments, the compositions of this disclosure comprise a RAS(ON) inhibitor therapy and three additional therapeutic agents. In some embodiments, the compositions of this disclosure comprise a RAS(ON) inhibitor therapy and four or more additional therapeutic agents.

[0164] Pharmaceutical compositions are also provided comprising the said combination or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Compositions comprising the therapeutic agent combination can be used in methods of modulating RAS (e.g., in a subject or in cells) and methods of treating RAS-related diseases and conditions (e.g., cancer), as described herein. This disclosure particularly provides compositions, methods, and kits for treating or preventing RAS-related diseases or conditions.

[0165] Compound A as disclosed herein may be administered before, after, or simultaneously with one or more of such additional therapies. When combined, the dosage of compound A and the one or more additional therapies (e.g., non-pharmacological or therapeutic agents) administered in the amounts disclosed herein provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). Compound A and additional therapies, such as anticancer agents, may be administered together, for example, as a single pharmaceutical composition, or separately, and when administered separately, the administration may occur simultaneously or sequentially. Such sequential administration may be close or distant in time.

[0166] All references herein are incorporated by way of citation for the agents described, including the compounds or molecular structures disclosed therein, whether or not so explicitly stated.

[0167] a) RAS(ON) Inhibitor

[0168] The compositions and methods of this disclosure include compound A plus a RAS(ON) inhibitor. In some embodiments, the RAS(ON) inhibitor is a multiselective RAS(ON) inhibitor (e.g., RMC-7977, RM-034, GFH547, ERAS-0015 and compound 6A of WO 2024 / 067857). Exemplary RAS(ON) multiselective inhibitors that can be used in combinations according to this disclosure are found in any of the following patent applications: WO 2021 / 091956, WO 2022 / 060836, WO 2023 / 240263, WO 2023 / 025832, WO 2024 / 008834, WO 2024 / 017859, WO 2024 / 060966, WO 2024 / 067857, WO 2024 / 104364, CN117534684, CN117534685, CN117534687, CN117720554, CN117720555 and CN117720556, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0169] In some embodiments, the RAS(ON) multiselective inhibitor is compound 6A of WO 2024 / 067857:

[0170] .

[0171] Some embodiments of combinations comprising RAS(ON) therapy include compositions comprising RAS(ON) mutant selective inhibitors. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G12C selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G12D selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G13C selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) Q61H selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G12V selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G13D selective inhibitor. Selective inhibitors of RAS(ON) mutants available according to the methods of this disclosure are found in any of the following patent applications: WO 2024008610, WO 2024102421, WO 2023240263, WO 2023133543, WOWO 2023015559, WO 2023086341, WO 2023208005, WO 2023232776, WO 2023060253, WO 2022235870, WO 2022235864, WO 2021091967, WO 2021091982, WO 2021108683, WO 2020132597, International Patent Applications PCT / US2024 / 023208 and PCT / US2024 / 30993, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0172] In some embodiments, the RAS(ON) mutant selective inhibitor available according to this disclosure is RMC-9805: Specification 26 / 82 pages 30 CN 121693329 A

[0173] .

[0174] In some embodiments, the RAS(ON) mutant selective inhibitor is the RAS(ON) G12C selective ternary complex inhibitor RMC-6291: (Schulze et al., Science. 18 Aug 2023; 381(6659): 794-799).

[0175] In some embodiments, a combination therapy comprising compound A may comprise one or more RAS(ON) inhibitors, for example, compound A plus one or more RAS(ON) multiselective inhibitors and / or one or more RAS(ON) mutant selective inhibitors.

[0176] In some embodiments, the RAS(ON) inhibitor therapy comprises compound A and RMC-6291. In some embodiments, the method includes administering a daily dose of compound A as disclosed herein and between 200 mg and 400 mg of RMC-6291, wherein RMC-6291 is administered twice daily (BID). In some embodiments, the method includes administering 100 mg of compound A and 200 mg of RMC-6291 daily to a subject in need, wherein RMC-6291 is administered twice daily (BID). In some embodiments, the method includes administering 100 mg of compound A and 300 mg of RMC-6291 daily to a subject in need, wherein RMC-6291 is administered twice daily (BID). In some embodiments, the method includes administering 100 mg of compound A and 400 mg of RMC-6291 daily to a subject in need, wherein RMC-6291 is administered twice daily (BID). In some embodiments, the method includes administering 200 mg of compound A and 200 mg of RMC-6291 daily to an eligible subject, wherein RMC-6291 is administered twice daily (BID). In some embodiments, the method includes administering 200 mg of compound A and 200 mg of RMC-6291 daily to an eligible subject.In some embodiments, the method includes administering 200 mg of compound A and 400 mg of RMC-6291 to a subject in need daily, with RMC-6291 administered twice daily (BID). In some embodiments, the method includes administering 300 mg of compound A and 200 mg of RMC-6291 to a subject in need daily, with RMC-6291 administered twice daily (BID). In some embodiments, the method includes administering 300 mg of compound A and 300 mg of RMC-6291 to a subject in need daily, with RMC-6291 administered twice daily (BID). In some embodiments, the method includes administering 300 mg of compound A and 400 mg of RMC-6291 to a subject in need daily, with RMC-6291 administered twice daily (BID).

[0177] As those skilled in the art will understand, the synthesis of RAS(ON) inhibitors and synthetic methods or variations thereof known in the synthetic organic chemistry techniques described in this specification (page 27 / 82, CN 121693329 A) are known, for example, as described in WO 2021 / 091956, WO 2021 / 091982 or WO 2022 / 060836.

[0178] b) RAS / MAPK Inhibitors

[0179] The compositions and methods described herein may include combinations of compound A with one or more RAS / MAPK pathway inhibitors. The RAS / MAPK pathway is a signal transduction cascade downstream of various cell surface growth factor receptors, in which activation of RAS (and its various isoforms and alloforms) is a central event driving a variety of cellular effector events that determine cell proliferation, activation, differentiation, mobilization and other functional properties. SHP2 transmits a positive signal from the growth factor receptor to the RAS activation / deactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs, such as SOS1), that load GTP onto the RAS to produce a functionally active GTP-binding RAS and a GTP-accelerating protein (GAP, such as NF1), which promotes the termination of the signal by converting GTP to GDP. The GTP-binding RAS generated by this cycle transmits the necessary positive signal to a series of serine / threonine kinases (including RAFs and MAP kinases), from which additional signals are emitted for various cellular effector functions. In some embodiments, therapeutic agents that can be combined with RAS(ON) inhibitors are inhibitors of the MAP kinase (MAPK) pathway (or "MAPK pathway inhibitors"). MAPK pathway inhibitors include, but are not limited to, Cancers (Basel).One or more MAPK pathway inhibitors described in September 2015;7(3): 1758-1784. For example, MAPK inhibitors can be selected from one or more of the following: trametinib, binimetinib, selumetinib, cobimetinib, LERAFAON (NeoPharm), ISIS 5132; vemurafenib, pimaertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. 25 November 2014; 9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 1 March 2011; 17(5):989-1000). MAPK pathway inhibitors may be PLX8394, LXH254, GDC-5573 or LY3009120. MAPK pathway inhibitors may be PI3Kα:RAS disruptors, such as BBO-10203.

[0180] i) RAS(OFF) inhibitors and RAS(OFF) degraders

[0181] The compositions and methods described herein may include a combination of compound A with one or more RAS(OFF) inhibitors. A variety of mutant-sensitive and pan-KRAS inhibitors have been disclosed and are known in the art. RAS(OFF) inhibitors may be administered or formulated in combination with RAS(ON) inhibitors described herein. RAS(OFF) inhibitors are designed to inhibit RAS activity by targeting different regions of the RAS protein in an inactive state (GDP-bound state), thereby preventing its activation and downstream signaling.

[0182] In some embodiments, the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor with a molecular weight of less than 700 Da. The term "KRAS(OFF) inhibitor" refers to any RAS(OFF) inhibitor that binds to KRAS at the GDP-binding "off" position. In some embodiments, the KRAS(OFF) inhibitor is specific for KRASG12C mutations. KRASG12C(OFF) inhibitors use covalent...The binding group allows the inhibitor to selectively target the KRASG12C mutant protein, and many of these inhibitors contain a pyrimidine core. KRASG12C(OFF) inhibitors all target the same cysteine ​​residues in the KRASG12C mutant protein, causing a conformational change that locks the protein into an inactive state. KRASG12C(OFF) inhibitors include, but are not limited to, AMG510 (sottorazib), MRTX849 (adagrasisib), MRTX1257, GDC-6036 (divarasib), JDQ443 (opnurasib), ERAS-3490, LY3537982 (olomorasib), BI 1823911, BPI-421286, JAB-3312, JAB-21000, JAB-21822 (glecirasib), D-1553 (garsorasib), D3S-001, HYP-209PTSA, HBI-2438, HS-10370, MK-1084, YL-15293, and BBO-8520. (ON / OFF inhibitor), FMC-376 (ON / OFF inhibitor), GEC255, BBO-11818 and GFH925 Specification 28 / 82 pages 32 CN 121693329 A (IBI351). In some embodiments, the KRAS(OFF) inhibitor is selected from AMG510 and MRTX849. In some embodiments, the KRAS(OFF) inhibitor is AMG510. In some embodiments, the KRAS(OFF) inhibitor is selected from BPI-421286, JNJ-74699157 (ARS-3248), LY3537982, MRTX1257, ARS853, ARS1620 or GDC-6036.

[0183] In some embodiments, the KRAS(OFF) inhibitor is specific for KRASG12D mutation. Starting with RASG12C (OFF) inhibitors, many KRASG12D (OFF) inhibitors have been developed, thus sharing the G12C inhibitor backbone, which can be combined with other chemical motifs (e.g., piperazine-based compounds). Non-limiting examples of KRASG12D (OFF) inhibitors include MRTX1133, MRTX282, JAB-22000, ERAS-4, ERAS-5024, HRS-4642, BI-2852, BI-2852, ASP3082, TH-Z827, TH-Z835, TSN1611, QTX-3046, and GFH375.(VS-7375), INCB161734, and KD-8.

[0184] In some embodiments, the small molecule RAS(OFF) inhibitor is specific for KRASG12V mutations. In some embodiments, the small molecule RAS(OFF) inhibitor is specific for KRASG13D mutations. In some embodiments, the small molecule RAS(OFF) inhibitor is a pan-KRAS(OFF) inhibitor.

[0185] In some embodiments, references to the term RAS(OFF) inhibitor include any such RAS(OFF) inhibitor disclosed in any of the following patent applications: WO 2024138486, WO 2024138206, WO 2024138052, WO 2024131829, WO 2024125642, WO 2024125600, WO 2024123913, WO 2024123102, WO 2024120433, WO 2024120419, WO 2024123913, WO 2024085661, WO 2024083258, WO 2024083256, WO 2024083246, WO 2024083168, WO 2024078555, WO 2024076674, WO 2024076672, WO 2024076670, WO 2024067714, WO 2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO 2024061370, WO 2024061333, WO 2024061267, WO 2024056063, WO 2024055112, WO 2024054926, WO 2024054647, WO 2024054625, WO 2024051763, WO 2024051721, WO 2024050742, WO 2024050640, WO 2024046406, WO 2024046370, WO 2024045066, WO 2024044667, WO 2024044649, WO 2024044334, WO 2024041621, WO 2024041606, WO 2024041589, WO 2024041573, WO 2024040131, WO 2024040109, WO 2024040080, WO 2024036270, WO 2024034657, WO 2024034593、WO 2024034591、WO 2024034123、WO2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024029613, WO 2024022507, WO 2024022444, WO 2024020159, WO 2024019103, WO 2024017859, WO 2024017392, WO 2024015731, WO 2024015262, WO 2024012456, WO 2024009191, WO 2024008179, WO 2024008178, WO 2024008068, WO 2024006445, WO 2024006424, WO 2024002373, WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023246914, WO 2023246903, WO 2023246777, WO 2023244713, WO 2023244615, WO 2023244604, WO 2023244600, WO 2023244599, WO 2023230190, WO 2023226630, WO 2023225302, WO 2023225252, WO 2023220421, WO 2023219941, WO 2023217148, WO 2023215802, WO 2023215801, WO 2023213269, WO 2023212548, WO 2023208005, WO 2023205719, WO 2023199180, WO 2023198191, WO 2023197984, WO 2023190748, WO 2023185864, WO 2023183755, WO 2023183585, WO 2023179703, WO 2023179629, WO 2023173017, WO 2023173016, WO 2023173014, WO 2023172737, WO2023171781, WO 2023159087, WO 2023159086, WO 2023154766, WO 2023152255, WO 2023151674, WO 2023151621, WO Description Page 29 / 82 Page 33 CN 121693329 A 2023150394, WO 2023150284, WO 2023143623, WO 2023143605, WO 2023143352, WO 2023143352, WO 2023143312, WO 2023141570, WO 2023141300, WO 2023138662, WO 2023138601, WO 2023138589, WO 2023138524, WO 2023133183, WO 2023133181, WO 2023130012, WO 2023125989, WO 2023125627, WO 2023122662, WO 2023122154, WO 2023120742, WO 2023119677, WO 2023117681, WO 2023116934, WO 2023116895, WO 2023114733, WO 2023105491, WO 2023104018, WO 2023103906, WO 2023103523, WO 2023101928, WO 2023099624, WO 2023099624, WO 2023099620, WO 2023099612, WO 2023099608, WO 2023099592, WO 2023098832, WO 2023098425, WO 2023097227, WO 2023081840, WO 2023081476, WO 2023078424, WO 2023077441, WO 2023072297, WO 2023072188, WO 2023066371, WO 2023064857, WO 2023061463, WO 2023061294, WO 2023057985, WO 2023056951, WO 2023056421, WO 2023051586, WO 2023049697, WO 2023046135, WO 2023045960, WO 2023041059, WO 2023041059, WO 2023040989, WO 2023040513, WO 2023039240, WO2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO 2023030385, WO 2023030495, WO 2023030517, WO 2023030685, WO 2023030687, WO2023034290, WO 2023036282, WO 2023039240, WO 203020347, WO 2023025116, WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023040989, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO 2023030385, WO 2023025116, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023020347, WO 2023018812, WO 2023018810, WO 2023018809, WO 2023018699, WO 2023014979, WO 2023014006, WO 2023004102, WO 2023003417, WO 2023001141, WO 2023001123, WO 2022271658, WO 2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO 2022265974, WO 2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO 2022237815, WO 2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO 2022223037, WO 2022221739, WO 2022221528, WO 2022221386, WO2022216762 (e.g., Compound 44 or Compound 66a), WO 2022212894, WO 2022192794, WO 2022192790, WO 2022188729, WO 2022187411, WO 2022184178, WO 2022173870, WO 2022173678, WO 2022135346, WO 2022133731, WO 2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO 2022109487, WO 2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO 2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, WO 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO Description Page 30 / 82 34 CN 121693329 A 2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2021113595, WO 2021107160, WO 2021106231, WO 2021088458, WO 2021086833, WO 2021085653, WO 2021081212, WO 2021058018, WO 2021057832, WO 2021055728, WO 2021031952, WO 2021027911, WO 2021023247, WO 2020259513, WO 2020259432, WO 2020234103, WO 2020233592, WO 2020216190, WO 2020178282, WO 2020146613, WO 2020118066, WO 2020113071, WO 2020106647, WO 2020102730, WO 2020101736, WO 2020097537, WO 2020086739, WO 2020081282, WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018218071, WO 2018218069, WO 2018217651, WO 2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO2017058902, WO 2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223, CN 118221700, CN 118221699, CN 118221698, CN 118221685, CN 118126064, CN 118078802, CN 118078801, CN 118005656, CN 117986263, CN 117986263, CN 117946135, CN 117924327, CN 117903117, CN 117800990, CN 117800989, CN 117800976, CN 117736226, CN 117683051, CN 117645627, CN 117624194, CN 117624190, CN 117586280, CN 117486901, CN 117466917, CN 117462688, CN 117362315, CN 117327102、CN 117327094、CN 117327074、CN 117285590、CN 117263959、CN 117247382、CN 117186095、CN 117164605、CN 116969977、CN 116925075、CN 116891489、CN 116731045、CN 116731044、CN 116554208、CN 116514846、CN 116478184、CN 116478141、CN 116410145、CN 116375742、CN 116354988、CN 116332948、CN 116332938、CN 116327956、CN 116262759、CN 116217592、CN 116199703、CN 116162099、CN 116143806、CN 116143805、CN 116120315、CN 116102559、CN 115960105、CN 115894520、CN 115872979、CN 115850267、CN 115785199、CN 115785124、CN115724842, CN 115724842, CN 115721720, CN 115716840, CN 115703775, CN 115611923, CN 115611898, CN 115583937, CN 115572278, CN 115557949, CN 115521312, CN 115504976, CN 115490709, CN 115466272, CN 115433183, CN 115433179, CN 115403575, CN 115385938, CN 115385937, CN 115385912, CN 115381786, CN 115368383, CN 115368382, CN 115368381, CN 115353506, CN 115322158, CN 115304623, CN 115304602, CN 115197245, CN 115181106, CN 114989195, CN 114989166, CN 114989147, CN 114920741, CN 114920739, CN 114907387, CN 114874234, CN 114874201, CN 114716436, CN 114716435, CN 114685532, CN 114685460, CN 114591319, CN 114539293, CN 114539286, CN 114539246, CN 114437107, CN 114437084, CN 114409653, CN 114380827, CN 114195804, CN 114195788, CN 114437107, CN 114409653, CN 114380827, CN 114195804, CN 114057776, CN 114057744, CN 114057743, CN 113999226, CN 113980032, CN 113980014, CN 113960193, CN Description Page 31 / 82 Page 35 CN 121693329 A 113929676, CN 113754653, CN 113683616, CN 113563323, CN 113527299, CN 113527294, CN 113527293, CN 113493440, CN 113429405, CN 113321654, CN 113248521, CNCN 113087700, CN 113024544, CN 113004269, CN 112920183, CN 112778284, CN 112390818, CN 112390788, CN 112300196, CN 112300194, CN 112300173, CN 112225734, CN 112142735, CN 112110918, CN 112094269, CN 112047937, CN 109574871 or EP 4389751, each of which is incorporated herein by reference in its entirety, including the structures of RAS compounds disclosed therein, which are expressly incorporated herein by reference.

[0186] In some embodiments, references to the term RAS(OFF) inhibitor refer to pan-KRAS inhibitors, such as pan-KRAS inhibitors disclosed from any of the following: WO 2024119277, WO 2024 120433, WO 2024115890, WO 2024112654, WO 2024104453, WO 2024104425, WO 2024107686, WO 2024104453, WO 2024103010, WO 2024085661, WO 2024083246, WO 2024083168, WO 2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO 2024051852, WO 2024051763, WO 2024046370, WO 2024044667, WO 2024041621, WO 2024041606, WO 2024041589, WO 2024040131, WO 2024040109, WO 2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024015262, WO 2024009191, WO 2024008068, WO 2024002373, WO 2023287896, WO 2023274324, WO 2023246914, WO 2023246777, WO 2023230190, WO 2023215802, WO 2023215801、WO 2023197984、WO 2023190748、WO 2023183585、WO 2023179703、WO2023173017、WO 2023173016、WO 2023173014、WO 2023172737、WO 2023154766、WO 2023143352、WO 2023143312、WO 2023138589、WO 2023133183、WO 2023122662、WO 2023114733、WO 2023099624、WO 2023099623、WO 2023099612、WO 2023099608、WO 2023099592、WO 2023097227、WO 2023064857、WO 2023056421, WO 2023049697, WO 2023046135, WO 2023039240, WO 2023034290, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023001123、WO 2022271823、WO 2022261210、WO 2022258974、WO 2022256459、WO 2022250170、WO 2022248885、WO 2022228543、WO 2022216762、WO WO 2022072783, WO 2016161361, KR 20240041720, KR 20240041719, CN 118221700, CN 118126064, CN 117924327, CN 117946135, CN 117800990, CN 117800989, CN 117683051, CN 117486901, CN 117263959, CN 116969977 or CN 116332948, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. In some embodiments, the combination therapy comprising compound A may include one or more additional RAS inhibitors, such as pan-KRAS inhibitors. In some embodiments, the combination therapy comprising a pan-KRAS inhibitor includes ERAS-4001. In some embodiments, the pan-KRAS inhibitor is the pan-KRAS inhibitor as described in a patent application filed under the name of Medshine Discovery. In some embodiments, the combination therapy comprising a pan-KRAS inhibitor includes BGB-53038, BBO-11818, YL-17231, QTX3034, ABT-200, ADT-1004,AN9025, OC211, JAB-23425, BI-2865, BI-2493, ABREV01, A2A-03, or PF-07934040.

[0187] In any embodiment employing a RAS(OFF) inhibitor herein, a RAS(OFF) degrading agent targeting the RAS-off state may be used. These degrading agents are known in the art. RAS degrading agents can be found, for example, in one or more of the following applications: WO 2024131777, WO 2024120424, WO 2024119278, WO 2024118966, WO 2024118960, WO 2024083258, WO 2024083256, WO 2024055112、WO 2024054625、WO 2024050742、WO 2024044334、WO 2024040080、WO 2024034657、WO 2024034593、WO 2024034591、WO 2024034123、WO 2024029613、WO WO 2024020159, WO 2024019103, WO 2024017392, WO Specification 32 / 82 pages 36 CN 121693329 A 2023185864, WO 2023171781, WO 2023141570, WO 2023138524, WO 2023130012, WO 2023116934, WO 2023099620, WO 2023081476, WO 2023077441, CN 118126040 and CN 115785199, each of which is incorporated herein by reference in its entirety.

[0188] In some embodiments, the RAS(OFF) inhibitor is a peptide-based inhibitor. Peptide-based RAS (OFF) inhibitors have been developed that target specific regions of the RAS protein, such as the transition II region or the RAS-effector interface. Non-limiting examples include the K-Ras-binding peptide (Krpep-2d), the Ras-inhibiting peptide (RasIn), and LUNA18 (NCT05012618). Peptide-based RAS (OFF) inhibitors are a class of compounds that target RAS proteins by disrupting their interactions with downstream effectors or other signaling proteins. These inhibitors are typically engineered to mimic the binding motifs of RAS-interacting proteins or other RAS effectors (e.g., RAF or PI3K). By binding to RAS at the same site as these effectors, peptide-based inhibitors can effectively compete with these proteins and prevent activation of downstream signaling pathways. See, for example, WO 2024101402, WOWO 2024101386, WO 2023214576, WO 2023140329, WO 2022234853, WO 2022234852, WO 2022234851 and WO 2022234639, each of which is incorporated herein by reference in its entirety.

[0189] Peptide-based RAS(OFF) inhibitors can be further divided into two main categories: inhibitors targeting the RAS-effector interface, and inhibitors targeting other regions of the RAS protein. Peptide-based inhibitors targeting the RAS-effector interface are designed to bind to the transition region of RAS, which is essential for the interaction of RAS with downstream effectors (e.g., RAF or PI3K). These inhibitors typically contain amino acid residues similar to those found in the binding motifs of RAS-interacting proteins or effectors, and are typically designed to form hydrogen bonds or other interactions with key residues on the RAS surface.

[0190] Peptide-based RAS(OFF) inhibitors targeting other regions of the RAS protein are typically designed to disrupt other interactions essential for RAS activation or signaling. For example, some peptide-based inhibitors are designed to bind to the hypervariable region of the RAS, which is thought to play a role in protein membrane localization and anchoring. By binding to this region, the peptide-based inhibitor prevents the proper localization of RAS to the plasma membrane, which is necessary for RAS activation and signaling.

[0191] Several common motifs have been identified as important for binding to RAS-interacting proteins and effectors and are commonly used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), which is present in many RAS-interacting proteins and is important for the interaction of RAS with downstream effectors such as RAF. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) that is essential for binding to RAS, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt the RAS-RAF interaction. Another example is the RAS-binding domain (RBD) of PI3K, which is important for the interaction between RAS and this downstream effector. The PI3K RBD contains several conserved amino acid residues (e.g., Arg-Arg-Trp) that are crucial for binding to RAS, and these motifs have been used to design peptide-based inhibitors targeting the RAS-PI3K interaction. Other common motifs used in peptide-based RAS(OFF) inhibitors include the Ras-binding domains (RBDs) of other RAS-interacting proteins (e.g., RalGDS and SOS), as well as sequences that mimic the structure of the RAS transition region itself. These motifs are often used to optimize the binding affinity and selectivity of the inhibitor to the desired target protein or interaction.

[0192] In some embodiments, RAS(OFF) inhibitors are antibodies or antigen-binding peptides specific to RAS(OFF). Antibodies have been developed that bind to specific regions of RAS proteins, such as the transition II region or the RAS-effector interface. For example, antibodies targeting the transition region of RAS proteins have been developed, regions essential for the activation of these proteins and their interaction with downstream effectors. Binding of these antibodies to the transition region prevents the conformational changes required for RAS activation and downstream signaling. Another approach involves using antibodies targeting RAS-interacting proteins or downstream effectors (e.g., RAF or PI3K). Binding of these antibodies to their target proteins disrupts RAS-dependent signaling pathways and inhibits cancer cell growth and survival. Additionally, antibodies that induce RAS protein internalization and degradation, leading to its depletion and inhibition of downstream signaling have been developed. For example, antibodies that recognize the unique structure of mutant RAS proteins and target said proteins for degradation via the ubiquitin-proteasome pathway have been developed, as described on page 33 / 82 of the specification, CN 121693329 A. Non-limiting examples of KRAS(OFF)-specific inhibitory antibodies include anti-p21ser and K27 (DARPin) (see, for example, Khan et al., Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118570). See also WO 2024136608 and WO 2024111590, each of which is incorporated herein by reference in its entirety.

[0193] ii) SOS1 inhibitors

[0194] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more SOS1 inhibitors. The SOS1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some implementations, the SOS1 inhibitor is one or more of the following: RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-3406, SDR5, MRTX-0902, ZG2001, and BAY-293. In some embodiments, references to the term SOS1 inhibitor include any such SOS1 inhibitor disclosed in any of the following patent applications: WO 2023109929, WO 2023059597, WO 2023029833, WO 2023041049, WO 2023022497, WO 2022157629, WO 2022184116, WO 2022170952, WO 2022170917, WO 2022171184, WO 2022170802, WOWO 2022161461, WO 2022121813, WO 2022028506, WO 2022139304, WO 2021228028, WO 2019122129, CN 115215847, CN 115028644, CN 114685488, CN 111393519, CN115677702 and CN115806560, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0195] iii) SHP Inhibitors

[0196] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more SHP inhibitors. The SHP inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the SHP inhibitor is an inhibitor of SHP1. In some embodiments, the SHP inhibitor is an inhibitor of SHP2. In some embodiments, the SHP1 inhibitor is SB6299, also known as DA-4511. In some embodiments, the SHP2 inhibitor is one or more of the following: SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, or BBP-398. In some embodiments, references to the term "SHP2 inhibitor" include any such SHP2 inhibitor disclosed in any of the following patent applications: WO 2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO 2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO 2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO 20222084008, WO 2022135568、WO 2022063190、WO 2022043865、WO 2022042331、WO 2022033430、WO 2022017444、WO 2022007869、WO 2021259077、WO 2021249449、WO 2021249057、WO 2021244659、WO 2021218755、WO 2021176072、WO2021171261, WO 2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO 2021143680, WO 2021281752, WO 2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO 2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO 2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO 2020156242, WO 2020108590, WO 2020104635, WO 2020094104, WO 2020094018, WO 2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO 2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO Description Page 34 / 82 38 CN 121693329 A 2020033828, WO 2020033286, WO 2020022323, WO 2019233810, WO 2019213318, WO 2019183367, WO 2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO 2019158019, WO 2019152454, WO 2019051469, WO 2019051084, WO 2018218133, WO 2018172984, WO 2018160731, WO 2018136265, WO 2018136264, WO 2018130928, WO 2018129402, WO 2018081091, WO 2018057884, WO2018013597、WO 2017216706、WO 2017211303、WO 2017210134、WO 2017156397、WO 2017100279、WO 2017079723、WO 2017078499、WO 2016203406、WO 2016203405, WO 2016203404, WO 2016196591, WO 2016191328, WO 2015107495, WO 2015107494, WO 2015107493, WO 2014176488, WO 2014113584, CN 115677661、CN 115677660、CN 115611869、CN 115521305、CN 115490697、CN 115466273、CN 115394612、CN 115304613、CN 115304612、CN 115300513、CN 115197225、CN 114957162、CN 114920759、CN 114716448、CN 114671879、CN 114539223、CN 114524772、CN 114213417、CN 114195799、CN 114163457、CN 113896710、CN 113248521、CN 113248449、CN 113135924、CN 113024508、CN 112920131、CN 112823796、CN 112409334、CN 112402385、CN 112174935, 111848599, CN 111704611, CN 111393459, CN 111265529, CN 110143949, CN 108113848, US 11179397, US 11044675, US 11034705, US 11033547、US 11001561、US 10988466、US US 10954243, US 10934302, or US 10858359, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0197] iv) MEK Inhibitors

[0198] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more MEK inhibitors. The MEK inhibitor may be administered in combination with compound A and / or any additional therapeutic agents described herein.Formulation. In some embodiments, the MEK inhibitor is one or more of pimasiteti, IMM-1-104, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and bimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation selected from the following type I MEK1 mutations: D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is selected from the following type II MEK1 mutations: ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N. In some embodiments, references to the term MEK inhibitor include any such MEK inhibitor disclosed in any of the following patent applications: WO 2022221866, WO 2022125941, WO 2022208391, WO 2022015736, WO 2022177557, WO 2021018866, WO 2021069486, WO 2021142144, WO 2021168283, WO 2021234097, WO 2019076947, WO 2018233696, WO 2016188472, WO 2014063024, WO 2013019906, WO 2011047238, WO US Patent 2007044515, US Patent 2023032403, and CN Patent 115813930 are all incorporated herein by reference in their entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0199] v) RAF Inhibitors

[0200] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more RAF inhibitors. The RAF inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the RAF inhibitor is VS-6766 or BTDX-4933. In some embodiments, the RAF inhibitor is a BRAF inhibitor. BRAF inhibitors that may be used in combination with compound A include, for example, VS6766, IK-595, vemurafenib, dabrafenib, and encorafenib. The BRAF may contain a type 3 BRAF mutation. In some implementations, the type 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R;V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; Instruction manual 35 / 82 pages 39 CN 121693329 A F595L; G596D; G596R and A762E. In some embodiments, references to the term RAF inhibitor include any such RAF inhibitor disclosed in any of the following patent applications: WO 2023076991, WO 2022226626, WO 2022226261, WO 2019084459, WO 2018203219, WO 201851306, WO 2017212442, WO 2015075483, WO 2013134243, WO 2013134298, WO 2011047238, WO 2011025965, WO 2011025947, WO 2011025951, WO 2011025940, WO 2011025938, WO 2010065893, WO WO 2009016460, WO 2009130015, WO 2009111278, WO 2009111279, WO 2008028141 and WO 2006024834, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0201] vi) ERK Inhibitors

[0202] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more ERK inhibitors. ERK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the ERK inhibitor is an ERK1 / 2 inhibitor, such as ERAS-007. In some embodiments, the ERK inhibitor is an ERK5 inhibitor. In some embodiments, the ERK inhibitor is one or more of ASTX-029 or I-75. In some embodiments, references to the term ERK inhibitor include any such ERK inhibitor disclosed in any of the following patent applications: WO 2023076305, WO 2022259222, WO 2022221547, WO 2021110169, WO 2021110168, WO 2021252316, WO 2020102686, WO 2020228817, WO 2020107987, WO 2019233456, WO 2019233457, WO 2016025561, WO 2016192063, WOWO 2016106029, WO 2016106009, WO 2015051341, WO 2014124230, WO 2014052563, WO 2011041152, WO 200910550, WO 2008153858, CN114315837, CN 115057860, CN 107973783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0203] vii) MAPK Inhibitors

[0204] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more mitogen-activated protein kinase (MAPK) inhibitors. MAPK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the MAPK inhibitor is a p38MAPK inhibitor or a MAP3K8 inhibitor. In some embodiments, the MAPK inhibitor is one or more of Tilpisertib (GS-4875) and neflamapimod (VX-745). In some embodiments, reference to the term MAPK inhibitor includes any such MAPK inhibitor disclosed in any of the following patent applications: WO 2016029263, CN 114767674, CN 115850179 and CN 1743006, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0205] In some embodiments, the therapeutic agent that can be combined with compound A is an inhibitor of MAP2K4. A non-limiting example of a MAP2K4 inhibitor available according to this disclosure is HRX-0233.

[0206] c) Kinase Inhibitors

[0207] The compositions and methods described herein may include a combination of compound A with one or more kinase inhibitors. Tyrosine kinases and serine / threonine kinases play key roles in various cellular processes, such as cell signaling, growth, and differentiation. In addition to therapies for disorders such as neurodegenerative diseases, autoimmune diseases, and inflammation, kinase inhibitors known in the art have been developed for the treatment of various types of cancer.

[0208] i) PKA Inhibitors

[0209] In some embodiments, the compositions and methods described herein may include one or more protein kinase A (PKA) inhibitors. PKA inhibitors may be administered or combined with compound A and / or any additional therapeutic agents described herein. (Instructions for Use 36 / 82 pages 40 CN 121693329 A)In some embodiments, the PKA inhibitor is H89. In some embodiments, reference to the term PKA inhibitor includes any such PKA inhibitor disclosed in any of the following patent applications: CN 106620678 and CN 114632155, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0210] ii) FAK inhibitor

[0211] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more focal adhesion kinase (FAK) inhibitors. The FAK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the FAK inhibitor is one or more of the following: BI853520, defactinib, GSK2256098, PF-00562271, and VS-4718. In some embodiments, references to the term FAK inhibitor include any such FAK inhibitor disclosed in any of the following patent applications: WO 2022152315, WO 2021098679, WO 2020135442, WO 2020191448, WO 2012022408, WO 2013134353, WO 2012110774, WO 2010062578, CN 111072571, and KR 101691536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0212] iii) ROCK inhibitors

[0213] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more Rho-associated coiled-coil protein kinase (ROCK) inhibitors. The ROCK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the ROCK inhibitor is GSK269962A. In some embodiments, references to the term "ROCK inhibitor" include any such ROCK inhibitor disclosed in any of the following patent applications: WO 2023051753, WO 2022237892, WO 2022012409, WO 2021093795, WO 2021214200, WO 2020177292, WO 202011751, WO 2019014304, WO 2019179525, WO 2019089868, WO 2019014300, WO 2018108156, WO 2018009627, WO 2018009625, WO2018009622, WO 2017123860, WO 2017205709, WO 2016112236, WO 2014068035, WO 2013030367, WO 2012146724, WO 2012067965, WO 2011107608, CN 108129453, CN 108191821, CN 110917352, CN 108558823, CN108047193, CN107973777, CN108047197, CN108129448, CN GB 115869304 and GB 202214708, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0214] iv) MSK1 Inhibitors

[0215] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more mitogen and stress-activated kinase (MSK1) inhibitors. The MSK1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the MSK1 inhibitor is one or more of the following: SB-747651A, SB 747651A, Ro 320432, CGP 57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, and AS601245.

[0216] v) RSK Inhibitor

[0217] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more ribosomal S6 kinase (RSK) inhibitors. The RSK1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the RSK inhibitor is one or more of the following: BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX 02565, LJI308, LJI308-S, LJI308-1, and LJH685-S. In some embodiments, the RSK inhibitor is PMD-026. In some embodiments, references to the term RSK inhibitor include any such RSK inhibitor disclosed in any of the following patent applications: WO 2021249558, WO 2020165646, CN 121693329 A, WO 2017141116, and CN 113801139, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0218] vi)ALK Inhibitors

[0219] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more anaplastic lymphoma kinase (ALK) inhibitors. The ALK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the ALK inhibitor is one or more of the following: crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), brigatinib (Alunbrig), lorlatinib (Lorbrena), ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (a ceritinib analog), CEP-37440; 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894. In some embodiments, references to the term ALK inhibitor include any such ALK inhibitor disclosed in any of the following patent applications: WO 2019142095, WO 2019179482, WO 2018130928, WO 2018127184, WO 2017101803, WO 2016192132, WO 2014100431, WO 2012082972, CN 111138492, CN 110526914, CN 109836415, CN 105801603, CN107987056 and CN 105878248, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0220] d) Receptor Tyrosine Kinase Inhibitors

[0221] The compositions and methods described herein may include a combination of compound A with one or more receptor tyrosine kinase inhibitors. Receptor tyrosine kinase (RTK) inhibitors are a class of molecules (e.g., small molecules, antibodies, and nucleic acids) that bind to receptor tyrosine kinases or their ligands and block the activity of the receptor tyrosine kinases or their ligands. RTKs are proteins found on the cell surface that play a vital role in cell signaling and growth and have been developed as therapeutics for a range of diseases, including cancer, diabetes, and autoimmune diseases. In some embodiments, the therapeutic may be a pan-RTK inhibitor, such as afatinib.

[0222] i) EGFR Inhibitors

[0223] In some embodiments, the compositions and methods described herein may include compound A with one or more EGFR inhibitors.Combinations of EGFR inhibitors. EGFR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include those described in the following: Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1: 1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. EGFR inhibitors may be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.) or Mab C225 (ATCC accession number HB-8508) or antibodies or antibody fragments that have binding specificity to them.

[0224] Small molecule antagonists of EGFR include gefitinib (Iressa®), lazertinib, erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Prescription Material 38 / 82 pages 42 CN 121693329 A Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy,Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). In some embodiments, the EGFR inhibitor is one or more of cetuximab, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif). Additional non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. The EGFR inhibitor may be ERAS-801. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4). In some implementation schemes, the EGFR inhibitor may be bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, vemurafenib, abrocitinib, asciminib, futibatinib, ibrutinib, imatinib, pacritinib, or sorafenib. In some embodiments, references to the term EGFR inhibitor include any such EGFR inhibitor disclosed in any of the following patent applications: WO 2023041071, WO 2023049312, WO 2023020600, WO 2023284747, WO 2022206797, WO 2022258977, WO 2022033416, WO 2022033410, WO 2022105908, WO 2022100641, WO 2022014639, WO 2022007841, WO 2021018009, WO 2021057882, WO 2021252661, WO 2021018003, WO 2021073498、WO 2021238827、WO 2020254547、WO 2020216371、WO 2020147838、WO 2020207483、WO 2020254572、WO2020001350、WO 2021001351、WO 2019164948、WO 2019218958、WO 2019046775、WO 2019015655、WO 2018121758、WO 2018218963、WO 2017220007、WO 2017205459、WO 2017161937、WO 2016192609、WO 199633980、WO 199630347、WO 199730034、WO 199730044、WO 199738994、WO 199749688、WO 199802434、WO 199738983、WO 199519774、WO 199519970、WO 199713771、WO 199802437、WO 199802438、WO 199732881、WO 199833798、WO 199732880、WO 199732880、WO 199702266、WO 199727199、WO 199807726、WO 1997 / 34895、WO 199631510、WO 199814449、WO 199814450、WO 199814451、WO 199509847、WO 199719065、WO WO 199817662, WO 199935146, WO 199935132, WO 199907701, WO 199220642, DE 19629652, EP 682027, EP 837063, EP 0787772, EP 0520722, EP 0566226, CN 115960018, CN 110283162, CN 114044774, CN111973601, CN 111973602 and CN113896744, each of which is incorporated herein by reference in its entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0225] ii) HER2 Inhibitors

[0226] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more HER2 inhibitors. The HER2 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the HER2 inhibitor is one or more of the following: tucatinib, rastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib(Tykerb), ado-trastuzumab emtansine (Kadcyla), and neratinib (Nerlynx). Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327. In some embodiments, references to the term HER2 inhibitor include any such HER2 inhibitor disclosed in any of the following patent applications: WO 2021156178, WO 2021156180, WO 2021213800, WO 2021088987, WO 2013561183 and WO 2013056108, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0227] iii) MET inhibitors

[0228] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more MET inhibitors. The MET inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the MET inhibitor is one or more of the following: crizotinib (Xalkori), cabozantinib (Cometriq, Cabometyx), capmatinib (Tabrecta), terpotetinib (Tepmetko), savolitinib (Volitinib), onartuzumab (MetMab), foretinib (GSK1363089), MGCD-265 (amuvatinib), SU11274, and SU5416. In some embodiments, references to the term MET inhibitor include the following:Any of the following MET inhibitors disclosed in any of the patent applications: WO 2022226168, WO 2021222045, WO 2020047184, WO 2020015744, WO 2020244654, WO 2020156453, WO 2019206268, WO 2018077227, WO 2017012539, WO 2016015653, WO 2016012963, WO 2012015677, WO 2011162835, WO 2010089507, WO 2009091374, WO 2009056692, WO 2008051547, WO US 2007130468, US 2012237524, CN 103497177, CN 107311983, CN 107382968, CN 110218191 and TW201331206, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0229] iv) AXL Inhibitors

[0230] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more AXL inhibitors. The AXL inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. AXL is a receptor tyrosine kinase belonging to the TAM receptor family, which also includes TYRO3 and MERTK. In some implementations, the AXL inhibitor is one or more of the following: bemcentinib, BGB324, R428, SGI-7079, TP-0903, BMS-777607, UNC2025, and TP-0903. In some embodiments, references to the term AXL inhibitor include any such AXL inhibitor disclosed in any of the following patent applications: WO 2023045816, WO 2022237843, WO 2022246179, WO 2021012717, WO 2021088787, WO 2021067772, WO 2021239133, WO 2021204713, WO 2020238802, WO 2019039525, WO 2019101178, WO 2019074116, WO 2017146236, WO 2016097918, WO 2015012298, WO 2010005876, WO 2010083465, CN 115073367 and JP 2022171109, each of which is incorporated herein by reference in its entirety, includingThe structures of the compounds disclosed herein are explicitly incorporated herein by reference.

[0231] v) IGFR Inhibitors

[0232] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more insulin-like growth factor receptor 1 (IGF-1R) inhibitors. IGFR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. IGFR inhibitors have been developed that target the IGFR receptor, which plays a key role in cancer progression and metastasis. In some embodiments, the IGFR inhibitor is one or more of the following: linsitinib, AXL1717, OSI-906 (linsitinib), BMS-754807, BI 836845, AZ12253801, PQIP (pyrrolo[1,2-a]quinoxaline), and NVP-AEW541. In some embodiments, the term IGFR inhibitor is referred to in the specification (pages 40 / 82, 44) CN 121693329 A and any such IGFR inhibitor disclosed in any of the following patent applications: WO 2022115946, WO 2022217923, WO 2021203861, WO 2021246413, WO 2020116398, WO 2019046600, WO 2018195250, WO 2018221521, WO 2018204872, WO 2017072196, WO 2016173682, WO 2015162291, WO 2015162292, WO 2010066868, WO 2006069202 and CN 121693329 A. 112125916, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0233] vi) RET Inhibitors

[0234] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more transfection rearrangement (RET) inhibitors. RET inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. RETs play a vital role in a variety of cellular processes, including cell growth, differentiation, survival, and migration. RETs are activated by binding to their ligands, such as glial cell line-derived neurotrophic factor (GDNF) family ligands, which leads to the activation of downstream signaling pathways that promote these cellular processes. In some embodiments, the RET inhibitor is one or more of the following: pralsetinib, selpercatinib (LOXO-292),BLU-667, RXDX-105, TPX-0046, GSK3179106, molidustat (BAY 85-3934), and RPI-1 (Retrophin). In some embodiments, references to the term RET inhibitor include any such RET inhibitor disclosed in any of the following patent applications: WO 2021211380, WO 2021057963, WO 2021043209, WO 2021222017, WO 2020035065, WO 2020114487, WO 2020200314, WO 2020200316, WO 2020114494, WO 2018071447, WO 2018213329, WO 2017079140, WO 2014050781, CN 113943285, CN 113683610, CN 113683611, CN 113620944, CN CN 113620945, CN 113527291, CN 113527292, CN 113527290, CN 113135896, CN 111057075, CN111233899 and CN111362923, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0235] vii) ROS1 Inhibitors

[0236] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more c-ros oncogene 1 (ROS1) inhibitors. ROS1 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. ROS1 is a receptor tyrosine kinase belonging to the insulin receptor family and plays a role in various cellular processes, including cell growth, differentiation, survival and migration. In some embodiments, the ROS1 inhibitor is one or more of the following: taletrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, reference to the term ROS1 inhibitor includes any such ROS1 inhibitor disclosed in any of the following patent applications: WO 2021098703, WO 2020024825, and US 2017079972, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0237] viii) PDGFR inhibitors

[0238] In some embodiments, the compositions and methods described herein may include compound A with one or more bloodCombinations of platelet-derived growth factor receptor (PDGFR) inhibitors. PDGFR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PDGFR is a family of receptor tyrosine kinases consisting of two members, PDGFRα and PDGFRβ. They are activated by binding to their ligands (e.g., platelet-derived growth factor (PDGF)), thereby causing activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, the PDGFR inhibitor is one or more of the following: CP-673451, imatinib, nintedanib (ofev), sunitinib, pazopanib (votrient), regorafenib (stivarga), and dasatinib (sprycel).

[0239] ix) FGF Inhibitor

[0240] In some embodiments, the compositions and methods described herein may include a combination of compound A and a fibroblast growth factor (FGF) inhibitor. The FGF inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. FGFR is a family of receptor tyrosine kinases consisting of four members, namely FGFR1–FGFR4. FGFR is activated by binding to its ligand (fibroblast growth factor (FGF)), thereby causing activation of downstream signaling pathways that promote cell growth, differentiation, and survival. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR2. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR4. In some implementations, the FGFR inhibitor is one or more of the following: fabatinib (TAK-659), erdafitinib (balversa), infigratinib (Truseltiq), Debio 1347, and rogaratinib (BAY 1163877). In some embodiments, references to the term "FGFR inhibitor" include any such FGFR inhibitor disclosed in any of the following patent applications: WO 2022033472, WO 2022152274, WO 2022166469, WO 2022206939, WO 2021037219, WO 2021089005, WO 2021113462, WO 2020185532, WO 2019213544, WO 2020164603, WO 2019154364, WO 2019034076, WO 2019213506, WO2019223766、WO 2018028438、WO 2018153373、WO 2018121650、WO 2018010514、WO 2017028816、WO 2017118438、WO 2016134320、WO 2015008844、WO 2014172644, WO 2014007951, WO 2013179033, WO 2013087578, WO 2012047699, CN 105906630, CN 115869315, CN 115141176, CN 115043832 and CN 115028634, each of which is incorporated herein by reference in its entirety. In some embodiments, the FGF pathway inhibitor targets FGF ligands. Such FGF pathway inhibitors include FGF ligand traps and antibodies. Non-limiting examples include FP-1039, an FGF ligand trap consisting of the extracellular domain of FGFR1 fused to the Fc portion of human IgG1, designed to isolate FGF ligands and inhibit FGF signaling; and MFGR1877S, a monoclonal antibody targeting FGF ligands, designed to block FGF-mediated signaling, including the compound structures disclosed herein, which are explicitly incorporated herein by reference.

[0241] x) VEGF Inhibitors

[0242] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more vascular endothelial growth factor (VEGF) signaling inhibitors. VEGF (vascular endothelial growth factor) signaling inhibitors are a class of drugs that target VEGF and its receptor-mediated signaling pathways. VEGF plays a crucial role in angiogenesis (the process of forming new blood vessels from existing ones) and is overexpressed in many cancer types, making it an attractive target for cancer therapy. VEGF inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the VEGF inhibitor is an antibody or antigen-binding region that specifically binds to VEGF (e.g., bevacizumab), or a soluble VEGF receptor or its ligand-binding region, such as VEGF-TRAP™, and an anti-VEGF receptor agent (e.g., an antibody or antigen-binding region that specifically binds thereto). In some embodiments, the VEGF inhibitor is one or more of the following: bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib.

[0243] e) PI3K / mTOR pathway inhibitors

[0244] The compositions and methods described herein may include combinations of compound A with one or more inhibitors of the PI3K-AKT-TOR signaling pathway. The PI3K-AKT-mTOR signaling pathway is a key intracellular pathway regulating a wide range of cellular processes, including cell growth, proliferation, metabolism, and survival. This pathway is initiated when growth factors such as insulin or IGF-1 bind to cell surface receptors and activate phosphatidylinositol 3-kinase (PI3K). Activated PI3K then phosphorylates phosphatidylinositol 4,5-diphosphate (PIP2) to produce phosphatidylinositol 3,4,5-triphosphate (PIP3), which in turn activates AKT. Activated AKT then phosphorylates various downstream targets, including the tuberous sclerosis complex (TSC1 / TSC2), leading to activation of mTOR (mammalian target of rapamycin) complex 1 (mTORC1). Activated mTORC1 promotes protein synthesis and cell growth by phosphorylating key regulators of translation initiation, such as S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1).

[0245] i) PI3K Inhibitor

[0246] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more PI3K inhibitors. The PI3K inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PI3K inhibitors include, but are not limited to, womanpemicin; 17-hydroxywomanpemicin analogs as described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methanesulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in WO06 / 122806); (S)-1-(4- ((2-(2-aminopyrimidin-5-yl)-7-methyl-4-(N-morpholinyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyridino-[3',2':4,5]furano[3',2':4,5]furano[3',2':4',5':4',5',3',2',4',3',4 ...[2-d]pyrimidin-2-yl]phenol hydrochloride (from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazolo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)nicotinamide (from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione (from Axon Medchem); TGX-221 (7-Methyl-2-(4-morpholino)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one (from Axon Medchem); XL-765; and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomida 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907) And AEZS-136. In some embodiments, the PI3K inhibitor is alpelisib or copanlisib.

[0247] ii) AKT inhibitors

[0248] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more AKT inhibitors. AKT inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. AKT inhibitors include, but are not limited to, ipatasertib, GSK-2141795, Akt-1-1 (inhibiting Akt1) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 (inhibiting Ak1 and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridyl compounds (e.g., WO4)05 / 011700); indole-3-methanol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Supplement): 3493S-3498S); perifolfenoxam (e.g., interfering with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15): 5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13: 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, Specification 43 / 82 pages 47 CN) 121693329 A 64:4394-9). PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancer (Basel) Sep 2015; 7(3): 1758-1784. For example, PI3K / AKT inhibitors may be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; and GSK2126458.

[0249] iii) mTOR inhibitors

[0250] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more mTOR inhibitors. The mTOR inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); ridaforolimus (also known as deforolimus or AP23573); and rapamycin analogs, such as WO98 / 02441 and WO01 / 14387.Rapamycin analogues disclosed in the literature, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapamycin (also known as CC1779); 40-epi-(tetrazole)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 16-pentynyloxy-32(S)-dihydrorapamycin; derivatives disclosed in WO05 / 005434; U.S. Patents 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842 and 5,256 Derivatives disclosed in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a dual-site inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0251] iv) MNK Inhibitors

[0252] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more mitogen-activated protein kinase-interacting kinase (MNK) inhibitors. The MNK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. MNK proteins are activated downstream of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a key role in the regulation of cell proliferation, differentiation, and survival. MNK phosphorylates eIF4E, a key component of the eukaryotic translation initiation complex, which enhances the translation of specific mRNAs, including those encoding proteins involved in cell cycle regulation and tumorigenesis. In some embodiments, the MNK inhibitor is one or more of tomivoserte (eFT508), CGP57380, and SEL201. In some embodiments, references to the term "MNK inhibitor" include any such MNK inhibitor disclosed in any of the following patent applications: WO 2021098691, WO 2020108619, WO 2020086713, WO 2018152117, WO 2018228275, WO2015200481 and CN115583942, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0253] v) eIF4 inhibitors

[0254] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more eukaryotic initiation factor 4A (eIF4A) inhibitors. The eIF4A inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. eIF4A is a key component of the eukaryotic translation initiation complex, in which it acts as an RNA helicase to untie the secondary structure of mRNA and facilitate ribosome binding. eIF4A is essential for the translation of many cancer-related genes, making it an attractive therapeutic target for cancer treatment. In some embodiments, the eIF4A inhibitor is one or more of zotatifin (eFT226), silvestrol, pateamine A, and rocaglate. In some embodiments, reference to the term eIF4A inhibitor includes any such eIF4A inhibitor disclosed in any of the following patent applications: WO 2023034813, WO 2021195128, and WO 2017091585, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0255] In some embodiments, the compositions and methods described herein may include one or more eukaryotic initiation factor 4G (eIF4G) inhibitors. The eIF4G inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The eIF4G family includes several proteins involved in the initiation of protein translation. eIF4G acts as a scaffold for other proteins, including eIF4E and eIF4A, to form the eIF4F complex, which is responsible for binding to the 5' cap of mRNA and unwinding the secondary structure of mRNA to allow ribosome scanning and translation initiation. In some embodiments, the eIF4G inhibitor is one or more of patamide A and equistallone.

[0256] f) DNA Damage Response Inhibitors

[0257] The compositions and methods described herein may include a combination of compound A with one or more DNA damage response (DDR) inhibitors. The DDR pathway is a key cellular pathway activated in response to DNA damage and is essential for maintaining genomic stability, thereby preventing cancer development. However, cancer cells are often defective in the DDR pathway, making them vulnerable to DDR inhibitors.More sensitive. DDR inhibitors have shown promise as potential cancer therapeutics in preclinical studies, especially in combination with other agents.

[0258] i) Wee1 inhibitors

[0259] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more Wee1 inhibitors. Wee1 is a kinase that plays a key role in regulating the cell cycle by inhibiting the activity of cyclin-dependent kinases (CDKs) and preventing cell progression through the G2 / M checkpoint. Wee1 is overexpressed in several cancer types and is associated with tumor growth and survival. In some embodiments, the Wee1 inhibitor is one or more of imp7068, adavosertib, or ZNL-02-096. In some embodiments, references to the term Wee1 inhibitor include any such Wee1 inhibitor disclosed in any of the following patent applications: WO 2022011391, WO 2022247641, WO 2021043152, WO 2020221358, WO 2020083404, WO 2020192581, WO 2019085933, WO 2018133829, WO 2015115355, WO 2015183776, WO 2014085216 and CN 114831993, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0260] ii) CHK Inhibitors

[0261] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more checkpoint kinase (CHK) inhibitors. The CHK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. CHK1 kinase is a key regulator of cell cycle and DNA damage response pathways. In some embodiments, the CHK inhibitor is a CHK1 inhibitor. In some embodiments, the CHK inhibitor is a CHK2 inhibitor. In some embodiments, the CHK1 inhibitor is one or more of rabusertib, LY2606368, GDC-0575, and MK-8776. In some embodiments, references to the term CHK1 inhibitor include any such CHK1 inhibitor disclosed in any of the following patent applications: WO 2021113661, WO 2021104461, WO 2019012030, WO 2010118390, WO 2008067027, WO 2002070494 and TW202126818, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0262] iii) ATM Inhibitor Specification Page 45 / 82 49 CN 121693329 A

[0263] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more telangiectatic ataxia mutation (ATM) inhibitors. The ATM inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. ATM plays a role in regulating replication stress response and maintaining genomic stability. In some embodiments, the ATM inhibitor is one or more of M4076, AZD0156, KU-60019, and VE-821. In some embodiments, references to the term ATM inhibitor include any such ATM inhibitor disclosed in any of the following patent applications: WO 2021197339, WO 2021098734, WO 2021260580, WO 2007026157, WO 2006085067 and US 2016113935, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0264] iv) ATR Inhibitors

[0265] In some embodiments, the compositions and methods described herein may comprise a combination of compound A with one or more telangiectatic ataxia and Rad3-related (ATR) inhibitors. ATR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some implementations, the ATR inhibitor is one or more of the following: ceralasertib, VE-821, RP-350, AZ20, VX-970, abd110, VX-803, and BAY 1895344. In some embodiments, references to the term ATR inhibitor include any such ATR inhibitor disclosed in any of the following patent applications: WO 2023016529, WO 2022237875, WO 2022268025, WO 2021012049, WO 2021023272, WO 2021260579, WO 2021228758, WO 2019050889, WO 2019154365, WO 2019133711, WO 2017059357, WO 2013049859, WO 2007046426, WO 2007015632 and CN113797341, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0266] v) PARP inhibitors

[0267] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more poly(ADP-ribose) polymerase (PARP) inhibitors. The PARP inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Seventeen members of the PARP (i.e., end-anchored polymerase) family have been identified. PARP enzymes play a crucial role in DNA damage repair, particularly in the repair of single-strand DNA breaks. PARP inhibitors block PARP enzyme activity, leading to the accumulation of DNA damage and ultimately cell death. In some embodiments, the PARP inhibitor is one or more of olaparib, rucaparib, niraparib, and veliparib (ABT-888). In some embodiments, references to the term PARP inhibitor include any such PARP inhibitor disclosed in any of the following patent applications: WO 2023051812, WO 2023051807, WO 2023051716, WO 2023278592, WO 2022228387, WO 2022022664, WO 2022000946, WO 2022222921, WO 2021163530, WO 2020122034, WO 2020239097, WO 2020142583, WO 2020156577, WO 2020098774, WO 2020196712, WO 2019200382, WO 2018125961、WO 2018205938、WO 2018192576、WO 2018218025、WO 2017032289、WO 2017177838、WO 2017029601、WO 2017088723、WO 2016155655、WO 2015154630、WO 2013097225、WO 2012130166、WO 2011006794、WO 2009046205、WO 2009063244、WO 2008084261、WO 2007138351、WO 2006110816、WO WO 2005053662, WO 2005012524, CN113698356, CN 113603647, CN 115073544, CN 108938634, CN 104887680, CN 110343088, CN108976236 and CN 107629071, each incorporated herein by reference in its entirety, including the structures of the compounds disclosed therein.The manner in which this is explicitly incorporated herein.

[0268] vi) DNA-PK Inhibitor Specification 46 / 82 pages 50 CN 121693329 A

[0269] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more DNA-dependent protein kinase (DNA-PK) inhibitors. The DNA-PK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. DNA-dependent protein kinase (DNA-PK) is a serine / threonine protein kinase that plays a key role in DNA repair and maintenance of genome stability. In some embodiments, the DNA-PK inhibitor is one or more of NU7441, AZD7648, VX-984, M3814, and CC-115. In some embodiments, references to the term DNA-PK inhibitor include any such DNA-PK inhibitor disclosed in any of the following patent applications: WO 2022187965, WO 2021197159, WO 2021260583, WO 2021204111, WO 2021104277, WO 2021098813, WO 2021022078, WO 2020259613, WO 2019143678, WO 2019143675, WO 2019201283, WO 2015058031, WO 2014159690, WO 2012028233, WO 2009010761, WO 2006032869, WO CN 1006109084, CN 112574179, CN 112300132 and CN 112300126, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0270] g) Cell Cycle Inhibitors

[0271] The compositions and methods described herein may include combinations of compound A with one or more cell cycle inhibitors. Cell cycle inhibitors target specific proteins involved in regulating the cell cycle, the process by which cells divide and replicate their DNA. Non-limiting examples of cyclins include cyclin-dependent kinases (CDKs), aurora kinases, and polo-like kinases (PLKs). CDKs are a family of kinases involved in regulating the cell cycle. CDK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis. Aurora kinases are a family of serine / threonine kinases that play a key role in regulating mitosis. Aurora kinase inhibitors block the activity of these kinases, leading to mitotic arrest and cell death. PLKs are a family of serine / threonine kinases involved in regulating multiple stages of the cell cycle. PLK inhibitors block these kinases.The activity of [the substance] leads to cell cycle arrest and / or apoptosis.

[0272] i) CDK inhibitors

[0273] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more CDK inhibitors. CDK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Cyclin-dependent kinases are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins and their associated cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, and CDK6), while other CDKs such as CDK7, CDK8, and CDK9 are essential for transcription. The binding of CDKs to cyclins forms a heterodimeric complex that phosphorylates its substrates at serine and threonine residues, thereby triggering events required for cell cycle transcription and progression. In some embodiments, the CDK inhibitor is a CDK2 inhibitor. In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, the CDK inhibitor is a CDK7 inhibitor. In some embodiments, the CDK inhibitor is a CDK9 inhibitor. In some embodiments, the CDK inhibitor is one or more of palbociclib, ribociclib, abemaciclib, and trilaciclib. In some embodiments, the CDK inhibitor is one or more of the following: tagtociclib (PF-07104091), seliciclib, voruciclib P1446A-05, BLU-222, dinaciclib, AT-7519, RGB286638, and AZD4573.

[0274] In some embodiments, references to the term CDK inhibitor include any such CDK inhibitor disclosed in any of the following patent applications: WO 2022166793, WO 2022187611, WO 2022130304, WO 2021227906, WO 2021057867, WO 2020207260, WO 2020138370, WO 2020125513, WO 2020148635, WO 2020215156, WO 2020052627, WO 2017177837, WO 2017162215, WO 2017177836, WO 2016193939, WO 2016014904, WO 2016015598, WO 2016015605, WO Instruction Manual 47 / 82 pages 51 CN121693329 A 2015181737, WO 2012061156 A1, WO 2012038411, WO 2010020675, WO 2010125004, WO 2007139732, WO 2006024945, CN 114478529, CN 108794496, CN 105294737, CN107652284, KR 20180106188 and US 2017152269, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0275] ii) Aurora Kinase Inhibitors

[0276] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more aurora kinase inhibitors. The aurora kinase inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Aurora kinases are a family of serine / threonine kinases that play a crucial role in regulating cell division and maintaining genome stability. The aurora kinase family consists of three members: aurora A, aurora B, and aurora C. In some embodiments, the aurora kinase inhibitor is one or more of pebocilib, ribociclib, and abecilibi. In some embodiments, the aurora kinase inhibitor is one or more of alisertib, danusertib, barasertib, and MLN8237. In some embodiments, references to the term "aurora kinase inhibitor" include any such aurora kinase inhibitor disclosed in any of the following patent applications: WO 2021110009, WO 2021008338, WO 2020112514, WO 2019129234, WO 2016077161, WO 2013143466, WO 2011103089, WO 2010081881, WO 2010133794, WO 2009134658, WO 2008001886, WO 2007095124, WO 2007003596, WO 2006129064, CN 114276227, CN 108078991, CN 106543155, CN CN 104211692 and CN 104098551, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0277] iii) PLK Inhibitors

[0278] In some embodiments, the compositions and methods described herein may include compound A with one or moreCombinations of polo-like kinase (PLK) inhibitors. PLK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PLKs are a family of serine / threonine kinases that play a crucial role in regulating cell division, DNA damage responses, and mitotic progression, and consist of four members: PLK1, PLK2, PLK3, and PLK4. In some embodiments, the PLK inhibitor is one or more of volasertib, onvansertib, BI 2536, and GSK461364. In some embodiments, references to the term PLK inhibitor include any such PLK inhibitor disclosed in any of the following patent applications: WO 2011012534 A1, WO 2010065134, WO 2009130453, WO 2009042806, WO 2004043936, WO 2007030361, WO 2006021547, CN 115804777, and EP 2325185, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0279] iv) Microtubule motor protein kinesin superfamily inhibitors

[0280] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more spindle kinesin (KSP) inhibitors. In some embodiments, the compositions described herein may include one or more kinesin family (KIF) inhibitors. In some embodiments, the KSP inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. KSP and KIF are subsets of the microtubule motor-kinesin superfamily. KSP, also known as Eg5, is a member of the motor-kinesin superfamily and plays a crucial role in spindle formation and cell division during mitosis. KSP inhibitors selectively target rapidly dividing cancer cells by disrupting spindle formation and inducing mitotic arrest. In some embodiments, the KSP inhibitor is one or more of the following: SB743921, monastrol, S-triphenylmethyl-L-cysteine ​​(STLC), and filanesib (ARRY-520). In some embodiments, the KIF inhibitor is an inhibitor of a kinesin-8 family microtubule motor protein. In some embodiments, as described on page 48 / 82 of CN 121693329 A, the kinesin-8 family protein is KIF18A. In some implementations, the KIF inhibitors are AMG650, BTB-1, and K03861.One or more of SJ000291942. In some embodiments, references to the term "microtubule motor protein kinin superfamily inhibitor" include any such microtubule motor protein kinin superfamily inhibitor disclosed in any of the following patent applications: WO 2015114854, WO 2015114855, WO 2010084186, WO 2006101761, WO 2006110390, WO 2006044825, WO 2006078574, WO 2005060654, WO 2004092147, WO 2004037171, WO 2004058700, WO 2003050064, WO 2003105855, WO 2022037665, WO 2018114804, WO 2017162663, WO 2016207089, WO 2012073375, JP 2014162787, JP 2019189590, JP2013166713 and KR 20220145566, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0281] v) DYRK1 Inhibitor

[0282] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more bispecific tyrosine phosphorylation-regulated kinase 1 (DYRK1) inhibitors. DYRK1 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. DYRK1 is a member of the DYRK (bispecific tyrosine phosphorylation-regulated kinase) family of protein kinases. It plays an important role in various cellular processes, including cell cycle regulation, neuronal development, and transcriptional control. In some embodiments, the DYRK1 inhibitor is one or more of dehydrocamellia, INDY, D4476, and AZ191. In some embodiments, reference to the term DYRK1 inhibitor includes any such DYRK1 inhibitor disclosed in any of the following patent applications: WO 2023277331 A1, WO 2023140846 A1, WO 2017181087 A1, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0283] h) Anti-apoptotic protein inhibitors

[0284] The compositions and methods described herein may include a combination of compound A with one or more anti-apoptotic protein inhibitors. In some embodiments, the anti-apoptotic protein inhibitor may be combined with compound A and / or any of the compounds described herein.Additional therapeutic agents may be administered or formulated in combination. Antiapoptosis inhibitors target proteins that play a role in preventing apoptosis (a form of programmed cell death). Apoptosis is a key mechanism for eliminating damaged or unwanted cells. Antiapoptosis proteins are a family of proteins that inhibit the apoptosis pathway, thereby preventing cell death. Several known classes of antiapoptosis inhibitors exist, including Bcl-2 inhibitors, XIAP inhibitors, survivin inhibitors, Mcl-1 inhibitors, and FLIP inhibitors. These inhibitors work by binding to specific antiapoptosis proteins and inhibiting their activity, thereby promoting cell death in cancer cells. In some embodiments, the compositions described herein may include one or more antiapoptosis protein inhibitors. Antiapoptosis protein inhibitors may be administered or formulated in combination with RAS(ON) inhibitors and / or any additional therapeutic agents described herein. In some embodiments, the antiapoptosis protein inhibitors include MCL-1 inhibitors. Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845. Myeloid leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance, which is not only resistance to conventional chemotherapy but also resistance to targeted therapies, including BCL-2 inhibitors such as ABT-263. In some embodiments, anti-apoptotic protein inhibitors include BCL protein inhibitors. Examples of BCL protein inhibitors include, but are not limited to, venetoclax (Venclexta), navitoclax (ABT-263), A-1331852, S63845, and AT-101.

[0285] k) Autophagy Inhibitors

[0286] The compositions and methods described herein may include combinations of compound A with one or more autophagy inhibitors. In some implementations, the autophagy inhibitor may be administered in combination with compound A and / or any additional therapeutic agents described herein (see page 49 / 82, 53 CN 121693329 A). Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), spautin-1, SAR405, bafloxacin A1, 5-amino-4-imidazolamide riboside (AICAR), leucocyanidin, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, inhibitory proteins, including but not limited to ATG5, may be used.(Involved in autophagy) expression of antisense RNA or siRNA. In some embodiments, one or more additional therapies include autophagy inhibitors.

[0287] A) ULK Inhibitors

[0288] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more Unc-51-like kinase (ULK) inhibitors. ULK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the ULK inhibitor is a ULK1 / 2 inhibitor. In some embodiments, the ULK inhibitor is one or more of the following: ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, and doxomorphin.

[0289] k) VPS Inhibitors

[0290] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more vacuole sorting protein (VPS) inhibitors. VPS inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. VPS proteins are a family of proteins that play a key role in autophagy by regulating the formation and function of autophagosomes, structures that engulf cellular components and transport them to lysosomes for degradation. Dysregulation of VPS proteins is associated with a variety of diseases, including cancer, neurodegenerative diseases, and infectious diseases. In some embodiments, the VPS inhibitor is a VPS34 inhibitor. In some embodiments, the VPS inhibitor is one or more of the following: PIK-III, VPS34-IN1, SAR405, Spautin-1, and NSC185058.

[0291] k) Macropinocytosis Inhibitors

[0292] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more macropinocytosis inhibitors. Macropinocytosis inhibitors may be administered or formulated in combination with RAS(ON) inhibitors and / or any additional therapeutic agents described herein. Macropinocytosis inhibitors are compounds that block or reduce the macropinocytosis process. In some embodiments, macropinocytosis inhibitors are one or more of the following: EIPA (ethyl isopropyl amiloride), womanpem, amiloride, apilimod, Dyngo-4a, and erythropoietin B.

[0293] j) WNT / β-catenin pathway inhibitors

[0294] The compositions and methods described herein may include a combination of compound A with one or more WNT / β-catenin pathway inhibitors. In some embodiments, WNT / β-catenin pathway inhibitors may be combined with compound A and / or any additional therapeutic agents described herein.Any additional therapeutic agents described herein may be administered or formulated. The WNT / β-catenin pathway is an important signaling pathway that plays a key role in development, tissue homeostasis, and disease. Dysregulation of this pathway is associated with various cancers, making it an attractive target for cancer therapy. WNT / β-catenin pathway inhibitors target various components of the pathway, including WNT ligands, receptors, and downstream effectors.

[0295] i) β-catenin inhibitors

[0296] In some embodiments, the compositions and methods described herein may include compound A and one or more β-catenin inhibitors. β-catenin inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. β-catenin is a protein that plays an important role in the WNT signaling pathway, which regulates various cellular processes, including cell proliferation, differentiation, and migration. In normal cells, β-catenin levels are regulated by the disruption complex, which marks the degradation status of β-catenin. However, in many cancer cells, the disruptive complex is impaired, leading to the accumulation of β-catenin in the cell nucleus and the activation of target genes involved in tumor growth and metastasis. In some implementations, the WNT / β-catenin inhibitor is one or more of the following: FOG-001, OMP-131R10, Foxy-5, LGK974, RXC004, ETC-159, OMP-54F28, Niclosamide, OMP-18R5, OTSA-101, BNC101, DKN-01, Sulindac, Pyrvinium, E7449, BC2059, PRI-724, SM08502, IWP1, IWP2, IWP3, IWP4, IWP12, IWP L6, C59, GNF-6231, GNF-1331, DK-520, DK-419, IgG-2919, Fz7-21, RHPD- P1, SRI37892, 1094-0205, 2124-0331, 3235-0367, NSC36784, NSC654259, IgG-2919, Salinomycin, BMD4702, 3289-8625, J01-017a, FJ9, KY-02061, KY-02327, NSC668036, Peptide Pen-N3, SSTC3, CCT031374, TCS 183, XAV939, AZ1366, G007-LK, MSC2504877, G244-LM, IWR-1. JW74, JW55, K-756, NVP-TNKS656, MN-64, RK-287107, WIKI4, KY1220, KYA1797K, MSAB, PKF115-584, CGP049090, AV-65, PNU-74654, Windorphen, IQ-1 tegavivint, foscenvivint, PNPB-29, ZW4864, SAH-BCL9, oxalic acid, xStAx-VHL, NRX-252114, cetuximab vedotin, PF-06647020, LGR5-mc-vc-PAB-MMAE, LGR5-NMS818, CWP232291, PRI-724 (Also known as ICG-001), C-82, and BC2059. In some embodiments, references to the term β-catenin inhibitor include any such β-catenin inhibitor disclosed in any of the following patent applications: CN 104388427 and CN 103830211, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0297] ii) PORCN inhibitors

[0298] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more porcupine protein (PORCN) inhibitors. PORCN inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PORCN is a membrane-bound O-acyltransferase that plays a key role in the WNT signaling pathway by mediating palmitoylation of WNT ligands. This palmitoylation is essential for the secretion and signaling activity of WNT proteins. Inhibition of PORCN leads to a decrease in WNT signaling activity. In some embodiments, the PORCN inhibitor is one or more of the following: LGK974 (WNT974), ETC-1922159, CGX1321, and CWP232291.

[0299] iii) GSK3 inhibitors

[0300] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more glycogen synthase kinase (GSK3) inhibitors. GSK3 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The GSK3 family consists of two closely related serine / threonine kinases: GSK3α and GSK3β. These kinases are involved in many cellular processes, including glycogen metabolism, cell cycle regulation, and Wnt signaling. GSK inhibitors have been investigated as potential therapeutic agents for various diseases, including cancer, diabetes, Alzheimer's disease, and bipolar disorder.In some embodiments, the GSK3 inhibitor is one or more of the following: tideglusib, laduviglusib, LiCl (lithium chloride), CHIR99021, SB216763, AZD1080, and LY2090314. In some embodiments, reference to the term GSK3 inhibitor includes any such GSK3 inhibitor disclosed in any of the following patent applications: WO 2017153834, WO 2014059383, WO 2010012398, WO 2009017455, WO 2003037891, CN 107151235, and CN 102258783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0301] iv) CLK Inhibitor

[0302] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more Cdc2-like kinase (CLK) inhibitors. CLK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. CLK (Cdc2-like kinases) are a family of serine / threonine kinases that play a key role in the regulation of precursor mRNA splicing, specifically alternative splicing. The CLK family has four members: CLK1, CLK2, CLK3, and CLK4. The CLK kinase family has been shown to be involved in several diseases, including cancer, neurodegenerative diseases, and viral infections. In some embodiments, the CLK inhibitor is a CLK2 inhibitor. In some embodiments, the CLK2 inhibitor is one or more of the following: Lorecivivint, SM08502, SM04690, TG003, KH-CB19, Cmpd-1, T3.5, and CX-4945. In some embodiments, reference to the term CLK inhibitor includes any such CLK inhibitor disclosed in WO 2020006115, which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0303] k) JAK / STAT pathway inhibitors

[0304] The compositions and methods described herein may include a combination of compound A with one or more JAK / STAT pathway inhibitors. In some embodiments, the JAK / STAT pathway inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The Janus kinase / signal transduction and transcription activator (JAK / STAT) pathway is involved in manyJAK / STAT pathways are signaling pathways involved in cellular processes, including immune responses, cell growth, and differentiation. Dysregulation of these pathways is associated with a variety of diseases, including inflammatory conditions, cancer, and autoimmune diseases. Inhibitors of the JAK / STAT pathway can be used to treat these diseases. In some embodiments, the JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2, and / or JAK3. In some embodiments, the JAK inhibitor is one or more of the following: ruxolitinib (Jakafi®), paclinib, fedatinib, tofacitinib (Xeljanz®), abrocitinib, filgotinib, olacritinib, peficitinib, upadacitinib, deucravacitinib, delgocitinib, and baricitinib (Olumiant®). In some embodiments, references to the term JAK inhibitor include any such JAK inhibitor disclosed in any of the following patent applications: WO 2023011301, WO 2023201044, WO 2022143629, WO 2022251434, WO 2022067106, WO 2022033551, WO 2021244323, WO 2021238817, WO 2021238818, WO 2021178991, WO 2021136345, WO 2021190647, WO 2020219639, WO 2020182159, WO 2020155931, WO 2020038457, WO WO 2020219524, WO 2020173400, WO 2018204233, WO 2018204238, WO 2018169875, WO 2018117152, WO 2017215630, WO 2016070697, WO 2016027195, CN 117815195, CN117815367 and CN 115969796, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0305] In some embodiments, the JAK / STAT pathway inhibitor is a STAT inhibitor. In some embodiments, the STAT inhibitor is an inhibitor of STAT3 and / or STAT5. In some embodiments, the STAT inhibitor is a STAT3 degrader. In aIn some implementation schemes, the STAT inhibitor is one or more of the following: TTI-101, C-188-9, WP1066, VVD-130850, LLL12B, STA-21, SD-36, Static, S3I-201, OPB-31121 and Napabucasin (BBI608). In some embodiments, references to the term STAT inhibitor include any such STAT inhibitor disclosed in any of the following patent applications: WO 2024030628, WO 2023164680, WO 2023192960, WO 2023133336, WO2020206424, WO 2023107706, WO 2021150543, WO 2008151037 and CN 109288845, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0306] L) Epigenetic regulators

[0307] The compositions and methods described herein may include a combination of compound A with one or more epigenetic regulators. (Specification 52 / 82 pages 56 CN 121693329 A) Epigenetic regulators are a class of therapeutic agents that target enzymes responsible for modifying the structure and function of chromatin, a complex of DNA and proteins that make up chromosomes. These enzymes, including histone deacetylases (HDACs), histone methyltransferases (HMTs), and DNA methyltransferases (DNMTs), play a key role in gene expression and regulation by modifying DNA packaging and influencing its reading and transcription. Epigenetic regulators work by altering the activity of these enzymes (by inhibiting or enhancing their function), thereby regulating gene expression in a specific manner. By targeting specific epigenetic modifications, such as acetylation, methylation, and DNA methylation, these therapies have the potential to treat a wide range of diseases, including cancer, inflammatory conditions, and neurological disorders.

[0308] i) HDAC Inhibitors

[0309] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more histone deacetylase (HDAC) inhibitors. The HDAC inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. There are several classes of HDACs, including Class I, Class IIa, Class IIb, Class III, and Class IV. Class I HDACs are further divided into HDAC1, HDAC2, HDAC3, and HDAC8, while Class IIa HDACs include HDAC4, HDAC5, HDAC7, and HDAC9. Class Ib HDACs consist of HDAC6 and HDAC10, and Class III HDACs are referred to as sirtuins. HDAC inhibition...Formulations can target different classes of HDACs, and their specific effects on gene expression may vary depending on the HDAC they target. In some implementations, HDAC inhibitors are one or more of the following: vorinostat (Zolinza), romidepsin (Istodax), belinostat (Beleodaq), panobinostat (Farydak), entinostat (MS-275), valproic acid (Depakene), trachostatin A (TSA), sodium butyrate, and mocetinostat (MGCD0103). Non-limiting examples of HDAC inhibitors include trachostatin, sodium butyrate, aspirin, succinylaminophenamide, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat. In some embodiments, references to the term HDAC inhibitor include any such HDAC inhibitor disclosed in any of the following patent applications: WO 2022110958, WO 2021252628, WO 2019204550, WO 2018178060, WO 2016126724, WO 2014143666, WO 2013041480, and WO 2006120456, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0310] ii) BET inhibitors

[0311] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more bromodomain and superterminal protein (BET) inhibitors. BET inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. BET (bromodomain and superterminal) proteins are a family of epigenetic reader proteins that recognize and bind to acetylated lysine residues on histones, leading to chromatin remodeling and regulation of gene expression. There are four BET proteins in humans: BRD2, BRD3, BRD4, and BRDT. BET inhibitors specifically target the bromodomains of BET proteins, inhibiting their binding to acetylated lysine residues on histones and resulting in altered gene expression. BET inhibitors can be used to treat cancer and other diseases characterized by dysregulation of gene expression. In some embodiments, the BET inhibitor is one or more of the following: JQ1, I-BET762, OTX015, RVX-208, and CPI-0610. In some embodiments, references to the term "BET inhibitor" include any such BET inhibitor disclosed in any of the following patent applications: WOWO 2022046682, WO 2022182857, WO 2021107657, WO 2021107656, WO 2020221006, WO 2020053660, WO 2018097977, WO 2017222977, WO 2017142881, WO 2015075665, WO 2015011084 and CN 113264930 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0312] iii) EZH2 Inhibitor Specification 53 / 82 pages 57 CN 121693329 A

[0313] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more Zeste homolog enhancer 2 (EZH2) inhibitors. EZH2 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. EZH2 is a histone-lysine N-methyltransferase and a member of the polycomb repressor complex 2 (PRC2) family. EZH2 plays a key role in gene expression regulation, specifically by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), causing transcriptional repression of target genes. EZH2 has been found to be overexpressed in several types of cancer and associated with tumor progression and poor prognosis. In some implementations, the EZH2 inhibitor is one or more of the following: tazemetostat, GSK2816126, and CPI-1205 (lirametostat). In some embodiments, references to the term "EZH2 inhibitor" include any such EZH2 inhibitor disclosed in any of the following patent applications: WO 2023030299, WO 2022179584, WO 2020224607, WO 2021243060, WO 2021086069, WO 2019206155, WO 2018133795, WO 2018137639, WO 2017184999, WO 2017218953, WO 2016201328, WO 2015195848, WO 2013155317, WO 2013138361, and CN. 114621191, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0314] iv) Co-REST inhibitors

[0315] In some embodiments, the compositions and methods described herein may include compound A with one or more Co-Combinations of REST inhibitors. Co-REST inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Co-REST is a transcriptional co-repressor protein that interacts with a variety of transcription factors to regulate gene expression. Co-REST works by recruiting histone deacetylases (HDACs) to chromatin, causing repression of gene expression. Inhibition of Co-REST has been proposed as a potential therapeutic strategy for treating a variety of diseases, including neurodegenerative diseases and cancer. In some embodiments, the co-REST inhibitor is one or more of the following: nocodazole, NSC 1892, and astaxanthin.

[0316] v) EP300

[0317] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more E1A-binding protein p300 (EP300) inhibitors. EP300 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. EP300 is a transcriptional coactivator involved in regulating numerous cellular processes, including chromatin remodeling, DNA damage responses, and cell cycle progression. EP300 acts as a histone acetyltransferase, catalyzing the transfer of acetyl groups to lysine residues on histones, leading to changes in chromatin structure and gene expression. EP300 activity is associated with diseases such as cancer, cardiovascular diseases, and neurological disorders. In some embodiments, EP300 inhibitors are one or more of C646, A-485, NU9056, and L002. In some embodiments, references to the term EP300 inhibitor include any such EP300 inhibitor disclosed in any of the following patent applications: WO 2021213521 and WO 2016044694, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0318] vi) LSD1

[0319] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more lysine-specific demethylase 1 (LSD1) inhibitors. The LSD1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. LSD1 is an enzyme that plays a key role in regulating gene expression through histone modification. It specifically removes a methyl group from lysine 4 on histone 3, thereby leading to gene repression. Dysregulation of LSD1 is associated with a variety of diseases, including cancer and neurodegenerative diseases. In some embodiments, the LSD1 inhibitor is one or more of the following: GSK2879552, IMG-7289, ORY-1001, IMG-8419, SP-2577, CC-90011, HCI-2509, and page 58 of the specification (54 / 82).CN 121693329 A INCB059872. In some embodiments, references to the term "LSD1 inhibitor" include any such LSD1 inhibitor disclosed in any of the following patent applications: WO 2021095840, WO 2021175079, WO 2021058024, WO 2020047198, WO 2020052649, WO 2020015745, WO 2020052647, WO 2018137644, WO 2017184934, WO 2017027678, WO 2017116558, WO 2017149463, WO 2016161282, WO 2015123465, WO 2015123424, WO 2013057322, WO 2013057320, WO 2012135113, CN 114805261, CN 111072610, CN107174584, CN 110478352, CN 106432248 and CN 106045881, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0320] vii) PRMT5

[0321] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more protein arginine methyltransferase 5 (PRMT5) inhibitors. PRMT5 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PRMT5 is a member of the PRMT family that catalyzes the transfer of methyl groups from S-adenosylmethionine (SAM) to the nitrogen atom of an arginine residue in a target protein. PRMT5 is involved in various biological processes, including gene expression regulation, signal transduction, and DNA repair. In some implementations, PRMT5 inhibitors are one or more of the following: TNG908, TNG462, AMG193, GSK591, EPZ015666, TC-E 5003, and MS023. In some embodiments, references to the term PRMT5 inhibitor include any such PRMT5 inhibitor disclosed in any of the following patent applications: WO 2023001133, WO 2022206964, WO 2022153161, WO 2021068953, WO 2021088992, WO 2020259478, WO 2020205660, WO 2020250123, WO 2020033288, WO 2019102494, WO 2019112719, WO 2019180631, WO 2018065365, WOWO 2017153186, WO 2017212385, WO 2017032840, WO 2016022605, WO2014100695, WO 2014145214, WO 2014100719, CN 111825656, CN 114558014, CN 11304554 and CN 112778275, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0322] viii) MAT2A

[0323] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more methionine adenosyltransferase 2A (MAT2A) inhibitors. The MAT2A inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. MAT2A is an enzyme that catalyzes the production of S-adenosylmethionine (SAM), an important cofactor in many biological processes, including DNA methylation, protein methylation, and polyamine synthesis. Elevated MAT2A expression is associated with various cancers. In some embodiments, the MAT2A inhibitor is one or more of the following: cyclic leucine and 2-hydroxy-4-methylthiobutyric acid. In some embodiments, reference to the term MAT2A inhibitor includes any such MAT2A inhibitor disclosed in any of the following patent applications: WO 2022256808, WO 2022256806, WO 2019191470, and CN 115716831, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0324] ix) DOT1L

[0325] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more telomere silencing interferon 1-like (DOT1L) inhibitors. The DOT1L inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. DOT1L is a histone methyltransferase that catalyzes the methylation of lysine 79 on histone H3. This modification is associated with transcriptional elongation and is important for maintaining gene expression programs. The DOT1L family includes enzymes involved in epigenetic regulation and transcriptional control, and their dysregulation is associated with a variety of diseases, including cancer. In some embodiments, the DOT1L inhibitor is one or more of the following: EPZ-5676 (Pimecrostat specification 55 / 82 pages 59 CN 121693329 A)(pinometostat)) and EPZ-004777. In some embodiments, references to the term DOT1L inhibitor include any such DOT1L inhibitor disclosed in any of the following patent applications: WO 2016090271, WO 2014100662 and CN 108997480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0326] x) UBA1

[0327] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more ubiquitin activator enzyme inhibitors (e.g., UBA1 inhibitors). UBA1 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. UBA1, also known as ubiquitin activator enzyme 1, is a key enzyme involved in the ubiquitination process, a fundamental cellular mechanism for protein degradation and regulation. Ubiquitination involves the covalent linkage of ubiquitin molecules to target proteins, marking their degradation by the proteasome or regulating their activity, localization, or interactions within the cell. Several inhibitors have been developed to modulate UBA1 activity, aiming to disrupt ubiquitination-mediated processes in diseased cells. These inhibitors include (but are not limited to) adenosine-based inhibitors, which typically compete with ATP for binding to the active site of UBA1, thereby preventing activation of ubiquitins (e.g., PYR-41 and MLN7243); covalent inhibitors, which form irreversible bonds with specific amino acid residues at the active site of UBA1, thereby inhibiting its activity (e.g., TAK-243 (formerly known as MLN4924)); allosteric inhibitors, which bind to sites on UBA1 different from the active site, thereby inducing conformational changes that inhibit its catalytic activity (e.g., compound 2i); and fragment-based inhibitors, which are designed based on smaller molecular fragments that bind to UBA1. In some embodiments, the UBA1 inhibitor is one or more of PYR-41, MLN7243, and TAK-243. In some embodiments, references to the term UBA1 inhibitor include any such UBA1 inhibitor disclosed in any of the following patent applications: WO 2016069393 A1, WO 2016069392 A1, and JP 2013237627 A2, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0328] M) Additional therapeutic agents that can be used in combination therapy

[0329] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more farnesyltransferase inhibitors. The farnesyltransferase inhibitor may be combined with compound A and / or any additional...Therapeutic agents are administered or formulated in combination. Farnesyltransferase inhibitors (FTIs) are a class of drugs that target farnesyltransferases, which play a role in a process called protein isoprenelation. Protein isoprenelation is an important step in the activation of certain proteins involved in signal transduction, cell growth, and differentiation. In some formulations, the farnesyltransferase inhibitor is one or more of tipifarnib, lonafarnib, and rilapladib. In some embodiments, references to the term farnesyltransferase inhibitor include any such farnesyltransferase inhibitor disclosed in any of the following patent applications: WO 2010057028, WO 2007042465, WO 200136395, WO 200064891, WO 200042849, WO 199938862, WO 199928315, WO 199829390, WO 199426723, CN 107312000, CN 107365310, KR 100375421, KR 100388790, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0330] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more casein kinase inhibitors. In some embodiments, the casein inhibitor is SR-3029, a potent and ATP-competitive CK1δ and CK1ε inhibitor.

[0331] In some embodiments, the compositions and methods described herein may include a combination of one or more FLT3 inhibitors with compound A disclosed herein. FLT3 (Fms-like tyrosine kinase 3), also known as CD135, is a receptor tyrosine kinase (RTK) that plays a key role in regulating hematopoiesis, the process of forming blood cells. It is primarily expressed on hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow, where it controls cell proliferation, survival, and differentiation. In some embodiments, the FLT3 inhibitors include, but are not limited to, midostaurin, gilteritinib, sorafenib, quizartinib, crenolanib, and ponatinib.

[0332] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more TGFβ pathway inhibitors. In some embodiments, the compositions and methods described herein may include...One or more TGFβ inhibitors. The TGFβ inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. TGFβ (transforming growth factor β) is a multifunctional cytokine involved in various cellular processes, including cell growth, differentiation, apoptosis, and immune responses. Dysregulation of the TGFβ signaling pathway is associated with a variety of diseases, including cancer, fibrosis, and autoimmune disorders. In some embodiments, the TGFβ inhibitor is one or more of galunisertib (LY2157299) and vactosertib (TEW-7197). In some embodiments, the TGFβ inhibitor is one or more of the following: galunisertib, LY2157299, Fresolimumab, Lerdelimumab, Trabedersen, curcumin, resveratrol, and small interfering RNA (siRNA) to silence TGFβ receptor expression. In some embodiments, references to the term TGFβ inhibitor include any such TGFβ inhibitor disclosed in any of the following patent applications: WO 2023043473, WO 2020104648, WO 2020128850, WO 2016140884, WO 2007018818, WO 2004024159, WO 200226935, WO 2002062753, WO 2002062776 and JP 2012087076, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0333] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more HSP90 inhibitors. The HSP90 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. HSP90, also known as heat shock protein 90, is a molecular chaperone that plays a crucial role in regulating the folding, stability, and activity of a large number of client proteins involved in various cellular processes, including cell cycle progression, signal transduction, and apoptosis. In some embodiments, HSP90 inhibitors are one or more of the following: gerdanamycin and its derivatives (e.g., 17-AAG, 17-DMAG), KOS 953, rhizobacterin and its derivatives (e.g., PU-H71), SNX-2112, Ganetspib, AT13387, Onalespib, Luminespib, and KW-2478. In some embodiments, references to the term HSP90 inhibitor include the following patent claims.Any of the following HSP90 inhibitors disclosed in any of the following: WO 2021137665, WO 2018200534, WO 2017151425, WO 2015200514, WO 2013053833, WO 2013009657, WO 2013119985, WO 2012138894, WO 2011044394, WO 2009097578, WO 2008115719, CN 105237533 and CN 104030904, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0334] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more glutathione peroxidase 4 (GPX4) inhibitors. GPX4 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. GPX4 is an antioxidant enzyme that plays a crucial role in protecting cells from oxidative stress-induced cell death. GPX4 catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols and acts as a regulator of ferroptosis (a regulated form of cell death driven by lipid peroxidation). In some embodiments, the GPX4 inhibitor is one or more of the following: RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, and TLN232. In some embodiments, reference to the term GPX4 inhibitor includes any such GPX4 inhibitor disclosed in any of the following patent applications: WO 2021132592, US 2021244715, and KR 20220115536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0335] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more NRF2 inhibitors as described in CN 121693329 A (page 57 / 82 of specification 61). The NRF2 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. NRF2 is a transcription factor that regulates gene expression involved in cellular antioxidant responses, detoxification, and other cell protection pathways. It plays a key role in cellular defense mechanisms against oxidative stress and other forms of cellular damage. In some embodiments, the NRF2 inhibitor is one or more of the following: ML385, crotonol, CDDO-Im, RTA-408, and trigonelline. In some embodiments, references to the term NRF2 inhibitor include any such NRF2 inhibitor disclosed in any of the following patent applications: WO2023051088, WO 2021202720, KR 2022013610 and CN 107519168, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0336] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more TEA domain (TEAD) inhibitors. TEAD inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. TEADs are a family of transcription factors that play a key role in regulating gene expression during embryonic development and tissue homeostasis. The four members of the TEAD family (TEAD1-4) are transcriptional coactivators that bind to DNA through their conserved TEA domains and interact with other transcription factors to activate the expression of target genes. In some implementations, the TEAD inhibitor is one or more of the following: VT-107, pan-TEAD, VT-104, verteporfin, CA3, IAG933, K-975, IK-595, and statins (see, for example, Chapeau, Emilie and Schmelzle, Tobias (2023) IAG933, an oral selective YAP1-TAZ / pan-TEAD protein-protein interaction inhibitor (PPIi) with pre-clinical activity in monotherapy and combinations with MAPK inhibitors. Nature Cancer). In some embodiments, reference to the term TEAD inhibitor includes any such TEAD inhibitor disclosed in any of the following patent applications: WO 2023280254, WO 2023031781, WO 2022258040, WO 2020070181, WO 2018185266, and WO 2017064277, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0337] In some embodiments, the compositions and methods described herein may comprise a combination of compound A with one or more NOTCH / γ secretase inhibitors. The NOTCH / γ secretase inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the NOTCH / γ secretase inhibitor is nirogacestat. In some embodiments, the term NOTCH / γ secretase inhibitor is referred to as nirogacestat.References to secretase inhibitors include any such NOTCH / γ secretase inhibitors disclosed in any of the following patent applications: WO 2020208572, WO 2017200969, WO 2014047390, WO 2014047372, WO 2011041336, WO 2010090954, WO 2009008980, WO 2009087130, WO 2007110335, CN 103664904, CN 105560244 and KR 20200077480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0338] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more hedgehog protein inhibitors. Hedgehog protein inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The hedgehog (Hh) protein family are secreted signaling molecules that play a crucial role in adult embryonic development and tissue homeostasis. The Hh signaling pathway is involved in regulating cell growth, differentiation, and survival. In some embodiments, the hedgehog protein inhibitor is one or more of Vismodegib (Erivedge), Sonidegib (Odomzo), and Glasdegib (Daurismo). In some embodiments, reference to the term hedgehog protein inhibitor includes any such hedgehog protein inhibitor disclosed in any of the following patent applications: WO 2011063309 and CN 107163028, each of which is incorporated herein by reference in its entirety, including the compound structure disclosed therein on pages 58 / 82 of CN 121693329 A, which is expressly incorporated herein by reference.

[0339] The compositions and methods described herein may include a combination of compound A with one or more NF-κB pathway inhibitors. NF-κB inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. NF-κB (NFκB) is a family of transcription factors involved in regulating various cellular processes, including inflammation, immunity, cell survival, and proliferation. Non-limiting examples of NF-κB inhibitors include bortezomib (Velcade), curcumin, parthenolide, IKK inhibitors (e.g., IKK-16, BAY 11-7082), resveratrol, andrographolide, and proteasome inhibitors (e.g., MG132, lactocinol).

[0340] In some embodiments, additional therapy is the administration of a side effect limiter (e.g., intended to reduce treatment side effects).The occurrence or severity of nausea). For example, in some embodiments, compound A may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0341] In some embodiments, one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy). In some embodiments, one or more additional therapies include therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors).

[0342] Examples of non-pharmacological treatments include, but are not limited to, radiotherapy, cryotherapy, hyperthermia, surgery (e.g., surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0343] In some embodiments, compound A may be used as postoperative adjuvant therapy. In some embodiments, compound A may be used as preoperative neoadjuvant therapy.

[0344] Radiotherapy can be used to inhibit abnormal cell growth or treat hyperproliferative conditions, such as cancer, in a subject (e.g., a mammal (e.g., a human)). Techniques for administering radiotherapy are known in the art. Radiotherapy can be administered by one or a combination of several methods, including, but not limited to, external beam therapy, internal radiation therapy, implanted radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and sustained or transient interstitial brachytherapy. As used herein, the term “brachytherapy” refers to radiotherapy delivered by means of a radioactive material inserted into or near a space defined by a tumor or other proliferative tissue disease site within the body. The term is intended, but not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu). Suitable radioactive sources used as cell conditioners in this disclosure include solids and liquids. As a non-limiting example, the radioactive source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides emitting photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be any radioactive nuclide.Fluids made from solutions of radioactive isotopes, such as solutions of I-125 or I-131, or radioactive fluids, can be produced using slurries of suitable fluids containing small particles of solid radioactive isotopes such as Au-198 or Y-90. Furthermore, radioactive isotopes can be embedded in gels or radioactive microspheres.

[0345] In some embodiments, compound A can make abnormal cells more sensitive to radiotherapy in order to kill such cells or inhibit their growth. Therefore, this disclosure further relates to a method for making abnormal cells in a mammal sensitive to radiotherapy, the method comprising administering to the mammal a quantity of the compound of this disclosure that effectively makes the abnormal cells sensitive to radiotherapy. The amount of the compound in the method can be determined according to the manner in which the effective amount of such compounds as described in page 59 / 82 of this specification, 63 CN 121693329 A, is determined. In some embodiments, compound A can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0346] In some embodiments, the non-pharmacological treatment is T-cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The source of the T cells is obtained from a subject before the T cells are expanded and genetically modified. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from sites of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of this disclosure, a variety of T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Whether before or after T cell genes are modified to express the desired protein (e.g., CAR), T cells can generally be activated and expanded using methods described, for example, in the following U.S. patents: 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0347] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more tight junction protein-18 targets. Tight junction protein-18 targets can interact with compound A and / or any of the compounds described herein.No additional therapeutic combinations may be administered or formulated. Tight junction protein-18 (e.g., tight junction protein 18.2; CLDN18.2) has emerged as a promising target for treating patients with gastrointestinal malignancies such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer, due to its limited expression in healthy tissues and aberrant overexpression in a range of malignancies. Numerous clinical trials of CLDN18.2-targeted therapies (including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies) are underway, some showing promising early results. Malignant transformation of gastric epithelial tissue leads to the disruption of cell polarity, which in turn results in the exposure of the CLDN18.2 epitope on the cell surface. Although targeting monoclonal antibodies are largely unable to access CLDN18.2 in the tight junction supramolecular complex located in normal tissues, the perturbation of cell polarity exposing the CLDN18.2 epitope could theoretically allow CLDN18.2 targets to bind to CLDN18.2 in malignant tissues with minimal off-target effects, making CLDN18.2 an attractive therapeutic target. In some embodiments, tight junction protein-18 targets are one or more of the following: zobetuximab, ASKB589, oxemitamab (TST001), PT886 (a bispecific antibody targeting CLDN18.2 and CD47), TJ-CD4B, CMG901 (an ADC consisting of an anti-CLDN18.2 monoclonal antibody conjugated to a cytotoxic payload of monomethylauristatin E), and CT041 (autologous T cells genetically engineered to express a CAR targeting CLDN18.2). In some embodiments, references to the term tight junction protein-18 target include any such tight junction protein-18 target disclosed in any of the following patent applications: WO 2024081544, WO 2024131683, WO 2024137619, WO 2024140670, WO 2024136594, WO 2023034922, WO 2023046202, WO 2022203090, WO 2022133169, WO 2022100613, WO 2022256449, WO 2022136642, WO 2021155380, WO 2021129765, WO 2021011885, WO 2021058000, WO 2021218874、WO 2021027850、WO 2020156554、WO 2020025792、WOWO 2020114480, WO 2020211792, WO 2020239005, WO 2019219089, WO 2018157147, WO 2018108106, WO 2016166122, WO 2014146778, CN 118290582, CN118203658 and CN 118286201, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0348] In some embodiments, the therapeutic agent used for combination therapy may be a steroid. Thus, in some embodiments of CN 121693329 A, page 64 of the specification on 60 / 82, one or more additional therapies include steroids. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, and cordivazol. (cortivazol), deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl ester, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, hydrochlorothiazideFlurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate furoate, paramethasone, prednicarbate, prednisolone, 2,5-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0349] Other examples of therapeutic agents that can be used together with compound A in combination therapy include compounds described in the following patents: U.S. Patents 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885; and International Patent Applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, and WO02 / 55501. WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0350] Additional therapeutic agents may be biological agents (e.g., cytokines) used to treat cancer or its related symptoms.Such as interferon or interleukin, such as IL-2). In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that activates the target to stimulate an anticancer response or antagonizes an antigen important for cancer. Antibody-drug conjugates are also included.

[0351] Additional therapeutic agents may be immunomodulators. For example, additional therapeutic agents may be T-cell checkpoint inhibitors. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L2 (e.g., a PD-L2 / Ig fusion protein) inhibitor or antagonist (e.g., an inhibitory antibody, an Fc fusion, or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some implementations, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies (e.g., avelumab, durvalumab, atezolizumab), pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or Preusser, M. et al. (2015) Nat. Rev.Checkpoint inhibitors disclosed in Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002. Non-limiting examples of immunomodulators include the targets identified in Table 2.

[0352] Table 2: Exemplary immunomodulatory targets

[0353]

[0354] CTLA4, cytotoxic T lymphocyte-associated antigen 4; LAG3, lymphocyte activation gene 3; PD-1, programmed cell death protein 1; PD-L1, PD-1 ligand; TIM3, T cell membrane protein 3; VISTA, T cell activation inhibitor containing V domain immunoglobulin (Ig); KIR, killer IgG-like receptor, APC (antigen-presenting cell); TREM2 (trigger receptor 2 expressed on myeloid cells); TGF-β (transforming growth factor β)

[0355] Additional therapeutic agents may be anti-TIGIT antibodies, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab). Instructions for Use, pages 62 / 82, CN 121693329 A

[0356] In some embodiments, the combination therapy comprises compound A and a cancer vaccine composition. In some embodiments, the cancer vaccine composition is HB-700, mRNA-4157, mRNA-5671, BNT111, GVAX Pancreas, IMA901, DCVax, SOT101, Sipuleucel-T, PROSTVAC-VF, or TG01.

[0357] Additional therapeutic agents may be agents for treating cancer or related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or related symptoms, collectively referred to as "anticancer agents"). Anticancer agents may be, for example, chemotherapeutic agents or targeted therapeutic agents.

[0358] Anticancer agents include mitosis inhibitors, insertional antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, and L-asparagine.Enzymes, topoisomerase inhibitors, interferons, platinum coordination complexes, anthraquinone-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, corticosteroids, progesterone, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, one or more additional therapies comprise two or more anticancer agents. Two or more anticancer agents may be used in mixtures for combined or separate administration. Suitable dosing regimens for combination anticancer agents are known in the art and described, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0359] Other non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; azacyclopropanes, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including altretamine. Triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and tris(hydroxymethyl)melamine; polyacetyl (especially bulbatacin and bulbatacinone); camptothecin (including its synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycin(Especially nostocin 1 and nostocin 8); dolastatin; duocalmycin (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, and mechlorethamine oxide. Hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, calicheamicin γ-II and calicheamicin ω-II (see, for example, product information, pages 63 / 82, CN 121693329 A Agnew, Chem. Intl. Ed Engl. 33:183-186) (1994)); dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophore and related chromogen chromophores, aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, spirochetinCalicamicin, Carabicin, Caminomycin, Carminomycin, Carzinophilin, Chromycins, Dactinomycin D, Daunorubicin, Detorubicin, 6-Diazon-5-oxo-L-leucine, Adriamycin (Doxorubicin), N-Morphyrin-Doxorubicin, Cyano(N-Morphyrin)-Doxorubicin, 2-Pyrrolin-Doxorubicin, Deoxydoxorubicin, Epirubicin, Esorubicin, Idarubicin, Marcellomycin, Mitomycin (e.g., Mitomycin C), Mycophenolic acid, Nogalamycin Olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6- Mercaptopurines, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluxuridine; androgens, such as calusterone and dromostanolone.Propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergic drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate); epothilone, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentos ta tin; phenametine; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene, such as T-2 toxin, verracurin A, lacryma-jobi A(roridin A) and serpentin package insert, page 64 / 82, CN 121693329 A (anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactone; pipebroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, such as Taxol® (paclitaxel), Abraxane® (a nanoparticle formulation of paclitaxel engineered with albumin, free of polyoxyethylene hydrogenated castor oil), and Taxotere® (docetaxel); chloranbucil; tamoxifen. (Nolvadex™); raloxifene; aromatase inhibitor 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esporam(esperamicins); capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above.

[0360] Additional non-limiting examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygerdmycin, Alpharadin, alvocidib, 3-aminopyridine-2-carbaldehyde thiohexacarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antitumor drugs (e.g., cell cycle nonspecific antitumor agents and other antitumor agents described herein), antitumor herbs, apaziquone, atipremod, azathioprine, belotecone, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, butionine sulfoximine, CBV (Chemotherapy), calyculin, dichloroacetic acid, discormolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecanMafosfamide, mitozolomide, naproxen, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatinum tetranitrate (Instructions for use, pages 65 / 82, 69, CN 121693329 A) tetranitrate, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0361] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vincristine, vinorelbine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin / actinomycin D, donomycin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, and plicamycin. Mitomycin, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and removes cells that cannot synthesize asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents (e.g., nitrogen mustard (e.g., methomyl mustard, cyclophosphamide and analogs, melphalan and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine (DTIC)), antiproliferative / antimitotic antimetabolites (e.g., folic acid analogs), pyrimidine analogs (e.g., fluorouracil, azuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, ...Thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, DNA binding agents (e.g., Zalypsis®), PI3K inhibitors (e.g., PI3K δ inhibitors (e.g., GS-1101 and TGR-1202), PI3K δ and γ inhibitors (e.g., CAL-130), cupanidine, Apellilis and idelalisib; multi-kinase inhibitors (e.g., TG02 and sorafenib); hormones (e.g., estrogens) and hormone agonists, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin); BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), P13K / Akt inhibitors (e.g., perifoxetine), PKC inhibitors (e.g., enzastaurin), FTI (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targets (e.g., MKC-3946), and cFMS inhibitors (e.g., ARRY-382).

[0362] In some embodiments, the anticancer agent is selected from methomyl mustard, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or derivative variant of the foregoing. In some embodiments, the anticancer agent is JAB-3312.

[0363] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0364] In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunomodulatory therapies, such as immune checkpoint inhibitors. In some implementations, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0365] In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors. See, for example, Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, the RAS(ON) inhibitor of this disclosure is used in combination with MEK inhibitors and SOS1 inhibitors. In some embodiments, the RAS(ON) inhibitor of this disclosure is used in combination with PD-L1 inhibitors and SOS1 inhibitors. In some embodiments, the RAS(ON) inhibitor of this disclosure is used in combination with a PD-L1 inhibitor and an SHP2 inhibitor. In some embodiments, the RAS(ON) inhibitor of this disclosure is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer, and the treatment includes administration of a combination of the Ras inhibitor of this disclosure with a second or third therapeutic agent.

[0366] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0367] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiD), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1 agents, anti-PD-L1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0368] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that regulate immune responses) containing imide groups. IMiD drugs include thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0369] Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 2007, 110(1): 186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 A1), and are also described elsewhere herein.

[0370] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent Nos. 6,111,090, 8,586,023, WO2010 / 003118, and WO2011 / 090754; or, for example, U.S. Patent Nos. 7,025,962, EP 1947183, 7,812,135, 8,388,967, 8,591,886, 7,618,632, EP 1866339, WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, and WO05 / 055808. Anti-GITR antibodies as described in WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451 and WO2011 / 051726.

[0371] Another example of a therapeutic agent that can be used in combination with compound A is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions synthesized in vitro, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally can be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or arresting cell growth. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0372] Anti-angiogenic agents can be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, tesiromoximide (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, and EP1181017.EP0818442, EP1004578, and US20090012085, as well as U.S. Patents 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are inhibitors with very low or no MMP-1 inhibitory activity. More preferably are inhibitors that selectively inhibit MMP-2 or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors include AG-3340, RO 32-3555, and RS 13-0830.

[0373] Other exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to the kinase domain receptor, as described on page 67 / 82 of the specification, CN 121693329 A), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to EGFR), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to Angle and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to Tie2 kinase). Other anti-angiogenic agents include Camppath, IL-8, β-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen-binding domains, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM integrin dissociation domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), and specifically binding anti-eph receptor or anti-pterygium antibodies or antigen-binding domains (US Patent Nos. 5,981,245, 5,728,813, 5,969,110, and 6, ). Patents Nos. 596,852, 6,232,447, 6,057,124 and others (and members of their patent family), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands), and antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to PDGFR kinases). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO).0770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands); DAC anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stalth (Johnson & Johnson, USA); Fibrinogen-E fragment (BioActa, UK); Angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Maspin (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan);Japan); FR-111142 (Fujisawa, Japan, JP 02233610); Platelet-4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); Second-generation α5β3 integrin MAb (Applied Molecular Evolution, USA and Medlmmune, USA); Enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA); PI 88 (Progen, Australia); Cilengilide (Merck KGaA, Germany; Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935. Instructions for use, 68 / 82 pages, 72 CN. 121693329 A (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); Vatalani (pINN)(Novartis, Switzerland and Schering AG, Germany); Tissue factor pathway inhibitor (EntreMed, USA); Pinn (Gilead Sciences, USA); Xanthorrhizol (Yonsei University, South Korea); Gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); Atemod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); Angiogenesis vaccine (EntreMed, USA); Urokinase plasminogen activator inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); InKine (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101(ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); Drug delivery system, intraocular 2-methoxyestradiol; Anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitor; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston) Children's Hospital, USA and EntreMed, USA); KDR Mab (ImClone Systems, USA); α5β Mab (Protein Design, USA); KDR kinase inhibitors (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); cobretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA; Takeda, Japan; and TAP, USA); AG 13925 (Agouron, USA); tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, USA) UK); CKD 732 (Chong Kun)Dang (South Korea); Irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (Genaera, USA); RPI 4610 (Sirna, USA); Heparinase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thromboprotein 1 inhibitor (Allegheny Health, specification 69 / 82 pages 73 CN 121693329 A Education and Research Foundation, USA).

[0374] Other examples of therapeutic agents that can be used in combination with compound A include agents that specifically bind to and inhibit the activity of growth factors (e.g., antibodies, antigen-binding domains, or soluble receptors), such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding domains that specifically bind to receptor c-Met.

[0375] Another example of a therapeutic agent that can be used in combination with compound A is an antitumor agent. In some embodiments, one or more additional therapies include an antitumor agent. Non-limiting examples of antitumor agents include acemannan and azolam.Aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, aifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac (HIT), interferon-alpha, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate Phosphate), exemestane, escitaline, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, formustin, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gemeraxyl(gimeracil) / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon α, natural interferon α, interferon α-2, interferon α-2a, interferon α-2b, interferon α-N1, interferon α-n3, compound interferon-1, natural interferon α, interferon β, interferon β-1a, interferon β-1b, interferon γ, natural interferon γ-1a, interferon γ-1b, interleukin-1 β, iobenguane, irinotecan, isoladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoxone, dibromoceroxyl, mitoxone, molgramostim, nafarelin, naloxone + Pentazocine, nartograstim, nedaplatin, niluamide, noscapine, new erythropoietin, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, pegylated interferon alpha-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirubicin, rabbit anti-thymocyte polyclonal antibody, polyethylene glycol. (Instructions for use, pages 70 / 82, CN 121693329 A)Interferon α-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium ethodole Re 186, retinamide (RII), rituximab, romurtid e, samarium lexid ronam (153 Sm), sargramostim, cizonan, sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide Teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, retinoic acid, trelostan, trimethoprim, triptorelin, natural tumor necrosis factor-alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysis product vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer or zoledronic acid; abarelix; AE 941, ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diazinon, EL 532 (Elan), EM 800 (Endorecherche), enuracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine-131 MAb (Techni clone), polymorphic epithelial mucin-yttrium-90 MAb Antisoma, marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl proerythrin etiopurpurin, tirapazamine, Biomira cancer vaccine, melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysis product vaccine (New York Medical College), viral melanoma cell lysis product vaccine (Royal Newcastle University).Hospital) or valspodar.

[0376] Additional examples of therapeutic agents that can be used in combination with compound A include ipilimumab (Yervoy®); trimemumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health) Services); huMAbOX40L; atacivib; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumab (page 71 / 82, CN 121693329 A); MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); trastuzumab (Kadcyla®); eylea®; alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); certolizumab pegol (Cimzia®); daculizumab (Zenapax®); daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); gemtuzumab (Omtuzumab)ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®) ); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); tositumomab; tositumomab-i-131; tositumomab and tositumomab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0377] In some embodiments of any of the methods described herein, a first therapy (e.g., compound A) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent may be administered immediately, for up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1–7 days, 1–14 days, 1–21 days, or 1–30 days, before or after the administration of one or more additional therapies.

[0378] The invention is further characterized by a medicine box comprising (a) a pharmaceutical composition including agents described herein (e.g., compounds of the invention), and (b) a packaging insert with instructions on performing any of the methods described herein.In some embodiments, the pillbox includes (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the present invention), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a packaging insert with instructions on performing any of the methods described herein.

[0379] Since one aspect of the invention covers the treatment of diseases or related symptoms with combinations of separately administerable pharmaceutically active compounds, the invention further relates to combining separate pharmaceutical compositions in the form of a pillbox. The pillbox may contain two separate pharmaceutical compositions: a compound of the present invention and one or more additional therapies. The pillbox may include a container for containing the separate compositions, such as a dispensing bottle or dispensing foil packaging. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the pillbox may include instructions on the use of the separate components. The pillbox form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dose intervals, or when a prescribing healthcare professional wishes to adjust the individual components in the combination.

[0380] Embodiments

[0381] Embodiment 1: A method for treating RAS protein-related conditions in a human subject in need, the method comprising orally administering 10 mg to 500 mg of compound A to the subject daily:

[0382] (Compound A)

[0383] or a pharmaceutically acceptable salt thereof.

[0384] Embodiment 2: The method of Embodiment 1, wherein the method comprises administering 20 mg to 500 mg of compound A to the subject.

[0385] Embodiment 3: The method of Embodiment 1, wherein the method comprises administering 40 mg to 500 mg of compound A to the subject.

[0386] Embodiment 4: The method of Embodiment 1, wherein the method comprises administering 80 mg to 500 mg of compound A to the subject.

[0387] Embodiment 5: The method of Embodiment 1, wherein the method comprises administering 120 mg to 500 mg of compound A to the subject.

[0388] Embodiment 6: The method of Embodiment 1, wherein the method includes administering 160 mg to 500 mg of compound A to the subject.

[0389] Embodiment 7: The method of Embodiment 1, wherein the method includes administering 220 mg to 500 mg of compound A to the subject.

[0390] Embodiment 8: The method of Embodiment 1, wherein the method includes administering 250 mg to 500 mg of compound A to the subject.

[0391] Embodiment 9: The method of Embodiment 1, wherein the method includes administering 300 mg to 500 mg of compound A to the subject.

[0392] Implementation Scheme 10: The method of Implementation Scheme 1, wherein the method includes administering 400 mg to 500 mg of compound A to the subject.

[0393] Implementation Scheme 11: The method of Implementation Scheme 1, wherein the method includes administering 450 mg to 500 mg of compound A to the subject.

[0394] Implementation Scheme 12: The method of Implementation Scheme 1, wherein the method includes administering 10 mg of compound A to the subject.

[0395] Implementation Scheme 13: The method of Implementation Scheme 1 or 2, wherein the method includes administering 20 mg of compound A to the subject.

[0396] Implementation Scheme 14: The method of any one of Implementation Schemes 1 to 3, wherein the method includes administering 40 mg of compound A to the subject.

[0397] Implementation Scheme 15: The method of any one of Implementation Schemes 1 to 4, wherein the method includes administering 80 mg of compound A to the subject.

[0398] Implementation Scheme 16: The method of any one of Implementation Schemes 1 to 5, wherein the method includes administering 120 mg of compound A to the subject. Instructions for Use, Pages 73 / 82, CN 121693329 A

[0399] Embodiment 17: The method of any one of Embodiments 1 to 6, wherein the method includes administering 160 mg of compound A to the subject.

[0400] Embodiment 18: The method of any one of Embodiments 1 to 6, wherein the method includes administering 200 mg of compound A to the subject.

[0401] Embodiment 19: The method of any one of Embodiments 1 to 7, wherein the method includes administering 220 mg of compound A to the subject.

[0402] Embodiment 20: The method of any one of Embodiments 1 to 8, wherein the method includes administering 250 mg of compound A to the subject.

[0403] Embodiment 21: The method of any one of Embodiments 1 to 9, wherein the method includes administering 300 mg of compound A to the subject.

[0404] Embodiment 22: The method of any one of Embodiments 1 to 9, wherein the method includes administering 350 mg of compound A to the subject.

[0405] Embodiment 23: The method of any one of embodiments 1 to 10, wherein the method includes administering 400 mg of compound A to the subject.

[0406] Embodiment 24: The method of any one of embodiments 1 to 11, wherein the method includes administering 450 mg of compound A to the subject.

[0407] Embodiment 25: The method of any one of embodiments 1 to 11, wherein the method includes administering 500 mg of compound A to the subject.

[0408] Implementation Scheme 26: The method of any one of Implementation Schemes 1 to 25, wherein compound A is administered once or more daily.

[0409] Implementation Scheme 27: The method of Implementation Scheme 26, wherein compound A is administered to the subject once daily.

[0410] Implementation Scheme 28: The method of any one of Implementation Schemes 1 to 13, wherein compound A is administered to the subject daily for one or more days per week.

[0411] Implementation Scheme 29: The method of any one of Implementation Schemes 1 to 13, wherein compound A is administered to the subject once daily for four days per week.

[0412] Implementation Scheme 30: The method of Implementation Scheme 29, wherein compound A is administered to the subject once daily on days 1, 2, 3, 4, 5, 6, and 7 of every seven days.

[0413] Implementation Scheme 31: The method of any one of Implementation Schemes 1 to 13, wherein compound A is administered to the subject six days per week.

[0414] Implementation Scheme 32: The method of any one of Implementation Schemes 1 to 13, wherein compound A is administered to the subject five days per week.

[0415] Embodiment 33: The method of any one of Embodiments 1 to 32, wherein the RAS protein-associated condition is a RAS lesion.

[0416] Embodiment 34: The method of any one of Embodiments 1 to 33, wherein the RAS protein-associated condition is cancer.

[0417] Embodiment 35: The method of Embodiment 34, wherein the cancer comprises a RAS mutation.

[0418] Embodiment 36: The method of Embodiment 35, wherein the RAS mutation is at position 12, 13, or 61.

[0419] Embodiment 37: The method of Embodiment 35 or 36, wherein the RAS mutation is at position 12.

[0420] Embodiment 38: The method of Embodiment 36, wherein the RAS mutation is a mutation selected from the group consisting of: G12C, G12D, G12V, G12R, G12A, G12S, G13C, G13D, and Q61H.

[0421] Embodiment 39: The method of Embodiment 38, wherein the RAS mutation is a mutation selected from the group consisting of: G12D, G12V, G12C, and G12R.

[0422] Embodiment 40: The method of Embodiment 39, wherein the RAS mutation is a mutation selected from the group consisting of: G12D and G12V.

[0423] Embodiment 41: The method of any one of Embodiments 34 to 40, wherein the cancer is pancreatic cancer.

[0424] Embodiment 42: The method of any one of Embodiments 34 to 40, wherein the cancer is lung cancer.

[0425] Embodiment 43: The method of any one of Embodiments 34 to 40, wherein the cancer is colorectal cancer.

[0426] Implementation Scheme 44: The method of any one of Implementation Schemes 34 to 43, wherein the method further comprises administering additional anticancer therapy.

[0427] Implementation Scheme 45: The method of Implementation Scheme 44, wherein the additional anticancer therapy is an EGFR inhibitor, a second RAS inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

[0428] Implementation Scheme 46: The method of Implementation Scheme 44 or 45, wherein the additional anticancer therapy is an SHP2 inhibitor.

[0429] Implementation Scheme 47: The method of Implementation Scheme 44 or 45, wherein the additional anticancer therapy comprises an SHP2 inhibitor and a PD-L1 inhibitor.

[0430] Implementation Scheme 48: The method of Implementation Scheme 44 or 45, wherein the additional therapy comprises a second RAS inhibitor and a PD-L1 inhibitor.

[0431] Embodiment 49: The method of Embodiment 45 or 48, wherein the second RAS inhibitor is a KRASG12C inhibitor.

[0432] Embodiment 50: The method of Embodiment 48 or 49, wherein the second RAS inhibitor is a KRASG12C(ON) inhibitor.

[0433] Embodiment 51: The method of Embodiment 48 or 49, wherein the second RAS inhibitor is a KRASG12C(OFF) inhibitor.

[0434] Embodiment 52: The method of Embodiment 48 or 49, wherein the second RAS inhibitor is a KRASG12D(ON) inhibitor.

[0435] Embodiment 53: The method of Embodiment 48 or 49, wherein the second RAS inhibitor is a KRASG12V(ON) inhibitor.

[0436] Embodiment 54: The method of Embodiment 48 or 49, wherein the second RAS inhibitor is a KRASG12D(OFF) inhibitor.

[0437] Embodiment 55: The method of Embodiment 44 or 45, wherein the additional anticancer therapy is pembrolizumab or a biosimilar thereof.

[0438] Embodiment 56: The method of Embodiment 44 or 45, wherein the additional anticancer therapy is cetuximab or a biosimilar thereof.

[0439] Embodiment 57: A method of treating a subject with non-small cell lung cancer, the method comprising administering to the subject 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A, wherein the cancer comprises a G12X RAS mutation.

[0440] Implementation Scheme 58: A method of treating a subject with non-small cell lung cancer, the method comprising administering to the subject 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A, wherein the cancer comprises a G13X RAS mutation. Specification 75 / 82 pages 79 CN 121693329 A

[0441] Implementation Scheme 59: A method of treating a subject with non-small cell lung cancer, the method comprising administering to the subject 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A, wherein the cancer comprises a Q61X RAS mutation.

[0442] Embodiment 60: A method of treating pancreatic ductal adenocarcinoma in a subject of need, the method comprising administering to the subject 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A, wherein the cancer comprises a G12X RAS mutation.

[0443] Embodiment 61: A method of treating pancreatic ductal adenocarcinoma in a subject of need, the method comprising administering to the subject 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A, wherein the cancer comprises a G13X RAS mutation.

[0444] Embodiment 62: A method of treating pancreatic ductal adenocarcinoma in a subject of need, the method comprising administering to the subject 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A, wherein the cancer comprises a Q61X RAS mutation.

[0445] Embodiment 63: A method of treating colorectal cancer in a subject of need, the method comprising administering to the subject 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A, wherein the cancer comprises a G12X RAS mutation.

[0446] Embodiment 64: A method of treating a subject with colorectal cancer, the method comprising administering to the subject 200 mg to 400 mg, 225 mg to 375 mg, 250 mg to 350 mg, or 275 mg to 325 mg of compound A, wherein the cancer comprises a G...

Claims

1. A method of treating cancer in a human subject in need thereof, the method comprising orally administering to the subject 10 mg to 500 mg of Compound A: Compound A or a pharmaceutically acceptable salt thereof, per day.

2. The method of claim 1, wherein the method comprises administering to the subject 120 mg to 500 mg of Compound A.

3. The method of claim 1, wherein the method comprises administering to the subject 160 mg to 500 mg of Compound A.

4. The method of claim 1, wherein the method comprises administering to the subject 250 mg to 500 mg of Compound A.

5. The method of claim 1, wherein the method comprises administering to the subject 300 mg to 500 mg of Compound A.

6. The method of claim 1, wherein the method comprises administering to the subject 400 mg to 500 mg of Compound A.

7. The method of claim 1 or claim 2, wherein the method comprises administering to the subject 120 mg of Compound A.

8. The method of any one of claims 1 to 3, wherein the method comprises administering to the subject 160 mg of Compound A.

9. The method of any one of claims 1 to 3, wherein the method comprises administering to the subject 200 mg of Compound A.

10. The method of any one of claims 1 to 4, wherein the method comprises administering to the subject 250 mg of Compound A.

11. The method of any one of claims 1 to 5, wherein the method comprises administering to the subject 300 mg of Compound A.

12. The method of any one of claims 1 to 5, wherein the method comprises administering to the subject 350 mg of Compound A.

13. The method of any one of claims 1 to 6, wherein the method comprises administering to the subject 400 mg of Compound A.

14. The method of any one of claims 1 to 6, wherein the method comprises administering to the subject 450 mg of Compound A.

15. The method of any one of claims 1 to 6, wherein the method comprises administering to the subject 500 mg of Compound A.

16. The method of any one of claims 1 to 15, wherein Compound A is administered to the subject once per day.

17. The method of any one of claims 1 to 16, wherein Compound A is administered 1, 2, 3, 4, 5, 6, or 7 times per week.

18. The method of any one of claims 1 to 17, wherein Compound A is administered to the subject for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months. ​ ​ 19. The method of any one of claims 1 to 18, wherein Compound A is administered in treatment cycles and each treatment cycle is 7 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year.

20. The method of claim 19, wherein the subject undergoes 1, 2, 3, or more treatment cycles.

21. The method of any one of claims 1 to 20, wherein the cancer comprises a RAS mutation.

22. The method of claim 21, wherein the RAS mutation is at position 12, 13, or 61.

23. The method of claim 22, wherein the RAS mutation is a mutation selected from the group consisting of G12C, G12D, G12V, G12R, G12A, G12S, G13C, G13D, and Q61H.

24. The method of any one of claims 1 to 23, wherein the cancer is pancreatic cancer.

25. The method of claim 24, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

26. The method of any one of claims 1 to 23, wherein the cancer is lung cancer.

27. The method of claim 26, wherein the lung cancer is non-small cell lung cancer (NSCLC).

28. The method of any one of claims 1 to 23, wherein the cancer is colorectal cancer.

29. The method or use of any one of claims 1 to 6, wherein the method further comprises administering an additional anti-cancer therapy.

30. A method of treating pancreatic ductal adenocarcinoma (PDAC) in a human subject in need thereof, the method comprising orally administering to the subject 120 mg to 500 mg of Compound A: Compound A or a pharmaceutically acceptable salt thereof, per day.

31. The method of claim 30, wherein the subject has previously received at least one cancer therapy.

32. The method of claim 30 or 31, wherein the subject has locally advanced or metastatic PDAC.

33. The method of any one of claims 30 to 32, wherein the PDAC comprises wild-type RAS or a RAS mutation at position 12, 13, or 61, or a combination thereof.

34. A method of treating non-small cell lung cancer (NSCLC) in a human subject in need thereof, the method comprising orally administering to the subject 120 mg to 500 mg of Compound A: Compound A or a pharmaceutically acceptable salt thereof, per day.

35. The method of claim 34, wherein the subject has previously received at least one cancer therapy.

36. The method of claim 34 or 35, wherein the subject has locally advanced or metastatic NSCLC. Compound A 37. The method of any one of claims 34 to 36, wherein the NSCLC comprises wild-type RAS or a RAS mutation at position 12, 13, or 61, or a combination thereof. ​ ​ ​

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