Methods of treating advanced solid tumors

Abstract

Provided herein are methods of treating advanced solid tumors using a compound of Formula (I) or a pharmaceutically acceptable form thereof, including methods of treating advanced solid tumors using a compound of Formula (I) or a pharmaceutically acceptable form thereof in combination with a VEGFR inhibitor.

Description

[0001] 1. Cross-reference

[0002] This application claims the priority benefits of U.S. Provisional Application No. 63 / 476,604, filed on December 21, 2022, U.S. Provisional Application No. 63 / 501,108, filed on May 9, 2023, and U.S. Provisional Application No. 63 / 582,448, filed on September 13, 2023, which are hereby incorporated by reference in their entireties. 2. Technical Field

[0003] Provided herein are methods for treating, preventing, or managing advanced solid tumors using a combination of a farnesyltransferase inhibitor and a vascular endothelial growth factor receptor (VEGFR) inhibitor, wherein the farnesyltransferase inhibitor is a compound of formula (I):

[0004]

[0005] or a pharmaceutically acceptable form thereof, and the vascular endothelial growth factor receptor (VEGFR) inhibitor such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzalintinib, or a pharmaceutically acceptable form thereof. Further provided herein are methods for using a compound of formula (I) or a pharmaceutically acceptable form thereof to reduce tyrosine kinase inhibitor (TKI) resistance, slow the progression of TKI resistance, or overcome TKI resistance in a subject with advanced solid tumors who is currently being treated with or has previously been treated with a TKI. Also provided herein are methods for using a compound of formula (I) or a pharmaceutically acceptable form thereof to prevent or delay the emergence of TKI resistance in a subject with advanced solid tumors who has not received TKI treatment.

[0006] The present invention also provides methods of treating advanced solid tumors having HRAS amplification and / or HRAS overexpression (optionally in combination with an HRAS mutation) with a compound of formula (I) or a pharmaceutically acceptable form thereof. The present invention also provides methods of treating, preventing or managing advanced solid tumors having a squamous histological architecture and HRAS amplification and / or HRAS overexpression (optionally in combination with an HRAS mutation) with a compound of formula (I) or a pharmaceutically acceptable form thereof. The present invention also provides methods of treating, preventing or managing advanced solid tumors having NRAS amplification and / or NRAS overexpression (optionally in combination with an NRAS mutation) with a compound of formula (I) or a pharmaceutically acceptable form thereof. In some aspects, the advanced solid tumor is (a) an advanced solid tumor having HRAS amplification, (b) HNSCC having HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer or pancreatic ductal adenocarcinoma having NRAS or HRAS amplification. 3. Background Art

[0007] Angiogenesis plays an important role in tumor progression, as new blood vessels support tumor growth, provide oxygen and nutrients to proliferating tumor cells, and facilitate metastasis formation. Notable angiogenesis inhibitors target the vascular endothelial growth factor (VEGF) signaling pathway and include VEGF receptor (VEGF) inhibitors, mainly VEGFR-2. Receptor tyrosine kinases and VEGFR mediate a series of signaling pathways in endothelial cells, such as the Ras / Raf, MEK / MAPK, phosphatidylinositol 3'-kinase (PI3K), Akt / PKB and mTOR pathways, which are involved in normal cell functions and pathological processes, such as tumorigenesis, proliferation, migration, metastasis, tumor angiogenesis, drug resistance and maintenance of the tumor microenvironment.

[0008] Inhibitors of this class have shown clinical efficacy in a wide variety of tumor types, including renal cell carcinoma, thyroid cancer, hepatocellular carcinoma, and gastrointestinal stromal tumors (GIST). Several small molecule VEGFR inhibitor therapies have been approved for the treatment of such cancers and include cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanubrutinib. VEGFR inhibitors can exhibit inhibitory activity against one or more VEGFR isoforms and can be multi-target kinase inhibitors with activity against additional receptor tyrosine kinases such as FGFR-1, -2, -3, or -4, PDGFR-α or -β, KIT, RET, MET, AXL, ROS1, TYRO3, MER, TRKB, FLT-3, TIE-2, DDR2, TRKA, EPH2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, ABL, FGFR-1 or -3, Itk, Lck, c-Fms, or CSF-1R, or combinations thereof. The platelet-derived growth factor (PDGF) family is also involved in tumor angiogenesis. Certain anti-angiogenic kinase inhibitors are inhibitors of both VEGFR and PDGFR signaling. VEGFR inhibitors can be type 1 kinase inhibitors that recognize the active conformation of the kinase (e.g., sunitinib), type II inhibitors that recognize the inactive conformation of the kinase (such as sorafenib), or covalent inhibitors (such as vandetanib).

[0009] Although anti-angiogenic VEGFR inhibitors have proven to be clinically useful, preclinical and clinical studies have revealed resistance to these drugs. Modulation of downstream signaling pathways by VEGFR inhibitors can induce resistance by driving the development of other pathways used to stimulate angiogenesis, such as AXL, MET, and PDGF / PDGFR, allowing cancer cells to evade VEGF / VEGFR blockade. In some instances, initial clinical responses are followed by tumor progression due to acquired drug resistance, while in other instances, tumors are intrinsically resistant to the inhibitor. In addition, treatment with anti-angiogenic drugs can lead to severe toxicities, including severe bleeding, impaired wound healing, gastrointestinal perforation, hypertension, fatigue, and QT prolongation.

[0010] Renal cell carcinoma (RCC) is the most common type of kidney cancer, with approximately 400,000 patients diagnosed globally each year, and it caused more than 180,000 deaths in 2020. Nearly one-third of newly diagnosed cases have unresectable advanced or metastatic disease at the time of diagnosis, and 20% to 30% of patients with local tumors will ultimately relapse after nephrectomy. The 5-year survival rate for patients with advanced RCC is 12%. Most RCC diagnoses (approximately 80%) fall into the clear cell renal cell carcinoma (ccRCC) category, which is a highly vascularized tumor type, most commonly due to inactivation of the Von Hippel-Lindau (VHL) gene. Loss of VHL stabilizes hypoxia-inducible factor α protein (HIFα), thereby driving the hypoxic transcriptional response, including induction of VEGF and PDGF2, which mediate tumor angiogenesis.

[0011] Anti-angiogenic TKIs, such as sunitinib (which primarily targets VEGFR and PDGFR) and axitinib (a specific inhibitor of VEGFR-1, -2, and -3), have shown therapeutic benefit in patients with ccRCC by exploiting the tumor's dependence on blood vessels for oxygen, nutrients, and growth factors. Sunitinib is the most commonly used TKI, but only 20% to 30% of patients respond to initial treatment, and nearly all initial responders develop resistance within two years. Anti-angiogenic TKI strategies have also been successfully applied to other tumor types, such as thyroid cancer, hepatocellular carcinoma, and neuroendocrine tumors. However, as noted above, resistance to TKIs typically develops, leading to disease progression.

[0012] Anti-angiogenic VEGFR inhibitors have been approved for clinical use in a series of advanced solid tumors. Cabozantinib is an inhibitor of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3 and TIE-2, and has been approved for the treatment of thyroid cancer, renal cell carcinoma and hepatocellular carcinoma. Lenvatinib is an inhibitor of VEGFR-1, -2 and -3, as well as FGFR-1, -2, -3 and -4, PDGFR-α, KIT and RET, and has been approved for the treatment of certain types of thyroid cancer, renal cell carcinoma, hepatocellular carcinoma and endometrial cancer. Axitinib is an inhibitor of VEGFR-1, -2 and -3, and has been approved for the treatment of renal cell carcinoma. Regorafenib is an inhibitor of VEGFR-1, -2 and -3, RET, KIT, PDGFR-α, PDGFR-β, FGFR-1 and -2, TIE-2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, Abl and CSF-1R, and has been approved for the treatment of colorectal cancer, hepatocellular carcinoma and GIST. Vandetanib is an inhibitor of VEGFR and its EGFR family members, RET, BRK, TIE-2, as well as EPH receptors and Src kinase family members, and has been approved for the treatment of thyroid cancer. Pazopanib is an inhibitor of VEGFR-1, -2 and -3, PDGFR-α and -β, FGFR-1 and -3, Kit, Itk, Lck and c-Fms, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Sunitinib is an inhibitor of VEGFR-1, -2 and -3, PDGFR-α and -β, KIT, FLT3, CSF-1R and RET, and has been approved for the treatment of renal cell carcinoma, GIST and pancreatic neuroendocrine tumors. Sorafenib is an inhibitor of VEGFR-1, -2 and -3, PDGFR-β, c-CRAF, BRAF, mutant BRAF, KIT, FLT-3, RET and RET / PTC, and has been approved for the treatment of renal cell carcinoma, hepatocellular carcinoma and thyroid cancer. Tivozanib is an inhibitor of VEGFR-1, -2 and -3, PDGFR-β and c-kit, and has been approved for the treatment of renal cell carcinoma. Zanazrutinib (e.g., zanazrutinib fumarate) is an inhibitor of tyrosine kinases such as MET, VEGFR, AXL and MER. Fruquintinib (e.g., fruquintinib free base) is an inhibitor of VEGFR-1, -2 and -3, and has been approved for the treatment of colorectal cancer, particularly metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, as well as anti-VEGF therapy, and anti-EGFR therapy (if RAS wild-type and medically appropriate).

[0013] Farnesylation is essential for the function of more than 140 proteins; however, due to compensatory mechanisms (including geranylgeranyltransferase type 1-mediated prenylation of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS)), blockade of farnesylation does not always significantly affect protein function. However, Harvey rat sarcoma viral oncogene homolog (HRAS) cannot be geranylgeranylated, and in in vitro and in vivo studies, the membrane localization and cellular functions (e.g., oncogenic signaling) of HRAS are suppressed by the selective non-peptidic farnesyltransferase inhibitor (FTI) tipifarnib. In patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC), HRAS-dependent tumors have been shown to be highly sensitive to FTI treatment. In addition, tipifarnib has shown a high response rate and good long-term outcomes in patients with HRAS-mutant HNSCC. Furthermore, tumor cell lines and mouse models of NRAS-dependent tumors have been shown to respond to tipifarnib, which inhibits angiogenesis and suppresses cell and tumor growth and induces apoptosis, which is associated with inhibition of farnesylation targets (including NRAS) (End et al., Cancer Res. 2001, 61, 131-137).

[0014] Although mutations are important drivers of tumor biology, there are other factors that can regulate tumor growth and survival, including overexpression of non-mutated oncogenic signaling proteins and the influence of the tumor microenvironment. For example, alterations in HRAS, KRAS, and / or NRAS are expressed in approximately 30% of human tumors. The Cancer Genome Atlas (TCGA) shows that HRAS is overexpressed in 25% to 30% of patients with HNSCC, suggesting a potential dependence on HRAS, which may be similar to HRAS acting as a driver oncogene in a broader HNSCC population ("cBioPortal for Cancer Genomics" (2020), https: / / www.cbioportal.org / ). High prevalence of oncogenic HRAS mutations and high levels (e.g., overexpression) of HRAS RNA and protein have been observed in multiple tumor types with squamous histology independent of the tumor origin site (e.g., esophagus, head and neck, lung, etc.), but such alterations also occur in non-squamous tumor types. Alterations in NRAS have been observed in a range of solid tumor types such as melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, small cell lung cancer), breast cancer, ovarian cancer, pancreatic cancer (e.g., carcinoma or ductal adenocarcinoma), glioma, HNSCC, and thyroid cancer, as well as other tumor types such as leukemia and lymphoma.

[0015] There is still a need in the art for therapies and regimens for the treatment of advanced solid tumors, including their metastatic, recurrent, or refractory forms. Similarly, there is still a need to reduce, avoid, delay, or overcome drug resistance associated with existing therapies, including existing therapies for the treatment of advanced solid tumors, as much as possible. The methods provided herein address one or more of the above - noted problems associated with the treatment of advanced solid tumors. 4. SUMMARY OF THE INVENTION

[0016] In one aspect, there is provided a method for treating advanced solid tumors in a subject, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same) and a VEGFR inhibitor.

[0017] In another aspect, there is provided a method for reducing drug resistance of advanced solid tumors in a subject, slowing the progression of drug resistance of advanced solid tumors in a subject, or overcoming drug resistance of advanced solid tumors in a subject, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same) and a VEGFR inhibitor.

[0018] In yet another aspect, there is provided a method for preventing or delaying the emergence of TKI drug resistance in advanced solid tumors in a subject who has not received TKI treatment, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same) and a VEGFR inhibitor.

[0019] In another aspect, there is provided a pharmaceutical composition comprising (a) a compound of formula (I) or a pharmaceutically acceptable form thereof and (b) a VEGFR inhibitor.

[0020] In another aspect, there is provided a drug kit comprising (a) a compound of formula (I) or a pharmaceutically acceptable form thereof and (b) a VEGFR inhibitor.

[0021] In another aspect, there is provided a drug package comprising: (1) (a) a compound of formula (I) or a pharmaceutically acceptable form thereof and (b) a VEGFR inhibitor; or (2) (a) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, excipient, or diluent, and (b) a pharmaceutical composition comprising a VEGFR inhibitor and a pharmaceutically acceptable carrier, excipient, or diluent.

[0022] In another aspect, there is provided a method for treating a subject with advanced solid tumors having HRAS amplification and / or HRAS overexpression (optionally in combination with an HRAS mutation), which comprises administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same). In another aspect, there is provided a method for treating a subject with advanced solid tumors having a squamous histological architecture and HRAS amplification and / or HRAS overexpression (optionally in combination with an HRAS mutation), which comprises administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same).

[0023] In another aspect, there is provided a method for treating a subject with advanced solid tumors having NRAS amplification and / or NRAS overexpression (optionally in combination with an NRAS mutation), which comprises administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same).

[0024] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof for use in the methods described herein. 5. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 : Tumor volume plots over time for the treatment of A498 RCC CDX with a compound of formula (I), axitinib, or a combination.

[0026] Figure 2 : Tumor volume plots over time for the treatment of KI-12-0073 RCC PDX with a compound of formula (I), axitinib, or a combination.

[0027] Figures 3A - 3B : Combination treatment with a compound of formula (I) and cabozantinib inhibited tumor growth in the RCC CDX model. Figure 3A : 786-O CDX treated with a compound of formula (I) (20 mg / kg, BID) and cabozantinib (20 mg / kg, QD) (lane 3) compared to treatment with the compound of formula (I) alone (lane 1) or cabozantinib alone (lane 2); Figure 3B : A498 CDX treated with a compound of formula (I) and cabozantinib (8 or 20 mg / kg, QD respectively) (lanes 4 and 5) compared to treatment with the compound of formula (I) alone (lane 1) or cabozantinib alone (lanes 2 and 3).

[0028] Figures 4A - 4F: For the compound of formula (I), cabozantinib, and the combination, the combination of the compound of formula (I) and cabozantinib inhibited tumor growth in RCC PDX and CDX models. Tumor volume plots over time in the KI-12-0073 VHL-mutant ccRCC PDX model ( Figure 4A ), and plots of percent change in tumor volume ( Figure 4B ); Tumor volume plots over time in the 786-O CDX model ( Figure 4C ), and plots of percent change in tumor volume ( Figure 4D ); and Tumor volume plots over time in the KI-0326 VHL-mutant ccRCC PDX model ( Figure 4E ), and plots of percent change in tumor volume ( Figure 4F ).

[0029] Figure 5 : Plot of percent change in tumor volume on day 28 relative to day 0 in mice bearing 786-O VHL-mutant CDX treated with the compound of formula (I) (20 mg / kg, BID) and cabozantinib (4, 8, 10, or 12 mg / kg, QD), either alone or in combination.

[0030] Figure 6 : Tumor volume plots over time in 786-O CDX mice treated with cabozantinib, the compound of formula (I), lenvatinib, lenvatinib plus everolimus, the compound of formula (I) plus cabozantinib, and the compound of formula (I) plus lenvatinib.

[0031] Figure 7 : Tumor volume plots over time in 786-O CDX mice treated with the compound of formula (I), cabozantinib, axitinib, or a combination of the compound of formula (I) and cabozantinib.

[0032] Figure 8 : Immunoblot of cell signaling markers from 786-O CDX cells following treatment with cabozantinib, the compound of formula (I), or the combination.

[0033] Figures 9A - 9C : Plots of percent cell viability of HUVEC cells treated with different concentrations of the compound of formula (I) and different concentrations of cabozantinib ( Figure 9A ), axitinib ( Figure 9B ), or lenvatinib ( Figure 9C ).

[0034] Figure 10 A-10F: The combination of the compound of formula (I) with axitinib or cabozantinib inhibited tube formation in HUVEC cells. Figure 10 A: Vehicle;Figure 10 B: Axitinib; Figure 10 C: Cabozantinib; Figure 10 D: Compound of formula (I); Figure 10 E: Axitinib and Compound of formula (I); Figure 10 F: Cabozantinib and Compound of formula (I).

[0035] Figures 11A - 11B : GFP imaging of the effect on tube formation in GFP-labeled HUVEC cells treated with vehicle, Compound of formula (I), Cabozantinib, or combinations Figure 11A ) and graphs of the number of primary segments and total primary segment length Figure 11B ).

[0036] Figure 12 : Graph of cell death over time (expressed as percentage normalized to baseline) in HUVEC cells treated with Compound of formula (I), Cabozantinib, or combinations (using staurosporine as a control).

[0037] Figure 13 : Immunoblot of HRAS levels in SCC9 and HSC3 cells after GTP pull-down.

[0038] Figure 14 : Graph of tumor volume over time for vehicle and Compound of formula (I) in a patient-derived xenograft model of HN2594 (HRAS WT-高 ).

[0039] Figure 15 : Graph of tumor volume over time for vehicle and different doses of Compound of formula (I) in a patient-derived xenograft model of HN2576 (HRAS WT-高 ) HNSCC.

[0040] Figure 16 : Graph of tumor volume over time for vehicle and different doses of Compound of formula (I) in a patient-derived xenograft model of HN2594 (HRAS WT-高 ) HNSCC. 6. DETAILED DESCRIPTION

[0041] All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, unless otherwise defined. If a term has more than one definition herein, the definition in this section shall control, unless otherwise stated.

[0042] As used herein, in the specification and the appended claims, the indefinite articles "a / an" and the definite article "the" include both plural and singular referents, unless the context clearly indicates otherwise.

[0043] As used herein and unless otherwise indicated, the terms "about" and "approximately" when used in connection with the dosage, amount, or weight percentage of a component of a composition or dosage form mean a dosage, amount, or weight percentage within 30%, 20%, 15%, 10%, or 5% of the specified dosage, amount, or weight percentage.

[0044] As used herein, "pharmaceutically acceptable forms" of the compounds disclosed herein include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopomers (i.e., isotopically labeled derivatives) of the compounds disclosed herein, including combinations thereof (e.g., solvates of pharmaceutically acceptable salts, or isomers and / or isotopomers of the compound or solvate, or solvates of salts of such compounds). In some embodiments, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers (e.g., tautomers or stereoisomers), and isotopomers (i.e., isotopically labeled derivatives) of the compounds of formula (I) as disclosed herein.

[0045] The term "isomer" as used herein includes stereoisomers or tautomers as defined herein. As used herein, the term "stereoisomer" is understood to mean isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomer" includes geometric double bond cis- and trans-isomers (also known as E- and Z-isomers); R- and S-enantiomers; diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof; and other mixtures thereof that fall within the scope of the present disclosure.

[0046] As used herein and unless otherwise indicated, the term "stereoisomerically pure" means that a stereoisomer of a compound is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. In some embodiments, the compound of formula (I) is stereoisomerically pure (i.e., (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocycloheptene-2 2 ,4 4 -dicarbonitrile), which is substantially free of the compound of formula (II) (i.e., (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocycloheptene-2 2 ,4 4-dicarbonitrile). The stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds comprise greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compound may have chiral centers and may occur in the form of a racemate, an individual enantiomer or a diastereomer, and mixtures thereof. All such isomeric forms (including mixtures thereof) are included in the embodiments provided herein.

[0047] It is understood that the compounds provided herein may contain chiral centers. Such chiral centers may be in the (R) configuration or the (S) configuration, or may be a mixture thereof. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, those skilled in the art will recognize that for compounds that undergo epimerization in vivo, administration of the (R) form of the compound is equivalent to administration of the (S) form of the compound.

[0048] The optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography on a chiral stationary phase.

[0049] The embodiments provided herein encompass the use of stereoisomerically pure forms of such compounds and the use of mixtures of such forms. For example, mixtures containing equal or unequal amounts of the enantiomers of a particular compound can be used in the methods and compositions provided herein. These isomers can be synthesized asymmetrically or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., (Wiley-Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0050] In certain embodiments, the pharmaceutically acceptable form is an atropisomer. Atropisomers are stereoisomers that arise due to hindered rotation about a single bond axis where the rotational barrier is sufficient to permit the isolation of the rotational isomers.

[0051] In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" refers to a class of isomers that includes two or more interconvertible compounds, which are generated by at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a double bond, or a triple bond becomes a single bond, or vice versa). "Tautomerization" includes prototropy or prototropic tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" involves the migration of a proton accompanied by a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. When tautomerization can occur (e.g., in solution), the tautomers can reach chemical equilibrium. Tautomerization (i.e., the reaction that provides tautomeric pairs) can be catalyzed by an acid or a base, or can occur in the absence or presence of external factors. The concentration of the isomeric forms will depend on the environment in which the compound is present and may vary, for example, depending on whether the compound is a solid or in an organic or aqueous solution. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(different) enamine tautomerization. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms that are referred to as tautomers of each other:

[0052]

[0053] As will be readily appreciated by those skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of a compound are within the scope of the compounds provided herein.

[0054] In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable" refers to those salts that are within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts in detail (see J. Pharm. Sci. (1977) 66:1-19). Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases (such as suitable inorganic and organic addition acids and bases).

[0055] In certain embodiments, the pharmaceutically acceptable forms of the compounds disclosed herein do not include the salt forms of the compounds disclosed herein (i.e., are not salts of the compounds disclosed herein), and are sometimes referred to as the free form or free base form. In some embodiments, they are solvates of such free base forms.

[0056] In certain embodiments, the compounds as described herein are in the form of solvates (e.g., hydrates). As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate can be the disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". In some embodiments, the solvate is a hydrate. Pharmaceutically acceptable solvates and hydrates are complexes that can, for example, include 0.1, 0.25, 0.50, 0.75, or 1 solvent or water molecule, or can include from 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein encompasses the compound (or its pharmaceutically acceptable salt) and the solvate of the compound or its pharmaceutically acceptable salt, as well as mixtures thereof.

[0057] The term "isotopologue" refers to an isotope-enriched compound that is identical to those described herein, but with one or more atoms replaced by atoms having an atomic mass or mass number different from that of the atoms typically found in nature. Unless otherwise indicated, the structures depicted herein are also intended to include such compounds that differ only in the presence of one or more isotope-enriched atoms. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 35 Cl, 36 Cl and 37Cl, each of these is also within the scope of this specification. For example, compounds having the structure of the present invention (but with hydrogen on one or more atoms in the molecule replaced or enriched with deuterium or tritium) are within the scope of the present disclosure. In one embodiment, isotopically labeled compounds are provided herein in which one or more hydrogen atoms are replaced or enriched with deuterium. When a compound is enriched with deuterium, the deuterium-to-hydrogen ratio of the deuterated atoms in the molecule is significantly greater than the naturally occurring deuterium-to-hydrogen ratio. In one embodiment, isotopically labeled compounds are provided herein in which one or more hydrogen atoms are replaced or enriched with tritium. Further, replacement with a heavier isotope such as deuterium (i.e., 2 H) can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose). The isotopically labeled compounds disclosed herein can generally be prepared by replacing a non-isotopically labeled reagent with an isotopically labeled reagent. Isotopically enriched compounds can generally be prepared by replacing a non-isotopically enriched reagent with an appropriately isotopically enriched reagent using procedures known to those of ordinary skill in the art. The embodiments described herein can include isotopologue forms, in which the isotopologue is replaced with one or more deuterium atoms that replace one or more hydrogen atoms on one or more atomic members of the compound. The embodiments described herein can include compounds in which a carbon atom can have 1 to 3 hydrogen atoms optionally replaced with deuterium.

[0058] As used herein, the compounds disclosed herein include, but are not limited to, their free base forms or pharmaceutically acceptable salts, and their solvates or hydrates, as well as isotopologues (i.e., isotopically labeled derivatives) of such compounds. In some embodiments, the free base or pharmaceutically acceptable salt of the compound of formula (I), or the hydrate or solvate and / or isotopologue (i.e., isotopically labeled derivative) or similar form of the VEGFR inhibitor is contemplated.

[0059] It should be noted that if there is a difference between the depicted structure and the name of the structure, the depicted structure shall be given more weight.

[0060] As used herein, the term "pharmaceutically acceptable carrier, excipient or diluent" means a carrier, excipient or diluent that is approved by a federal regulatory agency or a state government or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals and more particularly in humans. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), excipient or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a particular carrier for pharmaceutical compositions administered intravenously. Aqueous saline solutions as well as aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutically acceptable carrier, excipient or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions. Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants and lubricants.

[0061] As used herein, the term "VEGFR inhibitor" means a small molecule compound that inhibits one or more VEGFR isoforms (e.g., VEGFR-1, VEGFR-2, VEGFR-3) in a biochemical or cellular assay and has an IC 50 value less than or equal to 500 nM. In some embodiments, the IC 50Less than or equal to 250 nM, or 150 nM, or 100 nM, or 50 nM, or 30 nM, or 20 nM, or 10 nM, or 5 nM, or 1 nM. The VEGFR inhibitor includes its pharmaceutically acceptable forms. The VEGFR inhibitor can inhibit one or more VEGFR isoforms as well as other targets in addition to VEGF receptors, such as FGFR-1, -2, -3, or -4, PDGFR-α or -β, KIT, RET, MET, AXL, ROS1, TYRO3, MER, TRKB, FLT-3, TIE-2, DDR2, TRKA, EPH2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, ABL, or CSF-1R, or combinations thereof. In some embodiments, the VEGFR inhibitor inhibits at least one VEGFR isoform, as well as at least one of PDGFR-α and PDGFR-β. In some embodiments, the VEGFR inhibitor is a type I kinase inhibitor, or a type II inhibitor, or a covalent inhibitor. The VEGFR inhibitor can be a type I kinase inhibitor (such as sunitinib) that recognizes the active conformation of the kinase, a type II inhibitor (such as sorafenib) that recognizes the inactive conformation of the kinase, or a covalent inhibitor (such as vandetanib). In some embodiments, the VEGFR inhibitor is approved by the US Food and Drug Administration (FDA) or a similar regulatory agency in another jurisdiction for the treatment of renal cell carcinoma, thyroid cancer, hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor, soft tissue sarcoma, pancreatic neuroendocrine tumor, or endometrial cancer. In some embodiments, the advanced solid tumor is squamous cell carcinoma, large cell carcinoma, or adenocarcinoma. Exemplary VEGFR inhibitors include, but are not limited to, cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanidatamab. In some embodiments, the VEGFR inhibitor is cabozantinib, lenvatinib, axitinib, pazopanib, sunitinib, sorafenib, or tivozanib. In some embodiments, the VEGFR inhibitor is zanidatamab. In some embodiments, the VEGFR inhibitor is fruquintinib. In some embodiments, the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib. In some embodiments, the VEGFR inhibitor is cabozantinib. As used herein, a reference to a VEGFR inhibitor or its generic name includes a reference to its pharmaceutically acceptable forms. In some embodiments, the pharmaceutically acceptable forms of the VEGFR inhibitor are cabozantinib (S)-malate, lenvatinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib mesylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanidatamab fumarate.

[0062] As used herein, the term "advanced solid tumor" has its ordinary meaning in the art and refers to an abnormal mass of tissue that does not contain cysts or fluid-filled areas, particularly a tissue disease involving uncontrolled cell growth that can, in some cases, lead to metastasis. Advanced solid tumors can be benign or malignant and can develop in muscle, bone, or body organs. In some embodiments, the advanced solid tumor is renal cell carcinoma (RCC) (such as clear cell RCC, papillary RCC, chromophobe RCC, advanced RCC or unclassified RCC, as well as recurrent or refractory RCC, and RCC after nephrectomy), thyroid cancer (such as medullary thyroid cancer, differentiated thyroid cancer, including locally advanced, metastatic, symptomatic, progressive, and / or radioiodine-refractory forms), hepatocellular carcinoma (including unresectable forms), colorectal cancer (such as metastatic colorectal cancer), gastrointestinal stromal tumor (GIST; including locally advanced, unresectable, or metastatic GIST, and progressive / imatinib-intolerant, e.g., imatinib mesylate-intolerant), soft tissue sarcoma (including advanced soft tissue sarcoma), pancreatic neuroendocrine tumor (including progressive, well-differentiated, locally advanced, and metastatic forms), or endometrial cancer. In some embodiments, the advanced solid tumor is squamous cell carcinoma, large cell carcinoma, or adenocarcinoma. In some embodiments, the advanced solid tumor is thyroid cancer, thyroid carcinoma, head and neck cancer, head and neck squamous cell carcinoma, urothelial carcinoma, salivary gland carcinoma, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, brain cancer, gastric cancer, prostate cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, colorectal cancer, skin cancer, melanoma, liver cancer, pancreatic cancer, or pancreatic ductal cell carcinoma. In some embodiments, the advanced solid tumor is melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, small cell lung cancer), breast cancer, ovarian cancer, pancreatic cancer (e.g., carcinoma or ductal adenocarcinoma), glioma, HNSCC, or thyroid cancer.

[0063] In some embodiments, the advanced solid tumor having HRAS amplification and / or HRAS overexpression (optionally in combination with an HRAS mutation) is HNSCC. In some embodiments, the advanced solid tumor has HRAS amplification. In some embodiments, the advanced solid tumor overexpresses HRAS. In some embodiments, the advanced solid tumor has a squamous histological architecture. In some embodiments, the advanced solid tumor has NRAS amplification and / or NRAS overexpression. In some aspects, the advanced solid tumor is (a) an advanced solid tumor having HRAS amplification, (b) HNSCC having HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma having NRAS or HRAS amplification. In some embodiments, the advanced solid tumor is metastatic, advanced, recurrent, unresectable, refractory, or a combination thereof.

[0064] As used herein, the term “HNSCC” refers to head and neck squamous cell carcinoma (HNSCC). Head and neck squamous cell carcinoma (HNSCC) is the seventh most common invasive cancer globally, with approximately 830,000 new diagnosed cases and 200,000 deaths globally each year, and approximately 54,000 new cases in the United States each year. It is also the most common cancer in Central Asia. HNSCC has two different etiologies and corresponding tumor types. The first subtype is associated with smoking and alcohol consumption and is independent of human papillomavirus (HPV or HPV negative). The second subtype is associated with high-risk HPV infection (HPV+ or HPV positive). The second subtype is mainly limited to oropharyngeal cancer. HPV+ tumors are a unique entity with a better prognosis and may require differential treatment. A significant proportion of HNSCC, particularly oropharyngeal cancer, is caused by HPV infection. The high-risk HPV subtype 16 accounts for 85% of all HPV+ tumors in HNSCC. P16 can be used as a surrogate marker for HPV infection in HNSCC, particularly in the oropharynx. More accurate HPV tests are available and are based on E6 / E7 detection (Liang C et al., Cancer Res. 2012;72:5004-5013).

[0065] As used herein and unless otherwise indicated, the term “dysregulated HRAS” or “HRAS dysregulation” refers to a tumor that is dependent on HRAS caused by oncogenic alterations in the RAS pathway, including but not limited to oncogenic HRAS mutations, oncogenic amplification of the HRAS gene, and oncogenic copy number increases of the HRAS gene, or a combination thereof.

[0066] As used herein and unless otherwise indicated, the term “HRAS alteration” refers to a tumor that is dependent on a modified HRAS gene, such as a mutated HRAS gene or an amplified HRAS gene.

[0067] As used herein, the term "overexpression" refers to a tumor that produces an elevated copy number of a protein relative to a reference level. In some embodiments, the overexpressed protein is a wild-type protein. In some embodiments, the overexpressed protein is a mutant protein.

[0068] As used herein, the term "amplification" refers to an increase in the copy number of a gene relative to a reference level. In some embodiments, the amplified gene is a wild-type gene. In some embodiments, the amplified gene is a mutant gene.

[0069] As used herein and unless otherwise indicated, the term "copy gain" refers to gene amplification between diploid (n = 2) and a designated cut-off value for "amplification" of a particular gene (e.g., n = 4, 5, or 6). For example, the designated cut-off value for an amplified HRAS or NRAS gene may be n = 4 or 5 or 6, such that a copy gain of the HRAS or NRAS gene would cover n = 2 to n = 4 or 5 or 6, respectively.

[0070] As used herein, the term "HRAS mutation" or "H-Ras mutation" refers to an activating mutation located in the HRAS gene or the H-Ras protein. An H-Ras mutation can refer to a genetic alteration in the DNA sequence of the HRAS gene that results in the activation of the corresponding H-Ras protein, or an alteration in the amino acid sequence of the H-Ras protein that results in its activation. Thus, as used herein, the term "HRAS mutation" or "H-Ras mutation" does not include alterations in the HRAS gene that do not result in the activation of the H-Ras protein, or alterations in the H-Ras protein sequence that do not result in its activation. Thus, a sample or subject that does not have any "H-Ras mutation" as used herein can still have a mutation in the HRAS gene that does not affect H-Ras protein activity or impairs H-Ras protein activity, or can have a mutation in the H-Ras protein that does not affect its activity or impairs its activity. A sample or subject can have multiple copies of the HRAS gene. A sample or subject can also have both wild-type and mutant H-Ras proteins simultaneously. As used herein, a sample or subject determined to "have wild-type H-Ras" refers to a sample or subject that has only wild-type HRAS gene and wild-type H-Ras protein and no H-Ras mutation. In some embodiments, the mutant HRAS gene encodes a mutant H-Ras protein, wherein the HRAS gene mutation is or includes a modification in a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof in the encoded mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the amino acid substitution at position G12 in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is at the codon encoding the G12R substitution in the mutant H-Ras protein. The HRAS gene mutation can be a mutation at the codon encoding the G12C, G12D, G12A, G12V, G12S, G12F, G12R, or G12N substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the G12V substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the amino acid substitution at position G13 in the mutant H-Ras protein. The HRAS gene mutation can be a mutation at the codon encoding the G13A, G13C, G13V, G13D, G13R, G13S, G13N, or G13V substitution in the mutant H-Ras protein.In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the G13C substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the G13R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding an amino acid substitution at position Q61 in the mutant H-Ras protein. The HRAS gene mutation can be a mutation at the codon encoding the Q61E, Q61K, Q61H, Q61L, Q61P, or Q61R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the Q61L substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the Q61R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding an amino acid substitution at position Q22 in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the Q22K or Q22T substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding an amino acid substitution at position K117 in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the K117N or K117L substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding an amino acid substitution at position A146 in the mutant H-Ras protein. The HRAS gene mutation can be a mutation at the codon encoding the A146V, A146T, or A146P substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at the codon encoding the A146P substitution in the mutant H-Ras protein. In some embodiments, the mutation can be a mutation at another codon that results in activation of the H-Ras protein.

[0071] As used herein and unless otherwise indicated, the term "dysregulated NRAS" or "NRAS dysregulation" refers to a tumor that is dependent on NRAS caused by oncogenic alterations in the RAS pathway, including but not limited to oncogenic NRAS mutations, oncogenic amplification of the NRAS gene, and oncogenic copy number increases of the NRAS gene, or combinations thereof.

[0072] As used herein and unless otherwise indicated, the term "NRAS alteration" refers to a tumor that is dependent on a modified NRAS gene, such as a mutant NRAS gene or an amplified NRAS gene.

[0073] As used herein, the term "NRAS mutation" or "N-Ras mutation" refers to an activating mutation located in the NRAS gene or N-Ras protein, respectively. An N-Ras mutation can refer to a genetic alteration in the DNA sequence of the NRAS gene that results in the activation of the corresponding N-Ras protein, or an alteration in the amino acid sequence of the N-Ras protein that results in its activation. Thus, as used herein, the term "NRAS mutation" or "N-Ras mutation" does not include alterations in NRAS that do not result in the activation of the N-Ras protein, or alterations in the N-Ras protein sequence that do not result in its activation. Thus, a sample or subject that does not have any "N-Ras mutation" as used herein can still have a mutation in the NRAS gene that does not affect the activity of the N-Ras protein or impairs the activity of the H-Ras protein, or can have a mutation in the N-Ras protein that does not affect its activity or impairs its activity. A sample or subject can have multiple copies of the NRAS gene. A sample or subject can also have both wild-type and mutant N-Ras proteins simultaneously. As used herein, a sample or subject determined to "have wild-type N-Ras" refers to a sample or subject that has only wild-type NRAS gene and wild-type N-Ras protein and no N-Ras mutation. In some embodiments, the mutant NRAS gene encodes a mutant N-Ras protein, wherein the NRAS gene mutation is or includes a modification in a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant N-Ras protein. In some embodiments, the modification is a G12C, G12D, G12S, G12V, G12R, Q61H, Q61K, Q61L, Q61R, or A146T substitution.

[0074] Advanced solid tumors can be classified using the tumor node metastasis (TNM) staging system. See Spira, J. & Ettinger, D. S., N. Engl. J. Med., 350: 382 - (2004); Greene et al. (eds.). AJCC Cancer Staging Manual. 6th ed., New York: Springer - Verlag, 2002: 167 - 77; Sobin, L. H. & C. H. Wittekind (eds.). International Union Against Cancer. TNM Classification of malignant tumors. 6th ed., New York: Wiley - Liss (2002). Thus, in some embodiments, advanced solid tumors can be stratified into various stages (e.g., occult, stage 0, stage IA, stage IB, stage IIA, stage IIB, stage IIIA, stage IIIB, or stage IV).

[0075] As used herein and unless otherwise indicated, the terms "recurrent" or "relapsing" refer to a condition, disease, or disorder that responds to treatment (e.g., achieves a partial or complete response) but then progresses. The treatment can include one or more lines of therapy. For example, "recurrent" HNSCC or "relapsing" HNSCC can refer to HNSCC that has been previously treated with one or more lines of therapy. In one embodiment, recurrent HNSCC (or relapsing HNSCC) is HNSCC that has been previously treated with one, two, three, or four lines of therapy. In one embodiment, recurrent HNSCC (or relapsing HNSCC) is HNSCC that has been previously treated with two or more lines of therapy. In another example, an advanced solid tumor may have been treated with one or more TKIs prior to treatment. For example, the condition, disease, or disorder is RCC. In some embodiments, the RCC has been previously treated with one TKI, two TKIs, three TKIs, or at least one TKI.

[0076] As used herein and unless otherwise indicated, the term "refractory" refers to a condition, disease, or disorder that does not respond to prior treatment (which may include one or more lines of therapy). In some embodiments, the condition, disease, or disorder has previously been treated with one, two, three, or four lines of therapy. In some embodiments, the condition, disease, or disorder has previously been treated with two or more lines of therapy and has a response to the most recent regimen containing systemic therapy that is less than a complete response (CR). For example, the condition, disease, or disorder is HNSCC. For example, the condition, disease, or disorder is RCC. In some embodiments, the RCC has previously been treated with one TKI, two TKIs, three TKIs, or at least one TKI.

[0077] As used herein, the terms "prevention / preventing" refer to obtaining a beneficial or desired result, including but not limited to a prophylactic benefit. To obtain a prophylactic benefit, the compounds and pharmaceutical compositions disclosed herein may be administered to a patient at risk of developing advanced solid tumors, a patient reporting one or more of the physical symptoms of advanced solid tumors (even if a diagnosis of advanced solid tumors may not yet have been made), or a patient in remission from advanced solid tumors, according to the methods of treatment provided herein. In some cases, the prophylactic benefit may reduce the risk of recurrence of solid tumors after prior therapy, such as the risk of recurrence of RCC after nephrectomy.

[0078] As used herein and unless otherwise indicated, the term "effective amount" in relation to a compound means an amount capable of treating, preventing, or managing a disorder, disease, or affliction, or a symptom thereof. In some embodiments, an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, an effective amount of a VEGFR inhibitor, and / or an effective amount in the context of their combination can provide one or more benefits according to the treatment methods provided herein. For example, an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, an effective amount of a VEGFR inhibitor, and / or an effective amount in the context of their combination can prevent, treat, and / or improve one or more symptoms associated with advanced solid tumors; can prevent or delay the emergence of drug resistance in advanced solid tumors; can mitigate drug resistance in advanced solid tumors, slow the progression of drug resistance in advanced solid tumors, or overcome drug resistance in advanced solid tumors; can inhibit disease progression or tumor growth, reduce (in size, volume, or degree of metastasis) a primary tumor, relieve tumor-related symptoms, inhibit tumor-secreted factors, delay the emergence of a primary or secondary tumor, delay the time to emergence of drug resistance, slow the development of a primary or secondary tumor, reduce the incidence of a primary or secondary tumor, slow or reduce the severity of secondary effects of a disease, arrest tumor growth, produce tumor regression, increase time to progression (TTP), increase progression-free survival (PFS), increase overall survival (OS), increase overall response rate (ORR, e.g., complete response (CR) and partial response (PR) as determined based on the patient's best tumor response), increase CR rate, increase duration of response (DoR), or decrease time to response (TTR), or any combination thereof. CR, PR, DoR, and PFS can be evaluated according to the RECIST v.1.1 guidelines. In some cases, drug resistance is TKI resistance or VEGFR inhibitor resistance, or resistance to one or more specific VEGFR inhibitors.

[0079] In some embodiments, when describing the dose amount of a compound in the form of a pharmaceutically acceptable salt and / or solvate, the daily dose amount, or the amount in a pharmaceutical composition, pharmaceutical kit, or pharmaceutical package, the amount is expressed as the mass of the compound in its free form (e.g., free base) equivalent (i.e., the form of the compound that does not include the salt and is not solvated). This amount is referred to as the "free form equivalent" or "free base equivalent".

[0080] As used herein, the terms "continuous administration" and "continuous dosing schedule" or "continuous" and "continuously" in the context of administration refer to daily administration, such as once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID) administration of a compound of formula (I) or a pharmaceutically acceptable form thereof, a VEGFR inhibitor, or a combination thereof as disclosed herein.

[0081] As used herein, the term "simultaneously" or "concurrently" in the context of administration refers to the co - administration of two or more agents, such as a compound of formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor, to a subject during a single day, and the co - administration is carried out at times that are close to each other during the course of that day. For example, in certain embodiments, two or more agents are administered concurrently to a subject within 3 hours, 2 hours, 1 hour, 30 minutes, or simultaneously during a single day.

[0082] As used herein, the term "sequentially" or "in sequence" in the context of administration refers to the co - administration of two or more agents (such as a compound of formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor) to a subject during a single day in a specific order (such as in a predetermined order). For example, in certain embodiments, two agents, such as a compound of formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor, are administered concurrently to a subject such that: one agent is administered to the subject first, and then the second agent is administered to the subject on the same day, with no specific time limit, unless otherwise specified, during the course of that same day.

[0083] As used herein, the terms "intermittent dosing" and "intermittent dosing schedule" refer to a schedule in which an agent is administered on certain days and not administered on other days during the course of a treatment cycle (such as during a 28-day treatment cycle). For example, intermittent dosing of an agent (such as a compound of formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor) includes a predetermined dosing period of the agent during the course of a treatment cycle (such as during a 28-day treatment cycle), followed by a predetermined drug holiday period of the agent. For example, intermittent dosing of an agent includes, but is not limited to: administering the agent only every other day during the treatment cycle (such as during a 28-day treatment cycle), administering the agent continuously only every other week (e.g., dosing for one week and then having a one-week drug holiday, or vice versa, such as continuously administering on days 1-7 and days 15-21 of a 28-day treatment cycle, or on days 8-14 and days 22-28 of a 28-day treatment cycle), administering the agent continuously for only two consecutive weeks (e.g., dosing for two weeks and then having a two-week drug holiday, or vice versa, such as continuously administering on days 1-14 of a 28-day treatment cycle, on days 7-21 of a 28-day treatment cycle, or on days 15-28 of a 28-day treatment cycle), or administering the agent continuously for only three consecutive weeks (e.g., dosing for three weeks and then having a one-week drug holiday, or vice versa, such as continuously administering on days 1-21 of a 28-day treatment cycle, or on days 7-28 of a 28-day treatment cycle), or for example, administering the agent continuously for four consecutive weeks during a six-week treatment cycle. For example, in certain embodiments, during the course of a treatment cycle (such as during a 28-day treatment cycle), the compound of formula (I) or a pharmaceutically acceptable form thereof and / or a VEGFR inhibitor as disclosed herein can each independently be administered only every other day, only continuously every other week, or only continuously during week 1, week 2, or week 3.

[0084] As understood herein, a "treatment cycle" refers to a given period of time during which one or more treatments are administered to a subject in need thereof. In some embodiments, the treatment cycle is a 28-day treatment cycle.

[0085] As used herein, the terms “delayed administration,” “delayed dosing period,” and “delayed dosing schedule” refer to the time period between the administration of an initial dose of a VEGFR inhibitor and the subsequent administration of an initial dose of a compound of formula (I) or a pharmaceutically acceptable form thereof to a subject, according to the methods described herein. In some embodiments, the subject is a subject who has not been treated with a VEGFR inhibitor. In some embodiments, the subject has a recurrent or refractory advanced solid tumor. In some embodiments, the subject has a recurrent or refractory advanced solid tumor and has been previously treated with a VEGFR inhibitor that was discontinued prior to the administration of the initial dose of the VEGFR inhibitor. For example, the delayed dosing period can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.25 years, about 1.5 years, about 1.75 years, about 2 years, about 2.25 years, about 2.5 years, about 2.75 years, or about 3 years. For example, in certain embodiments, the delayed dosing period is no longer than about 12 months, about 9 months, about 6 months, about 3 months, about 2 months, about 8 weeks, about 6 weeks, about 5 weeks, about 1 month, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week. In some embodiments, the delayed dosing schedule includes administering the compound of formula (I) or a pharmaceutically acceptable form thereof according to an intermittent dosing schedule after the delayed dosing period.

[0086] As used herein, the terms "dose escalation", "dose escalation interval", "escalated dosing", "escalated dosing period", and "escalated dosing schedule" refer to the stepwise increase in the amount of an agent (such as a compound of formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor) administered to a subject over a period of time (sometimes referred to herein as the dose escalation period). In certain embodiments, the stepwise increase is an increase in the dose amount of the agent administered to the subject. In certain embodiments, the stepwise increase is an increase in the daily dose of the agent administered to the subject. In certain embodiments, the period of time (dose escalation period) over which the stepwise increase is completed is 2 days, 3 days, 7 days (1 week), 10 days, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments, during the dose escalation period, the stepwise increase in the amount of the agent occurs (or is scheduled to occur) every 1 day, 2 days, 3 days, 7 days (1 week), 10 days, or 2 weeks. In certain embodiments, the increase (such as a stepwise increase or a total increase) in the amount of the agent administered to the subject is 10%-99% of the amount of the agent administered to the subject at the start of the dose escalation period, or relative to the previously stepwise increased amount of the agent administered to the subject during the dose escalation period, such as a 10%, 25%, 30%, 33%, 50%, 66%, 75%, 90%, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, or 4-fold increase. In certain embodiments, the final amount of the agent administered at the end of the dose escalation period is an effective amount of the agent, such as an effective amount of the agent administered during a treatment cycle (e.g., a 28-day treatment cycle). In certain embodiments, only the amount of one agent in the combination of agents administered to the subject is stepwise increased over the course of the dose escalation period, while the amounts of the remaining agents in the combination are kept constant. For example, in certain embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable form thereof administered to the subject is increased over the course of the dose escalation period, while the amount of the VEGFR inhibitor administered to the subject is kept constant. In certain embodiments, the amount of the first agent (such as a compound of formula (I) or a pharmaceutically acceptable form thereof) and the amount of the second agent (such as a VEGFR inhibitor) in the combination of agents administered to the subject are each independently stepwise increased over the course of the dose escalation period.

[0087] As used herein, the terms "dose reduction", "dose reduction interval", "reduced dosing", "dose reduction period", and "dose reduction schedule" refer to a stepwise decrease in the amount of an agent (such as a compound of formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor) administered to a subject over a period of time (sometimes referred to herein as the dose reduction period). In certain embodiments, the stepwise decrease is a decrease in the dose amount of the agent administered to the subject. In certain embodiments, the stepwise decrease is a decrease in the daily dose of the agent administered to the subject. In certain embodiments, the period of time (dose reduction period) over which the stepwise decrease occurs is 2 days, 3 days, 7 days (1 week), 10 days, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments, the stepwise decrease in the amount of the agent occurs (or is scheduled to occur) every 1 day, 2 days, 3 days, 7 days (1 week), 10 days, or 2 weeks during the dose reduction period. In certain embodiments, the decrease (such as a stepwise decrease or a total decrease) in the amount of the agent administered to the subject is 10%-99% of the amount of the agent administered to the subject at the start of the dose reduction period, or relative to a prior stepwise-reduced amount of the agent administered to the subject during the dose reduction period, such as a 10%, 25%, 30%, 33%, 50%, 66%, 75%, 90%, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, or 4-fold decrease. In certain embodiments, the final amount of the agent administered at the end of the dose reduction period is an effective amount of the agent, such as an effective amount of the agent administered during a treatment cycle (e.g., a 28-day treatment cycle). In certain embodiments, the amount of only one agent in the combination of agents administered to the subject is stepwise decreased over the course of the dose reduction period, while the amounts of the remaining agents in the combination are kept constant. For example, in certain embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable form thereof administered to the subject is decreased over the course of the dose reduction period, while the amount of the VEGFR inhibitor administered to the subject is kept constant. In certain embodiments, the amount of the first agent (such as a compound of formula (I) or a pharmaceutically acceptable form thereof) and the amount of the second agent (such as a VEGFR inhibitor) in the combination of agents administered to the subject are each independently stepwise decreased over the course of the dose reduction period.

[0088] As used herein, the term "loading dosing period" refers to the administration of a dose (sometimes referred to herein as a loading dose) that is higher than the maintenance dose (e.g., the dose administered during a treatment cycle), such as a compound of formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor. In certain embodiments, the loading dosing period continues until a therapeutic steady-state concentration of the dose is achieved. In certain embodiments, the loading dose of the dose (such as a compound of formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor) can be in the range of about 1.1 to about 10 times the dose of the dose administered during the treatment cycle. In certain embodiments, the daily loading dose of the dose (such as a compound of formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor) can be in the range of about 1.1 to about 10 times the daily dose of the dose administered during the treatment cycle.

[0089] As used herein, the term "first-line therapy" refers to a therapy for treating advanced solid tumors that includes the use of platinum-based chemotherapy (e.g., cisplatin, carboplatin or oxaliplatin, and combinations such as cisplatin / 5-FU or carboplatin / paclitaxel), and for HNSCC or other advanced solid tumors, optionally in combination with anti-EGFR antibody therapy (e.g., cetuximab, panitumumab, afatinib). In some embodiments, the first-line therapy options can be surgery, chemotherapy and radiation after surgery, or systemic therapy such as pembrolizumab monotherapy, VEGFR monotherapy (such as pazopanib or sunitinib monotherapy), a combination of pembrolizumab and platinum-based chemotherapy, axitinib, or a combination of lenvatinib, nivolumab and cabozantinib or ipilimumab, a combination of axitinib and avelumab, or a combination of a TKI and an immune checkpoint inhibitor. In some embodiments, the first-line therapy is in the context of patients with recurrent or metastatic HNSCC or HNSCC patients who have only received therapy for local or locoregional disease. The first-line therapy for advanced solid tumors refers to the first treatment that a patient receives after recurrence or diagnosis of unresectable or metastatic disease.

[0090] As used herein, the term "second-line therapy" refers to a therapy for treating recurrent, unresectable or metastatic advanced solid tumors, or a therapy in the case where at least one prior treatment has failed to alleviate or reduce the severity of at least one symptom associated with the advanced solid tumor. For example, second-line therapy can include the use of taxanes, methotrexate and / or cetuximab to treat HNSCC. The second-line therapy for advanced solid tumors is the treatment after a patient has progressed after or following their first-line treatment.

[0091] As used herein and unless otherwise indicated, the term "subject" to which administration is contemplated can be an animal, including but not limited to a human (e.g., male or female of any age group, such as an adult subject or an adolescent subject); a primate (e.g., cynomolgus monkey, rhesus monkey) and / or other mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, dogs, rabbits, rodents and / or birds (e.g., commercially relevant birds such as chickens, ducks, geese, quails and / or turkeys). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adolescent. In some embodiments, the subject is an adult. In some embodiments, the subject is a patient, e.g., a human patient. In some embodiments, the subject is a smoker. In some embodiments, the subject is a non-smoker. In some embodiments, the subject is a non-smoker who was previously a smoker.

[0092] In some embodiments, the subject has advanced solid tumors, is suffering from advanced solid tumors, has symptoms associated with advanced solid tumors, or is diagnosed with advanced solid tumors. In some embodiments, the subject has or is suffering from advanced solid tumors. In some embodiments, the subject has symptoms associated with advanced solid tumors. In some embodiments, the subject is diagnosed with advanced solid tumors. In some embodiments, the subject can be diagnosed with advanced solid tumors by a person skilled in the art (e.g., a doctor, such as an oncologist). In some embodiments, the subject can be diagnosed with advanced solid tumors by analysis of plasma or a tissue biopsy of the subject (such as a tumor tissue biopsy). In some embodiments, the subject can be diagnosed with advanced solid tumors by one or more imaging tests (e.g., MRI, CT, PET, PET-CT, nuclear scan, ultrasound), optionally in combination with analysis of plasma or a tumor tissue biopsy. In some embodiments, the subject can be diagnosed with advanced solid tumors by blood analysis. In some embodiments, the analysis includes circulating tumor DNA (ctDNA) analysis. In some embodiments, the subject is a subject with advanced solid tumors who has been previously treated. In some embodiments, the subject has previously received a treatment for advanced solid tumors, and the current method includes "second-line" treatment. In some embodiments, the subject has previously received a treatment, relapsed or became refractory to that treatment, and then received a second treatment, such that the current method includes "third-line" treatment. In some embodiments, the subject is a subject who has not received treatment with a VEGR inhibitor. In some embodiments, the subject is a subject who has not received treatment with one or more of the following: cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanubrutinib. In some embodiments, the subject has previously been treated with a TKI (such as one TKI or two TKIs or three TKIs in a prior line of therapy). In some embodiments, the subject has previously been treated with a VEGFR inhibitor, e.g., the subject has previously been treated with a VEGFR inhibitor and is not currently being treated with a VEGFR inhibitor. In some embodiments, the subject has previously been treated with one or more of cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanubrutinib, optionally where the subject is not currently being treated with the same agent.In some embodiments, the subject has been treated with chemotherapy (such as platinum chemotherapy, oxaliplatin chemotherapy, or irinotecan chemotherapy), or with radioactive iodine (for thyroid cancer), imatinib (for GIST), systemic therapy, anti-VEGF therapy, anti-EGFR therapy, surgery (such as resection, nephrectomy), or radiation therapy, or in some cases, is intolerant to other therapies. In some embodiments, the subject is currently being treated with a VEGFR inhibitor, such as currently being treated with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib. In some embodiments, the advanced solid tumor is an advanced solid tumor resistant to drugs, such as an advanced solid tumor resistant to TKI or resistant to a VEGFR inhibitor. In some embodiments, the subject is an advanced solid tumor subject in remission. In some embodiments, the advanced solid tumor subject has a metastatic advanced solid tumor, a recurrent advanced solid tumor, or a refractory advanced solid tumor. In some embodiments, the subject has a metastatic advanced solid tumor. In some embodiments, the subject has a recurrent advanced solid tumor or a refractory advanced solid tumor.

[0093] As used herein and unless otherwise indicated, the terms “treat / treating / treatment” and “ameliorate” are used interchangeably and mean the partial or complete alleviation of one or more symptoms of a disorder, disease or affliction (such as advanced solid tumors), or of a symptom associated with a disorder, disease or affliction (e.g., advanced solid tumors), or the slowing or halting of the further progression or worsening of such symptoms, or the alleviation or eradication of one or more causative factors of the disorder, disease or affliction itself (such as advanced solid tumors). In some embodiments, these terms refer to methods for obtaining a beneficial or desired result, including but not limited to a therapeutic benefit or a prophylactic benefit. Therapeutic benefits resulting from the methods of treatment provided herein include eradicating or ameliorating the underlying disorder being treated (such as advanced solid tumors), eradicating or ameliorating one or more of the physical signs or symptoms associated with the underlying disorder (e.g., advanced solid tumors), such that an improvement is observed in the patient, even though the patient may still be afflicted with the underlying disease or disorder (e.g., advanced solid tumors). For example, when used with respect to a patient suffering from advanced solid tumors, a therapeutic benefit means an effect that reduces the severity of advanced solid tumors, or delays or slows the progression of advanced solid tumors, including (a) inhibiting the growth of advanced solid tumors, or arresting the development of advanced solid tumors, and (b) causing regression of advanced solid tumors, or delaying or minimizing one or more symptoms associated with the presence of advanced solid tumors. Prophylactic benefits resulting from the methods of treatment provided herein include delaying or eliminating the onset of a disease or disorder (e.g., advanced solid tumors), delaying or eliminating the onset of symptoms of a disease or disorder (e.g., advanced solid tumors), slowing, halting or reversing the progression of a disease or disorder (e.g., advanced solid tumors), or any combination thereof.

[0094] In the context of advanced solid tumors, treatment can be evaluated by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumors, alleviation of tumor-related symptoms, inhibition of tumor-secreted factors, delay in the appearance of primary or secondary tumors, delay in the time to emergence of drug resistance, slowdown in the development of primary or secondary tumors, reduction in the occurrence of primary or secondary tumors, alleviation or reduction in the severity of secondary effects of the disease, containment of tumor growth and regression of tumors, increase in time to progression (TTP), increase in progression-free survival (PFS), increase in overall survival (OS), etc. As used herein, OS means the time from the start of treatment until death from any cause. As used herein, TTP means the time from the start of treatment until tumor progression; TTP does not include death. In some embodiments, PFS means the time from the start of treatment until tumor progression or death. In some embodiments, PFS means the time from the first dose of the compound to the first occurrence of disease progression or death from any cause. In some embodiments, the PFS rate is calculated using Kaplan-Meier estimates. Event-free survival (EFS) means the time from the start of treatment until any treatment failure, including disease progression, discontinuation of treatment for any reason, or death. In some embodiments, the overall response rate (ORR) means the percentage of patients who achieve a response. In some embodiments, ORR means the sum of the percentages of patients who achieve a complete response (CR) and a partial response (PR). In some embodiments, ORR means the percentage of patients with a best response greater than or equal to a partial response (PR). In some embodiments, the duration of response (DoR) is the time from achieving a response until recurrence or disease progression. In some embodiments, DoR is the time from achieving a response greater than or equal to a partial response (PR) until recurrence or disease progression. In some embodiments, DoR is the time from the first record of a response until the first record of progressive disease or death. In some embodiments, DoR is the time from the first record of a response greater than or equal to a partial response (PR) until the first record of progressive disease or death. In some embodiments, time to response (TTR) means the time from the first dose of the compound or compound combination (e.g., a compound of formula (I) or a pharmaceutically acceptable form thereof and / or a VEGFR inhibitor) to the first record of a response. In some embodiments, TTR means the time from the first dose of the compound or compound combination to the first record of a response greater than or equal to a partial response (PR). In some embodiments, the efficacy results of the methods disclosed herein are determined according to applicable RECIST criteria (e.g., RECIST v.1.1).For example, in some embodiments, the RECIST criteria are applied to evaluate one or more target lesions (TLs), including a quantitative assessment (sum of lesion diameters); evaluate one or more non-target lesions (NTLs), including a qualitative assessment (presence, absence, or definite progression); and evaluate the presence of new lesions. In some embodiments, the efficacy results of the methods disclosed herein are relative to the treatment of advanced solid tumors with VEGFR inhibitor monotherapy, such as relative to the treatment of advanced solid tumors with VEGFR inhibitor monotherapy that ultimately results in recurrence and / or resistance in subjects with advanced solid tumors, e.g., relative to the treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib. In some embodiments, the efficacy results of the methods disclosed herein are relative to standard of care advanced solid tumor treatment (including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or combinations thereof). In some embodiments, the efficacy results of the methods disclosed herein are relative to the situation of not treating advanced solid tumors.

[0095] 6.1 Compounds

[0096] In some embodiments, the treatment methods provided herein include administering to a subject (a) a compound of formula (I) or a pharmaceutically acceptable form thereof and (b) a VEGFR inhibitor. The compound of formula (I) or a pharmaceutically acceptable form thereof is a farnesyl transferase inhibitor and is a selective farnesyl transferase inhibitor that selectively inhibits farnesyl transferase with a higher potency (lower IC 50 value) relative to the inhibition level of geranylgeranyl transferase type 1.

[0097] In some embodiments, it is a compound of formula (I), which can be named (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexaphane-2 2 ,4 4 -dicarbonitrile and has the following structure:

[0098]

[0099] In some embodiments, it is a compound of formula (II), which can be named (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-diphenylcyclohexaphane-2 2 ,4 4 -dicarbonitrile and has the following structure:

[0100]

[0101] In some embodiments, it is a compound of formula (III), which can be named 3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocycloheptene-2 2 , 4 4 -dicarbonitrile, and has the following structure:

[0102]

[0103] Compounds useful as described herein include compounds of formula (I), (II) and (III) and their pharmaceutically acceptable forms.

[0104] The synthesis and certain uses, inhibitory activities and metabolic stabilities of the compounds of formula (I), (II) and (III) and their pharmaceutically acceptable forms provided herein are described in International Patent Application No. PCT / US2022 / 80565, the entire content of which is incorporated herein by reference and illustrated in Example 1 disclosed herein. In some embodiments, the compound used in the treatment methods provided herein is a compound of formula (I) or its pharmaceutically acceptable form. Throughout this application, the disclosure relates to the use of a compound of formula (I) or its pharmaceutically acceptable form, and such disclosure equally applies to a compound of formula (II) or its pharmaceutically acceptable form, or a compound of formula (III) or its pharmaceutically acceptable form.

[0105] In certain embodiments, the use of farnesyltransferase inhibitors, particularly compounds of formula (I), (II) or (III) and their pharmaceutically acceptable forms, is applicable to the farnesyltransferase inhibitor tipifarnib.

[0106] In some embodiments, the VEGFR inhibitors used as provided herein are cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib and zanubrutinib, and this list includes their pharmaceutically acceptable forms. In some embodiments, the VEGFR inhibitors used as provided herein are cabozantinib (S)-malate, lenvatinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib mesylate, tivozanib hydrochloride hydrate, fruquintinib free base or zanubrutinib fumarate. In some embodiments, the VEGFR inhibitors used as provided herein are the pharmacologically active metabolites of the VEGFR inhibitors described herein. Such metabolites include, for example, regorafenib M-2 and M-5 metabolites and the demethylated metabolite of vandetanib.

[0107] 6.2 Pharmaceutical Compositions, Kits, and Packages

[0108] In some embodiments, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, provided herein is a pharmaceutical composition comprising a VEGFR inhibitor, such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanazartinib, or a pharmaceutically acceptable form thereof, such as cabozantinib (S)-malate, lenvatinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib mesylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanazartinib fumarate, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, a VEGFR inhibitor, such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanazartinib, or cabozantinib (S)-malate, lenvatinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib mesylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanazartinib fumarate, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable form thereof, and cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanazartinib, or cabozantinib (S)-malate, lenvatinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib mesylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanazartinib fumarate, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0109] In some embodiments, provided herein is a pharmaceutical kit that includes (a) a compound of formula (I) or a pharmaceutically acceptable form thereof and (b) a VEGFR inhibitor. In some embodiments, the pharmaceutical kit further contains instructions detailing a dosing regimen for administering each compound for one or more treatment cycles. In some embodiments, the pharmaceutical kit further includes a color-coding system detailing a dosing regimen for independently administering each compound for one or more treatment cycles. In some embodiments, the pharmaceutical kit is a pharmaceutical package.

[0110] In some embodiments, the pharmaceutical kit or pharmaceutical package further contains instructions for administering the contents of the kit to a subject having an advanced solid tumor. For example, in some embodiments, the instructions may detail a dosing regimen for administering the compound of formula (I) or a pharmaceutically acceptable form thereof, such as once or twice daily, or for example, during a 28-day treatment cycle, such as on days 1-7, on days 1-7 and 15-21, on days 1-21, or once or twice daily on each day of a 28-day treatment cycle; and detail a dosing regimen for administering the VEGFR inhibitor, such as once or twice daily, or for example, during a treatment cycle, such as once or twice daily on each day of a treatment cycle (such as a 28-day treatment cycle), or such as once or twice daily during weeks 1-4 of a 6-week treatment cycle. In some embodiments, the instructions for administering each agent may be color-coded, with different colors used for the instructions for each agent. In some embodiments, the instructions may include details about an escalating dosing period, a de-escalating dosing period, or a loading dosing period (optionally color-coded) for administering the compound of formula (I) or a pharmaceutically acceptable form thereof. For example, in some embodiments, the instructions may be color-coded to detail an escalating dosing period or a de-escalating dosing period for administering the VEGFR inhibitor.

[0111] In some embodiments, the pharmaceutical composition or a pharmaceutical kit or package containing the same comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent or excipient. For example, in some embodiments, the pharmaceutical composition or a pharmaceutical kit or package containing the same comprises 0.5 - 2400 mg of a compound of formula (I) or a pharmaceutically acceptable form thereof, such as an amount selected from the group consisting of 0.5 - 2.5 mg, 0.5 - 5 mg, 0.5 - 10 mg, 0.5 - 25 mg, 0.5 - 50 mg, 0.5 - 75 mg, 0.5 - 100 mg, 0.5 - 300 mg, 0.5 - 600 mg, 0.5 - 1200 mg, 1 - 5 mg, 1 - 10 mg, 1 - 25 mg, 1 - 50 mg, 1 - 75 mg, 1 - 100 mg, 1 - 300 mg, 1 - 600 mg, 1 - 1200 mg, 1 - 2400 mg, 20 - 100 mg, 40 - 75 mg, 50 - 75 mg, 50 - 100 mg, 50 - 150 mg, 75 - 100 mg, 100 - 200 mg, 125 - 200 mg, 150 - 300 mg, 200 - 250 mg, 200 - 400 mg, 300 - 600 mg, 250 - 500 mg, 400 - 600 mg, 500 - 750 mg, 600 - 900 mg, 700 - 100 mg, 650 - 1000 mg, 800 - 1200 mg, 900 - 1500 mg, 1000 - 1600 mg, 1000 - 2000 mg, 1200 - 1600 mg, 1500 - 2000 mg, 1500 - 2400 mg, 1800 - 2400 mg and 2000 - 2400 mg of a compound of formula (I) or a pharmaceutically acceptable form thereof.In some embodiments, the pharmaceutical composition or the pharmaceutical kit or pharmaceutical package containing the same comprises from about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, and about 2400 mg of the compound of formula (I) or a pharmaceutically acceptable form thereof.

[0112] It should be noted that there is an "and" in the middle of the original text which seems a bit inconsistent in the list. It might be a typo, but the translation is done as it is presented.In some embodiments, the pharmaceutical composition, or a pharmaceutical kit or package containing the same, comprises 0.2 to 1500 mg of a VEGFR inhibitor, such as a VEGFR inhibitor in an amount selected from 0.5 - 10 mg, 2 - 15 mg, 10 - 30 mg, 10 - 40 mg, 10 - 240 mg, 20 - 50 mg, 20 - 240 mg, 30 - 50 mg, 35 - 70 mg, 40 - 80 mg, 60 - 100 mg, 80 - 120 mg, 80 - 160 mg, 80 - 240 mg, 160 - 250 mg, 160 - 300 mg, 100 - 600 mg or 200 - 1000 mg. In some embodiments, the pharmaceutical composition, or a pharmaceutical kit or package containing the same, comprises 0.89 mg, 1 mg, 1.34 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 12.5 mg, 14 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, 30 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 400 mg, 500 mg, 600 mg or 800 mg of a VEGFR inhibitor. In some embodiments, the VEGFR inhibitor is in the form of a salt and / or solvate, in which case the amount of the VEGFR inhibitor is expressed as free base equivalents.

[0113] In some embodiments, the pharmaceutical composition, kit or package comprises (Table 1):

[0114] Table 1

[0115]

[0116]

[0117] In some embodiments, a pharmaceutical composition comprising a VEGFR inhibitor (such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib), or a pharmaceutical kit or package containing the same, is formulated as an oral preparation, such as a tablet or a capsule. In some embodiments, the pharmaceutical composition comprising the VEGFR inhibitor further comprises an excipient. In some embodiments, the excipient is selected from the group consisting of: mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, anhydrous lactose, lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, calcium carbonate, mannitol, talc, polyvinylpyrrolidone, dibasic calcium phosphate dihydrate, crospovidone, corn starch, and sodium starch glycolate. In some embodiments, the tablet comprises a film coating and the capsule comprises a capsule shell. In some embodiments, the VEGFR inhibitor is formulated with an excipient selected from the following (Table 2):

[0118] Table 2

[0119]

[0120] In some embodiments, an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, included in a pharmaceutical composition, pharmaceutical kit, or pharmaceutical package provided herein, and for combination methods with a VEGFR inhibitor, the VEGFR inhibitor is effective for: alleviating or improving one or more symptoms of advanced solid tumors, or treating advanced solid tumors, delaying the progression of advanced solid tumors, delaying the time to drug resistance in advanced solid tumors, as compared to: (a) for combination methods, as compared to treatment of advanced solid tumors with VEGFR inhibitor monotherapy, such as treatment of advanced solid tumors with VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, e.g., as compared to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib; (b) as compared to standard of care treatment for advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or combinations thereof; or (c) as compared to the situation of not treating advanced solid tumors. In some embodiments, an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, or for a VEGFR inhibitor combination, the VEGFR inhibitor, or a combination thereof, includes an amount effective for: reducing or delaying the risk of recurrence of advanced solid tumors, increasing PFS and / or OS, increasing PFS, increasing OS, increasing ORR, increasing CR, increasing TTP, increasing PFS, increasing EFS, or increasing DoS, or combinations thereof, as compared to: (a) for combination methods with a VEGFR inhibitor, as compared to treatment of advanced solid tumors with VEGFR inhibitor monotherapy, such as treatment of advanced solid tumors with VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, e.g., as compared to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib; (b) as compared to standard of care treatment for advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or combinations thereof; or (c) as compared to the situation of not treating advanced solid tumors. In some embodiments, the effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof and / or a VEGF inhibitor in a pharmaceutical composition or a pharmaceutical kit or pharmaceutical package containing the same may depend on the absorption, tissue distribution, metabolism, excretion rate of the active compound, dosage schedule, amount administered, specific formulation, and other factors known to those skilled in the art.The effective amount can be determined empirically by testing the compound in the in vitro and in vivo systems described herein and then extrapolating therefrom the dosage for humans.

[0121] In some embodiments, the pharmaceutical composition is provided for administration to a subject in unit dosage form, such as tablets, capsules, microcapsules, pills, powders, granules, lozenges, suppositories, injections, syrups, patches, creams, lotions, ointments, gels, sprays, sterile parenteral solutions or suspensions, as well as oral solutions or suspensions, and oil-in-water emulsions containing a suitable amount of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition provided herein is in the form of a tablet. In some embodiments, the pharmaceutical composition provided herein is in the form of a capsule. In some embodiments, the capsule contains the compound provided herein without additional carriers, excipients or vehicles. Generally, the compounds disclosed herein are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, 7th Edition, 1999). In some embodiments, the pharmaceutical composition is formulated and administered in unit dosage form or multiple dosage form. Such dosage forms contain a predetermined amount of the active ingredient and can be prepared by pharmaceutical methods well known to those skilled in the art. As used herein, a unit dosage form refers to a physically discrete unit suitable for human and animal subjects and individually packaged as known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dosage forms include ampoules and syringes as well as individually packaged tablets or capsules. Unit dosage forms can be administered in their fractions or multiples. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container and administered in separate unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules or pints or gallons of bottles. Thus, a multiple dosage form is a plurality of unit doses not separated in the package.

[0122] The compounds and pharmaceutical compositions provided herein can be administered as a single dose or can be divided into a number of smaller doses to be administered at intervals over time. It will be understood that the precise dosage and duration of treatment vary depending on the disease being treated (e.g., advanced solid tumors) and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that the concentration and dosage values may also vary with the severity of the condition to be alleviated. It should also be understood that for any particular subject, the specific dosage regimen can be adjusted over time according to the individual needs and the professional judgment of the person administering the pharmaceutical composition or supervising the administration thereof, and the concentration ranges set forth herein are only exemplary and are not intended to limit the scope or practice of the claimed pharmaceutical compositions.

[0123] The compounds and pharmaceutical compositions are intended to be administered by suitable routes, which include but are not limited to oral, parenteral, rectal, topical, and local administration. For oral administration, capsules and tablets can be formulated. The pharmaceutical compositions are in liquid, semi-liquid, or solid form and are formulated in a manner suitable for each route of administration. In one embodiment, when administered orally, the compounds provided herein are administered with food and water. In another embodiment, the compounds provided herein are dispersed in water or fruit juice (e.g., apple juice or orange juice) and are administered orally in the form of a solution or suspension. In one embodiment, the compounds provided herein are administered when the subject is eating. In one embodiment, the compounds provided herein are administered when the subject is eating a high-fat and / or high-calorie food. In one embodiment, the compounds provided herein are administered when the subject is eating an FDA-standard high-fat, high-calorie breakfast. In one embodiment, the compounds provided herein are administered when the subject is fasting. In one embodiment, the compounds provided herein are administered after the subject has fasted for at least 8 hours overnight. In one embodiment, the compounds provided herein are administered with or without food.

[0124] The compounds and pharmaceutical compositions provided herein can also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transcutaneously, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is at the discretion of the healthcare practitioner and can depend in part on the site of the medical disorder. Depending on the condition of the disease to be treated and the condition of the subject, the composition can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compound of formula (I) or its pharmaceutically acceptable form, and / or the VEGFR inhibitor can be formulated alone or together into suitable dosage units containing pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

[0125] In some embodiments, the pharmaceutical compositions provided herein can be formulated appropriately to delay or prolong pharmacokinetics. For example, in some embodiments, the pharmaceutical compositions provided herein delay or prolong the dissolution of the compound of formula (I) or its pharmaceutically acceptable form, or the VEGFR inhibitor, or a combination thereof. For example, slowly dissolving pellets of the compounds provided herein can be prepared and incorporated into tablets or capsules, or as a sustained-release implantable device. The technique also includes making pellets having several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Long-acting parenteral formulations can be prepared by dissolving or suspending a compound as provided herein in an oily or emulsified vehicle that permits its slow dispersion in serum.

[0126] 6.3 Methods, Dosage Regimens, and Schedules

[0127] 6.3.1 Treatment Methods

[0128] In some embodiments, provided herein is a method of treating a subject with advanced solid tumors, which comprises administering to the subject a compound of formula (I) or its pharmaceutically acceptable form (or a pharmaceutical composition comprising the same) and a VEGFR inhibitor. In some embodiments, provided herein is a method of treating a subject with advanced solid tumors, which comprises administering to the subject an effective amount of a compound of formula (I) or its pharmaceutically acceptable form (or a pharmaceutical composition comprising the same) and an effective amount of a VEGFR inhibitor.

[0129] In another aspect, there is provided a method for reducing drug resistance of advanced solid tumors in a subject, slowing the progression of drug resistance of advanced solid tumors in a subject, or overcoming drug resistance of advanced solid tumors in a subject, which comprises administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same) and a VEGFR inhibitor. In another aspect, there is provided a method for reducing drug resistance of advanced solid tumors in a subject, slowing the progression of drug resistance of advanced solid tumors in a subject, or overcoming drug resistance of advanced solid tumors in a subject, which comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same) and an effective amount of a VEGFR inhibitor. In some embodiments, the drug resistance is TKI resistance. In some embodiments, the drug resistance is TKI resistance in a subject with advanced solid tumors who is currently being treated with a TKI or has been previously treated with a TKI. In some embodiments, the drug resistance is VEGFR inhibitor resistance, such as VEGFR inhibitor resistance in advanced solid tumors that are resistant to a TKI or resistant to a VEGFR inhibitor, wherein the subject is currently being treated with a TKI or a VEGFR inhibitor or has been previously treated with a TKI or a VEGFR inhibitor.

[0130] In some embodiments, provided herein is a method for preventing or delaying the emergence of TKI resistance in advanced solid tumors in a subject who has not been treated with a TKI, which comprises administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor. In some embodiments, provided herein is a method for preventing or delaying the emergence of TKI resistance in advanced solid tumors in a subject who has not been treated with a TKI, which comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof and an effective amount of a VEGFR inhibitor. In some embodiments, the TKI resistance is TKI resistance in advanced solid tumors that have not been treated with a TKI or have not been treated with a VEGFR inhibitor.

[0131] In some embodiments, provided herein is a method of treating a subject having an advanced solid tumor with HRAS amplification and / or HRAS overexpression (optionally in combination with an HRAS mutation), comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof. In some embodiments, provided herein is a method of treating a subject having an advanced solid tumor with squamous histology and HRAS amplification and / or HRAS overexpression (optionally in combination with an HRAS mutation), comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof. In some embodiments, provided herein is a method of treating a subject having an advanced solid tumor with squamous histology and HRAS amplification and / or HRAS overexpression (optionally in combination with an HRAS mutation), comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof. In some embodiments, such method comprises administering the compound of formula (I) or a pharmaceutically acceptable form thereof as the sole anti-tumor agent in a treatment regimen, such as as monotherapy. In some aspects, the advanced solid tumor is (a) an advanced solid tumor having HRAS amplification, (b) HNSCC having HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma having HRAS amplification.

[0132] In some embodiments, provided herein is a method of treating a subject having an advanced solid tumor with squamous histology and NRAS amplification and / or NRAS overexpression (optionally in combination with an NRAS mutation), comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof. In some embodiments, provided herein is a method of treating a subject having an advanced solid tumor with squamous histology and NRAS amplification and / or NRAS overexpression (optionally in combination with an NRAS mutation), comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof. In some embodiments, such method comprises administering the compound of formula (I) or a pharmaceutically acceptable form thereof as the sole anti-tumor agent in a treatment regimen, such as as monotherapy. In some aspects, the advanced solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma having NRAS amplification.

[0133] In some embodiments, a subject being treated according to the treatment methods provided herein has an advanced solid tumor, is at risk of developing an advanced solid tumor, has symptoms associated with an advanced solid tumor, or is diagnosed with an advanced solid tumor. In some embodiments, the subject is a subject who has not received TKI treatment, or a subject who has not received VEGFR inhibitor treatment. In some embodiments, the subject is a subject with recurrent or refractory advanced solid tumor who has been previously treated with a TKI or a VEGFR inhibitor but is not currently being treated with a TKI or a VEGFR inhibitor.

[0134] In some embodiments, the subject to whom the compound is administered by the methods provided herein has advanced solid tumors, is suffering from advanced solid tumors, has symptoms associated with advanced solid tumors, or is diagnosed with advanced solid tumors. In some embodiments, the subject has or is suffering from advanced solid tumors. In some embodiments, the subject has symptoms associated with advanced solid tumors. In some embodiments, the subject is diagnosed with advanced solid tumors. In some embodiments, the subject is a subject with advanced solid tumors who has been previously treated. In some embodiments, the subject is a subject who has not received TKI treatment, or a subject who has not received VEGFR inhibitor treatment. In some embodiments, the subject has not received treatment with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib. In some embodiments, the subject has been previously treated with a TKI, or with a VEGFR inhibitor, or with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib. In some embodiments, the subject has been previously treated with cabozantinib. In some embodiments, the subject is a subject with advanced solid tumors in remission. In some embodiments, the subject with advanced solid tumors is a subject with advanced solid tumors resistant to a TKI, such as a subject with advanced solid tumors resistant to a VEGFR inhibitor. In some embodiments, the subject is a mammal, such as a human, such as a person having advanced solid tumors, suffering from advanced solid tumors, having symptoms associated with advanced solid tumors, or diagnosed with advanced solid tumors.

[0135] In some embodiments, the VEGFR inhibitor is cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib. In some embodiments, the VEGFR inhibitor is in the form of cabozantinib (S)-malate, lenvatinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib mesylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanubrutinib fumarate. In some embodiments, the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib. In some embodiments, the VEGFR inhibitor is cabozantinib, such as cabozantinib (S)-malate. In some embodiments, the VEGFR inhibitor is zanubrutinib, such as zanubrutinib fumarate. In some embodiments, the VEGFR inhibitor is fruquintinib, such as fruquintinib free base.

[0136] In some embodiments, the advanced solid tumor is a metastatic solid tumor, a recurrent solid tumor, an inoperable solid tumor, a relapsed solid tumor, or a refractory solid tumor. In some embodiments, the advanced solid tumor is a metastatic solid tumor. In some embodiments, the advanced solid tumor is an inoperable solid tumor. In some embodiments, the advanced solid tumor is a relapsed solid tumor. In some embodiments, the advanced solid tumor is a refractory solid tumor.

[0137] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof administered according to the methods provided herein inhibits protein farnesylation, such as inhibiting the farnesylation of farnesylation-dependent proteins. Without being bound by any theory, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof administered according to the methods provided herein inhibits the farnesylation of one or more farnesylation-dependent proteins selected from RhoB, RhoE, and Lamin B, or combinations thereof. In some embodiments, the farnesylation-dependent protein is a dysregulated farnesylation-dependent protein.

[0138] In some embodiments, inhibition of the farnesylation of a farnesylation-dependent protein occurs in a cell, such as in a cell of a subject, according to the methods of treatment provided herein. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. Without being bound by any theory, in some embodiments, inhibition of the farnesylation of a farnesylation-dependent protein by administration of a compound of formula (I) or a pharmaceutically acceptable form thereof in combination with a VEGFR inhibitor provides a therapeutic benefit to a subject, such as a synergistic benefit, relative to: (a) for the combination with a VEGFR inhibitor, relative to treatment of advanced solid tumors with a TKI monotherapy or a VEGFR inhibitor monotherapy, such as relative to treatment of advanced solid tumors with a TKI monotherapy or a VEGFR inhibitor therapy that ultimately results in recurrence and / or resistance in subjects with advanced solid tumors, e.g., relative to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib; (b) relative to standard of care treatment of advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiotherapy, chemotherapy, or combinations thereof; or (c) relative to the case of not treating advanced solid tumors.For example, in some embodiments, the therapeutic benefits provided by administering a compound of formula (I) or a pharmaceutically acceptable form thereof according to the methods provided herein, such as synergistic benefits, include but are not limited to increased efficacy (e.g., suppressing tumor growth and inducing tumor regression); increased PFS and / or OS, such as an increase in PFS of 10 - 99%, such as an increase of 10%, 25%, 50%, 80%, 90%, 95% or 99%, 2-fold, 3-fold or 4-fold, or an increase in OS of 10 - 99%, such as an increase of 10%, 25%, 50%, 80%, 90%, 95% or 99%, 2-fold, 3-fold or 4-fold; for combinations with VEGFR inhibitors, reducing the effective amount of the TKI or VEGFR inhibitor, reducing the toxicity associated with the TKI or VEGFR inhibitor, such as reducing the severity, incidence or risk of toxicity selected from severe bleeding, impaired wound healing, gastrointestinal perforation, hypertension, fatigue, arterial and venous thromboembolic events, bleeding, cardiovascular events, heart failure, hepatotoxicity and QT prolongation, or combinations thereof; or delaying the emergence of TKI or VEGFR inhibitor resistance, such as unexpectedly delaying the emergence of TKI or VEGFR inhibitor resistance, as compared to: treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy, such as treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, e.g., as compared to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanidatamab; for all methods, as compared to standard of care treatment of advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiotherapy or chemotherapy, or combinations thereof; or for all methods, as compared to the situation of not treating advanced solid tumors. In some embodiments, the efficacy results are determined according to applicable RECIST criteria (e.g., RECIST v.1.1). In some embodiments, administering a combination of a compound of formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor according to the methods disclosed herein may provide therapeutic benefits (including synergistic benefits) to a subject being treated, as compared to: treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy, such as treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, e.g., as compared to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanidatamab.In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable form thereof according to the methods disclosed herein can provide a therapeutic benefit (including a synergistic benefit) to a subject being treated, relative to standard of care advanced solid tumor treatment (including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or combinations thereof). In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable form thereof according to the methods disclosed herein can provide a therapeutic benefit (including a synergistic benefit) to a subject being treated, relative to a situation where advanced solid tumors are not treated. In some embodiments, inhibition of farnesyltransferase present in cells occurs in a subject having an advanced solid tumor.

[0139] In some embodiments, the methods provided herein provide one or more therapeutic benefits to a subject, relative to: (a) for combinations with VEGFR inhibitors, relative to treatment of advanced solid tumors with TKI or VEGFR inhibitor monotherapy, such as relative to treatment of advanced solid tumors with TKI or VEGFR monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, e.g., relative to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanidatinib; (b) relative to standard of care treatment of advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or combinations thereof; or (c) relative to the situation of not treating advanced solid tumors. For example, in some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include delaying the time to the emergence or progression of drug resistance, e.g., the time to the emergence or progression of TKI drug resistance or VEGFR inhibitor resistance, and in some embodiments, the delay is an unexpected delay. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include delaying, arresting, or preventing the progression of advanced solid tumors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include delaying, arresting, or preventing the growth of advanced solid tumors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include a reduction in a primary advanced solid tumor, such as a reduction in the size, volume, or appearance of a primary advanced solid tumor, or a reduction in the degree of metastasis of a primary advanced solid tumor. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include providing relief from advanced solid tumor-related symptoms. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include inhibiting the secretion of factors by advanced solid tumors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include delaying the appearance of primary or secondary solid tumors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include slowing the development of primary or secondary solid tumors, e.g., slowing the development of the solid tumor to an advanced stage. For example, in certain embodiments, one or more therapeutic benefits provided by the methods disclosed herein include slowing the progression of primary or secondary solid tumors to advanced solid tumors and / or progression to metastasis. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include reducing the incidence of primary or secondary solid tumors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein include slowing or reducing the severity of side effects associated with advanced solid tumors.In some embodiments, one or more of the therapeutic benefits provided by the methods disclosed herein include slowing, arresting (halting), or reducing the growth of advanced solid tumors and / or reducing the size of solid tumors. For example, in some embodiments, the methods provided herein reduce the volume or size of solid tumors. In some embodiments, one or more of the therapeutic benefits provided by the methods disclosed herein include increasing time to progression (TTP), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), overall response rate (ORR), complete response rate (CR rate), or duration of response (DoR), or a combination thereof. In some embodiments, one or more of the therapeutic benefits provided by the methods disclosed herein include reducing time to response (TTR). In certain embodiments, one or more of the above-described therapeutic benefits provided to a subject are relative to a combination method with a VEGFR inhibitor as compared to: treatment of advanced solid tumors with a TKI or VEGFR inhibitor monotherapy, such as treatment of advanced solid tumors with a TKI or VEGFR monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, for example treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib. In certain embodiments, one or more of the above-described therapeutic benefits provided to a subject are relative to standard of care treatment of advanced solid tumors (including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or a combination thereof). In certain embodiments, one or more of the above-described therapeutic benefits provided to a subject are relative to the case of not treating advanced solid tumors.

[0140] In some embodiments, the methods provided herein can be used in second-line therapy, third-line therapy, second-line or higher-line therapy, or third-line or higher-line therapy. In such cases, the subject may have received a prior treatment selected from: chemotherapy, a TKI, or a VEGFR inhibitor, wherein the method provides one or more therapeutic benefits to the subject relative to: (a) for a combination with a VEGFR inhibitor, relative to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy, such as relative to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, e.g., relative to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib; (b) relative to standard-of-care treatment of advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or combinations thereof; or (c) relative to the situation of not treating advanced solid tumors. In some embodiments, the methods provided herein include one or more prior treatments according to NCCN guidelines.

[0141] In some embodiments, the method of using a compound of formula (I) or a pharmaceutically acceptable form thereof in combination with a VEGFR inhibitor comprises administering a combination in one or more of the following embodiments (Table 3):

[0142] Table 3

[0143]

[0144]

[0145]

[0146]

[0147]

[0148] In some embodiments, the method comprises administering to a subject (a) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising a VEGFR inhibitor and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the method comprises administering to a subject (a) a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising an effective amount of a VEGFR inhibitor and a pharmaceutically acceptable carrier, diluent, or excipient.

[0149] In some embodiments, the methods provided herein comprise administering to a subject a pharmaceutical kit or package that comprises: (a) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising a VEGFR inhibitor (such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib) and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the methods provided herein comprise administering to a subject such a pharmaceutical kit or package that comprises: (a) a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising an effective amount of a VEGFR inhibitor (such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib) and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical kit or package includes instructions specifying a dosing regimen (optionally for one or more treatment cycles) for each agent.

[0150] In some embodiments of methods involving advanced solid tumors having a squamous histological structure and HRAS amplification and / or overexpression and optionally an HRAS mutation, the methods provided herein include administering to a subject a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments of methods involving advanced solid tumors having HRAS amplification and / or overexpression and optionally an HRAS mutation, the methods provided herein include administering to a subject a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the advanced solid tumor has a squamous histological structure. In some embodiments, the advanced solid tumor is (a) an advanced solid tumor having HRAS amplification, (b) HNSCC having HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma having HRAS amplification.

[0151] In some embodiments of methods involving advanced solid tumors having NRAS amplification and / or overexpression and optionally an NRAS mutation, the methods provided herein include administering to a subject a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments of methods involving advanced solid tumors having NRAS amplification and / or overexpression and optionally an NRAS mutation, the methods provided herein include administering to a subject a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier, diluent, or excipient. In some aspects, the advanced solid tumor is (a) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma having NRAS amplification.

[0152] 6.3.2 Dosage and Regimen

[0153] In some embodiments, the methods provided herein include administering to a subject (a) a compound of formula (I) or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor, such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib, such as cabozantinib. For example, in some embodiments, the methods provided herein include administering to a subject (a) an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor, such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib, such as cabozantinib. In some embodiments, the method includes administering to the subject a pharmaceutical composition of each agent as described herein. In some embodiments, the method includes administering to the subject a pharmaceutical composition comprising an effective amount of each agent as described herein.

[0154] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject at a dose of 1 - 2400 mg per day according to the methods provided herein. In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable form thereof is selected from 0.5 - 2.5 mg, 0.5 - 5 mg, 0.5 - 10 mg, 0.5 - 25 mg, 0.5 - 50 mg, 0.5 - 75 mg, 0.5 - 100 mg, 0.5 - 300 mg, 0.5 - 600 mg, 0.5 - 1200 mg, 1 - 5 mg, 1 - 10 mg, 1 - 25 mg, 1 - 50 mg, 1 - 75 mg, 1 - 100 mg, 1 - 300 mg, 1 - 600 mg, 1 - 1200 mg, 1 - 2400 mg, 20 - 100 mg, 40 - 75 mg, 50 - 75 mg, 50 - 100 mg, 50 - 150 mg, 75 - 100 mg, 100 - 200 mg, 125 - 200 mg, 150 - 300 mg, 200 - 250 mg, 200 - 400 mg, 300 - 600 mg, 250 - 500 mg, 400 - 600 mg, 500 - 750 mg, 600 - 900 mg, 700 - 100 mg, 650 - 1000 mg, 800 - 1200 mg, 900 - 1500 mg, 1000 - 1600 mg, 1000 - 2000 mg, 1200 - 1600 mg, 1500 - 2000 mg, 1500 - 2400 mg, 1800 - 2400 mg, and 2000 - 2400 mg per day.In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable form thereof is selected from about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg and about 2400 mg per day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered 1, 2, 3 or 4 times a day. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable form thereof is divided into two, three or four doses, such as two, three or four equal doses, and particularly two doses or two equal doses, which are administered to the subject according to the methods provided herein. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered once or twice a day, or once a day, or twice a day.

[0155] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject at a dose of 0.01 - 50 mg / kg body weight per day according to the methods provided herein. In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable form thereof is selected from 0.01 - 1 mg / kg, 0.01 - 2.5 mg / kg, 0.01 - 5 mg / kg, 0.1 - 5 mg / kg, 0.1 - 10 mg / kg, 0.1 - 20 mg / kg, 1 - 30 mg / kg, 1 - 40 mg / kg, 5 - 50 mg / kg, 10 - 50 mg / kg, 15 - 50 mg / kg, 20 - 50 mg / kg, 25 - 50 mg / kg, 30 - 50 mg / kg, 40 - 50 mg / kg, 20 - 40 mg / kg, and 25 - 25 mg / kg body weight per day. In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable form thereof is selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, and about 50 mg / kg body weight per day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered 1, 2, 3, or 4 times per day, such as once or twice per day, or once per day, or twice per day. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable form thereof is divided into two, three, or four doses, such as two, three, or four equal doses, and particularly two doses or two equal doses, which are administered to the subject according to the methods provided herein.

[0156] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject monthly, weekly, or daily according to the methods provided herein. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject 1, 2, 3, or 4 times per day for one or more treatment cycles. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable form thereof is divided into two doses, such as two equal doses, which are administered to the subject on certain days or daily for one or more treatment cycles. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered once or twice daily for one or more treatment cycles, such as a compound of formula (I) or a pharmaceutically acceptable form thereof is administered twice daily for one or more treatment cycles. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to the subject 1, 2, 3, or 4 times per day continuously or until the subject achieves remission. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to the subject once daily (sometimes referred to as QD) for one or more treatment cycles, such as for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to the subject twice daily (sometimes referred to as BID) for one or more treatment cycles, such as for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, the treatment cycle is 1 day, 7 days, or 28 days. In some embodiments, the treatment cycle is 1 day. In some embodiments, the treatment cycle is 7 days. In some embodiments, the treatment cycle is 28 days. In some embodiments, the treatment cycle is a 28-day treatment cycle. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to the subject twice daily for one or more 28-day treatment cycles. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to the subject twice daily for one or more 28-day treatment cycles. In some embodiments, during a 28-day treatment cycle, a compound of formula (I) or a pharmaceutically acceptable form thereof is administered to the subject once or twice daily every other week.

[0157] In some embodiments, according to the methods provided herein, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject once, twice, three times, or four times daily for one or more treatment cycles on days 1 - 7, days 8 - 14, days 15 - 21, days 22 - 28, days 1 - 7 and days 15 - 21, days 8 - 14 and days 21 - 28, days 1 - 14, days 1 - 21, or every day (i.e., days 1 - 28) of a 28 - day treatment cycle. For example, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject QD on days 1 - 7, days 8 - 14, days 15 - 21, days 22 - 28, days 1 - 7 and days 15 - 21, days 8 - 14 and days 21 - 28, days 1 - 14, days 1 - 21, or every day (i.e., days 1 - 28) of a 28 - day treatment cycle for one or more treatment cycles. For example, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject BID on days 1 - 7, days 8 - 14, days 15 - 21, days 22 - 28, days 1 - 7 and days 15 - 21, days 8 - 14 and days 21 - 28, days 1 - 14, days 1 - 21, or every day (i.e., days 1 - 28) of a 28 - day treatment cycle for one or more treatment cycles. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject QD on days 1 - 7 of a 28 - day treatment cycle for one or more treatment cycles. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject BID on days 1 - 7 of a 28 - day treatment cycle for one or more treatment cycles. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject QD on days 1 - 7 and days 15 - 21 of a 28 - day treatment cycle for one or more treatment cycles. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject BID on days 1 - 7 and days 15 - 21 of a 28 - day treatment cycle for one or more treatment cycles. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject QD on days 1 - 21 of a 28 - day treatment cycle for one or more treatment cycles. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject BID on days 1 - 21 of a 28 - day treatment cycle for one or more treatment cycles. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject QD every day (i.e., days 1 - 28) of a 28 - day treatment cycle for one or more treatment cycles. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered to a subject BID every day (i.e., days 1 - 28) of a 28 - day treatment cycle for one or more treatment cycles.

[0158] In some embodiments, the VEGFR inhibitors cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanubrutinib are administered to a subject at a dose of 0.2 to 1500 mg per day according to the treatment methods provided herein. In some embodiments, the dose of the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanubrutinib administered to a subject is selected from 0.5 - 10 mg, 2 - 15 mg, 10 - 30 mg, 10 - 40 mg, 10 - 240 mg, 20 - 50 mg, 20 - 240 mg, 30 - 50 mg, 35 - 70 mg, 40 - 80 mg, 60 - 100 mg, 80 - 120 mg, 80 - 160 mg, 80 - 240 mg, 160 - 250 mg, 160 - 300 mg, 100 - 600 mg, or 200 - 1000 mg per day. In some embodiments, the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanubrutinib is administered to a subject at a dose selected from the following: about 0.89 mg, 1 mg, 1.34 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 12.5 mg, 14 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, 30 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 400 mg, 500 mg, 600 mg or 800 mg per day. In some embodiments, the dose of the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanubrutinib administered to a subject is selected from (Table 4):

[0159] Table 4

[0160]

[0161]

[0162] In some embodiments, the VEGFR inhibitors cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib are administered 1, 2, 3, or 4 times per day. In some embodiments, the daily dose of the VEGFR inhibitors cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib is divided into two amounts, such as two equal amounts, which are administered to the subject according to the methods provided herein. In some embodiments, the VEGFR inhibitors cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib are administered once or twice a day, such as once a day.

[0163] In some embodiments, a dose of a VEGFR inhibitor, such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib, is administered daily to a subject according to the methods provided herein for one or more treatment cycles. For example, in some embodiments, the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib is administered 1, 2, 3, or 4 times per day for one or more treatment cycles. In some embodiments, the daily dose of the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib is divided into two amounts, such as two equal amounts, which are administered to the subject according to the methods provided herein. In some embodiments, the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib is administered once or twice per day for one or more treatment cycles, such as once per day for one or more treatment cycles. In some embodiments, the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib is administered to the subject 1, 2, 3, or 4 times per day continuously or until the subject achieves remission. In some embodiments, the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib is administered to the subject once per day (sometimes referred to as QD) for one or more treatment cycles, such as two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. For example, in some embodiments, the VEGFR inhibitor cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib is administered to the subject twice per day (sometimes referred to as BID) for one or more treatment cycles, such as for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, the treatment cycle is 1 day, 7 days, or 28 days. In some embodiments, the treatment cycle is 1 day. In some embodiments, the treatment cycle is 7 days. In some embodiments, the treatment cycle is 28 days.In some embodiments, a dose of a VEGFR inhibitor, such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib, is administered to a subject once daily for one or more 28-day treatment cycles. In some embodiments, a VEGFR inhibitor, such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib, is administered to a subject twice daily for one or more 28-day treatment cycles. In some embodiments, a VEGFR inhibitor, such as cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib, is administered to a subject once or twice daily every other week during a 28-day treatment cycle. In some embodiments, a VEGFR inhibitor (such as fruquintinib) is administered during the first 21 days of each 28-day cycle.

[0164] In some embodiments, the methods provided herein include (1) an escalating dosing period, followed by (2) one or more treatment periods. In some embodiments, the methods provided herein include (1) an escalating dosing period that includes administering (a) escalating doses of a compound of formula (I) or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor; followed by (2) one or more treatment periods that include administering (a) an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor. In some embodiments, the escalating dosing period lasts 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, or 28 days. For example, the escalating dosing period can include gradually increasing the amount of the compound of formula (I) or a pharmaceutically acceptable form thereof administered to the subject while maintaining the amount of the VEGFR inhibitor administered to the subject. For example, the escalating dosing period can include administering a first amount of the compound of formula (I) or a pharmaceutically acceptable form thereof to the subject at the start of the escalating dose period, and a second (or final) escalating amount of the compound of formula (I) or a pharmaceutically acceptable form thereof to the subject at the end of the escalating dosing period, optionally while maintaining the amount of the VEGFR inhibitor administered to the subject. For example, the escalating dosing period can include gradually increasing the amount of the VEGFR inhibitor administered to the subject while maintaining the amount of the compound of formula (I) or a pharmaceutically acceptable form thereof administered to the subject. In certain embodiments, the final escalating amount is an effective amount of the compound of formula (I) or a pharmaceutically acceptable form thereof or the VEGFR inhibitor administered to the subject during one or more treatment periods. In some embodiments, incorporating the escalating dosing period provides a synergistic or therapeutic benefit to the subject, including but not limited to identifying an effective dose for the subject, increasing efficacy, reducing or avoiding toxicity, adverse events, or adverse symptoms associated with the compound of formula (I) or a pharmaceutically acceptable form thereof or the VEGFR inhibitor (e.g., reducing the severity, incidence, or risk of such effects), or a combination thereof.

[0165] In some embodiments, the methods provided herein include (1) a loading dosing period, followed by (2) one or more treatment periods. In some embodiments, the methods provided herein include (1) a loading dosing period that includes administering (a) a loading dose of a compound of formula (I) or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor; followed by (2) one or more treatment periods that include administering (a) an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor. In some embodiments, the loading dose (sometimes referred to as a raised dose or bolus dose) of the compound of formula (I) or a pharmaceutically acceptable form thereof is 1.1 to 10 times the dose administered during one or more treatment periods. For example, in some embodiments, the loading dose is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the dose administered during one or more treatment periods. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered 1, 2, 3, or 4 times per day during the loading dosing period. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered once per day during the loading dosing period. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered twice per day during the loading dosing period. In some embodiments, the loading dosing period is 1, 2, 3, 4, 5, 6, 7, 14, 21, or 28 days. In some embodiments, incorporating a loading dosing period prior to one or more treatment periods provides a synergistic or therapeutic benefit to the subject, including but not limited to reducing or avoiding toxicity, adverse events, or adverse symptoms associated with the compound of formula (I) or a pharmaceutically acceptable form thereof or with the VEGFR inhibitor (e.g., reducing the severity, incidence, or risk of such effects), or a combination thereof.

[0166] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof and the VEGFR inhibitor are administered to a subject on an intermittent dosing schedule, while the other is administered to the subject on a continuous dosing schedule (e.g., once, twice, three times, or four times a day). In some embodiments, the intermittent dosing schedule includes administering the agent on some days of the treatment cycle and not administering the agent on other days of the treatment cycle, such as administering the agent only every other day during a 28-day treatment cycle, or only every other week (e.g., one week on, one week off, and vice versa), or only for two consecutive weeks (e.g., two weeks on, two weeks off, and vice versa), or only for three consecutive weeks (e.g., three weeks on, one week off, and vice versa). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered on an intermittent dosing schedule. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered on an intermittent dosing schedule, and the VEGFR inhibitor is administered on a continuous dosing schedule. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered QD or BID to the subject on days 1-7, days 1-7 and days 15-21, days 1-21, or every day of a 28-day treatment cycle, and the VEGFR inhibitor is administered QD or BID every day of the 28-day treatment cycle. For example, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered QD to the subject on days 1-7, days 1-7 and days 15-21, days 1-21, or every day of a 28-day treatment cycle, and the VEGFR inhibitor is administered QD every day of the 28-day treatment cycle. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered BID to the subject on days 1-7, days 1-7 and days 15-21, days 1-21, or every day of a 28-day treatment cycle, and the VEGFR inhibitor is administered QD every day of the 28-day treatment cycle. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered QD to the subject on days 1-7, days 1-7 and days 15-21, days 1-21, or every day of a 28-day treatment cycle, and the VEGFR inhibitor is administered BID every day of the 28-day treatment cycle. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof is administered BID to the subject on days 1-7, days 1-7 and days 15-21, days 1-21, or every day of a 28-day treatment cycle, and the VEGFR inhibitor is administered BID every day of the 28-day treatment cycle. In some embodiments, in each regimen, the VEGFR inhibitor is administered for the first 21 days of each 28-day cycle, rather than daily. In some embodiments, the two agents are administered at approximately the same time of day, in which case the two agents can be administered simultaneously or sequentially.For example, in the case where the compound of formula (I) or a pharmaceutically acceptable form thereof is administered QD in the morning, or BID in the morning and evening, and the VEGFR inhibitor is administered QD in the morning, the two morning administrations can be concurrent or sequential.

[0167] In some embodiments, the methods provided herein include (1) an initiation dosing cycle, followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein include (1) an initiation dosing cycle that includes administering (a) an effective amount of a VEGFR inhibitor; followed by (2) one or more treatment cycles that include administering (a) an effective amount of the compound of formula (I) or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor. In some embodiments, the methods provided herein include (1) a delayed dosing schedule, followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein include (1) a delayed dosing schedule that includes one or more initiation dosing cycles, wherein the one or more initiation dosing cycles include administering (a) an effective amount of a VEGFR inhibitor, followed by (2) one or more treatment cycles that include administering (a) an effective amount of the compound of formula (I) or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor. In some embodiments, the initiation dosing cycle is from 1 day to about 56 days, or 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the initiation dosing cycle is 28 days. In some embodiments, the initiation dosing cycle is 6 weeks or less. In some embodiments, the subject is a subject who has not been treated with a VEGFR inhibitor. In some embodiments, the subject is a subject with recurrent or refractory advanced solid tumors who has been previously treated with a VEGFR inhibitor but is not currently being treated with a VEGFR inhibitor.

[0168] In some embodiments, the methods provided herein provide a therapeutic benefit to a subject, such as a synergistic benefit, relative to: (a) for combinations with VEGFR inhibitors, relative to treatment of advanced solid tumors with TKI or VEGFR inhibitor monotherapy, such as relative to treatment of advanced solid tumors with TKI or VEGFR inhibitor monotherapy that ultimately results in recurrence and / or resistance in the subject, e.g., relative to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib; (b) relative to standard of care treatment of advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or combinations thereof; or (c) relative to the situation of not treating advanced solid tumors. For example, in some embodiments, the methods provided herein improve efficacy (e.g., suppress tumor growth and induce tumor regression). In some embodiments, the methods provided herein provide an unexpected synergistic efficacy relative to either agent alone, e.g., wherein the method increases PFS and / or OS. In some embodiments, the increased PFS is increased by 10-99%, such as increased by 10%, 25%, 50%, 80%, 90%, 95%, or 99%, 2-fold, 3-fold, or 4-fold. In some embodiments, the increased OS is increased by 10-99%, such as increased by 10%, 25%, 50%, 80%, 90%, 95%, or 99%, 2-fold, 3-fold, or 4-fold. In some embodiments, the effective amount of the VEGFR inhibitor in the combination is lower than the effective amount of the VEGFR inhibitor monotherapy. In some embodiments, the methods provided herein reduce VEGFR inhibitor-related toxicities (e.g., the severity, incidence, or risk of such toxicities). In some embodiments, the reduced toxicities include or consist of reduced severity, incidence, or risk of severe bleeding, impaired wound healing, gastrointestinal perforation, hypertension, fatigue, arterial and venous thromboembolic events, bleeding, cardiovascular events, heart failure, hepatotoxicity, and QT prolongation, or combinations thereof. In some embodiments, the methods provided herein delay the emergence of drug resistance (such as TKI resistance or VEGFR inhibitor resistance), optionally wherein the delay is an unexpected delay. In some embodiments, the delay in the emergence of resistance includes weeks, months, or years. In some embodiments, the efficacy results noted above are determined according to applicable RECIST criteria (e.g., RECIST v.1.1).In some embodiments, the efficacy results noted above are relative to: (a) for combinations with VEGFR inhibitors, relative to treatment of advanced solid tumors with TKI or VEGFR inhibitor monotherapy, such as relative to treatment of advanced solid tumors with TKI or VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, e.g., relative to treatment of advanced solid tumors with cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanubrutinib; (b) relative to standard of care treatment of advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiotherapy, or chemotherapy, or combinations thereof; or (c) relative to no treatment of advanced solid tumors. In some embodiments, according to the methods provided herein, the compound of formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor unexpectedly exhibit a synergistic effect.

[0169] 7. Examples

[0170] Abbreviations: ACN: acetonitrile; AIBN: azobisisobutyronitrile; BTEAC: benzyltriethylammonium chloride; Cu(OAc)2: copper(II) acetate; DCE: 1,2-dichloroethane; DCM: dichloromethane; DEA: diethylamine; DEAD: diethyl azodicarboxylate; DIAD: diisopropyl azodicarboxylate; DIBAL-H: diisobutylaluminum hydride; DIPEA: N,N-diisopropylethylamine; DIPEA: N,N-diisopropylethylamine; DMA: dimethylacetamide; DMF: dimethylformamide; DMI: 1,3-dimethyl-2-imidazolidinone; DMSO: dimethyl sulfoxide; DPPF: 1,1′-bis(diphenylphosphino)ferrocene; Et3SiCl: triethylchlorosilane; EtOAc: ethyl acetate; EtOH: ethanol; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; MeOH: methanol; NaOMe: sodium methoxide; NBS: N-bromosuccinimide; n-BuLi: n-butyllithium; PCC: pyridinium chlorochromate; Pd(Ph3)4: tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0); PPh3: triphenylphosphine; SFC: supercritical fluid chromatography; T3P: propanephosphonic anhydride; TBAF: tetrabutylammonium fluoride; t-BuOK: potassium tert-butoxide; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TIPSCl: triisopropylchlorosilane; TMEDA: tetramethylethylenediamine

[0171] LCMS conditions:

[0172] Each LCMS condition was carried out on a SHIMADZU LC20-MS2020 instrument at an oven temperature of 50 °C, using ESI mass spectrometry ionization and monitoring at wavelengths of 220 nm and 254 nm. It is understood that the molecular formula listed together with the calculated ESI is the molecular formula of the detected ion (e.g., [M+H]+). For example, the molecular formula of compound 1A-1 is C 17 H 12 BrNO (i.e., [M]), while the molecular formula listed together with the calculated ESI is the molecular formula of the detected ion C 17 H 13 BrNO (i.e., [M+H] + ).

[0173] The acidic LCMS methods are referred to by the "AB" labeling method. Each of the acidic LCMS methods uses an Xtimate C18 2.1x30 mm (3 μm particle size) column (unless otherwise indicated), mobile phase A (water (4 L) and TFA (1.5 mL)), and mobile phase B (ACN (4 L) and TFA (0.75 mL)) (unless otherwise indicated). The conditions for each of the acidic LCMS methods utilized include the following: The 1.5 min method 5-95 AB refers to using a MERCK, RP-18e, 25x2 mm column and utilizing a gradient starting at 5% B and ending at 95% B over a total time of 1.5 min at a flow rate of 1.5 mL / min.

[0174] The basic LCMS methods are referred to by the "CD" labeling method. Each of the basic LCMS methods utilizes a Titank C18 2.1x50 mm (5 μm particle size) column, mobile phase A (water (4 L) and ammonium hydroxide (0.8 mL)), and mobile phase B (ACN). The conditions for each of the basic LCMS methods utilized include the following: The 3.0 min method 10-80 CD refers to utilizing a gradient starting at 10% B and ending at 80% B over a total time of 3 min at a flow rate of 1.0 mL / min.

[0175] SFC chiral HPLC conditions:

[0176] Each SFC chiral HPLC method was carried out on (1) a Waters UPCC with a PDA detector and a QDa detector or (2) an Agilent 1260 with a DAD detector.

[0177] "AD_ETOH_DEA_5404ML_4MIN_5CM" refers to the use of a Chiralpak AD-3 chiral column (column length 5 cm), with CO2 (mobile phase A) and ethanol with 0.05% diethylamine (v / v) (mobile phase B), and a gradient of 5% B to 40% B is used at a flow rate of 4 mL / min over a total time of 4 minutes.

[0178] The following examples are for illustration only and not for limitation.

[0179] Example 1: Preparation of Compounds of Formulas (I), (II), and (III)

[0180] It should be understood that, in accordance with the above discussion regarding enantiomeric enrichment and enantiomeric excess, a reference to a compound having one or more stereocenters without specifying a particular chirality (e.g., R- or S-enantiomer) as disclosed herein should be understood to refer to the compound in the form of a racemic mixture (or diastereomeric mixture), while when an R- or S- designation is included, it should be understood to refer to the enantiomeric (or diastereomeric) form of the compound, such as an enantiomerically enriched form of the compound's enantiomer (or diastereomer), or an enantiomeric excess form of the compound's designated enantiomer. The notation for a compound having an R- or S- designation should be understood to include enantiomeric enrichment or enantiomeric excess of the compound's designated enantiomer and not be limited to only the single designated enantiomer of 100% of the compound. For example, a reference to the compound of formula (III) should be understood to refer to the compound prepared in Example 1 and in its racemic form: (rac)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocycloheptene-2 2 ,4 4 dicarbonitrile. For example, a reference to the compound of formula (I) should be understood to refer to the compound prepared in Example 1 and in its single stereoisomer (S) form: (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocycloheptene-2 2 ,4 4 dicarbonitrile.

[0181] Scheme 1

[0182]

[0183] Scheme 1, Step 1: Preparation of (1-1). A mixture of 4-bromo-3-methylbenzoic acid (200 g, 930.04 mmol), NBS (248.29 g, 1.40 mol), and AIBN (30.54 g, 186.01 mmol) in CCl4 (1600 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 85 °C under N2 for 12 h. The reaction mixture was filtered. The crude product was triturated with CH3CN (500 mL) to give a mixture of 1-1 as a yellow solid and the corresponding dibromomethyl compound (215 g, 731.44 mmol, yield 78.65%). 1 1H NMR (400 MHz, DMSO-d6) δ = 13.36 (br s, 1H), 8.17 (s, 1H) 7.78 - 7.82 (m, 2H), 4.82 (s, 2H).

[0184] Scheme 1, Step 2: Preparation of (1-2). To a solution of 1-1 and the dibromomethyl compound (160 g, 544.33 mmol) in H2O (1500 mL) was added Na2CO3 (230.77 g, 2.18 mol). The mixture was stirred at 75 °C for 12 h. The reaction mixture was adjusted with HCl (4 M in H2O) to give a white cake. The solvent was removed from the white cake. To the above product in MeOH (1000 mL) was added NaBH4 (24.00 g, 634.42 mmol) under N2, and then the mixture was stirred at 15 °C under N2 for 1 h. The reaction mixture was quenched with H2O (400 mL) and acidified to pH = 2 with HCl (1 M in H2O). The mixture was placed under reduced pressure to remove the solvent and then filtered. The white cake was placed under reduced pressure to remove the excess solvent to give 1-2 as a yellow solid (120 g, 519.38 mmol, yield 95.42%). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.08 - 8.15 (m, 1H), 7.66 - 7.76 (m, 2H), 4.53 (s, 2H).

[0185] Scheme 1, Step 3: Preparation of (1-3). To a solution of 1-2 (100 g, 432.90 mmol), N,O-dimethylhydroxylamine (57.97 g, 594.31 mmol, HCl), and DIPEA (223.76 g, 1.73 mol, 301.56 mL) in DCM (1000 mL) was added T3P (275.43 g, 865.64 mmol, 257.41 mL). The mixture was stirred at 15 °C for 5 min. Water (200 mL) was added to the reaction mixture and then the mixture was extracted with DCM (500 mL x 2). The organic layer was separated, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0% to 35%) to give 1-3 as a colorless oil (83 g, 302.80 mmol, yield 69.95%). 1 1H NMR (400 MHz, DMSO-d6) δ = 7.92 (s, 1H), 7.72 - 7.76 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 3.54 (s, 3H), 3.26 (s, 3H).

[0186] Scheme 1, Step 4: Preparation of 4-bromo-N-methoxy-N-methyl-3-(((triisopropylsilyl)oxy)methyl)benzamide (1-4). A solution of 1-3 (83 g, 302.80 mmol), TIPSCl (58.5 g, 303.42 mmol, 64.93 mL), and imidazole (51.54 g, 756.99 mmol) in DCM (800 mL) was stirred at 15 °C for 16 h. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (600 mL x 2). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0% to 10%) to give 1-4 as a colorless oil (104 g, 241.60 mmol, yield 79.79%). 1 1H NMR (400 MHz, DMSO-d6) δ = 7.81 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4, 2.4 Hz, 1H), 4.80 (s, 2H), 3.51 (s, 3H), 3.23 - 3.29 (m, 3H), 1.12 - 1.23 (m, 3H), 1.03 - 1.08 (m, 18H).

[0187] Scheme 2

[0188]

[0189] Scheme 2, Step 1: Preparation of 2-1. To a mixture of (2-amino-5-bromophenyl)(3-methoxyphenyl)methanone (500 g, 1.63 mol) in toluene (3000 mL) was added Ac2O (333.46 g, 3.27 mol, 305.93 mL), and the mixture was stirred at 110 °C for 14 h. The reaction mixture was concentrated under reduced pressure to give 2-1 as a brown solid (528 g, 1.52 mol, yield 92.85%). LC-MS: Method: 5-95AB, R t = 0.88 min, C 16 H 15 BrNO3[M+H] + The calculated M / Z value of is 350.0, and the measured value is 349.9.

[0190] Scheme 2, Step 2: Preparation of 2-2. To a solution of 2-1 (528 g, 1.52 mol) in DME (2000 mL) under ice-water was added t-BuOK (340.31 g, 3.03 mol) portionwise while maintaining the temperature at 20 °C under N2. The resulting mixture was stirred at 20 °C for 12 h, and then the reaction was quenched with water (200 mL). The mixture was concentrated under reduced pressure to remove DME. The residue was triturated with water (2000 mL, twice), and then stirred with EtOAc (1000 mL) at 25 °C for 1 h to give 2-2 as a yellow solid (487 g, 1.47 mol, yield 97.27%). 1 H NMR (400 MHz, DMSO-d6) δ = 7.73 - 7.64 (m, 1H), 7.50 - 7.34 (m, 3H), 7.15 - 6.93 (m, 3H), 6.46 (s, 1H), 3.81 (s, 3H).

[0191] Scheme 2, Step 3: Preparation of 2-3. To a solution of 2-2 (50 g, 143.42 mmol) in DCM (500 mL) under N2 at -40 °C was added BBr3 (53.90 g, 215.13 mmol, 20.73 mL). The mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into water (500 mL). The pH was adjusted to 7 with saturated NaHCO3 solution. The aqueous layer was extracted with DCM (300 mL x 2). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was triturated with petroleum ether (300 mL) at 25 °C for 30 min and then triturated with CH3CN (200 mL) at 25 °C for 30 min to give 2-3 as a yellow solid (42 g, 125.53 mmol, yield 87.52%). 1 1H NMR (400 MHz, DMSO-d6) δ = 9.92 (brs, 1H), 8.03 - 7.91 (m, 3H), 7.56 (s, 1H), 7.43 - 7.37 (m, 1H), 6.99 - 6.91 (m, 3H).

[0192] Scheme 2, Step 4: Preparation of 2-4. To a solution of 2-3 (170 g, 508.08 mmol) in MeOH (800 mL) and THF (800 mL) at 25 °C was added CH3ONa (54.89 g, 1.02 mol), and the mixture was stirred at 80 °C for 12 h. The solvent was removed under reduced pressure. The mixture was poured into water (1000 mL), stirred for 30 min, and then filtered. The filtrate was concentrated under reduced pressure. The crude product was triturated with CH3CN (500 mL) at 25 °C for 30 min to give 2-4 as a yellow solid (130 g, 393.73 mmol, yield 67.98%). 1 1H NMR (400 MHz, DMSO-d6) δ = 7.79 (s, 3H), 7.43 - 7.29 (m, 1H), 6.99 - 6.84 (m, 4H), 4.01 (s, 3H), 3.64 (s, 1H).

[0193] Scheme 2, Step 4: Preparation of 6-bromo-2-methoxy-4-(3-((triisopropylsilyl)oxy)phenyl)-quinoline (2-5). To a solution of 2-4 (130 g, 393.73 mmol) in DCM (1500 mL) at 0 °C under N2 was added imidazole (58.97 g, 866.21 mmol). The mixture was stirred until a clear solution appeared, TIPSCl (75.91 g, 393.73 mmol, 84.25 mL) was added dropwise, and the mixture was stirred at 0 °C for 1 h, after which the ice bath was removed and the mixture was stirred at 25 °C for 12 h. The residue was poured into water (1000 mL) and then extracted with DCM (1000 mL x 3). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0% to 5%) and then triturated with MeOH (300 mL) at 25 °C for 30 minutes to give 2-5 (160 g, 328.87 mmol, 83.52% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 7.88 (d, J = 2.0 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.67 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.03 - 6.97 (m, 2H), 6.96 - 6.93 (m, 1H), 6.83 (s, 1H), 4.07 (s, 3H), 1.32 - 1.23 (m, 3H), 1.13 - 1.09 (m, 18H).

[0194] Scheme 3

[0195]

[0196] Scheme 3, Step 1: Preparation of (3-1). To a solution of 6-bromo-2-methoxy-4-(3-((triisopropylsilyl)oxy)phenyl)quinoline (10 g, 20.55 mmol) in THF (100 mL) was added n-BuLi (2.5 M in hexane, 22.61 mmol, 9.04 mL), and the mixture was stirred at -70 °C under N2 for 0.5 h. A solution of 1-4 (9.00 g, 20.91 mmol) in THF (10 mL) was added to the above solution, and the mixture was stirred at -70 °C for 0.5 h. Water (150 mL) was added to the mixture, and the mixture was extracted with EtOAc (150 mL). The organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was blended with another batch prepared from 18 g of 6-bromo-2-methoxy-4-(3-((triisopropylsilyl)oxy)phenyl)quinoline. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0% to 5%) to give 3-1 (40 g, 51.48 mmol, 83.50% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 8.28 (s, 1H), 8.09 - 7.95 (m, 3H), 7.62 - 7.54 (m, 2H), 7.35 - 7.29 (m, 1H), 7.09 - 7.04 (m, 1H), 7.00 - 6.95 (m, 2H), 6.92 (s, 1H), 4.85 (s, 2H), 4.16 (s, 3H), 1.28 - 1.21 (m, 3H), 1.16 - 1.13 (m, 3H), 1.11 - 1.07 (m, 18H), 1.04 - 1.01 (m, 18H).

[0197] Scheme 3, Step 2: Preparation of (3-2). To a solution of 1-methyl-1H-imidazole (1.16 g, 14.16 mmol, 1.13 mL) in THF (50 mL) was added n-BuLi (2.5 M in hexane, 14.16 mmol, 5.66 mL), and the mixture was stirred at -70 °C under N2 for 20 min. Then Et3SiCl (2.13 g, 14.16 mmol, 2.41 mL) in THF (10 mL) was added to the above mixture, and the mixture was stirred at -70 °C for 20 min. Then n-BuLi (2.5 M in hexane, 14.16 mmol, 5.66 mL) was added to the above mixture, and the mixture was stirred at -70 °C for 20 min. Then 3-1 (10 g, 12.87 mmol) in THF (40 mL) was added to the above mixture, and the mixture was stirred at -70 °C for 20 min. Water (500 mL) was added to the mixture, and the mixture was extracted with EtOAc (500 mL). The organic phase was washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated. The mixture was blended with another batch prepared from 30 g of 3-1. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0% to 10%) to give 3-2 (34 g, 39.58 mmol, yield 76.88%) as a pale yellow solid. 1 1H NMR (400 MHz, CDCl3) δ = 7.70 - 7.63 (m, 2H), 7.36 - 7.32 (m, 1H), 7.30 - 7.25 (m, 2H), 7.11 - 7.04 (m, 3H), 6.81 - 6.76 (m, 2H), 6.75 - 6.71 (m, 1H), 6.69 (s, 1H), 6.14 (s, 1H), 4.63 - 4.54 (m, 2H), 3.96 (s, 3H), 3.18 (s, 3H), 1.13 - 1.06 (m, 3H), 0.96 - 0.92 (m, 18H), 0.89 - 0.84 (m, 3H), 0.80 - 0.77 (m, 18H).

[0198] Scheme 3, Step 3: Preparation of (3-3). A mixture of 3-2 (26.5 g, 30.85 mmol) and TBAF (1 M in THF, 46.27 mmol, 46.27 mL) in THF (250 mL) was stirred at 25 °C for 20 min. Water (500 mL) was added to the mixture, and the mixture was extracted with EtOAc (500 mL). The organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by trituration from EtOAc:petroleum ether = 1:5 (150 mL) to give 313 (16 g, 29.28 mmol, 94.93% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.64 - 7.54 (m, 2H), 7.53 - 7.44 (m, 2H), 7.29 - 7.21 (m, 1H), 7.04 - 6.96 (m, 1H), 6.91 - 6.84 (m, 3H), 6.83 - 6.75 (m, 2H), 6.05 (s, 1H), 5.42 - 5.35 (m, 1H), 4.52 - 4.41 (m, 2H), 4.03 - 3.98 (m, 3H), 3.35 (s, 3H). LCMS R t = 0.80 min (in a 1.5 min chromatogram), 5-95a B, C 28 H 25 BrN3O4 [M+H] - The ESI calculated value for is 546.1, and the measured value is 545.9.

[0199] Scheme 3, Step 4: Preparation of (3-4). SOCl2 (2.48 g, 20.86 mmol, 1.51 mL) was added to a solution of 3-3 (5.7 g, 10.43 mmol) in DMF (85 mL), and the mixture was stirred at 25 °C for 1 h. Cs2CO3 (50.96 g, 156.41 mmol) was added to the above solution, and the mixture was stirred at 70 °C for 0.5 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The crude product was blended with another batch prepared from 10.15 g of 3-3, triturated with water (150 mL) and filtered. The solid was redissolved in toluene (100 mL x 2) and concentrated to give 3-4 (13 g, 24.60 mmol, 84.84% yield) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6) δ = 8.09 - 8.01 (m, 1H), 7.92 - 7.87 (m, 1H), 7.69 - 7.53 (m, 4H), 7.38 - 7.34 (m, 1H), 7.26 (s, 1H), 7.19 - 7.10 (m, 3H), 7.07 - 7.00 (m, 2H), 6.29 (s, 1H), 5.49 - 5.37 (m, 2H), 4.05 (s, 3H), 3.50 (s, 3H). LCMS R t = 2.00 min (in a 3.0 min chromatogram), 10 - 80 cD, C 28 H 23 BrN3O3 [M + H] + The ESI calculated value for is 530.1, and the measured value is 530.1.

[0200] Scheme 3, Step 5: Preparation of (3 - 5). A mixture of 3 - 4 (12 g, 22.71 mmol), zn(CN)2 (27.23 g, 231.89 mmol, 14.72 mL), Pd2(dba)3 (3.12 g, 3.41 mmol), dppf (3.78 g, 6.81 mmol), and zn (891.01 mg, 13.63 mmol) in DMA (300 mL) was stirred at 120 °C under N2 for 2 h. The mixture was filtered through Celite. The filter cake was washed with EtOAc (100 mL x 2). The combined organic phases were concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 50% to 100%), and then triturated with MeOH (50 mL) to give 3 - 5 (6.55 g, 13.80 mmol, yield 60.78%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.05 - 8.01 (m, 1H), 7.95 - 7.90 (m, 1H), 7.85 - 7.78 (m, 2H), 7.63 - 7.44 (m, 2H), 7.40 - 7.32 (m, 2H), 7.18 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.07 - 7.01 (m, 3H), 6.94 (s, 1H), 5.52 (s, 2H), 4.06 (s, 3H), 3.62 (s, 3H). LCMS R t = 1.77 min (in a 3.0 min chromatogram), 10 - 80 cD, C 29 H 23 N4O3 [M + H] + The ESI calculated value for is 475.2, and the measured value is 475.2.

[0201] Scheme 3, Step 6: Preparation of (3-6). To a solution of 3-5 (0.12 g, 251.82 μmol) in THF (10 mL) was added HCl (4 M in H2O, 2.20 mL). The reaction mixture was stirred at 70 °C for 16 h. The mixture was cooled to 20 °C and added to water (20 mL). Saturated NaHCO3 solution was added to adjust the pH to 8. The aqueous phase was extracted with DCM (30 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 3-6 as a colorless oil (0.115 g, 249.74 μmol, yield 99.17%). 50 mg (108.58 μmol) of 3-6 was purified by Prep-HPLC (column: Phenomenex Gemini-NX 80x40 mm x 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 26%-56%, 7.8 min) to give 3-6 as an off-white solid (12.4 mg, 26.93 μmol, yield 24.80%). 1 H NMR (400 MHz, DMSO-d6) δ = 11.71 (br s, 1H), 7.89 (dd, J = 2.0, 8.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.38 - 7.31 (m, 1H), 7.10 - 7.02 (m, 3H), 6.75 (s, 1H), 6.65 (s, 1H), 6.52 (s, 1H), 6.34 (s, 1H), 5.55 - 5.46 (m, 2H), 3.49 (s, 3H). LCMS R t = 1.34 min (in 3 min chromatogram), 10 - 80 cD, C 28 H 21 N4O3[M+H] + The ESI calculated value for was 461.2, and the measured value was 461.1. HPLC R t = 2.22 min (in 8 min chromatogram), 220 nm, purity 100%.

[0202] Scheme 3, Step 7: Preparation of (3-7). Compound 3-6 (1.2 g, 2.61 mmol) was mixed with POCl3 (19.80 g, 129.13 mmol, 12.00 mL) at 25 °C. The mixture was stirred at 100 °C for 1 h. The mixture was concentrated. NaOH (1 M in H2O, 100 mL) was added to the residue. The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and the filter cake was washed with EtOAc (20 mL). The combined filtrates were concentrated. The crude product was blended with another batch prepared from 0.5 g of 3-6. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0% to 10%) to give 3-7 (1.3 g, 2.71 mmol, 73.35% yield) as a yellow solid. LCMS Rt = 1.79 min (in a 3.0 min chromatogram), 10-80 CD, C 28 H 20 ClN4O2 [M+H] + The ESI calculated value for was 479.1, and the measured value was 479.1.

[0203] Scheme 3, Step 8: Preparation of (3-8). Zn(CN)2 (2.69 g, 22.91 mmol, 1.45 mL) and Pd(PPh3)4 (579.07 mg, 501.12 μmol) were added to a solution of 3-7 (1.2 g, 2.51 mmol) in DMF (10 mL) in a three-necked round-bottom flask under N2 at 25 °C. The mixture was stirred at 100 °C for 2 h. The mixture was cooled to 25 °C and added to water (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0% to 3%) to give 3-8 (900 mg, 1.92 mmol, 76.51% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.33 - 8.22 (m, 2H), 8.10 (s, 1H), 7.94 - 7.76 (m, 2H), 7.69 (s, 1H), 7.52 - 7.39 (m, 2H), 7.28 - 7.02 (m, 5H), 6.36 (s, 1H), 5.54 (s, 2H), 3.56 (s, 3H).

[0204] Scheme 3, Step 9: (rac)-3-Amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocycloheptene-22 ,4 4 Preparation of 3,4-dicarbonitrile (Compound of Formula III). To a solution of 3,8 (800 mg, 1.70 mmol) in DMI (8 mL) was added SOCl2 (1.01 g, 8.52 mmol, 618.05 μL). The mixture was stirred at 40 °C for 1 h. The above mixture was added to NH3 in MeOH (7 M, 100 mL) at -10 °C. The mixture was stirred at 25 °C for 30 min. The reaction mixture was poured into H2O (100 mL). The aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and the filter cake was washed with EtOAc (20 mL). The combined filtrates were concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0 to 8%) to give Compound 3 (550 mg, 1.17 mmol, yield 68.89%) as a yellow solid. LCMS R t = 1.71 min (in a 3.0 min chromatogram), 10 - 80 cD, C 29 H 21 N6O[M + H] + The ESI calculated value for was 469.2, and the measured value was 469.2.

[0205] Scheme 2, Step 10: (S)-3-Amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolizino-1,4(1,3)-dibenzocyclooctene-2 2 ,4 4 -dicarbonitrile (Compound of Formula (I)) and (R)-3-Amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolizino-1,4(1,3)-dibenzocyclooctene-2 2 ,4 4 -dicarbonitrile (Compound of Formula (II)).

[0206] The compound of formula (III) (500 mg, 1.07 mmol) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O EtOH]; B%: 45% - 45%) to give the target compound (229.5 mg, 489.85 μmol, yield 45.90%) as an off-white solid. 11H NMR (400 MHz, DMSO-d6) δ = 8.37 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.48 - 7.19 (m, 4H), 7.18 - 7.04 (m, 2H), 6.44 (s, 1H), 5.64 - 5.45 (m, 2H), 3.48 (s, 3H), 3.18 (s, 2H). LCMS R t = 1.68 min (in a 3.0 min chromatogram), 10 - 80 CD, C 29 H 21 N6O [M + H] + The ESI calculated value for is 469.2, and the measured value is 469.2. HPLC R t = 3.03 min (in an 8 min chromatogram), 220 nm, purity is 100%. Chiral HPLC (S)-1: R t = 2.44 min (within 4 min) (ee 99.54%) (AD_ETOH_DEA_5_40_4ML_4MIN_5CM), ((R)-2: R t = 1.93 min (ee 99.44%).

[0207] Example 2: Combination studies in in vivo models of cell line-derived xenograft tumors (CDX) and patient-derived xenograft tumors (PDX)

[0208] The combination of a compound of formula (I) or a pharmaceutically acceptable form thereof with an anti-angiogenic TKI can result in a deeper and more durable response in the VHL mutant 786-O RCC CDX model and the RCC PDX model compared to either agent alone. Although either the anti-angiogenic TKI alone or the compound of formula (I) or a pharmaceutically acceptable form thereof can slow or occasionally arrest tumor growth, the agent combination can induce a greater degree of tumor growth arrest or can induce tumor regression in the treated animals.

[0209] VHL mutant 786-O tumor cells were maintained in vitro in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS). VHL mutant A498 tumor cells were maintained in vitro in Eagle's minimum essential medium supplemented with 10% FBS. Cells were grown at 37 °C in an atmosphere of air containing 5% CO2. Cells were harvested when in exponential growth phase and quantified by a cell counter prior to tumor inoculation. For the VHL mutant KI-0326 and KI-12-0073 ccRCC PDX models, fresh tumor tissues were harvested from mice bearing established primary human cancer tissues and cut into small pieces (approx. 2-3 mm in diameter). Tumor cells were subcutaneously inoculated at 5x10 6 per mouse (CDX model) in the right upper abdominal region of each female BALB / c mouse, or the mouse was inoculated surgically (approx. 30 mm 3 section; PDX model) for tumor development. Randomization started when the mean tumor size reached approximately 250-300 mm 3 . Based on the study design, animals were randomly assigned to study groups of 5-6 animals each, according to the "matched distribution" method / "stratified" method (StudyDirector TM software, version 3.1.399.19) / randomized block design. Administration of the test article was initiated on the same day as randomization. The compound of formula (I) was administered at 20 mg / kg twice daily, cabozantinib was administered at 8, 15 or 20 mg / kg p.o. once daily, and axitinib was administered at 36 mg / kg p.o. once daily. After inoculation of tumor cells, the morbidity and mortality of the animals were checked daily. During routine monitoring, the animals were examined to obtain any effects of tumor growth on behavior (including mobility, food and water consumption) and physical characteristics (including weight gain / loss, eye / hair entanglement and any other abnormalities). The mortality of individual animals and the clinical signs observed were recorded. After randomization, body weight and tumor volume were measured twice a week. For tumor volume, measurements were made two-dimensionally using calipers and recorded using the following formula in mm 3 : V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Administration of drugs and measurement of tumor and body weight were performed in a laminar flow cabinet. Body weight and tumor volume were measured using StudyDirector TM software (version 3.1.399.19). At the end of the study, tumors were harvested by taking sections for formalin fixation and paraffin embedding (FFPE) and snap-freezing the remainder. FFPE was performed using standard procedures.

[0210] As Figure 1 shown, tumor regression shown by A498 CDX treated continuously with the compound of formula (I) (20 mg / kg, BID) and axitinib (36 mg / kg, QD) was increased relative to either agent alone. Error bars represent standard error of the mean (n = 5).

[0211] As Figure 2 shown for KI-12-0073 PDX, continuous treatment with the compound of formula (I) (20 mg / kg, BID) and axitinib (36 mg / kg, QD) resulted in increased tumor growth inhibition compared to either agent alone. Error bars represent standard error of the mean (n = 8).

[0212] As shown in Figure 3, 786-O CDX ( Figure 3A ) treated continuously with the compound of formula (I) (20 mg / kg, BID) and cabozantinib (20 mg / kg, QD) (lane 3) showed increased percent tumor growth inhibition (TGI%) relative to the compound of formula (I) alone (lane 1) or cabozantinib (lane 2). A498 CDX ( Figure 3B ) treated continuously with the compound of formula (I) (20 mg / kg, BID) and cabozantinib (8 or 20 mg / kg, QD) (lanes 4 and 5, respectively) showed increased TGI% compared to the compound of formula (I) alone (20 mg / kg, BID) (lane 1) or cabozantinib alone (8 and 20 mg / kg, QD, respectively) (lanes 2 and 3). Error bars represent standard error of the mean (786-O, n = 6, TGI% calculated 16 days after start of treatment; A498, n = 5, TGI% calculated 14 days after start of treatment). TGI% was calculated using the following formula: [1 - (mean volume of treated tumors) / (mean volume of control tumors)] x 100%.

[0213] As shown in Figure 4, mice with KI-12-0073 VHL mutant PDX, 786-O VHL mutant CDX, and KI-0326 VHL mutant PDX treated continuously with the compound of formula (I) (20 mg / kg, BID) and cabozantinib (8, 15, and 20 mg / kg, QD, respectively) showed decreased tumor growth compared to either compound alone ( Figure 4A , 4C and 4E). Error bars represent standard error of the mean. Figure 4B , 4DFigures 4F and 0 show plots of the percentage change in tumor volume relative to day 0 at the end point for the KI-12-0073, 786-O, and KI-0326 models, to show the variability in response to cabozantinib compared to the combination of a compound of formula (I) that caused all tumors to regress except one, and cabozantinib.

[0214] As Figure 5 shown, mice with 786-O VHL mutant CDX treated continuously with a compound of formula (I) (20 mg / kg, BID) and different doses of cabozantinib (4, 8, 10, and 12 mg / kg, QD) showed dose-dependent tumor growth inhibition compared to the corresponding single agent (i.e., cabozantinib or the compound of formula (I)). The percentage change in tumor volume was calculated using the end point tumor volume value (day 28) relative to day 0.

[0215] Mice with 786-O CDX were treated continuously with cabozantinib (15 mg / kg, QD), a compound of formula (I) (20 mg / kg, BID), lenvatinib (10 mg / kg, QD), lenvatinib plus everolimus (2 mg / kg, QD), a compound of formula (I) plus cabozantinib, and a compound of formula (I) plus lenvatinib. As Figure 6 shown, the combination of a compound of formula (I) (20 mg / kg, BID) with cabozantinib or lenvatinib reduced tumor growth more than either agent alone and showed a favorable reduction in tumor growth compared to treatment with lenvatinib (10 mg / kg, QD) and everolimus (a kinase / mTOR inhibitor; 2 mg / kg, QD), which combination is an FDA-approved second-line treatment regimen for RCC. Error bars represent the standard error of the mean.

[0216] Mice with 786-O CDX were treated continuously with axitinib (36 mg / kg, QD) for 14 days. Starting on day 15, the animals were dosed with one of the following: a) vehicle; b) a compound of formula (I) (20 mg / kg, BID); (c) cabozantinib (15 mg / kg, QD); (d) axitinib (36 mg / kg, QD); or (e) a combination of a compound of formula (I) and cabozantinib. As Figure 7 shown, 786-O CDX that progressed during 14 days of axitinib treatment and was then treated continuously with a compound of formula (I) plus cabozantinib showed reduced tumor growth during the subsequent 18 days compared to any of the other arms. Results of dosing for a total of three to four weeks after axitinib pretreatment may provide similar results. Error bars represent the standard error of the mean.

[0217] Example 3: Mechanistic studies

[0218] Study 1. To explore the mechanism of action of the results of Example 2, VHL mutant RCC cell lines can be subjected to hypoxia (1% O2) in vitro to mimic the hypoxic conditions induced by anti-angiogenic TKIs in vivo, and the cell lines can be treated with the compound of formula (I) to evaluate the effect of the compound on the signaling pathways in cells exposed to hypoxia. In this study, hypoxia may initially reduce mTOR signaling, but it may rebound after 24 hours of hypoxia, indicating in this case that reactivation of the mTOR pathway is a potential mechanism of TKI resistance. Addition of the compound of formula (I) or its pharmaceutically acceptable form can block hypoxia-induced mTOR reactivation. Mechanistically, the compound of formula (I) potently inhibits farnesylation and thus inhibits the activity of the obligatory farnesylated protein RHEB (a positive regulator of mTOR), suggesting that synergy may occur through RHEB inhibition in this model. Mechanistic data in cell lines indicate that the ability of the compound of formula (I) or its pharmaceutically acceptable form to inhibit mTOR reactivation observed in ccRCC cell lines under hypoxic stress may contribute to enhancing the durability of treatment in vivo.

[0219] Study 2. 786-O CDX was snap-frozen after 14 days of treatment with vehicle, cabozantinib (15 mg / kg, QD), the compound of formula (I) (20 mg / kg, BID), or combination therapy. Tumors were thawed in 1X RIPA buffer (Thermo Scientific Cat#PI89901) supplemented with 1X HALT protease and phosphatase inhibitor cocktail (Thermo Scientific Cat#PI78446) and then homogenized for 30 seconds at 4.5 m / s using a bead mill homogenizer. Lysates were clarified by centrifugation at 12k xg for 10 min and quantified by BCA assay (Pierce). For SDS-PAGE and immunoblotting, 20 - 50 μg of lysate was loaded onto a 4 - 12% Bis-Tris gel (Invitrogen NuPAGE) and transferred to a nitrocellulose membrane. The membrane was probed with the following antibodies: anti-phospho-ERK1 / 2 (CST Catalog No. 4695); anti-phospho-AKT (CST Catalog No. 4060); anti-phospho-S6 (Ser235 / 236) (CST Catalog No. 2211); anti-phospho-S6 (Ser240 / 244) (CST Catalog No. 2215); anti-total S6 (CST Catalog No. 2217); anti-phospho-RB (CST Catalog No. 8516); anti-cyclin D1 (CST Catalog No. 55506); anti-RHEB (CST Catalog No. 13879) and anti-HSP90 (CST Catalog No. 4877). As Figure 8As shown, compared to either agent alone, the combination treatment resulted in a decrease in phosphorylation of two growth-promoting signaling proteins, AKT and S6, as well as a decrease in phosphorylated RB, a cell cycle arrest marker. A slight shift of RHEB was detected in the combination treatment, indicating that the compound of formula (I) underwent deprenylation. HSP90 was used as a loading control.

[0220] Study 3. All immunohistochemical (IHC) staining was performed at Histowiz, Inc. (Brooklyn, NY) using a Leica BOND RX automated stainer (Leica Microsystems). The slides were dewaxed using xylene- and alcohol-based dewaxing solutions. Epitope retrieval was performed by heat-induced epitope retrieval (HIER) for 20 min at 95 °C in a citrate-based pH 6 solution on formalin-fixed, paraffin-embedded tissues. The tissues were first incubated with a peroxidase blocking buffer (Leica Microsystems), then with a 1:100 diluted primary antibody for 30 min, and then with a DAB mouse secondary antibody reagent: polymer, DAB refined, and hematoxylin (Leica Microsystems). The slides were dried, coverslipped, and visualized using a Leica Aperio AT2 slide scanner (Leica Microsystems). The following primary antibodies were used: anti-CD31 antibody (Sigma, 131M-94) and anti-VEGFR2 antibody (Cell Signaling Technology 9698).

[0221] As shown in Table 5, consistent with the anti-angiogenic activity of cabozantinib, treatment of 786-OCDX with cabozantinib (15 mg / kg, QD) for 14 days resulted in a decrease in angiogenesis, which was manifested as a decrease in the expression of CD31 and VEGFR2 compared to the vehicle. However, compared to cabozantinib alone, the combination of the compound of formula (I) (20 mg / kg, BID) and cabozantinib (15 mg / kg, QD) resulted in a greater decrease in the expression of CD31 and VEGFR2.

[0222] Table 5.

[0223]

[0224] As shown in Table 6, treatment of KI-0326 PDX with cabozantinib (20 mg / kg, QD) for 14 days resulted in a decrease in tumor vessel distribution compared to the vehicle, as measured by CD31 immunohistochemistry. However, the combination of cabozantinib with the compound of formula (I) (20 mg / kg, BID) did not result in a greater reduction in CD31 expression. This indicates that the additive effect of these two drugs on tumor growth inhibition is not solely driven by the inhibition of angiogenesis.

[0225] Table 6.

[0226]

[0227] Study 4. Early passage (less than passage 6) human umbilical vein endothelial cells (HUVECs) were seeded at 1,000 cells per well in a 96-well plate in endothelial cell medium containing 0.2% fetal bovine serum (FBS) and allowed to settle overnight. The next day, the medium was replaced with fresh endothelial cell medium containing 5% fetal bovine serum (FBS), 100 ng / mL recombinant VEGF-A, and endothelial cell growth supplement (ECGS) plus test articles: DMSO as vehicle, axitinib at different concentrations in the presence or absence of 100 nM compound of formula (I); or cabozantinib at different concentrations in the presence or absence of 100 nM compound of formula (I). On day 5, cell viability was determined using Cell Titer-Glo 2 reagent (Promega) according to the manufacturer's instructions, and luminescence was recorded on a Tecan plate reader.

[0228] As shown in Table 7, addition of 100 nM compound of formula (I) to axitinib or cabozantinib resulted in more potent inhibition of HUVEC proliferation and a decrease in the IC 50 concentration compared to axitinib or cabozantinib alone.

[0229] Table 7.

[0230] Treatment <![CDATA[IC 50 (nM)]]> Axitinib 643.7±108.4 Axitinib + 100 nM Compound of Formula (I) 449.4±38.7 Cabozantinib 224.3±35.9 Cabozantinib + 100 nM Compound of Formula (I) 84.0±23.3

[0231] Study 5. Early passage (less than passage 6) human umbilical vein endothelial cells (HUVECs) were seeded at 1,000 cells per well in a 96-well plate in complete endothelial cell medium containing 5% fetal bovine serum (FBS) and endothelial cell growth supplement (ECGS) and allowed to settle overnight. The next day, test articles were added: DMSO as vehicle, cabozantinib, axitinib, or lenvatinib at different concentrations, and the compound of formula (I) at different concentrations. On day 7 after addition of the test articles, cell viability was determined using Cell Titer-Glo 2 reagent (Promega) according to the manufacturer's instructions, and luminescence was recorded on a Tecan plate reader.

[0232] As shown in Figure 9, the addition of increasing doses of the compound of formula (I) to cabozantinib ( Figure 9A ), axitinib ( Figure 9B ), or lenvatinib ( Figure 9C ) resulted in more potent inhibition of HUVEC viability compared to the respective individual TKI agents. In addition, the compound of formula (I) inhibited HUVEC viability as a single agent in vitro, with an IC 50 of 223.4 ± 84.02 nM.

[0233] Study 6. Early passage (less than passage 6) HUVEC or GFP-labeled HUVEC cells were serum-starved overnight and seeded at 6 x 10 4 cells per well the next day in 48-well plates pre-coated with a layer of growth factor-reduced basement membrane extract (BME). At the time of plating, the cells were treated with DMSO (vehicle), 100 nM axitinib, 10 nM cabozantinib, 300 nM or 1 mM of the compound of formula (I), 100 nM axitinib plus 1 mM of the compound of formula (I), or 10 nM cabozantinib plus 300 nM or 1 mM of the compound of formula (I). Each treatment group had two technical replicates. The plates were incubated in an Incucyte at 37 °C in an atmosphere of air containing 5% CO2. Tube formation was monitored by imaging every 30 min for 18 h.

[0234] As Figure 10 shown, treatment of primary endothelial cells with 100 nM axitinib or 10 nM cabozantinib in the presence or absence of 1 μM of the compound of formula (I) impaired the ability of the cells to form tubular structures on the extracellular matrix proteins in vitro. (A - vehicle; B - axitinib; C - cabozantinib; D - compound of formula (I); E - axitinib and compound of formula (I); F - cabozantinib and compound of formula (I).) Figure 11 shows that treatment with 10 nM cabozantinib inhibited in vitro tube formation of GFP-labeled primary endothelial cells, while 300 nM of the compound of formula (I) had no such effect ( Figure 11A , GFP imaging; Figure 11B , graphs of the number of main segments and total length of main segments). The combination of cabozantinib and the compound of formula (I) did not further reduce tube formation compared to cabozantinib alone, indicating that the compound of formula (I) does not affect this specific endothelial cell function.

[0235] Study 7. Early passage (less than passage 6) human umbilical vein endothelial cells (HUVECs) were seeded at 2,000 cells per well on Nunc 96-well flat-bottom plates in endothelial cell medium (ECM) supplemented with endothelial cell growth factor and 5% fetal bovine serum (FBS) and allowed to settle overnight. The next day, the medium was removed and replaced with Incucyte Annexin V Orange dye (Sartorius) diluted (1:200) in complete ECM medium. The following test articles were added directly to the medium prepared with Annexin V: DMSO as vehicle, 1000 nM staurosporine as positive control, 100 nM compound of formula (I), 100 nM cabozantinib, or a combination of the compound of formula (I) and cabozantinib. Live cell imaging and analysis were performed for four days using the Incucyte SX5 system.

[0236] As Figure 12 shown, treatment of primary endothelial cells with the compound of formula (I) and cabozantinib induced more apoptosis than either agent alone, as measured by Annexin V signal plots drawn over time. Staurosporine was included as a positive control.

[0237] Example 4: FTI Activity in the HRAS High Cell Line Tumor Spheroid Growth Model

[0238] Cell lines were obtained from ATCC (SCC9) or Sigma (HSC3) and maintained at 37°C in a humidified environment with 5% CO2, cultured in DMEM (HSC3) or DMEM / F12 (SCC9) supplemented with 10% FBS and penicillin / streptomycin. Mycoplasma testing was negative for all lines. Matrigel matrix was purchased from Corning and diluted in the appropriate medium before plating. Anti-GTPase HRAS antibody was purchased from Abcam. The Active GTPase Pull-Down Kit was purchased from ThermoFisher. Cells were plated in 10 cm dishes and lysed. Lysates were collected and pulled down based on the pull-down kit protocol. 500 μg of protein was loaded for pull-down and 10 μg of protein was loaded as input for comparison. The active level of HRAS in each cell line was blotted using the HRAS-specific antibody (ab32417). Cells were resuspended in 4% Matrigel and seeded in 96-well ultra-low attachment plates at a density of 1000 - 2000 cells / well. The next day, spheroids were treated with the compound of formula (I) and DMSO as a control for normalization. The spheroids were incubated with the test compound for 7 days and luminescence readings were obtained using the 3D Cell Titer Glo reagent (Promega). Results: The sensitivity of the compound of formula (I) to head and neck squamous cell carcinoma (HNSCC) cell lines was evaluated based on the HRAS activity level. The SCC9 and HSC3 cell lines were identified based on the HRAS activity level determined by the GTP pull-down kit, characterizing SCC9 as HRAS-high and HSC3 as HRAS-low, as shown by immunoblot ([ Figure 13 ). The cell lines were then cultured as 3D tumor spheroids and treated with the compound of formula (I) and DMSO for 7 days. Cell viability was calculated by normalizing compound-treated cells against DMSO-treated cells. As shown in Table 7, based on the percentage of cell viability, the compound of formula (I) was more effective in the high-HRAS activity cell line (SCC9) than in the low-HRAS level cell line (HSC3).

[0239] Table 8.

[0240] Concentration of Compound of Formula (I) (nM) SCC9 (%) HSC3 (%) 0 100 100 1 95.23 99.40 2.37 95.13 101.07 5.62 91.33 96.45 13.3 74.93 81.75 31.6 57.87 79.21 75 41.19 76.77 178 29.09 70.68 422 19.00 62.28 1000 11.08 62.01

[0241] Example 5: Activity of the Compound of Formula (I) in a Patient-Derived Xenograft Model with Altered HRAS

[0242] Tumor fragments of a primary human tumor xenograft model (human head and neck, HN2594 (HRAS WT-高, Crown Bioscience, Beijing; were subcutaneously inoculated (2 - 3 mm in diameter) into the right upper abdomen of female NOD / SCID mice for tumor development. All animals were randomly assigned to 4 study groups with 5 mice per group. Randomization was started when the average tumor size reached approximately 220 mm 3 . Randomization was performed based on the "matched distribution" method (StudvDirector TM software, version 3.1.399.19). Administration of the drug was initiated on the day of randomization (day 0). The mice were orally administered a control vehicle (QD) or the compound of formula (I) (20 mg / kg, BID) for 35 days. After tumor inoculation, the morbidity and mortality of the animals were examined daily. During routine monitoring, the tumor growth of the animals and any effects of the treatment on behavior such as locomotor activity, food and water consumption, weight gain / loss (weight was measured three times a day every week after randomization), eye / hair tangling, and any other abnormalities were examined. The mortality of individual animals and the observed clinical signs were recorded in detail. After randomization, the tumor volume was measured two-dimensionally using calipers three times a week, and the volume was expressed in mm 3 as follows: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Administration of the drug and tumor and weight measurements were performed in a laminar flow hood. The weight and tumor volume were measured using StudyDirector TM software (version 3.1.399.19). As Figure 14 shown, the compound of formula (I) caused tumor regression in this model.

[0243] Example 6: Activity of the compound of formula (I) in a patient-derived xenograft model with HRAS alteration

[0244] This study used patient-derived xenograft (PDX) models HN2576 and HN2594 of human head and neck squamous cell carcinoma in female NOD / SCID mice (HRAS WT-高 , Crown Bioscience, Beijing). Fresh tumor tissue was harvested from mice bearing established primary human cancer tissues and cut into small pieces (approximately 2 - 3 mm in diameter). Specific PDX tumor fragments (3 x 3 x 3 mm) were subcutaneously inoculated into the right anterior abdomen of each mouse for tumor development. Randomization was started when the average tumor size reached approximately 250 mm 3 . All animals were randomly assigned to 5 study groups with 5 mice per group. Randomization was performed based on the "matched distribution" method (StudyDirector TMSoftware, version 3.1.399.19). The randomization date was designated as Day 0. According to the study design, dosing was initiated on the day of randomization (Day 0). Oral treatment of HN2576 and HN2594 xenografts was performed with vehicle control (BID) or the compound of formula (I) (10 mg / kg, 20 mg / kg or 40 mg / kg, BID). After tumor inoculation, the morbidity and mortality of the animals were examined daily. During routine monitoring, the tumor growth of the animals and any effects of the treatment on behavior such as mobility, food and water consumption, weight gain / loss (weight was measured three times a day weekly after randomization), eye / hair tangling, and any other abnormalities were examined. The mortality and observed clinical signs of individual animals were recorded in detail. After randomization, the tumor volume was measured two-dimensionally three times a week using calipers and the volume was expressed in mm 3 as: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Administration of the drug and measurement of the tumor and body weight were performed in a laminar flow hood. Body weight and tumor volume were measured using Study Director TM Software (version 3.1.399.19). In these two wild-type HRAS overexpressing xenograft models HN2576 and HN2594, the compound of formula (I) alone had a significant anti-tumor effect compared to the vehicle control. Treatment with a single agent of the compound of formula (I) at increasing doses of 10 mg / kg, 20 mg / kg, and 40 mg / kg resulted in inhibition of tumor growth in the HN2576 PDX model ( Figure 15 ). In the HN2594 PDX model, increasing doses of the compound of formula (I) resulted in a dose-dependent decrease in tumor growth ( Figure 16 ). These results indicate that the compound of formula (I) has single-agent activity to produce anti-tumor efficacy in HRAS amplified HNSCC xenograft models.

[0245] Example 6: Clinical Study

[0246] This study was designed to evaluate the safety, tolerability, and preliminary efficacy of the compound of formula (I) or a pharmaceutically acceptable form thereof in patients with advanced solid tumors. Patients eligible for the Part 1a dose escalation phase (including the relevant pharmacodynamic cohorts) will have advanced solid tumors confirmed by histology or cytology, which have confirmed HRAS mutations and / or amplifications, or HRAS overexpression (e.g., for HNSCC), or have confirmed NRAS mutations and / or NRAS amplifications, such as NSCLC, CRC, or PDAC, and must have progressed after standard therapy or be refractory to standard therapy or ineligible for standard therapy or there is no standard therapy. Patients eligible for the Part 1b combination dose escalation (including the relevant pharmacodynamic cohorts) and Part 2 combination dose expansion will have locally advanced or metastatic RCC confirmed by histology or cytology, which is predominantly of the clear cell subtype (e.g., ccRCC), and optionally has received at least one prior line of systemic therapy for this cancer. Patients must have at least one measurable lesion according to RECIST v.1.1 confirmed by radiological assessment. Additional eligibility criteria may apply.

[0247] Dosing Regimen. During the Part 1a dose escalation phase, the daily dosing amounts and regimens to be studied may include the doses and regimens listed in Table 8. The amounts listed are free base equivalent amounts.

[0248] Table 9: Daily Dosing Amounts for Part 1a Dose Escalation

[0249]

[0250] The compound of formula (I) or a pharmaceutically acceptable form thereof will be administered on Days 1 to 7 and Days 15 to 21 of a 28-day treatment cycle. In some cases, the compound will be administered with or without food, e.g., 40 mg QD.

[0251] In the Part 1b dose escalation phase, the combination of the compound of formula (I) or a pharmaceutically acceptable form thereof with cabozantinib will be studied. Cabozantinib will be administered in the form of cabozantinib (S)-malate, and the amounts listed below are free base equivalent amounts. The doses and regimens to be studied may include the doses and regimens listed in Tables 9 and 10.

[0252] Table 10: Daily Dosing Amounts for Part 1b Combination Study

[0253]

[0254] Table 11. Dosing Regimens for Part 1b Combination Study

[0255] Regimen FTI Regimen Cabozantinib Regimen 1 1.6 mg QD 40 mg, 60 mg or 80 mg QD 2 3 mg QD 40 mg, 60 mg or 80 mg QD 3 3.2 mg QD 40 mg, 60 mg or 80 mg QD 4 5 mg QD 40 mg, 60 mg or 80 mg QD 5 10 mg QD 40 mg, 60 mg or 80 mg QD 6 20 mg QD 40 mg, 60 mg or 80 mg QD 7 40 mg QD 40 mg, 60 mg or 80 mg QD 8 80 mg QD 40 mg, 60 mg or 80 mg QD 9 100 mg QD 40 mg, 60 mg or 80 mg QD 10 150 mg QD 40 mg, 60 mg or 80 mg QD 11 300 mg QD 40 mg, 60 mg or 80 mg QD

[0256] In the combined dose expansion phase of Part 2, one or more dosing regimens from the dose escalation phase of Part 1b can be selected to continue to evaluate safety, tolerability, and preliminary efficacy.

[0257] Safety Evaluation. DLT will be evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE v5.0), and all patients in the dose escalation phase will be evaluated for DLT in the first cycle (28 days). A patient will be DLT evaluable if they have experienced a DLT or received at least 75% of the planned dose during the DLT evaluation period.

[0258] Efficacy Assessment. Efficacy will be evaluated throughout the first cycle (28 days). The objective response rate (complete response (CR) and partial response (PR)), as determined by the patient's best tumor response, DoR, and PFS, will be evaluated by the investigator using RECIST v1.1. Tumor response assessment will continue until disease progression, initiation of a new anticancer therapy, or withdrawal from the study. Overall survival will also be recorded.

[0259] Tumor lesions will be radiologically evaluated at screening and at least approximately every 8 weeks (±5 days) for the remainder of the first 12 months of the study intervention (up to and including Cycle 13), and approximately every 12 weeks (±5 days) in the second year of the study intervention and thereafter. Additional tumor evaluations may be performed.

[0260] Lesions to be included in tumor assessments should follow RECIST v1.1. Computed tomography (CT) with contrast is the preferred imaging method and the same technique should be used in screening and post-treatment evaluations. The CT scan coverage at screening should cover the chest and abdomen (including the liver and adrenals) and a scan of the pelvis. Any additional areas of disease involvement should be scanned based on the patient's signs and symptoms.

[0261] Pharmacokinetics and Pharmacodynamics. To evaluate the pharmacokinetics of the combination, blood samples will be collected at different time points and analyzed for the area under the concentration-time curve (AUC), maximum plasma concentration, time to reach the maximum observed concentration, terminal elimination rate constant, terminal half-life, apparent clearance rate, and apparent volume of distribution of each agent. Non-compartmental pharmacokinetic analysis (NCA) will be used to analyze plasma concentrations.

[0262] Pharmacodynamic biomarkers and ctDNA will be evaluated during pre-screening and during the study. Biomarker analysis may include, but is not limited to: HRAS overexpression, HRAS mutations (including G12D / N / S / V; G13C / D / R / V; Q22T; A59T; Q61R / K / L; K117N; A146T), HRAS amplification, NRAS mutations (including G12C / D / S, G13V / R, Q61H / K / L / R, A146T), NRAS amplification, farnesylated target proteins, farnesyltransferase activity, serum tumor markers, and ctDNA. These evaluations will be performed using a combination of biochemical, genomic, transcriptomic, and proteomic techniques, which may include profiling mutations, amplifications, and / or other somatic gene alterations at the DNA, RNA, or protein level in tumor tissue.

[0263] Biomarkers in tumor tissue and blood will be studied to determine potential correlations between efficacy and / or treatment resistance and underlying biological mechanisms (e.g., farnesylation status of target proteins, clearance rate).

[0264] 6.1 Exemplary Embodiments

[0265] One or more (including, for example, all) of the following exemplary embodiments may include each of the other embodiments or portions thereof.

[0266] A1. A method of treating advanced solid tumors in a subject, comprising administering to the subject a compound of formula (I):

[0267]

[0268] or a pharmaceutically acceptable form thereof; and

[0269] a VEGFR inhibitor.

[0270] A2. A method of reducing drug resistance in advanced solid tumors in a subject, slowing the progression of drug resistance in advanced solid tumors in a subject, or overcoming drug resistance in advanced solid tumors in a subject, comprising administering to the subject a compound of formula (I):

[0271]

[0272] or a pharmaceutically acceptable form thereof; and

[0273] a VEGFR inhibitor.

[0274] A3. A method of preventing or delaying the emergence of drug resistance in advanced solid tumors in a subject who has not received TKI treatment, comprising administering to the subject a compound of formula (I):

[0275]

[0276] or a pharmaceutically acceptable form thereof; and

[0277] a VEGFR inhibitor.

[0278] A4. The method according to any one of embodiments A1 to A3, wherein the subject has advanced solid tumor, is suffering from advanced solid tumor, has symptoms associated with advanced solid tumor, is diagnosed with advanced solid tumor, or is a subject with advanced solid tumor in remission.

[0279] A5. The method according to any one of embodiments A1 to A4, wherein the advanced solid tumor is metastatic, recurrent, unresectable, relapsed, or refractory, or a combination thereof.

[0280] A6. The method according to any one of embodiments A1 to A5, wherein the advanced solid tumor is selected from renal cell carcinoma (RCC) (optionally wherein the RCC is clear cell RCC, papillary RCC, chromophobe RCC, unclassified RCC, or RCC after nephrectomy), thyroid cancer (optionally wherein the thyroid cancer is medullary thyroid cancer, differentiated thyroid cancer, or radioiodine-refractory), hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST) (optionally wherein the GIST is progressive or intolerant to imatinib after treatment with imatinib), soft tissue sarcoma, pancreatic neuroendocrine tumor (optionally wherein the pancreatic neuroendocrine tumor is progressive, differentiated, locally advanced, or metastatic), or endometrial cancer, such as wherein the advanced solid tumor is RCC or clear cell RCC.

[0281] A7. The method according to any one of embodiments A1 to A6, which comprises orally administering the VEGFR inhibitor to the subject, optionally once or twice a day, optionally for one or more treatment cycles.

[0282] A8. The method according to any one of embodiments A1 to A7, wherein the VEGFR inhibitor is selected from cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanazartinib, optionally wherein the VEGFR inhibitor is selected from cabozantinib (S)-malate, lenvatinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib mesylate, tivozanib hydrochloride hydrate, fruquintinib free base or zanazartinib fumarate, optionally wherein the VEGFR inhibitor is cabozantinib, axitinib, sunitinib or sorafenib, optionally wherein the VEGFR inhibitor is cabozantinib. In some embodiments, the VEGFR inhibitor is zanazartinib. In some embodiments, the VEGFR inhibitor is fruquintinib.

[0283] A9. The method according to any one of embodiments A1 to A8, wherein the method reduces or alleviates the toxicity associated with the VEGFR inhibitor relative to a comparative therapy; enhances the efficacy of the VEGFR inhibitor; delays, halts or prevents the progression of the advanced solid tumor; or increases the time to progression (TTP), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), overall response rate (ORR), complete response rate (CR rate) or duration of response (DoR); or a combination of two or more thereof, optionally wherein the VEGFR inhibitor is cabozantinib, and optionally wherein the advanced solid tumor is renal cell carcinoma or clear cell RCC.

[0284] A10. A method of treating a subject having an advanced solid tumor with HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation and optionally in combination with a squamous histological architecture, comprising administering to the subject a compound of formula (I):

[0285]

[0286] or a pharmaceutically acceptable form thereof.

[0287] A11. The method according to embodiment A10, wherein the advanced solid tumor is HNSCC.

[0288] A12. The method according to embodiment A10 or A11, wherein the advanced solid tumor has a squamous histological architecture.

[0289] A13. The method according to any one of embodiments A10 to A12, wherein the advanced solid tumor has HRAS amplification.

[0290] A14. The method according to any one of embodiments A10 to A13, wherein the advanced solid tumor overexpresses HRAS.

[0291] A15. The method according to any one of embodiments A10 to A14, wherein the advanced solid tumor has an HRAS mutation.

[0292] A16. The method according to any one of embodiments A10 to A15, wherein the HRAS mutation is a mutation in the HRAS gene encoding the mutant H-Ras protein.

[0293] A17. The method according to embodiment A16, wherein the HRAS gene mutation is or comprises a modification in a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant H-Ras protein, optionally wherein the modification is G12C, G12D, G12A, G12V, G12S, G12F, G12R, G12N, G13A, G13C, G13V, G13D, G13R, G13S, G13N, G13V Q61E, Q61K, Q61H, Q61L, Q61P, Q61R, Q22K, Q22T, K117N, K117L, A146V, A146T, or A146P.

[0294] A18. A method of treating an advanced solid tumor in a subject having NRAS amplification and / or NRAS overexpression, optionally in combination with an NRAS mutation, comprising administering to the subject a compound of formula (I):

[0295]

[0296] or a pharmaceutically acceptable form thereof.

[0297] A19. The method according to embodiment A18, wherein the advanced solid tumor has NRAS amplification.

[0298] A20. The method according to embodiment A18 or A19, wherein the advanced solid tumor overexpresses NRAS.

[0299] A21. The method according to any one of embodiments A18 to A20, wherein the advanced solid tumor has an NRAS mutation.

[0300] A22. The method according to any one of embodiments A18 to A21, wherein the NRAS mutation is a mutation in the NRAS gene encoding the mutant N-Ras protein.

[0301] A23. The method as described in embodiment A22, wherein the NRAS gene mutation is or comprises a modification in a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant N-Ras protein, optionally wherein the modification is a G12C, G12D, G12S, G12V, G12R, Q61H, Q61K, Q61L, Q61R, or A146T substitution.

[0302] A23. The method as described in any one of embodiments A10 or A12 to A22, wherein the advanced solid tumor is melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, small cell lung cancer), breast cancer, ovarian cancer, pancreatic cancer (e.g., carcinoma or ductal adenocarcinoma), glioma, HNSCC, and thyroid cancer, optionally wherein the advanced solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with NRAS amplification.

[0303] A24. The method as described in any one of embodiments A10 to A23, wherein the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with HRAS amplification.

[0304] A25. The method as described in any one of embodiments A1 to A24, wherein the advanced solid tumor is metastatic, advanced, recurrent, unresectable, repetitive, or refractory, or a combination thereof.

[0305] A26. The method as described in any one of embodiments A1 to A25, which comprises orally administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof.

[0306] A27. The method as described in embodiment A26, which comprises administering to the subject a compound of formula (I) or a pharmaceutically acceptable form thereof at a dose of 0.5 mg to 2400 mg per day.

[0307] A28. The method according to embodiment A27, wherein the dose of the compound of formula (I) or its pharmaceutically acceptable form is 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg and about 2400 mg per day.

[0308] A29. The method according to any one of embodiments A1 to A28, which comprises administering the compound of formula (I) or its pharmaceutically acceptable form once or twice a day, optionally once or twice a day, on days 1 to 7, days 8 to 14, days 15 to 21, days 21 to 28, days 1 to 7 and days 15 to 21, days 1 to 21, or days 1 to 28 during a 28-day treatment cycle.

[0309] A30. The method as described in embodiment A29, which comprises administering a compound of formula (I) or a pharmaceutically acceptable form thereof once daily, optionally once daily, on days 1 to 7, days 8 to 14, days 15 to 21, days 21 to 28, days 1 to 7 and days 15 to 21, days 1 to 21, or days 1 to 28 during a 28-day treatment cycle.

[0310] The above-described embodiments are intended to be illustrative only, and those skilled in the art will recognize or be able to determine using only routine experimentation, many equivalents to specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the present invention and are covered by the appended claims.

[0311] Incorporated by reference

[0312] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference in their entirety, to the same extent as if each individual publication, patent, and patent application were specifically and individually indicated to be incorporated by reference in its entirety. In case of conflict, the present application (including any definitions herein) shall govern.

Claims

1. A method for treating advanced solid tumors in a subject, comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor.

2. A method for reducing drug resistance of advanced solid tumors in a subject, slowing the progression of drug resistance of advanced solid tumors in a subject, or overcoming drug resistance of advanced solid tumors in a subject, comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor.

3. A method for preventing or delaying the emergence of drug resistance in advanced solid tumors in a subject who has not received TKI treatment, comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor.

4. The method according to any one of claims 1 to 3, wherein the subject has advanced solid tumors, is suffering from advanced solid tumors, has symptoms associated with advanced solid tumors, is diagnosed with advanced solid tumors, or is a subject with advanced solid tumors in remission.

5. The method according to any one of claims 1 to 4, wherein the advanced solid tumors are metastatic, recurrent, unresectable, relapsed, or refractory, or a combination thereof.

6. The method according to any one of claims 1 to 5, wherein the advanced solid tumors are selected from renal cell carcinoma (RCC) (optionally wherein the RCC is clear cell RCC, papillary RCC, chromophobe RCC, unclassified RCC, or RCC after nephrectomy), thyroid cancer (optionally wherein the thyroid cancer is medullary thyroid cancer, differentiated thyroid cancer, or radioiodine-refractory), hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST) (optionally wherein the GIST is progressive or intolerant to imatinib after treatment with imatinib), soft tissue sarcoma, pancreatic neuroendocrine tumor (optionally wherein the pancreatic neuroendocrine tumor is progressive, differentiated, locally advanced, or metastatic), or endometrial cancer, such as wherein the advanced solid tumor is RCC or clear cell RCC.

7. The method according to any one of claims 1 to 6, which comprises orally administering the VEGFR inhibitor to the subject, optionally once or twice a day, optionally for one or more treatment cycles.

8. The method according to any one of claims 1 to 7, wherein the VEGFR inhibitor is selected from cabozantinib, lenvatinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanazartinib, optionally wherein the VEGFR inhibitor is selected from cabozantinib (S)-malate, lenvatinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib mesylate, tivozanib hydrochloride hydrate, or fruquintinib free base, zanazartinib fumarate, optionally wherein the VEGFR inhibitor is cabozantinib, axitinib, sunitinib or sorafenib, optionally wherein the VEGFR inhibitor is cabozantinib, optionally wherein the VEGFR inhibitor is zanazartinib or fruquintinib.

9. The method according to any one of claims 1 to 8, wherein the method reduces or alleviates the toxicity associated with the VEGFR inhibitor relative to a comparator therapy; enhances the efficacy of the VEGFR inhibitor; delays, halts or prevents the progression of the advanced solid tumor; or increases the time to progression (TTP), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), overall response rate (ORR), complete response rate (CR rate) or duration of response (DoR); or a combination of two or more thereof, optionally wherein the VEGFR inhibitor is cabozantinib, and optionally wherein the advanced solid tumor is renal cell carcinoma or clear cell RCC.

10. A method of treating a subject having an advanced solid tumor with a squamous histological architecture and HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, comprising administering to the subject a compound of formula (I): or a pharmaceutically acceptable form thereof.

11. The method according to claim 10, wherein the solid tumor is HNSCC.

12. The method according to claim 10 or claim 11, wherein the advanced solid tumor having a squamous histological architecture has HRAS amplification.

13. The method according to any one of claims 10 to 12, wherein the advanced solid tumor having a squamous histological architecture overexpresses HRAS.

14. The method according to any one of claims 10 to 13, wherein the advanced solid tumor has an HRAS mutation.

15. The method according to any one of claims 1 to 14, wherein the advanced solid tumor is metastatic, advanced, recurrent, unresectable, refractory or recurrent, or a combination thereof.

16. The method according to any one of claims 1 to 15, which comprises orally administering to the subject the compound of formula (I) or a pharmaceutically acceptable form thereof.

17. The method according to claim 16, which comprises administering to the subject the compound of formula (I) or a pharmaceutically acceptable form thereof at a dose of 0.5 mg to 2400 mg per day.

18. The method according to claim 17, wherein the dose of the compound of formula (I) or its pharmaceutically acceptable form is 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg and about 2400 mg per day.

19. The method according to any one of claims 1 to 18, which comprises administering the compound of formula (I) or its pharmaceutically acceptable form once or twice a day, optionally once or twice a day, on days 1 to 7, days 8 to 14, days 15 to 21, days 21 to 28, days 1 to 7 and days 15 to 21, days 1 to 21, or days 1 to 28 during a 28-day treatment cycle.

20. The method according to claim 19, which comprises administering the compound of formula (I) or its pharmaceutically acceptable form once a day, optionally once a day, on days 1 to 7, days 8 to 14, days 15 to 21, days 21 to 28, days 1 to 7 and days 15 to 21, days 1 to 21, or days 1 to 28 during a 28-day treatment cycle.

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